In February 2013, Glaxosmithkline (GSK) Announced a Commitment

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure:  Information will be excluded in order to protect the privacy of patients and all named persons associated with the study  Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.  Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered CONFIDENTIAL RM2007/00260/00RM2007/00260/00 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies VLX105832VLX105832

Division: Worldwide Development Retention Category: GRS019

Information Type: Clinical Study Report

Title: The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection

Phase: IV

Compound Number: GW282358

Effective Date: 19-Jun-2007 Description:

This study compared valacyclovir 1g and placebo each administered once daily in a crossover design for 60 days for the reduction of HSV-2 viral shedding in immunocompetent subjects newly diagnosed with genital herpes infection. Eligible subjects were males or females, 18 years or older, and newly diagnosed with a first recognized episode of genital herpes. Subjects were required to have documented signs and symptoms of genital HSV infection at the time of the screening visit or within 4 months prior to the randomization visit, and laboratory confirmation of genital HSV-2 infection.

During each 60-day Treatment Period and a 7-day washout period, swabs were self-collected daily from the genital/anal-rectal area for HSV-2 detection. Subjects used a telephonic interactive voice response system daily to capture information on genital lesions, genital symptoms and oral outbreaks, and attended the clinic for routine visits, and for genital herpes recurrences.

This study is the first to demonstrate a significant reduction in viral shedding over 60 days with valacyclovir 1g daily compared to placebo in a population of subjects newly diagnosed with HSV-2 infection. Valacyclovir was not associated with any significant safety risk compared to placebo.

Subject: Herpes, genital herpes, HSV-2, asymptomatic viral shedding, valacyclovir hydrochloride, valaciclovir

Author(s):

Indication Studied: Genital Herpes

Initiation Date: 20Feb2006

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Completion Date: 28Nov2006

Date of Report: June 2007

Sponsor Signatory: MD (and Medical Officer) Director Infectious Diseases Medicine Development Center GlaxoSmithKline

This study was performed in compliance with Good Clinical Practices and GlaxoSmithKline Standard Operating Procedures for all processes involved, including the archiving of essential documents.

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Synopsis

Identifier: RM2007/00260/00

Study Number: VLX105832

Title: The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection

Investigator(s): Multicenter Study

Study center(s): 14 centers in the United States

Publication(s): None at time of this report

Study Period: 20Feb2006 – 28Nov2006

Phase of Development: IV

Objectives

Primary: • To compare the effect of valacyclovir 1g administered once daily for 60 days vs. placebo on total HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. Total shedding includes both clinical (genital lesion present) and subclinical (no genital lesions present) shedding. Secondary: • To compare the effect of valacyclovir 1g administered once daily for 60 days vs. placebo on subclinical HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. • To evaluate the safety of valacyclovir 1g administered once daily for 60 days in immunocompetent HSV-2 seropositive subjects newly diagnosed with HSV-2 infection. Methodology

During each 60-day Treatment Period and during a 7-day washout period, swabs were self-collected daily from the genital/anal-rectal area for HSV-2 detection by polymerase chain reaction (PCR). During an outbreak, lesion swabs were also collected for HSV-2 detection by PCR.

Subjects used an interactive voice response (IVR) system daily to record study-related information.

Subjects in both treatment groups who experienced lesions consistent with genital herpes (GH) during the study temporarily discontinued their blinded treatment assignment to receive open-label episodic treatment with VALTREX 500mg twice daily for 3 days, after which double-blind therapy resumed.

Number of Subjects

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Approximately 66 subjects were determined to be sufficient to obtain 47 subjects who completed the study. A high drop-out rate was anticipated because of the demanding nature of the study, e.g., self-collection of genital swabs for 127 days. For these reasons, the study was overenrolled by approximately 10%.

Seventy (70) subjects were randomized, and all were exposed to study medication (ITT population): 35 subjects to the valacyclovir:placebo treatment sequence; 35 subjects to the placebo:valacyclovir treatment sequence. 52 subjects had at least one PCR result in both Treatment Periods.

VAL:Placebo Placebo:VAL Number of Subjects: Planned, N 33 33 Randomized, N 35 35 Completed, n (%) 26 (74) 24 (69) Total Number Subjects Withdrawn, N (%) 9 (26) 11 (31) Withdrawn due to Adverse Events n (%) 1 (3) 1 (3) Withdrawn for other reasons n (%) 8 (23) 10 (29)

Diagnosis and main criteria for inclusion

Eligible subjects were males or females, 18 years or older, immunocompetent and newly diagnosed with a first recognized episode of genital herpes. Subjects were required to have documented signs and symptoms of genital HSV infection at the time of the screening visit or within 4 months prior to the randomization visit, and laboratory confirmation (positive culture, PCR or serology) of genital HSV-2 infection. Subjects were excluded if they were immunocompromised, had clinically significant impaired renal or hepatic function, or had received either daily suppressive therapy for GH prior to randomization or systemic antiherpetic treatments within 3 days of randomization.

Treatment administration

All study medication was taken orally. Eligible subjects were randomly assigned in a 1:1 ratio to receive valacyclovir 1g once daily or placebo once daily for 60 days in a two-way crossover design study, with a washout period of seven days between Treatment Periods.

The daily dosing regimen for each phase of the study is summarized in the following table.

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Study Phase Drug Daily Dosage Dosing Period Double-blind Valacyclovir 1 gram once daily (2 x Treatment Period 1 = Treatment Period 1 500mg caplets) or 60 days and Placebo Matching Treatment Period 2 = Treatment Period 2 Placebo (2 caplets) 60 days

Washout Period None None 7-day washout Open-Label VALTREX 500mg twice daily 3 days Episodic Treatment

Criteria for Evaluation

The primary endpoint was the percent of all days with HSV-2 shedding as determined by type-specific PCR assay for HSV-2. Secondary endpoints were the percent of days with subclinical HSV-2 shedding, the percent of days with clinical shedding, the proportion of subjects with no shedding, the proportion of subjects with at least one genital herpes recurrence, and time to first genital herpes recurrence.

For each subject, each study day was classified by PCR as 'shedding' or 'no shedding'; additionally each day was classified as 'clinical' (i.e., presence of genital lesions) or 'subclinical’ (i.e., no genital lesions). The total shedding rate was defined as the proportion of all days (clinical and subclinical) on treatment during which shedding was detected by PCR. The subclinical shedding rate was defined as the proportion of all days on treatment during which subclinical shedding was detected by PCR

Subjects used a telephonic, interactive voice response system (IVRS) daily to capture information on genital lesions, genital symptoms and oral outbreaks. Safety was assessed by adverse event reporting at each visit, and by routine clinical chemistry and hematology monitoring.

HSV Virology: Among subjects with a GH recurrence on study who did not respond fully to 3 days of open-label episodic treatment (VALTREX 500mg twice daily), the percent of HSV-2 isolates resistant to acyclovir was tabulated.

Statistical Methods

In this crossover study, 47 completed subjects provided over 90% power to detect a reduction in the mean percent days of total HSV-2 shedding from 9.6% in the placebo treatment phase to 2.8% in the valacyclovir treatment phase, assuming standard deviations of 9.8% and 5.6%, respectively, and a correlation of 0.4.

Four populations were considered in the analysis:

Intent-to-Treat (ITT) Exposed: The ITT Exposed population was defined as all subjects who received at least one dose of investigational product. This was the primary population for assessing safety.

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Intent-to-Treat Crossover (ITTC): all subjects in ITT who had at least one PCR swabbing result in each Treatment Period. This was the primary population for assessing efficacy.

Per Protocol (PP): This population included all subjects who completed the study without a major protocol violation and had PCR data on at least 85% of days on study. This was the secondary population for assessing the primary and secondary efficacy endpoints.

First Period Efficacy: This population included subjects in the ITT and was used for efficacy analyses restricted to the first Treatment Period.

Swab samples for two subjects were irreconcilable. Data from these two subjects were excluded from all efficacy analyses.

Nonparametric methods were used to perform all tests of treatment differences.

Summary

Seventy (70) subjects were randomized, and all were exposed to study medication (ITT population); 52 subjects had at least one PCR result in both Treatment Periods (ITTC population).

Efficacy

Valacyclovir significantly reduced HSV-2 shedding during all days compared to placebo [mean 2.9% vs. 13.5% of all days (p<0.001), a 78% reduction]. Valacyclovir also significantly reduced subclinical HSV-2 shedding during all days compared to placebo [mean 2.4% vs. 11.0% of all days (p<0.001), a 78% reduction]. Sixty percent (60%) of subjects had no viral shedding while receiving valacyclovir compared to 29% of subjects on placebo (p<0.001). Seventy-nine percent (79%) of subjects had no GH recurrences while receiving valacyclovir compared to 52% of subjects receiving placebo (p<0.01). In the first Treatment Period, valacyclovir significantly reduced the time to first GH recurrence (p=0.010). Median time to first GH recurrence was >68 days for valacyclovir and 61 days for placebo.

Safety

Valacyclovir was not associated with any significant safety risk compared to placebo. The most frequently reported adverse events among valacyclovir and placebo recipients, respectively, were fungal infection (5%, 10%), upper respiratory tract infection (5%, 2%), sinusitis (3%, 2%), bacterial vaginosos (3%, 2%), diarrhea (2%, 3%), and headache (2%, 3%). One subject with baseline elevations in ALT and AST experienced further increases in ALT and AST at Day 61 while receiving valacyclovir. Bilirubin levels remained normal. Investigational product was discontinued and the subject was withdrawn from the study. The investigator considered the ALT and AST elevations not attributable to study medication. ALT and AST were returning to baseline levels by the end of the study.

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No serious adverse events were reported during the study.

VAL Placebo N, ITT 62 62 Most Frequent Adverse Events – On-Therapy n (%) n (%) Subjects with any AE(s), n (%) 19 (31) 26 (42) Fungal Infection 3 (5) 6 (10) Upper Respiratory Tract Infection 3 (5) 1 (2) Sinusitis 2 (3) 1 (2) Vaginitis bacterial 2 (3) 1 (2) Sinus congestion 2 (3) 0 Ear Infection 2 (3) 0 Bronchitis 2 (3) 0 Vulvovaginal mycotic infection 2 (3) 0 Diarrhea 1 (2) 2 (3) Headache 1 (2) 2 (3) Pharyngolaryngeal pain 1 (2) 1 (2) Folliculitis 1 (2) 1 (2) UTI 1 (2) 1 (2) Labyrnthitis 1 (2) 0 Onychomycosis 1 (2) 0 Tendon injury 1 (2) 0 ALT increased1 1 (2) 0 AST increased1 1 (2) 0 Blood Pressure increased 1 (2) 0 Smear cervix abnormal 1 (2) 0 Pollakiuria 1 (2) 0 Vulvovaginal dryness 1 (2) 0 1. *Both AEs occurred in the same subject.

The following AEs occurred only in subjects while receiving placebo: trichomonal vulvovaginitis, muscle spasms, pain in extremity, depression, contusion, abdominal pain, dental caries, oral paraesthesia, toothache, back pain, musculoskeletal pain, neck pain, migraine, paraesthesia, cough, anorexia, hypercholesterolaemia, sleep disorder, stress, urinary tract disorder, vulvovaginal discomfort, abnormal sensation in eye, rash, anogenital warts, human papilloma virus (HPV) cervicitis, hordeolum, pelvic inflammatory disease, sialoadenitis, concussion, fall, muscle strain, and procedural pain.

HSV Virology

Six subjects did not respond fully to 3 days of episodic treatment with open-label VALTREX 500 mg BID. Positive isolates were obtained from 4 subjects. Resistance testing was performed on these isolates and none were resistant to acyclovir.

Conclusions

7 CONFIDENTIAL RM2007/00260/00 VLX105832 subclinical HSV-2 shedding was greater than reported in earlier studies involving subjects with a history of symptomatic genital recurrences. Valacyclovir was generally well-tolerated in this population.

Date of Report: June 2007

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TABLE OF CONTENTS

Page SYNOPSIS ...... 3 ABBREVIATIONS ...... 14 1. ETHICS ...... 16 1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ...... 16 1.2. Ethical Conduct of the Study ...... 16 1.3. Subject Information and Consent...... 16 2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE ...... 16 3. INTRODUCTION ...... 16 4. STUDY OBJECTIVE(S) AND ENDPOINTS ...... 18 4.1. Primary Objective ...... 18 4.2. Secondary Objective ...... 18 4.3. Primary Endpoint ...... 19 4.4. Secondary Endpoints ...... 19 4.5. Other Endpoints ...... 19 4.6. Ad hoc Endpoints ...... 19 5. INVESTIGATIONAL PLAN ...... 19 5.1. Overall Study Design ...... 20 5.1.1. Discussion of Study Design, Including the Choice of Control Group(s)...... 21 5.2. Protocol Amendment(s) ...... 22 5.3. Selection of Study Population ...... 22 5.3.1. Inclusion Criteria ...... 22 5.3.2. Exclusion Criteria ...... 23 5.3.3. Predetermined Criteria for Subject Withdrawal ...... 24 5.4. Investigational Product(s)...... 24 5.4.1. Description of Investigational Product(s) ...... 24 5.4.2. Dosages and Administration ...... 25 5.4.3. Dose Rationale...... 25 5.4.4. Blinding...... 26 5.4.5. Treatment Assignment ...... 26 5.4.6. Assessment of Compliance ...... 27 5.4.7. Treatment of Investigational Product Overdose...... 27

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5.5. Prior and Concomitant Medications and Non-Drug Therapies . . . . . 27 5.5.1. Permitted Medications ...... 27 5.5.2. Prohibited Medications ...... 27 5.6. Study Assessments and Procedures ...... 28 5.6.1. Demographic and Baseline Assessments ...... 28 5.6.2. Efficacy Assessment ...... 28 5.6.3. Safety Assessments...... 29 5.7. Data Quality Assurance ...... 32 5.8. Data Analysis Methods ...... 33 5.8.1. Timings of Planned Analyses ...... 33 5.8.2. Sample Size Considerations ...... 33 5.8.3. Analysis Populations ...... 33 5.8.4. Treatment Comparisons...... 34 5.8.5. General Considerations for Data Analyses ...... 34 5.8.6. Data Handling Conventions ...... 34 5.8.7. Study Population ...... 35 5.8.8. Efficacy Analyses ...... 35 5.8.9. Safety Analyses ...... 37 6. STUDY POPULATION RESULTS...... 39 6.1. Disposition of Subjects ...... 39 6.2. Protocol Deviations ...... 40 6.3. Populations Analyzed...... 40 6.4. Demographics and Other Baseline Characteristics ...... 40 6.4.1. Demographic Characteristics ...... 41 6.4.2. Baseline Characteristics...... 41 6.4.3. Other Current Medical Conditions ...... 41 6.4.4. Previous Medications ...... 41 6.4.5. Other Factors Affecting Response to Therapy...... 42 6.5. Concomitant Medications ...... 42 6.6. Treatment Compliance ...... 42 7. EFFICACY RESULTS ...... 43 7.1. Primary Efficacy Results ...... 43 7.2. Secondary Efficacy Results ...... 43 7.2.1. Mean Percent of Days with Subclinical Shedding ...... 43 7.2.2. Mean Percent of Days with Clinical Shedding ...... 44 7.2.3. Proportion of subjects with no shedding ...... 44 7.2.4. Proportion of subjects with at least one GH recurrence...... 44

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7.2.5. Time to First GH Recurrence ...... 45 7.3. Other Efficacy Results ...... 45 7.3.1. Time to First Oral Herpes Recurrence ...... 45 7.3.2. Acyclovir Resistance ...... 45 7.4. Ad hoc Endpoints ...... 46 7.5. Subgroup Analyses ...... 46 7.6. Efficacy Conclusion(s) ...... 47 8. SAFETY RESULTS ...... 48 8.1. Extent of Exposure ...... 48 8.2. Adverse Events ...... 48 8.2.1. All Adverse Events ...... 48 8.2.2. Drug-Related Adverse Events ...... 49 8.2.3. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study ...... 50 8.3. Serious Adverse Events ...... 50 8.3.1. Deaths ...... 50 8.4. Other Relevant Adverse Events...... 50 8.5. Pregnancies ...... 51 8.6. Clinical Laboratory Evaluations ...... 51 8.6.1. Laboratory Values over Time ...... 51 8.7. Safety Conclusion(s) ...... 51 9. DISCUSSION AND CONCLUSIONS ...... 52 9.1. Discussion ...... 52 9.2. Conclusions ...... 53 10. REFERENCES ...... 55 11. CASE NARRATIVES...... 57 STUDY POPULATION DATA SOURCE TABLES ...... 63 EFFICACY DATA SOURCE FIGURE AND TABLES ...... 101 SAFETY DATA SOURCE TABLES...... 193 ATTACHMENTS ...... 252 Attachment 1: Eligibility Flowchart ...... 252 Attachment 2 - Reporting and Analysis Plan for VLX105832 ...... 254

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LIST OF FIGURES

Page Figure 1 Study Design ...... 20

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LIST OF TABLES

Page Table 1 Dosages and Administration...... 25 Table 2 Threshold Values ...... 38 Table 3 Disposition of Subjects ...... 39 Table 4 Study Populations...... 40 Table 5 Demographics ...... 41 Table 6 Summary of Percent of All Days with Shedding ...... 43 Table 7 Summary of Percent of Days with Subclinical Shedding ...... 43 Table 8 Summary of Percent of Days with Clinical Shedding ...... 44 Table 9 Summary of Proportion of Subjects with No Shedding ...... 44 Table 10 Summary of Proportion of Subjects Recurrence-Free ...... 45 Table 11 Summary of Ad hoc Analyses ...... 46 Table 12 Most Frequently Reported Adverse Events ...... 49

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Abbreviations

AE Adverse Event ALT (SGPT) Alanine Transaminase AST (SGOT) Aspartate Transaminase BID Twice daily CD-ROM Compact Disc- read only memory CIB Clinical Investigator’s Brochure CRF Case Report Form DNA Deoxyribonucleic acid eCRF Electronic Case Report Form ELISA Enzyme-Linked ImmunoSorbent Assay FDA US Food and Drug Administration GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilance GH Genital Herpes GSK GlaxoSmithKline hCG Human Chorionic Gonadotropin HIV Human Immunodeficiency Virus HPV Human papilloma virus HSV-2 Herpes Simplex Virus Type 2 HUS Hemolytic Uremic Syndrome ICF Informed Consent Form IEC Independent Ethics Committee IRB Institutional Review Board ITT Intent to Treat ITTC Intent to Treat Crossover IUD Intrauterine Device IVRS Interactive Voice Response System LLN Lower limit of normal MedDRA Medical Dictionary for Regulatory Activities mg milligram min minute mm3 Cubic millimeter PBO Placebo PCR Polymerase chain reaction PDF Portable document format PP Per Protocol QD Once daily RAMOS Registration and Medication Ordering System RAP Reporting and Analysis Plan SAE Serious Adverse Event SI Standard international SOS System Organ Classes STD Sexually Transmitted Disease TMA Thrombotic Microangiopathy TTP Thrombotic Thrombocytopenic Purpura

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ULN Upper limit of normal range UTI Urinary tract infection URL Uniform resource locator US United States VAL VALTREX, valacyclovir hydrochloride, valacyclovir, valaciclovir

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies VALTREX Inform HerpeSelect Effexor Nuva ring Ortho Evra Maxide DayQuil Oxavar Yasmin

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1. ETHICS

1.1. Independent Ethics Committee (IEC) or Institutional Review Board (IRB)

The study protocol, any amendments, the informed consent, and other information that required pre-approval were reviewed and approved by a national, regional, or investigational center ethics committee or institutional review board.

1.2. Ethical Conduct of the Study

This study was conducted in accordance with "good clinical practice" (GCP) and all applicable regulatory requirements, and, the guiding principles of the Declaration of Helsinki.

1.3. Subject Information and Consent

Written informed consent was obtained from each subject prior to the performance of any study-specific procedures. Informed consent for study participation was obtained from potential subjects at the Screening Visit. Electronic Case Report Forms (CRF) were provided for each subject’s data to be recorded.

2. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE

Study VLX105832 was a multicenter study conducted at 14 centers in the United States (US).

GlaxoSmithKline (GSK), the study sponsor, was responsible for administration of the study including clinical trial supply management.

The central laboratories used during the conduct of this study were Quest Diagnostics Clinical Trials Laboratory, Van Nuys, CA, University of Washington Virology Research Laboratories, Seattle, WA, and ViroMed Laboratories, Inc., Minnetonka, MN, USA.

3. INTRODUCTION

Genital herpes (GH) is most commonly caused by infection with herpes simplex virus type 2 (HSV-2) and is one of the most prevalent sexually transmitted disease (STD) worldwide [Smith, 2002; Corey, 2000; Xu, 2006]. The annual incidence rate of new infections is 1 million cases per year in the United States [Cates, 1999]. GH is characterized classically by painful, recurrent genital ulcers, although episodes may also manifest as blisters, erythema, swelling, excoriation or other similar clinical signs. At least 50 million persons in the United States have genital HSV infection [Centers for Disease Control, 2006]. Approximately ninety percent (90%) of these individuals are

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Although HSV is most contagious during active (visible) outbreaks, asymptomatic viral shedding is considered to be the primary means of transmitting HSV to sexual partners and neonates [Mertz, 1992; Brown, 1991]. Indeed, studies in couples discordant for HSV-2 infection have shown that transmission can occur even among partners who abstain from sexual contact during GH recurrences (i.e., transmission occurs during a time when subjects are asymptomatic) and that 70% of transmission events took place when the source partner was asymptomatic [Mertz, 1988; Mertz, 1992]. Therefore, some experts now believe that the management of GH and its transmission should focus on safer sex practices, including the use of condoms, in conjunction with antiviral therapy to reduce the number of GH recurrences and reduce viral shedding. This approach potentially is applicable to any subject who has HSV-2 infection, independent of how long the subject has been infected, frequency of recurrences, or whether the subject has overt clinical signs and symptoms.

Viral shedding that occurs during the presence of GH lesions is referred to as clinical shedding, while shedding that occurs in the absence of lesions is referred to as subclinical shedding. The terms, “subclinical” and “asymptomatic” are sometimes used interchangeably however, subclinical shedding includes days with symptoms (e.g., prodrome) but no lesions, whereas asymptomatic shedding includes only days when no signs or symptoms are present.

More than 85% of people who have HSV-2 antibodies but do not report lesions shed virus from the genital tract [Langenberg, 1999; Wald, 2000]. In immunocompetent young adults studied within the first few years after infection, HSV-2 typically can be isolated by culture from genital or perianal swabs on 1% to 5% of days, and HSV-2 DNA can be detected by polymerase chain reaction (PCR) testing on 15% to 20% of days [Wald, 1995; Wald, 1997; Corey, 2000]. Asymptomatic shedding occurs at a similar rate in individuals with one to twelve recurrences annually compared to those who report no symptoms [Wald, 1995]. Furthermore, up to one half of subclinical HSV-2 shedding episodes occur more than seven days before or after a symptomatic recurrence [Wald, 1995]. Collectively, these data indicate that shedding is independent of outbreak frequency. It also has been determined that both viral shedding and recurrences are more frequent in the first year after initial HSV-2 infection [Wald, 1995; Benedetti, 1999].

Suppressive antiviral therapy with nucleoside analogues significantly reduces the frequency of total and asymptomatic shedding [Barton, 1996; Patel, 1997; Gupta, 2004; Diaz-Mitoma, 1996; Wald, 1997; Straus, 1996]. A large randomized clinical trial in monogamous, heterosexual couples discordant for HSV-2 infection demonstrated VALTREX™ (valacyclovir hydrochloride, valaciclovir) 500mg, used once a day by the infected source partner with nine or fewer recurrences per year, in combination with safer sex practices, reduced transmission of symptomatic HSV-2 infection by 75% and overall HSV-2 infection by 48% [Corey, 2004]. Of note, a viral shedding sub-study of 89 patients studied for 60 days demonstrated a 73% reduction in total days of viral shedding and a 64% reduction in days of subclinical viral shedding in infected source partners receiving valacyclovir compared to those receiving placebo.

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In a recently completed study of valacyclovir 1g once daily for the reduction of HSV-2 viral shedding in 152 subjects with a history of ≥6 GH recurrences per year, the mean percent of days with HSV-2 shedding was 9.3% in the placebo group, and 2.7% in the valacyclovir group (p<0.001), representing a 71% reduction in total days of viral shedding compared to placebo. The mean percent of subclinical days with shedding was 6.4% on placebo and 2.7% in the valacyclovir group (p<0.001), a 58% reduction compared to placebo [Fife, 2006].

The efficacy of valacyclovir for the suppression of viral shedding also was investigated in a study by Gupta et al [Gupta, 2004]. In this study, 69 participants with genital HSV-2 infection received oral valacyclovir 500 mg BID, acyclovir 400 mg BID and placebo in random order for 7 weeks each, in a three-period crossover design. There was a one week washout between treatment periods. Twenty seven (27) subjects (39%) had a diagnosis of a first episode of GH ≤6 months before randomization. Overall, for the 69 subjects randomized, HSV DNA was detected by PCR from at least one anatomical site on 27.1% of the days while receiving placebo, compared with 6.1% of days receiving valacyclovir and 6.4% of days while receiving acyclovir.

Viral shedding (both clinical and subclinical) is an important source of transmissible virus, therefore medical management of shedding is important from both a scientific and public health perspective [Corey, 2004]. Newly diagnosed individuals are at risk for frequent shedding and frequent recurrences suggesting that management is particularly important in this patient population. This study will provide additional natural history data in this population and will also provide the first robust evaluation of the efficacy of valacyclovir to reduce HSV-2 shedding in individuals who have been given a new diagnosis of GH.

4. STUDY OBJECTIVE(S) AND ENDPOINTS

4.1. Primary Objective

• To compare the effect of valacyclovir 1g administered once daily for 60 days vs. placebo on total HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. Total shedding includes both clinical (genital lesion present) and subclinical (no genital lesions present) shedding.

4.2. Secondary Objective

• To compare the effect of valacyclovir 1g administered once daily for 60 days vs. placebo on subclinical HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. • To evaluate the safety of valacyclovir 1g administered once daily for 60 days in immunocompetent HSV-2 seropositive subjects newly diagnosed with HSV-2 infection.

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4.3. Primary Endpoint

• Mean percent days of total shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2.

4.4. Secondary Endpoints

• Mean percent days subclinical shedding (no genital lesions present) • Mean percent days clinical shedding (presence of genital lesions) • Proportion of subjects with no shedding • Proportion of subjects with at least one GH recurrence • Time to first GH recurrence

4.5. Other Endpoints

• Time to first oral herpes recurrence • Among subjects with a GH recurrence on study who did not respond fully to 3 days of open-label episodic treatment (VALTREX 500mg twice daily), the percent of HSV-2 isolates resistant to acyclovir was tabulated.

4.6. Ad hoc Endpoints

Four additional ad hoc endpoints were analyzed in both the Intent to Treat Crossover (ITTC) and the Per Protocol (PP) populations:

• Percent of clinical days with HSV-2 shedding • Percent of subclinical days with HSV-2 shedding • Average log HSV-2 DNA copy number per day on days with subclinical shedding • Average log HSV-2 DNA copy number per day on days with shedding (clinical and subclinical)

5. INVESTIGATIONAL PLAN

This was a randomized, double-blind, placebo-controlled, multicenter, two-way crossover study. Subjects were randomized to receive valacyclovir 1g or matching placebo once daily for 60 days in each of two Treatment Periods in a two-way crossover design. There was a washout period of seven days between Treatment Periods (Figure 1).

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Figure 1 Study Design

21 days 60 days 7 days 60 days

Washout Valtrex 1g QD Valtrex 1g QD

Placebo QD Placebo QD

Screening Visit Clinic Visits Clinic Visits 15 days apart 15 days apart

Randomization Visit

5.1. Overall Study Design

A typical subject’s total participation in this study was approximately 148 days and included the following: a screening evaluation (to be performed within 21 days of randomization), a randomization visit, and eight study visits (four visits per Treatment Period, with a 15-day interval between each visit). See Table 1.1 for a Time and Events Table with additional information on study assessments and procedures.

Subjects may have received episodic therapy to treat an initial outbreak or a recurrence in accordance with US approved dosing regimens. However, they were to undergo a three day (72 hours) washout period PRIOR to randomization/initiation of study treatment, but were to be randomized within 4 months of the initial diagnosis of GH to ensure only newly diagnosed subjects were enrolled.

In the event a subject experienced a genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, the subject was to be provided a prescription for antiherpetic therapy. Once healed, and following at least a 72 hour washout period, the subject was permitted to resume the schedule of assessments and proceed to the randomization visit. For subjects who presented with a genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, swabs of the lesion were collected in the clinic for baseline HSV culture and PCR.

During each 60-day Treatment Period and during washout, subjects were required to collect a single daily swab from their genital/anal-rectal area for HSV-2 detection by

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PCR. During a recurrence, swabs of the lesion also were collected in the clinic for HSV-2 detection by culture and PCR.

Once randomized into the study, subjects who experienced a GH recurrence were required to attend the clinic for an additional visit(s), as necessary, to allow the investigator to confirm that the genital lesion(s) were consistent with a GH recurrence. Regardless of Treatment Period, a subject whom the investigator deemed to be experiencing a GH recurrence temporarily discontinued blinded study medication and received open-label episodic treatment with VALTREX 500mg twice daily for 3 days, after which double-blind therapy resumed. The investigator/designated clinician was required to confirm all GH recurrences by the presence of at least the macular/papular (erythema or elevation of skin without fluid) lesion stage of development, before open- label episodic treatment was initiated. The presence of symptoms alone (e.g., pain, tingling, burning, itching) was not sufficient to initiate open-label episodic treatment.

A swab for HSV culture was collected in the clinic on Day 1 of a GH recurrence. For any subjects who received an additional course of open-label VALTREX, an additional swab for HSV culture was obtained at that time. HSV-2 isolates from subjects not responding fully to 3 days of episodic treatment were sent to a designated central laboratory at the end of the study for antiviral sensitivity testing by plaque reduction assay [Collins, 1986].

Subjects used a telephonic, interactive voice response system (IVRS) daily to capture information on genital lesions, genital symptoms and oral outbreaks.

5.1.1. Discussion of Study Design, Including the Choice of Control Group(s)

A two-period crossover design with a seven-day washout period was used in this study. Given the short study duration of up to approximately 148 days and the small likelihood in spontaneous change in the disease over time, a crossover design was considered an appropriate strategy for this study. A crossover design also assured that all subjects enrolled in the study would receive active valacyclovir during their participation. In addition, the crossover design required a smaller sample size than a parallel cohort study.

To reduce the likelihood of a carryover effect of treatment, a washout period was employed. A one week washout period was selected based on the design of an earlier 3-period crossover study that investigated the effect of valacyclovir and acyclovir for suppression of genital HSV shedding [Gupta, 2004]. In that study, a one week washout period of placebo followed the first 2 treatment arms. With the initiation of valacyclovir or acyclovir, 5 days of therapy were needed to achieve suppression of genital HSV shedding. After the discontinuation of therapy, viral shedding consistently reappeared within 5 days.

In all studies of valacyclovir in volunteers with normal renal function, the plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects,

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45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively [VALTREX Product Information, 2006].

For these reasons, a 7-day washout period was considered sufficient time for adequate clearance of study medication.

5.2. Protocol Amendment(s)

There were no amendments to this study.

5.3. Selection of Study Population

Subjects were to be randomized within 4 months of the initial diagnosis of GH, or be newly diagnosed with a first recognized episode of GH at the screening visit. Subjects were required to have documented signs and symptoms of genital HSV-2 infection, as well as laboratory confirmation (positive culture, PCR or serology) of genital HSV-2 infection to be eligible for the study (see Attachment 1).

It was accepted that a subject’s first recognized episode of GH might not represent new infection. It was possible that prior episodes may have escaped detection.

5.3.1. Inclusion Criteria

A subject was eligible for inclusion in this study only if all of the following criteria applied:

1. Subject was in overall general good health. 2. Subject was a male or female and aged 18 years or older. 3. If female, subject must have been of: a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who was pre-menarchial or post-menopausal or surgically sterile); or b. Childbearing potential, but must have had a negative pregnancy test at randomization, and must have been compliant with one of the following: • Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period of 1 week after study completion or premature discontinuation from the study (to account for elimination of the drug) • Had a male partner who was confirmed to be sterile prior to the female subject's entry into the study and was the sole sexual partner for that female subject • Use of contraceptive(s) with a documented failure rate of less than 1% per year, including but not limited to: implants of levonorgestrel, use of

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injectable progestogen, oral contraceptives (either combined or progestogen only), an intrauterine device (IUD) or spermacide plus a mechanical barrier (condom/diaphragm) 4. Subjects must have been newly diagnosed with a first recognized episode of GH as described in (a) or (b): a) HSV-2 seropositive at screen, with documented clinical signs and symptoms consistent with GH at screen or within 4 months prior to randomization OR

b) HSV-2 seronegative at screen, AND HSV-2 culture positive or HSV-2 PCR positive with documented clinical signs and symptoms consistent with GH at screen or within 4 months prior to randomization. 5. Subject must have been willing and able to provide written informed consent and comply with the protocol.

5.3.2. Exclusion Criteria

A subject was not eligible for inclusion in this study if any of the following criteria applied:

1. Subject was known or suspected to be immunocompromised (e.g., subjects who were receiving immunosuppressive therapy or chemotherapy for malignancy, or were seropositive for HIV). 2. Subject received an investigational drug in the 30 days prior to the randomization visit. 3. Subject was receiving systemic antiviral or immunomodulatory treatments. Subjects must not have received systemic antiherpetic treatments (e.g., valacyclovir, acyclovir, ganciclovir, famciclovir) within 3 days of starting study drug, or immunomodulatory treatments in the 30 days before starting study drug. 4. Subject had clinically significant impaired renal function as defined by creatinine clearance less than 50mL/min (calculated using the Cockcroft-Gault formula). 5. Subjects with a history or evidence of decompensated liver disease, or clinically significant impaired hepatic function defined as an ALT (alanine transaminase) level >3 times the normal upper limit. 6. Subject was known to be hypersensitive to valacyclovir, acyclovir, ganciclovir or famciclovir. 7. Subject had malabsorption or vomiting syndrome or other gastrointestional dysfunction that might have impaired drug pharmacokinetics. 8. Female subject who was contemplating pregnancy within the duration of the study drug dosing period. 9. Female subject who was pregnant and/or nursing. 10. Subject with alcohol or drug abuse at the time of enrollment.

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11. Subjects who had received suppressive (daily) therapy for GH prior to randomization. Suppressive therapy was defined as daily antiherpetic therapy of at least 4 weeks duration. 12. Subjects with a history of ocular HSV infection.

5.3.3. Predetermined Criteria for Subject Withdrawal

5.3.3.1. Subject withdrawal from the investigational product

Premature discontinuation of study drug was defined as complete discontinuation of study drug, with no intention of restarting medication, at any point before the full course of medication was taken as prescribed. Subjects who prematurely discontinued investigational product were required to complete all End of Study procedures (Day 60 of Treatment Period 2), unless consent to be followed in the study was specifically withdrawn. The investigator was required to make every effort to perform the assessments and procedures as described for the End of Study Visit. These data were to be recorded, as they comprised an essential evaluation that was to be done prior to discharging any subject from the study.

Temporary discontinuation of double-blind medication for treatment of outbreaks was required.

There were no plans to replace subjects who withdrew from the investigational product.

5.3.3.2. Subject withdrawal from the study

A subject could voluntarily discontinue participation in the study at any time. The investigator could also, at his or her discretion, discontinue the subject from participating in this study at any time. If a subject was prematurely discontinued from participation in the study for any reason, the investigator was required to make every effort to perform the assessments and procedures as described for the End of Study Visit.

There were no plans to replace subjects who withdrew from the study.

5.4. Investigational Product(s)

5.4.1. Description of Investigational Product(s)

GlaxoSmithKline produced valacyclovir and matching placebo in accordance with established standards. The following batch numbers were used:

Double-blind valacyclovir- batch number and

Double-blind placebo – batch number

Open-label VALTREX – batch number and

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Study medication was stored in a secure area, free of environmental extremes and in accordance with the instructions printed on the medication labels. Investigational products were stored according to product specifications (store at 15° to 25°C / 59° to 77°F), and protected from light.

5.4.2. Dosages and Administration

All study medication was taken orally. Dose adjustments were not permitted. Temporary discontinuation of double-blind medication for treatment of recurrences was required.

The daily dosing regimen for each phase of the study is summarized in the following table.

Table 1 Dosages and Administration

Study Phase Drug Daily Dosage Dosing Period Double-blind Valacyclovir 1 gram once daily Treatment Period 1 = (2 x 500mg caplets) 60 days Treatment Period 1 or or and Treatment Period 2 = Treatment Period 2 Placebo Matching Placebo 60 days (2 caplets) Washout Period None None 7-day washout Open-Label Episodic VALTREX 500mg twice daily 3 days Treatment

5.4.3. Dose Rationale

The recommended dosage of valacyclovir for chronic suppressive therapy of recurrent GH is 1g once daily in patients with normal immune function (in subjects with a history of nine or fewer recurrences per year, an approved alternative dose is 500mg once daily). A study to investigate the effect of valacyclovir 1g once daily on total and subclinical viral shedding in subjects with a history of frequent recurrences (6 or more per year) recently was completed [Fife, 2006]. The present study utilized the same dose of valacyclovir; however, VLX105832 evaluated shedding rates in a population with no established recurrence pattern, i.e., in newly diagnosed subjects. Dose selection was based on several factors: i) HSV-2 seropositive subjects with no symptoms shed virus at similar rates as do those with one to twelve annual recurrences [Wald, 1995]; ii) no recurrence history is available in this study population, therefore valacyclovir 1g once daily, which is approved for all HSV-2 infected patients, is the most appropriate dose, and iii) the ability to contrast results from this study with those from the recently completed study of valacyclovir 1g once daily on viral shedding in subjects with ≥6 recurrent GH infections per year.

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For this study in subjects newly diagnosed with GH infection, subjects received the following two treatments in a two-way crossover design: valacyclovir 1g once daily or matching placebo once daily for 60 days on each Treatment Period.

Subjects who experienced GH recurrences during the study received episodic treatment with open-label VALTREX 500mg twice daily for 3 days. This is the approved treatment regimen in the US; the rationale for this dose of valacyclovir for the treatment of GH recurrences is found in the GlaxoSmithKline Document RM2001/00020/01 Clinical Investigator’s Brochure (CIB) and the US Product label [VALTREX Product Information, 2006].

5.4.4. Blinding

The study was double-blinded. RAMOS [Registration And Medication Ordering System, a GSK telephonic IVRS] was used for central randomization and distribution of blinded study medication. RAMOS also was to be utilized for unblinding; the relevant investigational site personnel were trained in the use of the system to unblind a subject’s treatment assignment. The study blind was maintained by the central randomization organization; investigators were provided a telephone number to call, if necessary in an emergency, to break the study blind.

Only in the case of an emergency, when knowledge of the investigational product was essential for the clinical management or welfare of the subject, was the investigator permitted to unblind a subject’s treatment assignment. The investigator was required to, whenever possible, discuss options with the GSK Medical Monitor, on-call physician, or appropriate GSK study personnel before unblinding. If the blind was broken for any reason and the investigator was unable to contact GSK prior to unblinding, the investigator was required to notify GSK as soon as possible following the unblinding incident without revealing the subject’s study treatment assignment, unless the information was important to the safety of subjects remaining in the study. In addition, the investigator was required to record the date and reason for revealing the blinded treatment assignment for that subject in the Case Report Form (CRF).

If a serious adverse event (SAE) was reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff could unblind the treatment assignment for the individual subject. If an expedited report to one or more regulatory agencies was required, the report would identify the subject’s treatment assignment.

The treatment assignment information was not unblinded for any subjects during the conduct of this study.

5.4.5. Treatment Assignment

Subjects were assigned to study treatment in accordance with the randomization schedule. Central randomization procedures were used. The randomization schedule was computer-generated by GSK. The investigator contacted a central randomization organization (RAMOS) for allocation of treatment assignment. The randomization block size was 4.

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5.4.6. Assessment of Compliance

The investigator or designee was responsible for study medication accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designee maintained study medication accountability records throughout the course of the study, and documented the amount of study drug received from the sponsor, and the amount supplied and/or administered to and returned by subjects, as applicable.

All subjects were instructed to return containers of study medication at each clinic visit. The investigator or designee assessed study medication compliance by counting and recording the number of returned caplets in the dispensing record. Following drug accountability, the start and stop dates of each subject’s study treatment were recorded in the CRF. Non-compliance with investigational product was defined as failure to take study medication for at least 80% of the time on double-blind therapy.

5.4.7. Treatment of Investigational Product Overdose

For the purpose of this study, an overdose was defined as a single oral valacyclovir dose of 3 grams or greater. Subjects were to be observed closely for signs of toxicity. Investigators were informed that, in the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function was restored.

5.5. Prior and Concomitant Medications and Non-Drug Therapies

5.5.1. Permitted Medications

All concomitant medications taken during the study were recorded in the CRF.

5.5.2. Prohibited Medications

5.5.2.1. Pre-Study Prohibited Medications

Subjects who had received suppressive (daily) therapy for GH prior to randomization were ineligible for the study. Suppressive therapy was defined as daily antiherpetic therapy of at least 4 weeks duration. Subjects must not have received systemic antiviral treatments (e.g., valacyclovir, famciclovir, acyclovir, ganciclovir) within 3 days of starting study drug, or systemic immunomodulatory treatments in the 30 days before starting study drug.

5.5.2.2. On-Study Prohibited Medications

The use of systemic anti-herpetics was not allowed during the study for the treatment of oral herpes outbreaks. Open-label episodic therapy supplied to investigational sites for treatment of GH recurrences was not to be dispensed for the treatment of oral herpes outbreaks.

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The use of systemic immunomodulatory treatments was not allowed during the study.

5.6. Study Assessments and Procedures

A brief description of the study activities and when they occurred at each visit can be found in Table 1.1.

5.6.1. Demographic and Baseline Assessments

Demographic assessments included date of birth, gender, race, height, and weight. Baseline assessments included hematology and clinical chemistry, HSV-1 and HSV-2 serology, current medical conditions, concurrent medications, genital examination, and human chorionic gonadotropin (hCG) pregnancy testing.

HSV infection was confirmed by Focus Diagnostics HerpeSelect -2 ELISA glycoprotein G-based assay.

5.6.2. Efficacy Assessment

As laboratory techniques have evolved, recent studies have used PCR analysis in addition to viral culture to measure viral shedding in the presence of lesions as well as between outbreaks [Corey, 2004; Wald, 2000; Wald, 1995]. PCR analysis is a more sensitive test for HSV detection than culture [Ryncarz, 1999; Ramaswamy, 2004: Wald, 1997].

Subjects collected daily genital/anal-rectal swab samples (one swab for entire region each day) during Treatment Period 1, washout, and Treatment Period 2. Swab samples were analyzed for HSV-2 shedding by type-specific PCR assay, performed by the University of Washington Virology Research Laboratory, Seattle, WA. For each subject, each study day was classified by PCR as 'shedding' or 'no shedding'; each day was also categorized as 'clinical' (i.e., presence of genital lesions) or 'subclinical" (i.e., no genital lesions). Subjects used a telephonic IVRS daily to capture information on genital lesions, genital symptoms and oral outbreaks.

5.6.2.1. Primary efficacy endpoint(s)

The primary endpoint of the study was mean percent days of total shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2.

5.6.2.2. Secondary efficacy endpoint(s)

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5.6.2.3. Other efficacy endpoint(s)

• Time to first oral herpes recurrence

• Among subjects with a GH recurrence on study who do not respond fully to 3 days of episodic treatment (VALTREX 500mg twice daily), the percent of HSV-2 isolates resistant to acyclovir was tabulated. Such HSV-2 isolates were sent to a designated central laboratory at the end of the study for antiviral sensitivity testing by plaque reduction assay [Collins, 1986].

5.6.2.4. Ad hoc Endpoints

Four additional ad hoc endpoints were analyzed in both the ITTC and the PP populations:

• Percent of clinical days with HSV-2 shedding. • Percent of subclinical days with HSV-2 shedding. • Average log HSV-2 DNA copy number per day on days with subclinical shedding • Average log HSV-2 DNA copy number per day on days with shedding (clinical and subclinical)

5.6.3. Safety Assessments

The safety and tolerability of valacyclovir was assessed by evaluation of changes in serum chemistry and hematology, and adverse event reporting. Blood samples for laboratory assessments were collected at Screening, and at the end of each 60-day Treatment Period. Following discussion with the subject and at each clinic visit, the investigator or designee was responsible for recording adverse events.

Per the original protocol, it was intended to collect adverse information, concomitant medications, and information on treatment compliance within an E-diary system. However, based on the sponsor’s prior experience, compliance with an E-diary system had been poor. In addition, clinic visits occurred frequently (every 15 days). Therefore, adverse events, concomitant medications and treatment compliance information were collected at each clinic visit, based on recall and discussion with the subject.

If a subject did not report a previous history of oral herpes outbreaks, oral herpes outbreaks were to be reported as adverse events. Otherwise, signs or symptoms of a HSV recurrence (genital or oral) were not reported to GSK as AEs.

The investigator was responsible for recording AEs observed after study drug initiation (Randomization Visit) until the End of Study Visit on Day 60 of Treatment Period 2.

From the time a subject consented to participate in the study until he or she had completed the study, any SAEs assessed as related to study participation or related to a GSK concomitant medication, were to be reported promptly to GSK.

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5.6.3.1. Adverse events

An adverse event was defined as any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE could be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also included failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE included: a Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. b New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study. c Signs, symptoms, or the clinical sequelae of a suspected interaction. d Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication. e “Lack of efficacy” or “failure of expected pharmacological action” per se were not to be reported as an AE or SAE. However, the signs and symptoms and /or clinical sequelae resulting from lack of efficacy were to be reported if they fulfilled the definition of an AE or SAE.

5.6.3.2. Serious adverse events

A serious adverse event was any untoward medical occurrence that, at any dose:

a Resulted in death. b Was life-threatening. c Required hospitalization or prolongation of existing hospitalization. d Resulted in disability/incapacity, or e Was a congenital anomaly/birth defect. f Medical or scientific judgement was to be exercised in deciding whether reporting was appropriate in other situations, such as important medical events that may not have been immediately life-threatening or resulted in death or hospitalization but might have jeopardized the subject or required medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These were also to be considered serious.

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5.6.3.3. Pregnancies

A urine sample was collected for hCG pregnancy testing (female subjects only) at the screening visit, randomization visit, Day 60 of Treatment Period 1, the End of Study visit at Day 60 of Treatment Period 2, and at any time pregnancy was suspected.

Pregnancy information on female subjects was to be collected after study drug initiation until the End of Study visit at Day 60 of Treatment Period 2.

Any female subject who became pregnant while participating in this study was to be withdrawn from the study and discontinued from the investigational product.

The investigator collected pregnancy information on any female subject who became pregnant while participating in the study. The investigator recorded pregnancy information on the appropriate form and submitted it to GSK within 2 weeks of learning of a subject's pregnancy. The subject was to be followed to determine the outcome of the pregnancy. Information on the status of the mother and child was to be forwarded to GSK. Generally, follow-up was to be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy was to be reported.

5.6.3.4. Clinical laboratory evaluations

Blood and urine samples were collected for hematology, clinical chemistry and urinalysis at the screening visit and at the end of each Treatment Period. The following laboratory parameters were evaluated: • Hematology: Hemoglobin, MCV, platelets, WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils. • Clinical Chemistry: calcium, phosphorous, sodium, potassium, chloride, AST (SGOT), total bilirubin, ALT (SGPT), alkaline phosphatase, albumin, BUN, creatinine. • Urinalysis: hematuria, proteinuria.

Central laboratories were used for evaluation of blood and urine samples (Quest Diagnostics Clinical Trials Laboratory, Van Nuys, CA, HSV cultures (Quest Diagnostics, Van Nuys, CA), and for PCR testing (University of Washington Virology Research Laboratory, Seattle, WA). ViroMed Laboratories, Minnetonka, MN, was used as the central laboratory for acyclovir sensitivity testing.

Clinically significant abnormal laboratory findings that were detected during the study or were present at baseline and significantly worsened following the start of the study were reported as AEs or SAEs. However, clinically significant abnormal laboratory findings that were associated with the disease being studied, unless judged by the investigator as more severe than expected for the subject’s condition, or that were present or detected at the start of the study and did not worsen, were not reported as AEs or SAEs.

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5.7. Data Quality Assurance

This study used Phase Forward’s InForm system. InForm is a web-based clinical trials data management system that provides investigational sites a standardized and validated, remote, electronic data capture system for the collection of clinical trial data. Activities performed using InForm include data entry, modification, review and validation. Each activity performed carries a unique user identification code and a date-time stamp.

InForm training for this multicenter study was provided electronically to site staff. Study-specific Electronic Case Report Form (eCRF) training was provided via webcast for the monitors, and at the investigator meeting for the site staff by GSK Data Management. Additionally, an InForm interactive training database was available to site staff and study monitors for independent follow-up training. The application was fully validated using test data, prior to distributing the URL for site use. Encrypted clinical trial data was transmitted from the site via the internet to a firewall-protected network server, and then via an application server into the clinical database (e.g., InForm puts data into a shared drive). An electronic audit trail of all changes made to the eCRF was kept within the InForm system. This audit trail identified the user making the change by User ID, and date and time of change.

Pre-defined data validation checks were run within the eCRF as the data were entered and submitted by authorized site staff. The resulting data queries were then resolved. Additional queries were generated within the eCRF by authorized GSK staff as a result of data review (e.g., source document review, external data reconciliation).

Subjects used a telephonic IVRS daily to capture information on genital lesions, genital symptoms and oral outbreaks. In addition to the IVRS data and InForm eCRF data, electronic laboratory data were delivered to GSK by external vendors. These data were reconciled with the eCRF data and resulting discrepancies were queried within the eCRF.

Additional QC was carried out by extracting SAS datasets, and comparing printed copies against the eCRF for approximately 10% of the cases.

Adverse events and concomitant medications were coded by the autoencoder using company standard dictionaries (GSK Drug) and industry standard dictionaries (MedDRA).

The principal investigator electronically signed and dated each InForm casebook attesting to his/her responsibility for the quality of all data included therein, and that the data represented a complete and accurate record of each subject's participation in the study. At the end of the study once all data queries were resolved, a CD-ROM containing eCRF PDFs (the PDF contains all of the patient's eCRF data, the data queries, and a copy of the audit trail) was sent to site along with a letter explaining how to view the data on the PDF. Upon delivery of the CD-ROM, the study site notified GSK of receipt of the CD.

After data management procedures were completed, the database was released on 16Jan2007. Following release, the database was frozen on 23Jan2007.

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The original validated data (eCRFs, etc.) were archived according to company standard procedures.

5.8. Data Analysis Methods

5.8.1. Timings of Planned Analyses

All planned analyses were performed after sign-off of the Reporting and Analysis Plan (RAP, Attachment 2). After the database was authorized, the study treatments were unblinded and data displays were released.

5.8.1.1. Interim analyses and data monitoring

No formal interim analysis was planned or conducted.

5.8.2. Sample Size Considerations

In this crossover study, it was estimated 47 completed subjects would provide over 90% power to detect a reduction in the mean percent days of total HSV-2 shedding from 9.6% in the placebo treatment phase to 2.8% in the valacyclovir treatment phase, assuming standard deviations of 9.8% and 5.6%, respectively, and a correlation of 0.4.

5.8.3. Analysis Populations

There were four populations considered in the analysis:

Intent-to-Treat (ITT) Exposed: The ITT Exposed population was defined as all subjects who received at least one dose of investigational product. This was the primary population for assessing safety.

Intent-to-Treat Crossover (ITTC): all subjects in the ITT who had at least one PCR swabbing result in each Treatment Period. This was the primary population for assessing efficacy.

First Period Efficacy: This population included subjects in the ITT and was used for efficacy analyses restricted to the first Treatment Period.

Swab samples for two subjects were irreconcilable. Data from these two subjects were excluded from all efficacy analyses.

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5.8.4. Treatment Comparisons

The primary objective of the study was to compare the effect of valacyclovir 1g administered once daily for 60 days vs. placebo on the percent of days with total HSV-2 viral shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. The comparison was conducted in the ITT Exposed population and results were tested at the two-sided 5% level.

5.8.5. General Considerations for Data Analyses

All programming was performed using SAS version 8, or a later release, in a UNIX environment. Other general analysis considerations and data handling conventions are described in the VLX105832 RAP (Attachment 2).

5.8.5.1. Examination of subgroups

Subgroups of interest were: gender, age (<=30/>30), and race (Caucasian/non- Caucasian). The primary and secondary endpoint summaries were provided for each of these subgroups.

5.8.5.2. Multiple comparison/multiplicity

Multiplicity was not an issue as there was only one primary endpoint and two treatments.

There were multiple secondary endpoints and multiple subpopulations of endpoints, but each was examined on its own in separate analyses and with respect to its effect on the endpoint, without adjustment for multiplicity.

5.8.6. Data Handling Conventions

Treatment Period 2 begins with the administration of Treatment Period 2 study medication.

Any on-study event that occurred during the washout period was assigned to the treatment that was taken during Treatment Period 1. Any event that occurred during the follow-up period (after Treatment Period 2) was assigned to the treatment that was taken during Treatment Period 2.

5.8.6.1. Premature discontinuation and missing data

Subjects who prematurely withdrew from the study were not included in the Per Protocol Population. They were, however, candidates for inclusion in the Intent-to-Treat Exposed Population and the Intent-to-Treat Crossover Population.

Missing PCR data (e.g., swabbing not done or assay result not available) were not imputed, regardless of lesion status. If the swab was missing for any reason, then the subject’s shedding status was missing for that day and was excluded from both the numerator and denominator of percent days with shedding.

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Each day subjects took one combined swab of the genital area and the anal/rectal areas. If a subject mistakenly collected multiple swabs on a day, the maximum of the multiple PCR measurements for the day was used. If a sample had low-quantity positive DNA copy numbers and was unable to be typed (HSV-1 or HSV-2), it was considered to be no shedding.

If no recurrence onset date was present for the entire study, then all days on study were considered subclinical. Further details are presented in the RAP (see Attachment 2).

5.8.6.2. Derived and transformed data

The daily value for HSV-2 PCR copy number was log-transformed to stabilize the variance prior to averaging over the relevant set of days, e.g. days with total shedding, days with subclinical shedding.

5.8.7. Study Population

5.8.7.1. Protocol deviations

Any unforeseen circumstance occurring during the study period was reviewed in a blinded fashion to determine whether it constituted a major protocol deviation. In particular, the database was examined to check for the following deviations:

• Evidence of failure to satisfy inclusion/exclusion criteria as recorded by the investigator. • Failure to visit doctor for on-treatment visits (Visits 2-4 and 6-8) within the desired window, or failure to return for end-of-Treatment Period visits (Visits 5 and 9). • Failure to comply with dosing regimen. Compliance of less than 80% was considered a major deviation. • Swabbing PCR results on fewer than 85% of days on study. • Subjects took at least one of the unapproved drugs listed in the protocol.

Subjects were instructed to return any unused study medication to the study site at each follow up visit. Treatment compliance was calculated as a percentage of caplets that should have been taken per protocol, assuming that all caplets not returned to the study site were taken as prescribed.

5.8.8. Efficacy Analyses

Each subject’s study day was classified by PCR as either ‘shedding’ (i.e., positive HSV-2 result from the daily swab(s)), ‘no shedding’ (i.e., negative HSV-2 result from the daily swab(s)), or ‘unknown’ (swabbing not done or assay result not available). In addition, each study day was classified as either ‘clinical’ (i.e., presence of genital lesions) or ‘subclinical’ (i.e. no genital lesions) by the investigator during recurrence visits and by

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the subject via an IVRS diary. The IVRS daily diary captured information on genital lesions, genital symptoms and oral outbreaks.

5.8.8.1. Primary efficacy measure(s)

The percent of days with total HSV-2 viral shedding was defined for each subject as the number of days with positive HSV-2 PCR shedding divided by the total number of days with PCR data. Treatment differences were tested using a Wilcoxon rank-sum test after first testing for the equality of residual effects using a Wilcoxon rank-sum test at the 5% level of significance [Koch, 1972].

If the test for equality of residual effects was significant, then treatment differences only could be assessed using the Treatment Period 1 data of the ITT Exposed population as if the study were a one-period parallel design. This analysis would be carried out as a supporting analysis in any case.

All primary and secondary endpoints were analyzed using the ITT Exposed population. An analysis using the Per Protocol population was also carried out.

Summaries of the primary endpoint were also provided for the following subgroups: gender, age (<=30/>30), and race (Caucasian/non-Caucasian).

5.8.8.2. Secondary efficacy measure(s)

Treatment differences in each of the following secondary endpoints were tested at the two-sided 5% level of significance:

5.8.8.3. Other efficacy measure(s)

Time to first oral herpes recurrence was evaluated using Kaplan-Meier estimates.

Among subjects with a GH recurrence on study who did not respond fully to 3 days of open-label episodic treatment with VALTREX, the percent of HSV-2 isolates resistant to acyclovir was tabulated.

5.8.8.4. Ad hoc Endpoints

Four additional ad hoc endpoints were analyzed in both the ITTC and the PP populations:

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• Percent of clinical days with HSV-2 shedding. Note that only subjects with clinical days in both Treatment Periods were evaluable for this endpoint. • Percent of subclinical days with HSV-2 shedding. Note that only subjects with subclinical days in both Treatment Periods were evaluable for this endpoint. • Average log HSV-2 DNA copy number per day on days with subclinical shedding. Note that only subjects with subclinical shedding in both Treatment Periods were evaluable for this endpoint. • Average log HSV-2 DNA copy number per day on days with shedding (clinical and subclinical). Note that only subjects with shedding in both Treatment Periods were evaluable for this endpoint.

Percent of days with total shedding, percent of clinical days with HSV-2 shedding, percent of subclinical days with HSV-2 shedding, average log HSV-2 DNA copy number per day on days with subclinical shedding, and average log HSV-2 DNA copy number per day on days with total shedding was compared using a Wilcoxon rank-sum test, after first testing for the equality of residual effects as described in the RAP (Attachment 2).

The primary analysis (for which Treatment Period 2 begins with the initiation of study medication in Treatment Period 2) is conservative because it provides the benefit of the residual effect of 7 days of valacyclovir to a Treatment Period 2 placebo treatment. Thus any bias created should favor placebo. If any subjects received valacyclovir in Treatment Period 1 and inadvertently skipped Washout and progressed directly to Treatment Period 2, a sensitivity analysis of the primary endpoint ignoring the first 7 days of Treatment Period 2 was planned.

5.8.9. Safety Analyses

Adverse events were coded using the MedDRA dictionary and grouped by MedDRA System Organ Classes (SOC) and preferred term. The summary of the number and percent of subjects with all adverse events and drug-related adverse events were displayed by body system and preferred term for each treatment arm.

Summary statistics were produced for laboratory values at baseline and at the post treatment visit. Laboratory values were converted to standard international (SI) units and summarized descriptively. Laboratory values were assessed for shifts relative to the normal range and for post-dose changes from baseline to values outside the following pre-defined threshold values.

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Table 2 Threshold Values

Measure Change Category a CLINICAL CHEMISTRY Alkaline phosphatase To > 1.50 x ULN ALT To > 2.00 x ULN AST To > 2.00 x ULN Creatinine To > 1.50 x ULN HEMATOLOGY Hemoglobin To < 0.8 x LLN Neutrophils To < 0.8x LLN Platelets < 100,000/mm3 WBC To < 0.75x LLN a. Laboratory abnormalities were defined in accordance with previous requests from FDA on the presentation of laboratory abnormality data.

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6. STUDY POPULATION RESULTS

6.1. Disposition of Subjects

Seventy (70) subjects from 14 centers in the United States were randomized into the study, 35 subjects to the valacyclovir-placebo treatment sequence (VAL-PBO), and 35 subjects to the placebo-valacyclovir treatment sequence (PBO-VAL) (Table 6.1- Table 6.2). Two subjects in the VAL-PBO sequence group had compromised efficacy data, leaving 68 subjects in the First Period Efficacy population.

During the course of routine monitoring visits, duplicate samples for the same subject were discovered at one site. These errors in sample identification and labelling were felt to compromise the integrity of the data to a degree considered unacceptable to the sponsor.

These subjects were included in the safety analysis.

Of the 35 ITT subjects randomized to the VAL-PBO sequence, 8 subjects withdrew from the study while receiving valacyclovir in Treatment Period 1, and the remaining 27 subjects entered Treatment Period 2. Of these 27 subjects, 1 withdrew while receiving placebo in Treatment Period 2.

Of the 35 ITT subjects randomized to the PBO-VAL sequence, 8 withdrew from the study while receiving placebo in Treatment Period 1, and the remaining 27 subjects entered Treatment Period 2. Of these 27 subjects, 3 withdrew while receiving valacyclovir in Treatment Period (Table 6.3, Table 6.4).

In total, twenty of the 70 (29%) subjects in the ITT population prematurely withdrew from the study (11 while receiving valacyclovir, 9 while receiving placebo). The primary reasons for withdrawal were “Lost to follow-up” (n=8, 11%), “Other” (n=6, 9%), and “Subject decided to withdraw” (n=4, 6%, Table 6.3). Sixteen of the 20 (80%) subjects who withdrew from the study withdrew during Treatment Period 1 (Table 6.4).

Table 3 Disposition of Subjects

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6.2. Protocol Deviations

Per the original protocol, it was intended to collect adverse event information, concomitant medications, and information on treatment compliance within an E-diary system. However, based on the sponsor’s prior experience, compliance with an E-diary system had been poor. In addition, clinic visits occurred frequently (every 15 days). Therefore, adverse events, concomitant medications and treatment compliance information were collected at each clinic visit, based on recall and discussion with the subject.

One subject entered the protocol with significantly impaired renal function, in violation of entry criteria (Table 6.7).

At least one major protocol deviation was recorded for 35 (50%) subjects randomized into the study (Table 6.8). Of those 35 subjects with at least one major protocol deviation, the deviations included use of an unapproved drug during the study (n=1, 3%), failure to take at least 80% of double-blind study medication (n=13, 37%), genital/anal- rectal swab PCR results on fewer than 85% of the days on study (n=20, 57%), and failure to comply with study visit schedule (n=29, 83%).

6.3. Populations Analyzed

Four populations were considered in the analysis.

Table 4 Study Populations

Population n Definition ITT Exposed 70 All subjects who received at least one dose of investigational product ITT Crossover 52 All subjects in ITT (with the exception of two subjects whose efficacy data were compromised) who had at least one PCR swabbing result in each Treatment Period Per Protocol 36 All subjects (with the exception of two subjects whose efficacy data were compromised) who completed the study without a major protocol violation and had PCR data on at least 85% of days on study First Period 68 All subjects in the ITT (with the exception of two subjects whose Efficacy efficacy data were compromised). This population was used for efficacy analyses restricted to the first Treatment Period

6.4. Demographics and Other Baseline Characteristics

Participating subjects were newly diagnosed with a first recognized episode of GH at the screening visit or were randomized within 4 months of the initial diagnosis of GH. Subjects were required to have documented clinical signs and symptoms of genital HSV infection, as well as laboratory confirmation of genital HSV-2 infection.

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6.4.1. Demographic Characteristics

Key demographic characteristics of the ITT population are provided in Table 6.9 and Table 6.10.

Overall, the study population was primarily female (70%) and white/Caucasian (51%). The mean age was similar for subjects in each group (29 years for VAL-PBO, 33 years for PBO-VAL).

Table 5 Demographics

Demographics VAL-Placebo Placebo-VAL N (ITT) 35 35 Females: Males 22:13 27:8 Mean Age, years (SD) 29 (9) 33 (10) White/Caucasian, n (%) 19 (54) 17 (49) HSV-2 Positive Serostatus, n (%) 30 (86) 31 (89) HSV-1 Positive Serostatus, n (%) 18 (51) 19 (54) Source: Table 6.9, Table 6.10, Table 6.20

Table 6.11 – Table 6.14 summarize demographic characteristics in the ITTC and PP populations, which were similar to those for the ITT population.

Of the 70 subjects randomized, 9 (13%) were HSV-2 seronegative at entry. These subjects presented with laboratory confirmation of HSV-2 infection by culture or PCR at screen or upon initial diagnosis made within 4 months of randomization. As such, these subjects recently acquired a new HSV-2 infection, and had not yet seroconverted.

6.4.2. Baseline Characteristics

Baseline demographics and characteristics for all patients randomized were similar across the two treatment groups (Table 6.9, Table 6.10).

6.4.3. Other Current Medical Conditions

In each treatment group, a majority of subjects reported at least one current medical condition (Table 6.15). The most commonly reported conditions were nervous system disorders [9 subjects (26%) VAL-PBO; 7 subjects (20%) PBO-VAL], respiratory, thoracic and mediastinal disorders [7 (20%) VAL-PBO; 9 (26%) PBO-VAL] and gastrointestinal disorders [4 (11%) VAL-PBO; 11 (31%) PBO-VAL].

6.4.4. Previous Medications

Subjects who had received daily suppressive antiherpetic therapy of at least 4 weeks duration for management of GH prior to randomization were ineligible for the study. Subjects must not have received systemic antiviral treatments (e.g., valacyclovir, famciclovir, acyclovir, ganciclovir) within three days of starting study drug, or systemic immunomodulatory treatments in the 30 days before starting study drug.

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6.4.5. Other Factors Affecting Response to Therapy

Subjects known to be hypersensitive to valacyclovir, acyclovir, ganciclovir, or famciclovir; or who had malabsorption or vomiting syndrome or other gastrointestional dysfunction that might impair drug pharmacokinetics were excluded from study participation.

6.5. Concomitant Medications

Seventy-six percent (76%) of subjects receiving valacyclovir and 79% of subjects receiving placebo took at least one concomitant medication during the respective Treatment Periods (Table 6.16). Medications related to the genitourinary system were used most frequently, with 53% and 55% of subjects reporting use of these medications while receiving valacyclovir or placebo, respectively. With the exception of medications related to the sensory organs and systemic hormones, similar proportions of subjects took medications related to other body systems. Sensory organ medications were used by a greater percentage of subjects while receiving valacyclovir compared to placebo (18% VAL, 6% PBO), as were systemic hormonal medications (13% VAL, 5% PBO).

6.6. Treatment Compliance

Non-compliance with investigational product was defined as failure to take study medication for at least 80% of the time on therapy.

Table 6.18 summarizes the double-blind treatment compliance for the ITT population. The mean percent compliance while taking double-blind study medication was high, with a compliance rate of 87% among subjects receiving valacyclovir, and 91% among subjects receiving placebo. Interestingly, subjects receiving valacyclovir in Treatment Period 1 who remained on study became more compliant with study medication in Treatment Period 2 (87% compared to 95%). Among subjects receiving placebo, there was no appreciable difference in compliance rates between Treatment Period 1 and Treatment Period 2.

Table 6.19 summarizes compliance with open-label valacyclovir for treatment of recurrences in the ITT population. Eleven subjects received open-label VALTREX while in the double-blind valacyclovir treatment sequence, with a mean percent compliance rate for open-label therapy of 91%. Twenty-seven (27) subjects received open-label VALTREX while in the double-blind placebo treatment sequence; the mean percent compliance rate for open-label therapy in these subjects was 84%.

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7. EFFICACY RESULTS

7.1. Primary Efficacy Results

The primary efficacy endpoint was the mean percent of all days with HSV-2 shedding as determined by type-specific PCR assay for HSV-2. For the ITTC population, shedding was reported on a mean 13.5% of all days in subjects while receiving placebo compared to a mean 2.9% of days in subjects while receiving valacyclovir (p<0.001), a significant decrease representing a 78% reduction in total HSV-2 shedding (Table 7.1).

The results for the PP population also demonstrate a similar significant reduction in total shedding (80%, p<0.001) (Table 7.2).

Total shedding during Treatment Period 1 only was evaluated as a supporting analysis in the ITT population. In the first Treatment Period, total shedding was reported on a mean 14.9% of all days in subjects while receiving placebo, compared to a mean 2.6% of all days in subjects while receiving valacyclovir, an 83% reduction (p<0.001) (Table 7.3).

Table 6 Summary of Percent of All Days with Shedding

Population Valacyclovir Placebo p-value % Reduction ITTC (n=52) (n=52) Mean (SD) 2.9 (5.6) 13.5 (7.6) <0.001 78% Source: Table 7.1

7.2. Secondary Efficacy Results

7.2.1. Mean Percent of Days with Subclinical Shedding

For the ITTC population, subclinical shedding was reported on a mean 11% of days in subjects while receiving placebo compared to a mean 2.4% of days in subjects while receiving valacyclovir (p<0.001), a significant decrease representing a 78% reduction in subclinical shedding (Table 7.4).

Table 7 Summary of Percent of Days with Subclinical Shedding

Population Valacyclovir Placebo p-value % Reduction ITTC (n=52) (n=52) Mean (SD) 2.4 (4.8) 11 (15.1) <0.001 78% Source: Table 7.4

A similar significant reduction (80%, p<0.001) in subclinical shedding in subjects while on valacyclovir was observed in the PP population (Table 7.5).

Subclinical shedding during Treatment Period 1 only was analyzed in the ITT population. In the first Treatment Period, subclinical shedding was reported on a mean 11.6 % of

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days in subjects while receiving placebo, compared to a mean 2% of days in subjects while receiving valacyclovir, a reduction of 83% (p<0.001) (Table 7.6).

7.2.2. Mean Percent of Days with Clinical Shedding

For the ITTC population, clinical shedding was reported on a mean 2.4% of days in subjects while receiving placebo compared to a mean 0.6% of days in subjects while receiving valacyclovir (p=0.014), a significant decrease representing a 77% reduction in clinical shedding (Table 7.7).

Table 8 Summary of Percent of Days with Clinical Shedding

Population Valacyclovir Placebo p-value % Reduction ITTC (n=52) (n=52) Mean (SD) 0.6 (1.7) 2.4 (4.4) 0.014 77% Source: Table 7.7

A similar reduction (77%, p=0.040) in clinical shedding in subjects while on valacyclovir was observed in the PP population (Table 7.8).

Clinical shedding during Treatment Period 1 only was analyzed in the ITT population. In the first Treatment Period, clinical shedding was reported on a mean 3.3 % of days in subjects while receiving placebo, compared to a mean 0.6% of days in subjects while receiving valacyclovir, a reduction of 82% (p=0.031) (Table 7.9).

7.2.3. Proportion of subjects with no shedding

In subjects while receiving valacyclovir, a significant difference was seen compared to the placebo group in the percent of subjects with no shedding (Table 7.10). Sixty percent (31/52, 60%) of subjects experienced no shedding days while receiving valacyclovir compared to 15/52 (29%) of subjects while receiving placebo (p<0.001) (Table 7.10, Table 7.11). A similar significant reduction in the proportion of subjects with no shedding was observed in the PP population (Table 7.12, Table 7.13).

Table 9 Summary of Proportion of Subjects with No Shedding

Population Valacyclovir Placebo p-value ITTC (n=52) (n=52) Proportion of Subjects with No Shedding, n (%) 31 (60) 15 (29) <0.001 1. Source: Table 7.10 and Table 7.11

7.2.4. Proportion of subjects with at least one GH recurrence

Significantly more subjects were recurrence-free while receiving valacyclovir. Seventy-nine percent (41/52) of subjects were recurrence-free while receiving valacyclovir compared to 52% (27/52) of subjects while receiving placebo (p=0.003) (Table 7.14, Table 7.15).

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Table 10 Summary of Proportion of Subjects Recurrence-Free

Population Valacyclovir Placebo p-value ITTC (n=52) (n=52) Proportion of Subjects Recurrence-Free, n (%) 41 (79) 27 (52) 0.003 1. Source: Table 7.14 and Table 7.15

A similar significant reduction in the proportion of subjects recurrence-free during the study was observed in the PP population (Table 7.16, Table 7.17).

7.2.5. Time to First GH Recurrence

Because fewer than half of subjects experienced a GH recurrence while receiving valacyclovir, the median time to first recurrence was >68 days for subjects receiving valacyclovir compared to 61 days for subjects receiving placebo. The time to first GH recurrence in the first Treatment Period was significantly shorter while receiving valacyclovir compared to placebo (p=0.010). Descriptively, the Kaplan-Meier estimate of the proportion of subjects who were recurrence-free at the end of Treatment Period 1 was 0.82 on valacyclovir compared to 0.48 on placebo (Figure 7.1, Table 7.18).

The short treatment period and the infrequency of recurrences among subjects while receiving valacyclovir makes it difficult to characterize the time to first GH recurrence for valacyclovir recipients.

7.3. Other Efficacy Results

7.3.1. Time to First Oral Herpes Recurrence

The median time to first oral herpes recurrence was >68 days for subjects receiving valacyclovir compared to >74 days for subjects receiving placebo. There was no significant difference in time to first oral recurrence in the first Treatment Period while receiving valacyclovir compared to placebo (p=0.058). Descriptively, the Kaplan-Meier estimate of the proportion of subjects who were oral recurrence-free at the end of Treatment Period 1 was 1.0 on valacyclovir compared to 0.88 on placebo (Figure 7.3, Table 7.20).

7.3.2. Acyclovir Resistance

To evaluate the in vitro sensitivity of HSV-2 isolates to acyclovir, HSV-2 isolates obtained from subjects not responding fully to 3 days of open-label episodic treatment with VALTREX 500 mg twice daily were sent to ViroMed Laboratories, Inc.

Six subjects in the study required greater than 3 days of open-label treatment with VALTREX for management of GH outbreaks. Six HSV-2 isolates from four subjects were tested for sensitivity to acyclovir; all isolates were sensitive to acyclovir with IC50

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values of less than 2.0 µg/mL (Table 7.44). Viral cultures from the remaining two subjects were negative.

7.4. Ad hoc Endpoints

Table 11 Summary of Ad hoc Analyses

Population VALTREX PLACEBO p-value ITTC Percent of Clinical Days with Shedding n 7 7 Mean (SD) 26.2 (28.5) 34.7 (37.1) 0.860 Percent of Subclinical Days with Shedding n 52 52 Mean (SD) 2.5 (5.2) 12 (16.2) <0.001 Average Log DNA Copy Number Per Day on Subclinical Shedding Days n 13 13 Mean (SD) 4 (0.7) 4.6 (0.8) 0.078 Average Log DNA Copy Number Per Day on All Shedding Days n 17 17 Mean (SD) 4 (0.6) 4.8 (0.8) 0.018 Source: Table 7.22, Table 7.25, Table 7.28, Table 7.31

7.5. Subgroup Analyses

Exploratory subgroup analyses were performed for the primary and select secondary endpoints. The primary endpoint (mean percent of days with total HSV-2 shedding) is summarized in Table 7.34 – Table 7.35 for the following subgroups of interest: gender, age (≤30/>30), and Caucasian/non-Caucasian in the ITTC and PP populations, respectively. In general, these subgroup analyses must be interpreted with caution as they are exploratory in nature, often involve small sample sizes, and are descriptive only and do not involve formal statistical testing.

In the ITTC population, a similar reduction in mean percent of all days with HSV-2 shedding was measured in males compared to females (78% in each group), and in subjects ≤30 years of age vs. >30 years of age (77% vs. 80%). A greater reduction in mean percent of all days with HSV-2 shedding was measured in Caucasians vs. non- Caucasians (86% vs. 68%, Table 7.34).

The trends in the Per Protocol subgroup analysis of the primary endpoint were similar to that of the ITTC subgroup analysis (Table 7.35).

Select secondary endpoints were summarized for the same subgroups of interest in the ITTC and PP populations. Summaries by subgroup of the percent of days with subclinical shedding, and the percent of days with clinical shedding, are displayed in

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Table 7.36 - Table 7.39. Trends in the subgroups were similar to that shown for the primary endpoint.

Summaries by subgroup of the proportion of subjects with no shedding are displayed in Tables 7.40 and Table 7.41. Trends in the gender and age subgroups were similar to that shown for the secondary endpoint. In both the ITTC and PP population, the proportion of subjects with shedding while on placebo was similar for Caucasians compared to non- Causasians, yet the treatment effect was greater among Caucasians. Summaries by subgroup of the proportion of subjects with at least one GH recurrence are displayed in Table 7.42 and Table 7.43. A greater proportion of males vs. females, and subjects aged >30 compared to <=30 remained recurrence-free while on placebo. The sizes of the subgroups in these analyses are too small to comment upon trends.

7.6. Efficacy Conclusion(s)

• Valacyclovir 1g QD significantly decreased total HSV-2 shedding compared to placebo (mean 2.9% vs. 13.5% of days with total shedding; p<0.001), a reduction of 78%. • Valacyclovir 1g QD significantly decreased subclinical HSV-2 shedding compared to placebo (mean 2.4% vs. 11% of days with subclinical shedding; p<0.001), a reduction of 78%. • Valacyclovir 1g QD significantly decreased clinical HSV-2 shedding compared to placebo (mean 0.6% vs. 2.4% of days with clinical shedding; p=0.014), a reduction of 77%. • Sixty percent (60%) of subjects did not shed virus while receiving valacyclovir, compared to 29% of subjects while receiving placebo (p<0.001). • Significantly more subjects remained recurrence-free while receiving valacyclovir compared to subjects while receiving placebo (79% vs. 52%, p=0.003). • The time to first GH recurrence in the first Treatment Period was significantly shorter while receiving valacyclovir compared to placebo (p=0.010). The median time to first GH recurrence was >68 days for subjects receiving valacyclovir compared to 61 days for subjects receiving placebo. • There was no significant difference in time to first oral recurrence in the first Treatment Period while receiving valacyclovir compared to placebo (p=0.058). The median time to first oral recurrence was >68 days for subjects receiving valacyclovir compared to >74 days for subjects receiving placebo. • There were no cases of HSV-2 isolates resistant to acyclovir in those individuals who required more than 3 days of open-label VALTREX for treatment of a GH recurrence.

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8. SAFETY RESULTS

8.1. Extent of Exposure

Subjects were instructed to take two 500mg caplets (1g) once daily for 60 days in each of two Treatment Periods.

Exposure to study medication was similar in the two treatment groups with a mean exposure of 56.3 days of double-blind valacyclovir and mean of 55.6 days of double- blind placebo (Table 8.1).

8.2. Adverse Events

In the ITT population, 35 subjects began the study on the VAL-PBO sequence. Of these, 8 subjects withdrew from the study in Treatment Period 1, leaving 27 subjects in this group to receive placebo in Treatment Period 2. Thirty five (35) subjects began the study on the PBO-VAL sequence. Of these, 8 withdrew from the study in Treatment Period 1, leaving 27 subjects in this group to receive valacyclovir in Treatment Period 2.

Thus, in the safety analyses, 62 subjects were exposed to valacyclovir (the original 35 VAL-PBO subjects from Treatment Period 1, plus the 27 PBO-VAL subjects who received valacyclovir in Treatment Period 2). Similarly, 62 subjects were exposed to placebo (the original 35 PBO-VAL subjects from Treatment Period 1, plus the 27 VAL- PBO subjects who received placebo in Treatment Period 2).

8.2.1. All Adverse Events

Adverse events were reported in 19/62 (31%) of subjects while taking valacyclovir and 26/62 (42%) of subjects while taking placebo (Table 8.3).

Overall, the most commonly reported AEs among subjects while receiving valacyclovir vs. placebo, respectively, were fungal infection (5% vs. 10%), upper respiratory tract infection (5% vs. 2%), sinusitis (3% vs. 2%), bacterial vaginitis (3% vs. 2%), diarrhea (2% vs. 3%), and headache (2% vs. 3%).

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Table 12 Most Frequently Reported Adverse Events

VAL Placebo N, ITT 62 62 Most Frequent Adverse Events – On-Therapy n (%) n (%) Subjects with any AE(s), n (%) 19 (31) 26 (42) 3 (5) 6 (10) Upper Respiratory Tract Infection 3 (5) 1 (2) Sinusitis 2 (3) 1 (2) Vaginitis bacterial 2 (3) 1 (2) Sinus congestion 2 (3) 0 Ear Infection 2 (3) 0 Bronchitis 2 (3) 0 Vulvovaginal mycotic infection 2 (3) 0 Diarrhea 1 (2) 2 (3) Headache 1 (2) 2 (3) Pharyngolaryngeal pain 1 (2) 1 (2) Folliculitis 1 (2) 1 (2) UTI 1 (2) 1 (2) Labyrnthitis 1 (2) 0 Onychomycosis 1 (2) 0 Tendon injury 1 (2) 0 ALT increased1 1 (2) 0 AST increased1 1 (2) 0 Blood Pressure increased 1 (2) 0 Smear cervix abnormal 1 (2) 0 Pollakiuria 1 (2) 0 Vulvovaginal dryness 1 (2) 0 1. Both AEs occurred in the same subject Source: Table 8.3

8.2.2. Drug-Related Adverse Events

Two (3%) subjects while receiving valacyclovir and three (5%) subjects while receiving placebo reported at least one drug-related AE (Table 8.4). With the exception of one report of a severe headache in a subject receiving placebo, all drug-related AEs were described as either mild or moderate in intensity. One subject (2%) receiving valacyclovir experienced diarrhea considered by the investigator to be attributable to

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study medication; a second subject experienced a vaginal yeast infection considered to be study drug-related.

Three (5%) subjects receiving placebo reported at least one drug-related AE. The first subject reported tingling in the eye, mouth and hand; all events were considered by the investigator to be attributable to study medication. A second subject experienced a severe headache, abdominal pain, and diarrhea, and a third subject reported a headache of moderate intensity. All of these events were considered to be drug-related (placebo).

8.2.3. Adverse Events Leading to Premature Discontinuation of Investigational Product and/or Study

Investigational product was withdrawn because of AEs in two subjects.

Investigational product also was discontinued in a subject receiving placebo. This subject experienced a headache of moderate intensity, and was withdrawn from the study.

8.3. Serious Adverse Events

No SAEs were reported during the conduct of this study.

8.3.1. Deaths

No deaths were reported during the conduct of this study.

8.4. Other Relevant Adverse Events

There were no reports of thrombotic microangiopathy (TMA), thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS).

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8.5. Pregnancies

Five study participants became pregnant during the conduct of this study, three while receiving valacyclovir and two while receiving placebo. Of these five subjects, there were three reports of elective termination, one report of spontaneous abortion, and for the remaining subject, pregnancy outcome was unknown at the time of this report (See Section 11).

8.6. Clinical Laboratory Evaluations

Blood and urine samples were collected for hematology, clinical chemistry and urinalysis at the screening visit and at the end of each Treatment Period. Routine clinical laboratory testing was performed by a central laboratory, Quest Diagnostics Clinical Trials.

8.6.1. Laboratory Values over Time

No clinically meaningful differences between the valacyclovir and placebo treatment groups were observed in the mean or median values of any hematology or clinical chemistry assessments over time (Table 8.9 - Table 8.14).

8.7. Safety Conclusion(s)

• The nature and incidence of AEs were similar for subjects receiving valacyclovir compared to placebo, with fungal infection and upper respiratory tract infection reported most frequently among valacyclovir recipients. • No clinically important trends in clinical chemistry or hematology laboratory values were noted during the study. • No SAEs were reported during the conduct of this study. • No deaths were reported during the conduct of this study. • No cases of TMA were reported during the conduct of this study.

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9. DISCUSSION AND CONCLUSIONS

9.1. Discussion

Study VLX105832 investigated the effect of suppressive therapy with valacyclovir 1g once daily on HSV-2 shedding in subjects newly diagnosed with GH. Study participants were newly diagnosed with a first recognized episode of GH at the screening visit, or were randomized within 4 months of an initial diagnosis of GH. Subjects were required to have documented signs and symptoms of genital HSV-2 infection, as well as laboratory confirmation of GH.

Previous studies have demonstrated both viral shedding and recurrences are more frequent in the first year after initial HSV-2 infection [Wald, 1995; Benedetti, 1999]. In one study, women who had acquired GH within a year before enrollment had more frequent shedding compared to women who had been infected for one year or more [Wald, 1995]. Benedetti reported a significant decrease in median recurrence rates between years 1 and 2 for patients with primary HSV-2 infection [Benedetti, 1999]. Thus, individuals newly infected with HSV-2 are at risk for frequent shedding and frequent outbreaks. Since viral shedding is an important source of transmissible virus, medical management of shedding is important from both a scientific and public health perspective [Corey, 2004].

Results from a landmark clinical study in monogamous heterosexual couples discordant for HSV-2 infection demonstrated that valacyclovir 500mg used once daily by the infected source partner with nine or fewer recurrences per year, in combination with safer sex practices, reduced transmission of symptomatic HSV-2 infection by 75% and total transmission of virus (symptomatically or asymptomatically) by 48% [Corey, 2004]. Within this study, a viral shedding sub-study of 89 patients studied for 60 days demonstrated a 73% reduction in total days of viral shedding (mean 2.9% vs. 10.8%, as measured by PCR) and a 64% reduction in days of subclinical viral shedding (mean 2.8% vs. 7.8%) in infected source partners receiving valacyclovir compared to those receiving placebo.

A recently completed study of valacyclovir 1g QD in subjects with a known recurrence pattern of six or more recurrences/year demonstrated a statistically significant decrease (71%) in total days of viral shedding (mean 2.7% vs. 9.3%), and a 58% reduction in subclinical days with shedding (mean 2.7% vs. 6.4%) among subjects receiving valacyclovir compared to placebo. In another HSV-2 viral shedding study that enrolled a heterogeneous population of subjects (newly diagnosed with GH, and diagnosed >6 months prior to study entry), valacyclovir 500 mg twice daily reduced subclinical shedding by 77% compared to placebo.

For the primary endpoint in study VLX105832, (mean percent of days with total HSV-2 shedding), a statistically significant decrease (78%, mean 2.9% vs. 13.5%, p<0.001) was demonstrated among subjects while receiving valacyclovir 1g QD compared to subjects while receiving placebo. A 78% reduction in all days with subclinical shedding also was observed for the secondary endpoint (mean 2.4% vs. 11.0%, p<0.001). The results of the

- 4452 - CONFIDENTIAL RM2007/00260/00RM2007/00260/00 VLX105832VLX105832 primary endpoint reflect the fact that newly diagnosed subjects are shedding at a rate higher than that observed in earlier studies in subjects with a known GH recurrence pattern.

Significantly more subjects experienced no days of viral shedding while receiving valacyclovir compared to placebo; sixty percent (60%) of subjects did not shed virus while receiving valacyclovir, compared to 29% of subjects while receiving placebo. In other words, 71% of newly diagnosed subjects shed virus while on placebo and were at risk for transmission, compared to 40% of subjects while receiving valacyclovir.

Exploratory subgroup analyses were performed for the primary and select secondary endpoints. A greater reduction in mean percent of all days with HSV-2 shedding was measured in Caucasians vs. non-Caucasians. Although the proportion of subjects with shedding was similar for Caucasians compared to non-Causasians while receiving placebo, the treatment effect was greater among Causasians. The sizes of the subgroups in these analyses are too small to comment upon trends.

Valacyclovir 1g QD was well-tolerated as evidenced by the safety information collected during this study. Two subjects receiving valacyclovir and three subjects receiving placebo experienced AEs considered by the investigator to be related to study medication. With the exception of one report (severe headache in a subject receiving placebo), all drug-related AEs were described as either mild or moderate in intensity. There were no clinically significant trends in laboratory findings.

In this study of subjects newly diagnosed with HSV-2 infection, the frequency of total and subclinical HSV-2 shedding was greater than reported in earlier studies involving subjects with a history of symptomatic genital recurrences. This study is the first to demonstrate a significant reduction in viral shedding over 60 days with valacyclovir 1g daily compared to placebo in a population of subjects newly diagnosed with HSV-2 infection. This reduced frequency of viral shedding may translate to a reduced risk of transmission to an uninfected partner.

9.2. Conclusions

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• Significantly more subjects remained recurrence-free while receiving valacyclovir compared to subjects while receiving placebo (79% vs. 52%, p=0.003). • The time to first GH recurrence in the first Treatment Period was significantly shorter while receiving valacyclovir compared to placebo (p=0.010). The median time to first GH recurrence was >68 days for subjects receiving valacyclovir compared to 61 days for subjects receiving placebo. • There was no significant difference in time to first oral recurrence in the first Treatment Period while receiving valacyclovir compared to placebo (p=0.058). The median time to first oral recurrence was >68 days for subjects receiving valacyclovir compared to >74 days for subjects receiving placebo. • There were no cases of HSV-2 isolates resistant to acyclovir. • The nature and incidence of AEs were similar for subjects receiving valacyclovir compared to placebo, with fungal infection and upper respiratory tract infection reported most frequently among valacyclovir recipients. • No clinically important trends in clinical chemistry or hematology laboratory values were noted during the study. • No SAEs were reported during the conduct of this study. • No deaths were reported during the conduct of this study. • No cases of TMA were reported during the conduct of this study.

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10. REFERENCES

Barton S, Munday P, Patel R. Asymptomatic shedding of herpes simplex virus from the gential tract: uncertainty and its consequences for patient management. Int J STD AIDS 1996;7:229-232.

Benedetti JK, Zeh J and Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Int Med 1999; 131:14-20.

Brown Z, Benedetti J, Ashley R, et al., Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 1991;324:1247-1252.

Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Transm Dis 1999; 26 (suppl); S2-S7.

Centers for Disease Control(CDC) and Prevention. Sexually Transmitted Diseases Treatment Guidelines. MMWR 2006; 55 (RR:11); 1-92.

Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 1986;18 (Suppl B):103-12.

Corey L, Handsfield H. Genital herpes and public health. JAMA 2000;283:791-794.

Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20.

Diaz-Mitoma F, Ruben M, Sacks S, McPherson P, Caisse G. Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes. J Clin Microbiol 1996;34:657-663.

Fleming D, McQuillan G, Johnson R, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111.

Fife K, Warren T, Ferrera D, et al. Effect of valacyclovir on viral shedding in immunocompetent patients with recurrent herpes simplex virus 2 genital herpes: A US-based randomized, double-blind, placebo-controlled trial. May Clin Proc 2006; 81:1321-1327.

GlaxoSmithKline Document RM2001/00020/01, International Clinical Investigator's Brochure - VALTREX (Valacyclovir). 2003.

Gupta R, Wald A, Krantz E, et. al, Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374-1381.

Koch, G. The Use of Non-Parametric Methods in the Statistical Analysis of the Two- Period Change-Over Design. Biometrics 1972;328:579-584.

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Langenberg A, Corey L, Ashley R, et al. A prospective study of new infections with HSV-1 and HSV-2. N Engl J Med 1999;341:1432-1438.

Mertz G, Coombs R, Ashley R, et al. Transmission of genital herpes in couples with one symptomatic and one asymptomatic partner: a prospective study. J.Infect Dis 1988;157:1169-1177.

Mertz G, Benedetti J, Ashley R, Selke S, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116:197-202.

Ramaswamy M, McDonald C, Smith M, Thomas D, Maxwell S, Tenant-Flowers M, Geretti AM. Diagnosis of genital herpes by real time PCR in routine clinical practice. Sex Transm Infect 2004;80:406-410.

Ryncarz, A, Goddard J, Wald A, Huang M, Roizman, B, Corey L. Development of a high-throughput quantitative assay for detecting herpes simplex virus DNA in clinical samples. J Clin Microbiol 1999;37:1941-1947.

Patel R, Cowan F, Barton S. Advising patients with genital herpes. BMJ 1997;314:85-86.

Smith JS; Robinson NJ. Age-specific prevalence of infection with herpes siimplex virus types 2 and 1: a global review. J Infect Dis 2002:186:S3-S28.

Straus S, Rooney J, Hallahan C. Acyclovir suppresses subclinical shedding of herpes simplex virus. Ann Intern Med 1996;125:776-777.

VALTREX (valacyclovir hydrochloride) Product Information. July 2006.

Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995;333:770-775.

Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women: effect of acyclovir treatment. J Clin Invest 1997;99:1092-1097.

Wald A, Zeh J, Selke S, Warren T, et al. Reactivation of genital herpes virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000;342:844-850.

Wald A, Zeh J, Selke S, Warren T, Ashley R, Corey L. Genital shedding of herpes simplex virus among men. J Infect Dis 2002;186:S34-S39.

XuF, Sternberg MR, Kottiri BJ, et al. Trends in Herpes Siimplex Virus Type 1 and Type 2 Seroprevalence in the United States. JAMA 2006;296: 964-73.

- 4856 - This section contained patient narratives which are textual descriptions of medical history, treatment and outcome for individual patients who experienced a clinically important adverse event including serious adverse events during the trial. They have been excluded to protect patient privacy. This data may be made available subject to an approved research proposal and a determination of the ability to provide information from the specific narratives whilst protecting the patient’s privacy. For further information please see the Patient Level Data section of the GSK Clinical Study Register. CONFIDENTIAL RM2007/00260/00 VLX105832

Table 1.1 Time and Events Table

Screen Randomization Treatment Arm 1 Washout Treatment Arm 2 GH [15 days between [15 days between visits] Recurrence visits] Visit No. 1 2 3 4 5 6 7 8 9 10 Within 21 days of Day 1 Day Day Day Day 60 7 days Day Day Day Day 60 Recurrence Description of Activity randomization 15 30 45 15 30 45 End of Study Visit Clinic Visit X X X X X X X X X X X Written Informed Consent X HSV-1 and HSV-2 Serology X Hematology and Clinical Chemistry X X X Urinalysis X X X Pregnancy Test1 X X X X Demographic Data X CONFIDENTIAL Current Medical Conditions X Genital Examination X2 X X 61 Investigational product Dispensed X X X X X X X X Investigational product Accountability X X X X X X X X X Diary Dispensed X Diary Review X X X X X X X X X Education/Counseling on Genital Herpes X X X X X X X X X X Telephone Contact to Subject X Dispense and/or Collect Genital/Anal-rectal X X X X X X X X X X X Swabs for HSV-2 PCR Analysis3 Collect Lesion Swab for HSV-2 PCR Analysis X4 X Collect Viral Swab for HSV culture X5 X

Open-label VALTREX Dispensed for X RM2007/00260/00 treatment of GH recurrence

VLX105832

Continued

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Table 1.1 Time and Events Table (Continued)

Screen Randomization Treatment Arm 1 Washout Treatment Arm 2 GH [15 days between [15 days between visits] Recurrence visits] Visit No. 1 2 3 4 5 6 7 8 9 10 Within 21 days of Day 1 Day Day Day Day 60 7 days Day Day Day Day 60 Recurrence Description of Activity randomization 15 30 45 15 30 45 End of Study Visit Adverse Events6 X X X X X X X X X X X X Concomitant Medications X X X X X X X X X X X 1. A pregnancy test (serum hCG at screen; urine hCG at randomization) will be performed at the visits indicated and at any other time pregnancy is suspected. 2. A genital examination must be conducted at the screening visit for subjects who present with genital herpes signs or symptoms 3. The subject will collect viral swabs daily during each entire 60-day treatment period, and the washout period. CONFIDENTIAL 4. Viral swab for HSV-2 PCR will be obtained at screen for subjects who present with a genital herpes lesion at screen. 5. Viral swab for HSV culture will be obtained at screen for subjects who present with a genital herpes lesion at screen. 62 6. SAEs due to study participation will be collected between the screening and randomization visit.

RM2007/00260/00 VLX105832

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Study Population Data Source Tables

Page Table 6.1 Summary of Subjects Randomized by Investigator (Randomized Population) ...... 65 Table 6.2 Summary of Populations (Randomized Population) ...... 66 Table 6.3 Summary of Subject Disposition (Intent-to-Treat Exposed Population) ...... 67 Table 6.4 Summary of Subject Disposition by Period (Intent-to-Treat Exposed Population) ...... 68 Table 6.5 Summary of Investigational Product Status (Intent-to-Treat Exposed Population) ...... 69 Table 6.6 Summary of Investigational Product Status by Period (Intent-to-Treat Exposed Population) ...... 70 Table 6.7 Summary of Inclusion/Exclusion Criteria Deviations (Randomized Population) ...... 71 Table 6.8 Major Protocol Deviations Leading to Exclusion From Per Protocol Population (Randomized Population) ...... 72 Table 6.9 Summary of Demographic Characteristics (ITT) (Intent-to-Treat Exposed Population) ...... 73 Table 6.10 Summary of Race and Racial Combinations (ITT) (Intent-to-Treat Exposed Population) ...... 74 Table 6.11 Summary of Demographic Characteristics (ITTC) (Intent-to-Treat Crossover Population) ...... 75 Table 6.12 Summary of Race and Racial Combinations (ITTC) (Intent-to-Treat Crossover Population) ...... 76 Table 6.13 Summary of Demographic Characteristics (PP) (Per Protocol Population) ...... 77 Table 6.14 Summary of Race and Racial Combinations (PP) (Per Protocol Population) ...... 78 Table 6.15 Summary of Current Medical Conditions (Intent-to-Treat Exposed Population) ...... 79 Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1 (Intent-to-Treat Exposed Population) ...... 80

63 CONFIDENTIAL RM2007/00260/00 VLX105832

Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text (Intent-to-Treat Exposed Population) ...... 91 Table 6.18 Summary of Treatment Compliance - Suppression Treatment (Intent-to-Treat Exposed Population) ...... 98 Table 6.19 Summary of Treatment Compliance - Open-Label Treatment (Intent-to-Treat Exposed Population) ...... 99 Table 6.20 Summary of HSV-2/HSV-1 Cross-Classification (Intent-to-Treat Exposed Population) ...... 100

64 Protocol: VLX105832 Page 1 of 1 Population: Randomized Table 6.1 Summary of Subjects Randomized by Investigator

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total Investigator name and id number (N=35) (N=35) (N=70) ------2 (6%) 0 2 (3%) 2 (6%) 2 (6%) 4 (6%) 2 (6%) 2 (6%) 4 (6%) 2 (6%) 3 (9%) 5 (7%) 3 (9%) 0 3 (4%) 7 (20%) 6 (17%) 13 (19%) 0 2 (6%) 2 (3%) 1 (3%) 3 (9%) 4 (6%)

4 (11%) 2 (6%) 6 (9%) CONFIDENTIAL 5 (14%) 6 (17%) 11 (16%) 1 (3%) 3 (9%) 4 (6%) 2 (6%) 0 2 (3%) 65 3 (9%) 4 (11%) 7 (10%) 1 (3%) 2 (6%) 3 (4%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Randomized Table 6.2 Summary of Populations

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total (N=35) (N=35) (N=70) ------Number of Subjects Randomized 35 (100%) 35 (100%) 70 (100%)

Intent-to-Treat Exposed Population 35 (100%) 35 (100%) 70 (100%)

First Period Efficacy Population 33 (94%) 35 (100%) 68 (97%)

Intention to Treat Crossover Population 25 (71%) 27 (77%) 52 (74%)

Per Protocol Population 17 (49%) 18 (51%) 35 (50%) CONFIDENTIAL 66 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.3 Summary of Subject Disposition

Valtrex 1g QD Placebo Total (N=35) (N=35) (N=70) ------Completion Status Completed 24 (69%) 26 (74%) 50 (71%) Prematurely Withdrawn 11 (31%) 9 (26%) 20 (29%) Primary reason for withdrawal Adverse Event 2 (6%) 0 2 (3%) Lost to follow-up 4 (11%) 4 (11%) 8 (11%) Protocol Violation 0 0 0 Subject decided to withdraw 2 (6%) 2 (6%) 4 (6%) from study

Other 3 (9%) 3 (9%) 6 (9%) CONFIDENTIAL 67 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Note: The treatment group column will indicate the treatment that the subject was taking at the time of premature withdrawal. Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.4 Summary of Subject Disposition by Period

Period 1 Period 2 Valtrex 1g Period 1 Period 1 Valtrex 1g Period 2 Period 2 QD Placebo Total QD Placebo Total (N=8) (N=8) (N=16) (N=27) (N=27) (N=54) ------Completion Status Completed 0 0 0 24 (89%) 26 (96%) 50 (93%) Prematurely Withdrawn 8 (100%) 8 (100%) 16 (100%) 3 (11%) 1 (4%) 4 (7%) Primary reason for withdrawal Adverse Event 1 (13%) 0 1 (6%) 1 (4%) 0 1 (2%) Lost to follow-up 3 (38%) 4 (50%) 7 (44%) 1 (4%) 0 1 (2%) Protocol Violation 0 0 0 0 0 0

Subject decided to withdraw 2 (25%) 2 (25%) 4 (25%) 0 0 0 CONFIDENTIAL from study Other 2 (25%) 2 (25%) 4 (25%) 1 (4%) 1 (4%) 2 (4%) 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Valtrex 1g QD Placebo Total (N=35) (N=35) (N=70) ------Completion Status Completed 24 (69%) 25 (71%) 49 (70%) Prematurely discontinued 11 (31%) 10 (29%) 21 (30%)

Reason for Discontinuation Adverse event 2 (6%) 0 2 (3%) Lost to follow-up 4 (11%) 4 (11%) 8 (11%) Protocol violation 0 0 0 Subject decided to withdraw 2 (6%) 2 (6%) 4 (6%)

Lack of efficacy 0 0 0 CONFIDENTIAL Sponsor terminated study 0 0 0 Disease progression 0 0 0 Other, specify 3 (9%) 4 (11%) 7 (10%) 69 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Reason for Discontinuation Adverse event 1 (13%) 0 1 (6%) 1 (4%) 0 1 (2%) Lost to follow-up 3 (38%) 4 (50%) 7 (44%) 1 (4%) 0 1 (2%)

Protocol violation 0 0 0 0 0 0 CONFIDENTIAL Subject decided to withdraw 2 (25%) 2 (25%) 4 (25%) 0 0 0 Lack of efficacy 0 0 0 0 0 0 Sponsor terminated study 0 0 0 0 0 0 70 Disease progression 0 0 0 0 0 0 Other, specify 2 (25%) 2 (25%) 4 (25%) 1 (4%) 2 (7%) 3 (6%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Note: The treatment group column will indicate the treatment that the subject was taking at the time of premature withdrawal. Protocol: VLX105832 Page 1 of 1 Population: Randomized Table 6.7 Summary of Inclusion/Exclusion Criteria Deviations

Total Criterion (N=70) ------Any criteria deviations 1 (1%)

Exclusion criteria Significantly impaired renal function 1 (1%) CONFIDENTIAL 71 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Randomized Table 6.8 Major Protocol Deviations Leading to Exclusion From Per Protocol Population

Total (N=70) ------Total number of major protocol deviators 35 (50%)

Unapproved drug 1 (3%) Compliance < 80% 13 (37%) Swab count < 85% 20 (57%) Visits not within window 29 (83%) CONFIDENTIAL 72 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Note: A subject may have more than one major protocol deviation leading to exclusion. Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.9 Summary of Demographic Characteristics (ITT)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total (N=35) (N=35) (N=70) ------Age (y) n 35 35 70 Mean 28.9 32.8 30.9 SD 8.68 10.28 9.64 Median 26.0 29.0 28.0 Min. 18 20 18 Max. 49 58 58

Sex n 35 35 70

Female 22 (63%) 27 (77%) 49 (70%) CONFIDENTIAL Male 13 (37%) 8 (23%) 21 (30%)

Ethnicity n 35 35 70 73 Hispanic/Latino 4 (11%) 1 (3%) 5 (7%) Not Hispanic/Latino 31 (89%) 34 (97%) 65 (93%)

Weight (kg) n 35 35 70 Mean 74.9 79.4 77.1 SD 20.88 18.99 19.94 Median 72.3 82.0 76.6 Min. 47 40 40 Max. 154 124 154

Height (cm) n 35 35 70 Mean 166.8 167.2 167.0 SD 10.92 11.84 11.31 Median 165.0 166.0 166.0 RM2007/00260/00 Min. 151 130 130 Max. 184 185 185 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.10 Summary of Race and Racial Combinations (ITT)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total Race (N=35) (N=35) (N=70) ------n 35 35 70 African American/African Heritage 13 (37%) 15 (43%) 28 (40%) American Indian or Alaska Native 1 (3%) 1 (3%) 2 (3%) Asian - Central/South Asian Heritage 0 0 0 Asian - East Asian Heritage 1 (3%) 1 (3%) 2 (3%) Asian - Japanese Heritage 0 0 0 Asian - South East Asian Heritage 0 0 0 Asian - Mixed Race 0 0 0

Native Hawaiian or other Pacific Islander 0 0 0 CONFIDENTIAL White - Arabic/North African Heritage 0 1 (3%) 1 (1%) White - White/Caucasian/European Heritage 19 (54%) 17 (49%) 36 (51%) White - Mixed Race 0 0 0 74 Mixed Race 1 (3%) 0 1 (1%) Missing 0 0 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 6.11 Summary of Demographic Characteristics (ITTC)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total (N=25) (N=27) (N=52) ------Age (y) n 25 27 52 Mean 30.1 35.1 32.7 SD 9.60 10.34 10.22 Median 28.0 34.0 29.5 Min. 18 20 18 Max. 49 58 58

Sex n 25 27 52

Female 18 (72%) 21 (78%) 39 (75%) CONFIDENTIAL Male 7 (28%) 6 (22%) 13 (25%)

Ethnicity n 25 27 52 75 Hispanic/Latino 2 (8%) 1 (4%) 3 (6%) Not Hispanic/Latino 23 (92%) 26 (96%) 49 (94%)

Weight (kg) n 25 27 52 Mean 73.5 83.0 78.4 SD 22.02 18.31 20.54 Median 69.0 84.1 76.6 Min. 47 54 47 Max. 154 124 154

Height (cm) n 25 27 52 Mean 166.2 167.7 167.0 SD 9.99 9.90 9.88 Median 165.0 166.0 166.0 RM2007/00260/00 Min. 151 147 147 Max. 184 185 185 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 6.12 Summary of Race and Racial Combinations (ITTC)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total Race (N=25) (N=27) (N=52) ------n 25 27 52 African American/African Heritage 8 (32%) 10 (37%) 18 (35%) American Indian or Alaska Native 1 (4%) 0 1 (2%) Asian - Central/South Asian Heritage 0 0 0 Asian - East Asian Heritage 1 (4%) 1 (4%) 2 (4%) Asian - Japanese Heritage 0 0 0 Asian - South East Asian Heritage 0 0 0 Asian - Mixed Race 0 0 0

Native Hawaiian or other Pacific Islander 0 0 0 CONFIDENTIAL White - Arabic/North African Heritage 0 1 (4%) 1 (2%) White - White/Caucasian/European Heritage 14 (56%) 15 (56%) 29 (56%) White - Mixed Race 0 0 0 76 Mixed Race 1 (4%) 0 1 (2%) Missing 0 0 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 6.13 Summary of Demographic Characteristics (PP)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total (N=17) (N=18) (N=35) ------Age (y) n 17 18 35 Mean 29.2 34.7 32.0 SD 9.52 9.82 9.94 Median 27.0 33.0 29.0 Min. 18 20 18 Max. 44 58 58

Sex n 17 18 35

Female 13 (76%) 17 (94%) 30 (86%) CONFIDENTIAL Male 4 (24%) 1 (6%) 5 (14%)

Ethnicity n 17 18 35 77 Hispanic/Latino 1 (6%) 0 1 (3%) Not Hispanic/Latino 16 (94%) 18 (100%) 34 (97%)

Weight (kg) n 17 18 35 Mean 76.7 84.2 80.6 SD 24.32 19.01 21.75 Median 72.3 85.6 76.2 Min. 48 57 48 Max. 154 124 154

Height (cm) n 17 18 35 Mean 166.6 166.4 166.5 SD 9.85 7.11 8.42 Median 166.0 165.5 166.0 RM2007/00260/00 Min. 151 155 151 Max. 184 180 184 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 6.14 Summary of Race and Racial Combinations (PP)

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total Race (N=17) (N=18) (N=35) ------n 17 18 35 African American/African Heritage 7 (41%) 9 (50%) 16 (46%) American Indian or Alaska Native 0 0 0 Asian - Central/South Asian Heritage 0 0 0 Asian - East Asian Heritage 1 (6%) 1 (6%) 2 (6%) Asian - Japanese Heritage 0 0 0 Asian - South East Asian Heritage 0 0 0 Asian - Mixed Race 0 0 0

Native Hawaiian or other Pacific Islander 0 0 0 CONFIDENTIAL White - Arabic/North African Heritage 0 0 0 White - White/Caucasian/European Heritage 8 (47%) 8 (44%) 16 (46%) White - Mixed Race 0 0 0 78 Mixed Race 1 (6%) 0 1 (3%) Missing 0 0 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.15 Summary of Current Medical Conditions

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total Medical condition classification (N=35) (N=35) (N=70) ------Any Condition 21 (60%) 25 (71%) 46 (66%)

Blood and lymphatic system disorders 2 (6%) 1 (3%) 3 (4%) Cardiac disorders 1 (3%) 4 (11%) 5 (7%) Congenital, familial and genetic disorders 1 (3%) 0 1 (1%) Ear and labyrinth disorders 1 (3%) 3 (9%) 4 (6%) Endocrine disorders 1 (3%) 0 1 (1%) Eye disorders 7 (20%) 7 (20%) 14 (20%)

Gastrointestinal disorders 4 (11%) 11 (31%) 15 (21%) CONFIDENTIAL General disorders and administration site conditions 2 (6%) 5 (14%) 7 (10%) Immune system disorders 0 1 (3%) 1 (1%) Infections and infestations 0 4 (11%) 4 (6%) 79 Metabolism and nutrition disorders 1 (3%) 0 1 (1%) Musculoskeletal and connective tissue disorders 7 (20%) 6 (17%) 13 (19%) Neoplasms benign, malignant and unspecified (incl cysts 0 1 (3%) 1 (1%) and polyps) Nervous system disorders 9 (26%) 7 (20%) 16 (23%) Psychiatric disorders 8 (23%) 5 (14%) 13 (19%) Renal and urinary disorders 4 (11%) 2 (6%) 6 (9%) Reproductive system and breast disorders 6 (17%) 6 (17%) 12 (17%) Respiratory, thoracic and mediastinal disorders 7 (20%) 9 (26%) 16 (23%) Skin and subcutaneous tissue disorders 8 (23%) 3 (9%) 11 (16%) Vascular disorders 1 (3%) 5 (14%) 6 (9%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------Any medication 47 (76%) 49 (79%)

UNGROUPED Any medication 3 (5%) 4 (6%) ORANGE 1 (2%) 1 (2%) PHYTOCHEMICALS 1 (2%) 1 (2%) SHEA BUTTER 1 (2%) 1 (2%) BUCKWHEAT 0 1 (2%)

GENITO URINARY SYSTEM AND SEX HORMONES CONFIDENTIAL Any medication 33 (53%) 34 (55%) ETHINYLOESTRADIOL 12 (19%) 14 (23%) IBUPROFEN 12 (19%) 13 (21%) 80 NORGESTIMATE 5 (8%) 5 (8%) METRONIDAZOLE 2 (3%) 4 (6%) DROSPIRENONE 2 (3%) 3 (5%) NORELGESTROMIN 2 (3%) 2 (3%) NORETHISTERONE ACETATE 1 (2%) 2 (3%) CLINDAMYCIN 2 (3%) 1 (2%) DIMETHYL SULFONE 1 (2%) 2 (3%) MICONAZOLE NITRATE 3 (5%) 0 NORETHISTERONE 1 (2%) 2 (3%) MEDROXYPROGESTERONE ACETATE 1 (2%) 1 (2%) NAPROXEN SODIUM 1 (2%) 1 (2%) NYSTATIN 2 (3%) 0 PRASTERONE 1 (2%) 1 (2%) PROGESTERONE 1 (2%) 1 (2%) RM2007/00260/00 TOLTERODINE TARTRATE 1 (2%) 1 (2%) CLINDAMYCIN PHOSPHATE 1 (2%) 0

CLOTRIMAZOLE 1 (2%) 0 VLX105832 ETONOGESTREL 1 (2%) 0 LEVONORGESTREL 0 1 (2%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 2 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------MESTRANOL 0 1 (2%) METHYLTHIONINIUM CHLORIDE 0 1 (2%) NORGESTREL 1 (2%) 0 NORMETHANDRONE 1 (2%) 0 PHENYL SALICYLATE 0 1 (2%) TINIDAZOLE 0 1 (2%) VAGISIL (NOS) 0 1 (2%)

NERVOUS SYSTEM

Any medication 29 (47%) 30 (48%) CONFIDENTIAL IBUPROFEN 12 (19%) 13 (21%) PARACETAMOL 9 (15%) 14 (23%) ACETYLSALICYLIC ACID 3 (5%) 3 (5%) 81 CAFFEINE 2 (3%) 2 (3%) DEXTROPROPOXYPHENE NAPSILATE 2 (3%) 2 (3%) SERTRALINE HYDROCHLORIDE 2 (3%) 2 (3%) SUMATRIPTAN 2 (3%) 2 (3%) BUPROPION HYDROCHLORIDE 2 (3%) 1 (2%) DICHLORALPHENAZONE 1 (2%) 2 (3%) ISOMETHEPTENE MUCATE 1 (2%) 2 (3%) OXYCODONE HYDROCHLORIDE 1 (2%) 2 (3%) ALPRAZOLAM 1 (2%) 1 (2%) CYCLOBENZAPRINE HYDROCHLORIDE 1 (2%) 1 (2%) DOXYLAMINE SUCCINATE 2 (3%) 0 EXCEDRIN (NOS) 1 (2%) 1 (2%) GABAPENTIN 1 (2%) 1 (2%) LORAZEPAM 1 (2%) 1 (2%) RM2007/00260/00 METHADONE HYDROCHLORIDE 1 (2%) 1 (2%) NORTRIPTYLINE 1 (2%) 1 (2%)

OXITRIPTAN 1 (2%) 1 (2%) VLX105832 PREGABALIN 1 (2%) 1 (2%) TOPIRAMATE 1 (2%) 1 (2%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 3 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------TRAZODONE 1 (2%) 1 (2%) ANESTHETIC, NOS 0 1 (2%) CHLORASEPTIC (NOS) 1 (2%) 0 ESCITALOPRAM OXALATE 1 (2%) 0 LIDOCAINE 1 (2%) 0 MORPHINE 0 1 (2%) RIBONUCLEIC ACID 1 (2%) 0 ZOLPIDEM TARTRATE 1 (2%) 0

ALIMENTARY TRACT AND METABOLISM CONFIDENTIAL Any medication 21 (34%) 19 (31%) VITAMINS NOS 6 (10%) 7 (11%) ACETYLSALICYLIC ACID 3 (5%) 3 (5%) 82 ASCORBIC ACID 3 (5%) 3 (5%) METRONIDAZOLE 2 (3%) 4 (6%) MINERALS NOS 2 (3%) 3 (5%) CALCIUM 2 (3%) 2 (3%) TOCOPHEROL 2 (3%) 2 (3%) BISMUTH SUBSALICYLATE 1 (2%) 2 (3%) CALCIUM CARBONATE 1 (2%) 2 (3%) ISOMETHEPTENE MUCATE 1 (2%) 2 (3%) MICONAZOLE NITRATE 3 (5%) 0 ALOE BARBADENSIS 1 (2%) 1 (2%) BETAINE HYDROCHLORIDE 1 (2%) 1 (2%) CALCIUM CITRATE 1 (2%) 1 (2%) CALCIUM LACTATE 1 (2%) 1 (2%) CAROTENOIDS 1 (2%) 1 (2%) RM2007/00260/00 CHOLINE BITARTRATE 1 (2%) 1 (2%) DIGESTIVE ENZYMES 1 (2%) 1 (2%)

DIMETICONE, ACTIVATED 1 (2%) 1 (2%) VLX105832 ERGOCALCIFEROL 1 (2%) 1 (2%) FIBER 1 (2%) 1 (2%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 4 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------HYOSCINE METHOBROMIDE 1 (2%) 1 (2%) LANSOPRAZOLE 1 (2%) 1 (2%) LEVOGLUTAMIDE 1 (2%) 1 (2%) MAGNESIUM CITRATE 1 (2%) 1 (2%) NYSTATIN 2 (3%) 0 OMEPRAZOLE 1 (2%) 1 (2%) POTASSIUM NOS 1 (2%) 1 (2%) PRASTERONE 1 (2%) 1 (2%) PYRIDOXINE HYDROCHLORIDE 1 (2%) 1 (2%)

RABEPRAZOLE SODIUM 1 (2%) 1 (2%) CONFIDENTIAL RANITIDINE HYDROCHLORIDE 1 (2%) 1 (2%) RETINOL 1 (2%) 1 (2%) RIBOFLAVIN 1 (2%) 1 (2%) 83 SACCHAROMYCES SICCUM 1 (2%) 1 (2%) SENNA 1 (2%) 1 (2%) SIBUTRAMINE HYDROCHLORIDE 1 (2%) 1 (2%) SODIUM CHLORIDE 1 (2%) 1 (2%) THIAMINE 1 (2%) 1 (2%) THIOCTIC ACID 1 (2%) 1 (2%) ATROPINE SULFATE 0 1 (2%) BONE MEAL (NOS) 1 (2%) 0 CHOLINE 0 1 (2%) CLOTRIMAZOLE 1 (2%) 0 DIMENHYDRINATE 0 1 (2%) FAMOTIDINE 1 (2%) 0 HYOSCYAMINE SULFATE 0 1 (2%) L-CARNOSINE 1 (2%) 0 RM2007/00260/00 LOPERAMIDE HYDROCHLORIDE 1 (2%) 0 POLYCARBOPHIL 1 (2%) 0

TRIAMCINOLONE ACETONIDE 1 (2%) 0 VLX105832

ANTIINFECTIVES FOR SYSTEMIC USE

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 5 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------Any medication 12 (19%) 15 (24%) FLUCONAZOLE 1 (2%) 6 (10%) METRONIDAZOLE 2 (3%) 4 (6%) AMOXICILLIN 1 (2%) 2 (3%) CLINDAMYCIN 2 (3%) 1 (2%) DOXYCYCLINE 1 (2%) 2 (3%) MICONAZOLE NITRATE 3 (5%) 0 AMOXICILLIN TRIHYDRATE 1 (2%) 1 (2%) CIPROFLOXACIN HYDROCHLORIDE 1 (2%) 1 (2%)

CLAVULANATE POTASSIUM 1 (2%) 1 (2%) CONFIDENTIAL ERYTHROMYCIN 1 (2%) 1 (2%) SULFAMETHOXAZOLE 1 (2%) 1 (2%) TRIMETHOPRIM 1 (2%) 1 (2%) 84 AMPICILLIN 1 (2%) 0 ANTIFUNGALS NOS 0 1 (2%) AZITHROMYCIN 1 (2%) 0 CEFALEXIN 0 1 (2%) CEFAZOLIN SODIUM 0 1 (2%) CIPROFLOXACIN 1 (2%) 0 CLINDAMYCIN PHOSPHATE 1 (2%) 0 DIPHTHERIA TOXOID 0 1 (2%) LEVOFLOXACIN 0 1 (2%) METHENAMINE 0 1 (2%) PERTUSSIS TOXOID ACELLULAR 0 1 (2%) TETANUS TOXOID 0 1 (2%) TINIDAZOLE 0 1 (2%) VALACICLOVIR HYDROCHLORIDE 0 1 (2%) RM2007/00260/00

MUSCULO-SKELETAL SYSTEM

Any medication 17 (27%) 17 (27%) VLX105832 IBUPROFEN 12 (19%) 13 (21%) DIMETHYL SULFONE 1 (2%) 2 (3%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 6 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------CELECOXIB 1 (2%) 1 (2%) CHONDROITIN SULFATE SODIUM 1 (2%) 1 (2%) CYCLOBENZAPRINE HYDROCHLORIDE 1 (2%) 1 (2%) GLUCOSAMINE 1 (2%) 1 (2%) GLUCOSAMINE HYDROCHLORIDE 1 (2%) 1 (2%) METAXALONE 1 (2%) 1 (2%) NAPROXEN SODIUM 1 (2%) 1 (2%) RIBONUCLEIC ACID 1 (2%) 0

RESPIRATORY SYSTEM CONFIDENTIAL Any medication 18 (29%) 17 (27%) LORATADINE 4 (6%) 5 (8%) PSEUDOEPHEDRINE HYDROCHLORIDE 6 (10%) 3 (5%) 85 BENADRYL (NOS) 2 (3%) 4 (6%) FEXOFENADINE HYDROCHLORIDE 3 (5%) 3 (5%) DEXTROMETHORPHAN HYDROBROMIDE 3 (5%) 2 (3%) HYDROCODONE BITARTRATE 1 (2%) 3 (5%) SALBUTAMOL 2 (3%) 2 (3%) CETIRIZINE HYDROCHLORIDE 2 (3%) 1 (2%) CHLORPHENAMINE MALEATE 0 2 (3%) DOXYLAMINE SUCCINATE 2 (3%) 0 MONTELUKAST SODIUM 1 (2%) 1 (2%) RETINOL 1 (2%) 1 (2%) SODIUM CHLORIDE 1 (2%) 1 (2%) ATROPINE SULFATE 0 1 (2%) BENZONATATE 1 (2%) 0 DEXTROMETHORPHAN 1 (2%) 0 RM2007/00260/00 DIMENHYDRINATE 0 1 (2%) DIMETAPP NOS 1 (2%) 0

GUAIFENESIN 1 (2%) 0 VLX105832 LIDOCAINE 1 (2%) 0 PHENYLEPHRINE HYDROCHLORIDE 0 1 (2%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 7 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------PSEUDOEPHEDRINE SULFATE 0 1 (2%) TRIAMCINOLONE ACETONIDE 1 (2%) 0 VICKS VAPORUB NOS 1 (2%) 0

DERMATOLOGICALS Any medication 16 (26%) 15 (24%) FLUCONAZOLE 1 (2%) 6 (10%) BENADRYL (NOS) 2 (3%) 4 (6%) METRONIDAZOLE 2 (3%) 4 (6%)

TOCOPHEROL 2 (3%) 2 (3%) CONFIDENTIAL CLINDAMYCIN 2 (3%) 1 (2%) MICONAZOLE NITRATE 3 (5%) 0 ALOE BARBADENSIS 1 (2%) 1 (2%) 86 BENZOYL PEROXIDE 1 (2%) 1 (2%) BUTOCONAZOLE NITRATE 0 2 (3%) CENTELLA ASIATICA 1 (2%) 1 (2%) ERYTHROMYCIN 1 (2%) 1 (2%) METHYLPREDNISOLONE 2 (3%) 0 NYSTATIN 2 (3%) 0 RETINOL 1 (2%) 1 (2%) AMINOBENZOIC ACID 0 1 (2%) BENZOIC ACID 0 1 (2%) CLINDAMYCIN PHOSPHATE 1 (2%) 0 CLOBETASOL PROPIONATE 1 (2%) 0 CLOTRIMAZOLE 1 (2%) 0 GLYCERYL TRINITRATE 0 1 (2%) LIDOCAINE 1 (2%) 0 RM2007/00260/00 PHENYL SALICYLATE 0 1 (2%) TERBINAFINE HYDROCHLORIDE 1 (2%) 0

TRIAMCINOLONE ACETONIDE 1 (2%) 0 VLX105832

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 8 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS Any medication 14 (23%) 15 (24%) ETHINYLOESTRADIOL 12 (19%) 14 (23%) MEDROXYPROGESTERONE ACETATE 1 (2%) 1 (2%) SOY ISOFLAVONES 1 (2%) 0

SENSORY ORGANS Any medication 11 (18%) 4 (6%)

MICONAZOLE NITRATE 3 (5%) 0 CONFIDENTIAL CIPROFLOXACIN HYDROCHLORIDE 1 (2%) 1 (2%) ERYTHROMYCIN 1 (2%) 1 (2%) METHYLPREDNISOLONE 2 (3%) 0 87 RETINOL 1 (2%) 1 (2%) SODIUM CHLORIDE 1 (2%) 1 (2%) AMPICILLIN 1 (2%) 0 ATROPINE SULFATE 0 1 (2%) CIPROFLOXACIN 1 (2%) 0 LIDOCAINE 1 (2%) 0 PHENYLEPHRINE HYDROCHLORIDE 0 1 (2%) TRIAMCINOLONE ACETONIDE 1 (2%) 0

CARDIOVASCULAR SYSTEM Any medication 10 (16%) 11 (18%) HYDROCHLOROTHIAZIDE 2 (3%) 1 (2%) TRIAMTERENE 2 (3%) 1 (2%) DIUREX (NOS) 1 (2%) 1 (2%) RM2007/00260/00 EZETIMIBE 1 (2%) 1 (2%) FISH OIL 1 (2%) 1 (2%)

LOVASTATIN 1 (2%) 1 (2%) VLX105832 PROPRANOLOL 1 (2%) 1 (2%) SIMVASTATIN 1 (2%) 1 (2%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 9 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------ATENOLOL 0 1 (2%) GLYCERYL TRINITRATE 0 1 (2%) LIDOCAINE 1 (2%) 0 PHENYLEPHRINE HYDROCHLORIDE 0 1 (2%) RAMIPRIL 0 1 (2%) UBIDECARENONE 1 (2%) 0

BLOOD AND BLOOD FORMING ORGANS Any medication 11 (18%) 10 (16%)

ACETYLSALICYLIC ACID 3 (5%) 3 (5%) CONFIDENTIAL FOLIC ACID 2 (3%) 2 (3%) LYSINE 2 (3%) 2 (3%) TYROSINE 2 (3%) 1 (2%) 88 FERROUS SULPHATE 1 (2%) 1 (2%) MAGNESIUM CITRATE 1 (2%) 1 (2%) POTASSIUM NOS 1 (2%) 1 (2%) SODIUM CHLORIDE 1 (2%) 1 (2%)

SYSTEMIC HORMONAL PREPARATIONS, EXCL. SEX HORMONES Any medication 8 (13%) 3 (5%) HALOBETASOL 1 (2%) 1 (2%) LEVOTHYROXINE SODIUM 1 (2%) 1 (2%) LIOTHYRONINE SODIUM 1 (2%) 1 (2%) METHYLPREDNISOLONE 2 (3%) 0 THYROID 1 (2%) 1 (2%) MELATONIN 1 (2%) 0 RM2007/00260/00 THYMUS EXTRACT 1 (2%) 0 TRIAMCINOLONE ACETONIDE 1 (2%) 0 VLX105832 VLX105832 VARIOUS Any medication 7 (11%) 5 (8%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 10 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------HERBALS NOS 3 (5%) 3 (5%) DIMETHYL SULFONE 1 (2%) 2 (3%) HYDRASTIS CANADENSIS 2 (3%) 1 (2%) TYROSINE 2 (3%) 1 (2%) ANTIOXIDANTS NOS 1 (2%) 1 (2%) ARCTIUM LAPPA EXTRACT 1 (2%) 1 (2%) BORAGO OFFICINALIS OIL 1 (2%) 1 (2%) CENTELLA ASIATICA 1 (2%) 1 (2%) CHONDROITIN SULFATE SODIUM 1 (2%) 1 (2%)

DAUCUS CAROTA 1 (2%) 1 (2%) CONFIDENTIAL HELIANTHUS ANNUUS OIL 1 (2%) 1 (2%) ILEX PARAGUARIENSIS 1 (2%) 1 (2%) MACROCYSTIS PYRIFERA 1 (2%) 1 (2%) 89 MEDICAGO SATIVA 1 (2%) 1 (2%) OENOTHERA BIENNIS OIL 1 (2%) 1 (2%) PAULLINIA CUPANA EXTRACT 1 (2%) 1 (2%) SPINACIA OLERACEA 1 (2%) 1 (2%) SPIRULINA 1 (2%) 1 (2%) TILLANDSIA USNEOIDES 1 (2%) 1 (2%) TURNERA DIFFUSA 1 (2%) 1 (2%) WHEAT GRASS 1 (2%) 1 (2%) AMBIGUOUS MEDICATION 1 (2%) 0 CYSTEINE 0 1 (2%) ECHINACEA 1 (2%) 0 METHIONINE 0 1 (2%) METHYLTHIONINIUM CHLORIDE 0 1 (2%) THYMUS EXTRACT 1 (2%) 0 RM2007/00260/00

ANTIPARASITIC PRODUCTS, INSECTICIDES AND

REPELLENT VLX105832 Any medication 2 (3%) 5 (8%) METRONIDAZOLE 2 (3%) 4 (6%)

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 11 of 11 Population: Intent-to-Treat Exposed Table 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1

ATC Level 1 Valtrex 1g QD Placebo Ingredient (N=62) (N=62) ------TINIDAZOLE 0 1 (2%) CONFIDENTIAL 90 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

Note: A medication may be included in more than one ATC Level category and appear more than once. Protocol: VLX105832 Page 1 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------ALIMENTARY TRACT AND ACETYLSALICYLIC ACID Aspirin METABOLISM ASCORBIC ACID Vitamin C BISMUTH SUBSALICYLATE Pepto Bismal Pepto-Bismol CALCIUM Calcium CALCIUM CARBONATE Tums CALCIUM CITRATE Calcium citrate CLOTRIMAZOLE Clotrimazole 1% DIMENHYDRINATE Dramamine

DIMETICONE, ACTIVATED Simethicone CONFIDENTIAL FAMOTIDINE Pepcid AC FIBER Natural Fiber supplement HYOSCINE METHOBROMIDE Pamine 91 L-CARNOSINE L-CARNOSINE LANSOPRAZOLE Prevacid LEVOGLUTAMIDE L-glutamine LOPERAMIDE HYDROCHLORIDE Imodium METRONIDAZOLE Metrogel Metrogel vaginal Metronidazole flagyl metronidazole MICONAZOLE NITRATE Monistat Monistat-1 MINERALS NOS Organic Minerals Multiple Ingredient Catalyn Maxi Hair RM2007/00260/00 Multivitamin Multivitamins

Ultra Mega Green Multivitamin VLX105832 (GNC) NYSTATIN Nystatin OMEPRAZOLE Prilosec OTC Protocol: VLX105832 Page 2 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------ALIMENTARY TRACT AND POLYCARBOPHIL Replens METABOLISM PRASTERONE DHEA RABEPRAZOLE SODIUM Aciphex RANITIDINE HYDROCHLORIDE Zantac SENNA Senokot prn SIBUTRAMINE HYDROCHLORIDE Meridia THIOCTIC ACID Alpha Lipoic Acid TOCOPHEROL Vitamin E

ANTIINFECTIVES FOR SYSTEMIC AMOXICILLIN Amoxicillin CONFIDENTIAL USE amoxicillin AMPICILLIN ampicillin 92 ANTIFUNGALS NOS Over The Counter Yeast Infection Treatment AZITHROMYCIN Azithromycin Pack CEFALEXIN Keflex CEFAZOLIN SODIUM Ancef CIPROFLOXACIN ciprofloxacin CIPROFLOXACIN HYDROCHLORIDE cipro DOXYCYCLINE Doxycycline doxycycline LEVOFLOXACIN Levaquin Multiple Ingredient Augmentin Bactrim Bactrim DS Tdap RM2007/00260/00 VALACICLOVIR HYDROCHLORIDE VALTREX Valtrex VLX105832 VLX105832 ANTINEOPLASTIC AND SOY ISOFLAVONES SOY SUPPLEMENT IMMUNOMODULATING AGENTS Protocol: VLX105832 Page 3 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------BLOOD AND BLOOD FORMING FERROUS SULPHATE Ferrous Sulphate prn ORGANS FOLIC ACID Folic Acid LYSINE Lysiene Lysine (over the counter medication) TYROSINE L-TYROSINE

CARDIOVASCULAR SYSTEM ATENOLOL Atenolol DIUREX (NOS) Diurex

EZETIMIBE Zetia CONFIDENTIAL FISH OIL Fish Oil GLYCERYL TRINITRATE Nitroglycerin Ointment HYDROCHLOROTHIAZIDE hydrochlorothiazide 93 LIDOCAINE Xylocaine LOVASTATIN Lovastatin Multiple Ingredient Maxzide PROPRANOLOL Propanolol RAMIPRIL Altace SIMVASTATIN Zocar TRIAMTERENE Triamterene UBIDECARENONE COQ10

DERMATOLOGICALS ACYCLOVIR Acyclovir acyclovir acycolvir BENADRYL (NOS) Benadryl BUTOCONAZOLE NITRATE Gynazole 1 RM2007/00260/00 gynozole CLINDAMYCIN Clindamycin

CLINDAMYCIN PHOSPHATE Clindesse VLX105832 CLOBETASOL PROPIONATE Clobetasol 5% cream ERYTHROMYCIN Erythromycin Erythromycin ointment Protocol: VLX105832 Page 4 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------DERMATOLOGICALS FLUCONAZOLE Diflucan Fluconazole diflucan METHYLPREDNISOLONE Medro Dose Pack Medrol Dosepak Multiple Ingredient Benzoclin Cream Mycolog II TERBINAFINE HYDROCHLORIDE Lamisil

GENITO URINARY SYSTEM AND IBUPROFEN ADVIL

SEX HORMONES CONFIDENTIAL Advil Advil prn Ibuprofen 94 Motrin advil extra strength ibuprofen ibuprofen prn MEDROXYPROGESTERONE ACETATE Depo Provera Depo-Provera Multiple Ingredient Estrostep Lo-Ovral 28 LoEstrin 1/20 Nuva-Ring Ortho Evra Ortho Evra Patch Ortho Novum Ortho Tri Cyclen RM2007/00260/00 Ortho Tri-Cyclen OrthoTriCyclenLO

Ovcon 35 VLX105832 Tinessa Urised Yasmin Protocol: VLX105832 Page 5 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------GENITO URINARY SYSTEM AND Multiple Ingredient alesse SEX HORMONES nuva ring sprintec NAPROXEN SODIUM ALEVE Aleve NORMETHANDRONE oxavar TINIDAZOLE Tindamax TOLTERODINE TARTRATE Detrol VAGISIL (NOS) Vagisil CONFIDENTIAL MUSCULO-SKELETAL SYSTEM CELECOXIB Celebrex CYCLOBENZAPRINE HYDROCHLORIDE Flexeril flexeril 95 GLUCOSAMINE Glucosamine METAXALONE Skelaxin

NERVOUS SYSTEM ALPRAZOLAM Xanax ANESTHETIC, NOS General anesthesia (unknown) BUPROPION HYDROCHLORIDE Wellbutrin Wellbutrin XL CHLORASEPTIC (NOS) chorlaceptic ESCITALOPRAM OXALATE Lexapro EXCEDRIN (NOS) Excedrin GABAPENTIN Neurontin LORAZEPAM Ativan METHADONE HYDROCHLORIDE Methadose MORPHINE Morphine RM2007/00260/00 Multiple Ingredient Darvocet Darvocet-N 100

Excedrin Migraine VLX105832 Midrin Percocet Vicodin Protocol: VLX105832 Page 6 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------NERVOUS SYSTEM Multiple Ingredient vicodin NORTRIPTYLINE Nortriptyline OXITRIPTAN 5HTP PARACETAMOL Extra Strength Tylenol Tylenol Tylenol 8 hour Tylenol Arthritis Tylenol prn tylenol PREGABALIN Lyrica

SERTRALINE HYDROCHLORIDE Zoloft CONFIDENTIAL SUMATRIPTAN Imitrex Imitrex prn TOPIRAMATE Topomax 96 TRAZODONE Trazodone ZOLPIDEM TARTRATE Ambien

RESPIRATORY SYSTEM BENZONATATE Benzonatate CETIRIZINE HYDROCHLORIDE Zyrtec DIMETAPP NOS Dimetapp FEXOFENADINE HYDROCHLORIDE Allegra allegra LORATADINE Alavert Claritin MONTELUKAST SODIUM Singulair Multiple Ingredient Allegra D Claritin D Cofex-DM RM2007/00260/00 Dayquil Histinex HC Cough syrup

Nyquil VLX105832 Robitussin Maximum Strength Cough and Cold Liquid Tylenol Cold Capsules Protocol: VLX105832 Page 7 of 7 Population: Intent-to-Treat Exposed Table 6.17 Relationship between ATC Level 1, Ingredient and Verbatim Text

ATC Level 1 Ingredient Verbatim Text ------RESPIRATORY SYSTEM Multiple Ingredient Zyrtec-D nyquil PSEUDOEPHEDRINE HYDROCHLORIDE Sudafed SALBUTAMOL Albuterol VICKS VAPORUB NOS Vicks Vaporub Ointment

SYSTEMIC HORMONAL HALOBETASOL Halobetasol PREPARATIONS, EXCL. SEX HORMONES LEVOTHYROXINE SODIUM Levoxyl

LIOTHYRONINE SODIUM Cytomel CONFIDENTIAL MELATONIN Melatonin THYROID Armour Thyroid

97 VARIOUS AMBIGUOUS MEDICATION Zicam ECHINACEA Echinacea HYDRASTIS CANADENSIS Golden Seal Golden Seal Herbal Supplement Multiple Ingredient 7-Day Miracle Cleanse-Super Boost Greens Cataplex ACP Congaplex Leptopril Progensa Senaplex Triflex Vitamins (GNC) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.18 Summary of Treatment Compliance - Suppression Treatment

Valtrex 1g QD Placebo (N=62) (N=62) ------Period 1 n 35 35 Mean 87.0 87.1 SD 28.88 22.45 Median 96.4 96.3 Min. 0 0 Max. 122 111

Period 2 n 27 27 Mean 86.9 95.1

SD 23.28 9.09 CONFIDENTIAL Median 96.6 98.3 Min. 0 73 Max. 122 106 98 Overall n 62 62 Mean 87.0 90.6 SD 26.38 18.23 Median 96.5 96.6 Min. 0 0 Max. 122 111 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.19 Summary of Treatment Compliance - Open-Label Treatment

Valtrex 1g QD Placebo (N=62) (N=62) ------Period 1 n 5 16 Mean 80.0 78.1 SD 44.72 40.70 Median 100.0 100.0 Min. 0 0 Max. 100 100

Period 2 n 6 11 Mean 100.0 92.4

SD 0.00 13.15 CONFIDENTIAL Median 100.0 100.0 Min. 100 67 Max. 100 100 99 Overall n 11 27 Mean 90.9 84.0 SD 30.15 32.76 Median 100.0 100.0 Min. 0 0 Max. 100 100 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 6.20 Summary of HSV-2/HSV-1 Cross-Classification

Sequence 1 Sequence 2 (Val-Pbo) (Pbo-Val) Total (N=35) (N=35) (N=70) ------HerpeSelect 2 ELISA (HSV-2) test n 35 35 70 Negative 5 (14%) 4 (11%) 9 (13%) Positive 30 (86%) 31 (89%) 61 (87%)

HSV-2 Positive Subjects n 30 31 61 HSV-1 Negative 13 (43%) 12 (39%) 25 (41%) HSV-1 Equivocal 1 (3%) 1 (3%) 2 (3%) HSV-1 Positive 16 (53%) 18 (58%) 34 (56%) CONFIDENTIAL HerpeSelect 1 ELISA (HSV-1) test n 35 35 70 Negative 16 (46%) 15 (43%) 31 (44%) Equivocal 1 (3%) 1 (3%) 2 (3%) 100 Positive 18 (51%) 19 (54%) 37 (53%)

HSV-1 Positive Subjects n 18 19 37 HSV-2 Negative 2 (11%) 1 (5%) 3 (8%) HSV-2 Equivocal 0 0 0 HSV-2 Positive 16 (89%) 18 (95%) 34 (92%)

HSV-2/HSV-1 Combinations n 35 35 70 HSV-2 Negative/HSV-1 Negative 3 (9%) 3 (9%) 6 (9%) HSV-2 Negative/HSV-1 Equivocal 0 0 0 HSV-2 Negative/HSV-1 Positive 2 (6%) 1 (3%) 3 (4%) HSV-2 Equivocal/HSV-1 Negative 0 0 0 HSV-2 Equivocal/HSV-1 Equivocal 0 0 0 HSV-2 Equivocal/HSV-1 Positive 0 0 0 RM2007/00260/00 HSV-2 Positive/HSV-1 Negative 13 (37%) 12 (34%) 25 (36%) HSV-2 Positive/HSV-1 Equivocal 1 (3%) 1 (3%) 2 (3%)

HSV-2 Positive/HSV-1 Positive 16 (46%) 18 (51%) 34 (49%) VLX105832 CONFIDENTIAL RM2007/00260/00 VLX105832

Efficacy Data Source Figure and Tables

Page Figure 7.1 Kaplan-Meier Curves for Time to First Genital Herpes Recurrence (ITT) ...... 105 Figure 7.2 Kaplan-Meier Curves for Time to First Genital Herpes Recurrence (PP) ...... 106 Figure 7.3 Kaplan-Meier Curves for Time to First Oral Herpes Recurrence (ITT)...... 107 Figure 7.4 Kaplan-Meier Curves for Time to First Oral Herpes Recurrence (PP) ...... 108 Table 7.1 Summary of Percent of Days with HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 109 Table 7.2 Summary of Percent of Days with HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 110 Table 7.3 Summary of Percent of Days with HSV-2 Viral Shedding in First Treatment Period (ITT) (First Period Efficacy Population) ...... 111 Table 7.4 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 112 Table 7.5 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 113 Table 7.6 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding in First Treatment Period (ITT) (First Period Efficacy Population) ...... 114 Table 7.7 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 115 Table 7.8 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 116 Table 7.9 Summary of Percent of Days with Clinical HSV-2 Viral Shedding in First Treatment Period (ITT) (First Period Efficacy Population) ...... 117 Table 7.10 Summary of Proportion of Subjects With No Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 118 Table 7.11 Test of Proportion of Subjects With No Shedding (ITTC) Response (Period 1,Period 2) (Intent-to-Treat Crossover Population) . . . 119

101 CONFIDENTIAL RM2007/00260/00 VLX105832

Table 7.12 Summary of Proportion of Subjects With No Shedding (PP) (Per Protocol Population) ...... 120 Table 7.13 Test of Proportion of Subjects With No Shedding (PP) Response (Period 1,Period 2) (Per Protocol Population)...... 121 Table 7.14 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) (Intent-to-Treat Crossover Population) . . . . . 122 Table 7.15 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) Response (Period 1,Period 2) (Intent-to-Treat Crossover Population)...... 123 Table 7.16 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) (Per Protocol Population) ...... 124 Table 7.17 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) Response (Period 1,Period 2) (Per Protocol Population) ...... 125 Table 7.18 Summary of Time to First Genital Herpes Recurrence (ITT) (First Period Efficacy Population) ...... 126 Table 7.19 Summary of Time to First Genital Herpes Recurrence (PP) (Per Protocol Population) ...... 128 Table 7.20 Summary of Time to First Oral Herpes Recurrence (ITT) (First Period Efficacy Population) ...... 129 Table 7.21 Summary of Time to First Oral Herpes Recurrence (PP) (Per Protocol Population) ...... 131 Table 7.22 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 132 Table 7.23 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 133 Table 7.24 Summary of Percent of Clinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT) (First Period Efficacy Population) ...... 134 Table 7.25 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 135 Table 7.26 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 136

102 CONFIDENTIAL RM2007/00260/00 VLX105832

Table 7.27 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT) (First Period Efficacy Population) ...... 137 Table 7.28 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (ITTC) (Intent-to-Treat Crossover Population) ...... 138 Table 7.29 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (PP) (Per Protocol Population) ...... 139 Table 7.30 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days In First Treatment Period (ITT) (First Period Efficacy Population) ...... 140 Table 7.31 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (ITTC) (Intent-to-Treat Crossover Population)...... 141 Table 7.32 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (PP) (Per Protocol Population) ...... 142 Table 7.33 Summary of Average Log DNA Copy Number Per Day on All Shedding Days in First Treatment Period (ITT) (First Period Efficacy Population) ...... 143 Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 144 Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 150 Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) . . . 156 Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 162 Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 168 Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP) (Per Protocol Population) ...... 174 Table 7.40 Summary by Subgroups of Proportion of Subjects With No Shedding (ITTC) (Intent-to-Treat Crossover Population) ...... 180 Table 7.41 Summary by Subgroups of Proportion of Subjects With No Shedding (PP) (Per Protocol Population) ...... 183

103 CONFIDENTIAL RM2007/00260/00 VLX105832

Table 7.42 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) (Intent-to-Treat Crossover Population) ...... 186 Table 7.43 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) (Per Protocol Population) ...... 189 Table 7.44 Summary of Percent of HSV-2 Isolates Resistant to Acyclovir Among Subjects Not Responding to 3 Days of Episodic Treatment (Intent-to-Treat Exposed Population) ...... 192

104 CONFIDENTIAL RM2007/00260/00 VLX105832

105 CONFIDENTIAL RM2007/00260/00 VLX105832

106 CONFIDENTIAL RM2007/00260/00 VLX105832

107 CONFIDENTIAL RM2007/00260/00 VLX105832

108 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.1 Summary of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From P-value (N=52) (N=52) Placebo [1] ------Percent of Days with HSV-2 Viral Shedding

Period 1 n 25 27 Mean 3 14.3 -79% Median 0 8.8 SD 4.6 16.6 Min. 0 0 Max. 17 68 CONFIDENTIAL Period 2 n 27 25 Mean 2.9 12.6 -77% Median 0 3.5 109 SD 6.5 17.4 Min. 0 0 Max. 29 61

Overall n 52 52 <0.001 Mean 2.9 13.5 -78% Median 0 7.6 SD 5.6 16.9 Min. 0 0 Max. 29 68

Test of Residual Effects 0.401

Test of Period Differences 0.362 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.2 Summary of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From P-value (N=35) (N=35) Placebo [1] ------Percent of Days with HSV-2 Viral Shedding

Period 1 n 17 18 Mean 3.1 14 -78% Median 1.7 6.9 SD 4.1 17.5 Min. 0 0 Max. 12 68 CONFIDENTIAL Period 2 n 18 17 Mean 3 16.1 -81% Median 0 8.5 110 SD 7.2 19.4 Min. 0 0 Max. 29 61

Overall n 35 35 <0.001 Mean 3 15 -80% Median 0 8.5 SD 5.8 18.2 Min. 0 0 Max. 29 68

Test of Residual Effects 0.844

Test of Period Differences 1.000 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.3 Summary of Percent of Days with HSV-2 Viral Shedding in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Percent of Days with HSV-2 Viral Shedding

Period 1 n 30 35 <0.001 Mean 2.6 14.9 -83% Median 0 8.5 SD 4.3 18.3 Min. 0 0 Max. 17 68 CONFIDENTIAL 111 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric tests based on Wilcoxon Rank Sum. Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.4 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From P-value (N=52) (N=52) Placebo [1] ------Percent of Days with Subclinical HSV-2 Viral Shedding

Period 1 n 25 27 Mean 2.3 11.9 -81% Median 0 7.1 SD 4.2 16.3 Min. 0 0 Max. 17 68 CONFIDENTIAL Period 2 n 27 25 Mean 2.5 10.1 -75% Median 0 2 112 SD 5.4 14 Min. 0 0 Max. 24 48

Overall n 52 52 <0.001 Mean 2.4 11 -78% Median 0 4.8 SD 4.8 15.1 Min. 0 0 Max. 24 68

Test of Residual Effects 0.511

Test of Period Differences 0.476 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.5 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From P-value (N=35) (N=35) Placebo [1] ------Percent of Days with Subclinical HSV-2 Viral Shedding

Period 1 n 17 18 Mean 2.1 11.1 -81% Median 0 4.2 SD 3.4 17.4 Min. 0 0 Max. 12 68 CONFIDENTIAL Period 2 n 18 17 Mean 2.6 12.7 -80% Median 0 3.5 113 SD 6.1 15.7 Min. 0 0 Max. 24 48

Overall n 35 35 <0.001 Mean 2.3 11.9 -80% Median 0 3.5 SD 4.9 16.3 Min. 0 0 Max. 24 68

Test of Residual Effects 0.706

Test of Period Differences 0.831 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.6 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Percent of All Days with Subclinical HSV-2 Viral Shedding

Period 1 n 30 35 <0.001 Mean 2 11.6 -83% Median 0 6.1 SD 3.9 15.6 Min. 0 0 Max. 17 68 CONFIDENTIAL 114 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.7 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From P-value (N=52) (N=52) Placebo [1] ------Percent of Days with Clinical HSV-2 Viral Shedding

Period 1 n 25 27 Mean 0.7 2.3 -70% Median 0 0 SD 2 3.6 Min. 0 0 Max. 7 11 CONFIDENTIAL Period 2 n 27 25 Mean 0.4 2.5 -84% Median 0 0 115 SD 1.3 5.3 Min. 0 0 Max. 5 23

Overall n 52 52 0.014 Mean 0.6 2.4 -77% Median 0 0 SD 1.7 4.4 Min. 0 0 Max. 7 23

Test of Residual Effects 0.526

Test of Period Differences 0.795 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.8 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From P-value (N=35) (N=35) Placebo [1] ------Percent of Days with Clinical HSV-2 Viral Shedding

Period 1 n 17 18 Mean 1 2.9 -64% Median 0 0 SD 2.4 4.1 Min. 0 0 Max. 7 11 CONFIDENTIAL Period 2 n 18 17 Mean 0.4 3.4 -88% Median 0 0 116 SD 1.3 6.1 Min. 0 0 Max. 5 23

Overall n 35 35 0.040 Mean 0.7 3.1 -77% Median 0 0 SD 1.9 5.1 Min. 0 0 Max. 7 23

Test of Residual Effects 0.928

Test of Period Differences 0.842 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.9 Summary of Percent of Days with Clinical HSV-2 Viral Shedding in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Percent of All Days with Clinical HSV-2 Viral Shedding

Period 1 n 30 35 0.031 Mean 0.6 3.3 -82% Median 0 0 SD 1.8 7.1 Min. 0 0 Max. 7 36 CONFIDENTIAL 117 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.10 Summary of Proportion of Subjects With No Shedding (ITTC)

Proportion of Subjects w/no Valtrex Placebo Shedding (N=52) (N=52) ------

Period 1 n 25 27 No 13 (52%) 5 (19%) Yes 12 (48%) 22 (81%)

Period 2 n 27 25 No 18 (67%) 10 (40%) Yes 9 (33%) 15 (60%)

Overall n 52 52 CONFIDENTIAL No 31 (60%) 15 (29%) Yes 21 (40%) 37 (71%) 118 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.11 Test of Proportion of Subjects With No Shedding (ITTC) Response (Period 1,Period 2)

Treatment Sequence (NS,NS) (NS,S) (S,NS) (S,S) Total p-value[1] ------Sequence 1 (Val-Pbo) 7 6 3 9 25 <0.001

Sequence 2 (Pbo-Val) 4 1 14 8 27

Total 11 7 17 17 52 CONFIDENTIAL 119 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1] calculated using Prescott's method Note: NS=No shedding, S=Shedding Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.12 Summary of Proportion of Subjects With No Shedding (PP)

Proportion of Subjects w/no Valtrex Placebo Shedding (N=35) (N=35) ------

Period 1 n 17 18 No 8 (47%) 4 (22%) Yes 9 (53%) 14 (78%)

Period 2 n 18 17 No 12 (67%) 5 (29%) Yes 6 (33%) 12 (71%)

Overall n 35 35 CONFIDENTIAL No 20 (57%) 9 (26%) Yes 15 (43%) 26 (74%) 120 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.13 Test of Proportion of Subjects With No Shedding (PP) Response (Period 1,Period 2)

Treatment Sequence (NS,NS) (NS,S) (S,NS) (S,S) Total p-value[1] ------Sequence 1 (Val-Pbo) 3 5 2 7 17 0.008

Sequence 2 (Pbo-Val) 3 1 9 5 18

Total 6 6 11 12 35 CONFIDENTIAL 121 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1] calculated using Prescott's method Note: NS=No shedding, S=Shedding Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.14 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC)

Proportion of Subjects w/at Valtrex Placebo Least One GH Recurrence (N=52) (N=52) ------

Period 1 n 25 27 No 20 (80%) 13 (48%) Yes 5 (20%) 14 (52%)

Period 2 n 27 25 No 21 (78%) 14 (56%) Yes 6 (22%) 11 (44%)

Overall n 52 52 CONFIDENTIAL No 41 (79%) 27 (52%) Yes 11 (21%) 25 (48%) 122 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.15 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) Response (Period 1,Period 2)

Treatment Sequence (NR,NR) (NR,R) (R,NR) (R,R) Total p-value[1] ------Sequence 1 (Val-Pbo) 13 7 1 4 25 0.003

Sequence 2 (Pbo-Val) 10 3 11 3 27

Total 23 10 12 7 52 CONFIDENTIAL 123 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1] calculated using Prescott's method Note: NR=No Recurrence, R=Recurrence Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.16 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP)

Proportion of Subjects w/at Valtrex Placebo Least One GH Recurrence (N=35) (N=35) ------

Period 1 n 17 18 No 13 (76%) 8 (44%) Yes 4 (24%) 10 (56%)

Period 2 n 18 17 No 14 (78%) 10 (59%) Yes 4 (22%) 7 (41%)

Overall n 35 35 CONFIDENTIAL No 27 (77%) 18 (51%) Yes 8 (23%) 17 (49%) 124 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.17 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) Response (Period 1,Period 2)

Treatment Sequence (NR,NR) (NR,R) (R,NR) (R,R) Total p-value[1] ------Sequence 1 (Val-Pbo) 9 4 1 3 17 0.013

Sequence 2 (Pbo-Val) 7 1 7 3 18

Total 16 5 8 6 35 CONFIDENTIAL 125 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1] calculated using Prescott's method Note: NR=No Recurrence, R=Recurrence Protocol: VLX105832 Page 1 of 2 Population: First Period Efficacy Table 7.18 Summary of Time to First Genital Herpes Recurrence (ITT)

Valtrex Placebo (N=33) (N=35) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------1 33 0 3 1.000 35 0 0 1.000 4 30 0 0 1.000 35 2 0 0.943 5 30 0 0 1.000 33 1 0 0.914 8 30 0 0 1.000 32 2 0 0.857 9 30 0 0 1.000 30 1 0 0.829 11 30 1 0 0.967 29 0 0 0.829

12 29 0 0 0.967 29 1 0 0.800 CONFIDENTIAL 13 29 0 1 0.967 28 0 0 0.800 14 28 0 0 0.967 28 2 0 0.743 15 28 0 0 0.967 26 1 1 0.714 126 16 28 0 0 0.967 24 1 0 0.685 18 28 0 1 0.967 23 0 0 0.685 21 27 1 0 0.931 23 0 0 0.685 24 26 1 0 0.895 23 0 0 0.685 29 25 0 0 0.895 23 1 0 0.655 30 25 0 0 0.895 22 0 1 0.655 31 25 0 0 0.895 21 0 2 0.655 38 25 0 1 0.895 19 0 0 0.655 41 24 1 0 0.858 19 0 0 0.655 43 23 0 0 0.858 19 2 0 0.586 47 23 0 0 0.858 17 0 1 0.586 50 23 1 0 0.820 16 0 0 0.586 55 22 0 2 0.820 16 0 0 0.586 57 20 0 2 0.820 16 1 4 0.549 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had a GH recurrence VLX105832 [3] Events: Subjects who had a GH recurrence [4] Censored: Subjects who did not have a GH recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having a GH recurrence Protocol: VLX105832 Page 2 of 2 Population: First Period Efficacy Table 7.18 Summary of Time to First Genital Herpes Recurrence (ITT)

Valtrex Placebo (N=33) (N=35) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------58 18 0 2 0.820 11 0 1 0.549 59 16 0 2 0.820 10 0 0 0.549 60 14 0 3 0.820 10 0 2 0.549 61 11 0 3 0.820 8 1 2 0.481 62 8 0 2 0.820 5 0 0 0.481 63 6 0 2 0.820 5 0 2 0.481

64 4 0 1 0.820 3 0 0 0.481 CONFIDENTIAL 65 3 0 2 0.820 3 0 0 0.481 67 1 0 0 0.820 3 0 1 0.481 68 1 0 1 0.820 2 0 0 0.481 127 71 0 0 0 0.820 2 0 1 0.481 74 0 0 0 0.820 1 0 1 0.481 RM2007/00260/00 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had a GH recurrence VLX105832 [3] Events: Subjects who had a GH recurrence [4] Censored: Subjects who did not have a GH recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having a GH recurrence Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.19 Summary of Time to First Genital Herpes Recurrence (PP)

Valtrex Placebo (N=17) (N=18) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------4 17 0 0 1.000 18 2 0 0.889 8 17 0 0 1.000 16 1 0 0.833 11 17 1 0 0.941 15 0 0 0.833 14 16 0 0 0.941 15 2 0 0.722 16 16 0 0 0.941 13 1 0 0.667 21 16 1 0 0.882 12 0 0 0.667

29 15 0 0 0.882 12 1 0 0.611 CONFIDENTIAL 41 15 1 0 0.824 11 0 0 0.611 43 14 0 0 0.824 11 2 0 0.500 50 14 1 0 0.765 9 0 0 0.500 128 55 13 0 1 0.765 9 0 0 0.500 57 12 0 2 0.765 9 1 4 0.444 58 10 0 0 0.765 4 0 1 0.444 59 10 0 2 0.765 3 0 0 0.444 60 8 0 1 0.765 3 0 1 0.444 61 7 0 1 0.765 2 0 2 0.444 62 6 0 1 0.765 0 0 0 0.444 63 5 0 2 0.765 0 0 0 0.444 64 3 0 1 0.765 0 0 0 0.444 65 2 0 2 0.765 0 0 0 0.444 RM2007/00260/00 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had a GH recurrence VLX105832 [3] Events: Subjects who had a GH recurrence [4] Censored: Subjects who did not have a GH recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having a GH recurrence Protocol: VLX105832 Page 1 of 2 Population: First Period Efficacy Table 7.20 Summary of Time to First Oral Herpes Recurrence (ITT)

Valtrex Placebo (N=33) (N=35) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------1 33 0 3 1.000 35 0 0 1.000 2 30 0 0 1.000 35 1 0 0.971 11 30 0 0 1.000 34 1 0 0.943 13 30 0 1 1.000 33 0 0 0.943 15 29 0 0 1.000 33 0 1 0.943 18 29 0 1 1.000 32 0 0 0.943

30 28 0 0 1.000 32 0 1 0.943 CONFIDENTIAL 31 28 0 0 1.000 31 1 2 0.912 38 28 0 1 1.000 28 0 0 0.912 41 27 0 0 1.000 28 1 0 0.880 129 44 27 0 0 1.000 27 0 1 0.880 47 27 0 0 1.000 26 0 1 0.880 55 27 0 2 1.000 25 0 0 0.880 57 25 0 2 1.000 25 0 7 0.880 58 23 0 2 1.000 18 0 3 0.880 59 21 0 3 1.000 15 0 1 0.880 60 18 0 5 1.000 14 0 2 0.880 61 13 0 3 1.000 12 0 5 0.880 62 10 0 4 1.000 7 0 2 0.880 63 6 0 2 1.000 5 0 1 0.880 64 4 0 1 1.000 4 0 0 0.880 65 3 0 2 1.000 4 0 0 0.880 66 1 0 0 1.000 4 0 1 0.880 67 1 0 0 1.000 3 0 1 0.880 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had an oral recurrence VLX105832 [3] Events: Subjects who had an oral recurrence [4] Censored: Subjects who did not have an oral recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having an oral recurrence Protocol: VLX105832 Page 2 of 2 Population: First Period Efficacy Table 7.20 Summary of Time to First Oral Herpes Recurrence (ITT)

Valtrex Placebo (N=33) (N=35) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------68 1 0 1 1.000 2 0 0 0.880 71 0 0 0 1.000 2 0 1 0.880 74 0 0 0 1.000 1 0 1 0.880 CONFIDENTIAL 130 RM2007/00260/00 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had an oral recurrence VLX105832 [3] Events: Subjects who had an oral recurrence [4] Censored: Subjects who did not have an oral recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having an oral recurrence Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.21 Summary of Time to First Oral Herpes Recurrence (PP)

Valtrex Placebo (N=17) (N=18) ------Time (days) Number at Events Censored SDF Number at Events Censored SDF [1] Risk [2] [3] [4] [5] Risk [2] [3] [4] [5] ------41 17 0 0 1.000 18 1 0 0.944 55 17 0 1 1.000 17 0 0 0.944 57 16 0 2 1.000 17 0 6 0.944 58 14 0 0 1.000 11 0 3 0.944 59 14 0 3 1.000 8 0 1 0.944 60 11 0 3 1.000 7 0 1 0.944

61 8 0 1 1.000 6 0 4 0.944 CONFIDENTIAL 62 7 0 2 1.000 2 0 1 0.944 63 5 0 2 1.000 1 0 0 0.944 64 3 0 1 1.000 1 0 0 0.944 131 65 2 0 2 1.000 1 0 0 0.944 66 0 0 0 1.000 1 0 1 0.944 RM2007/00260/00 RM2007/00260/00

[1] Only Treatment Period 1 data

[2] Number at Risk: Subjects who have not yet had an oral recurrence VLX105832 [3] Events: Subjects who had an oral recurrence [4] Censored: Subjects who did not have an oral recurrence through Treatment Period 1 [5] SDF: Survival distribution function based on Kaplan-Meier estimation - probability of not having an oral recurrence Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.22 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From P-value (N=7) (N=7) Placebo [1] ------Percent of Clinical Days with HSV-2 Viral Shedding

Period 1 n 4 3 Mean 33 11.1 197% Median 32.7 0 SD 33.7 19.2 Min. 0 0 Max. 67 33 CONFIDENTIAL Period 2 n 3 4 Mean 17.1 52.4 -67% Median 8.3 58.3 132 SD 22.7 39.1 Min. 0 0 Max. 43 93

Overall n 7 7 0.860 Mean 26.2 34.7 -25% Median 8.3 33.3 SD 28.5 37.1 Min. 0 0 Max. 67 93

Test of Residual Effects 0.502

Test of Period Differences 0.150 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.23 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From P-value (N=6) (N=6) Placebo [1] ------Percent of Clinical Days with HSV-2 Viral Shedding

Period 1 n 3 3 Mean 44 11.1 296% Median 57.1 0 SD 31.3 19.2 Min. 8 0 Max. 67 33 CONFIDENTIAL Period 2 n 3 3 Mean 17.1 69.8 -76% Median 8.3 66.7 133 SD 22.7 21.6 Min. 0 50 Max. 43 93

Overall n 6 6 0.536 Mean 30.6 40.5 -25% Median 25.6 41.7 SD 28.6 37 Min. 0 0 Max. 67 93

Test of Residual Effects 0.247

Test of Period Differences 0.182 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.24 Summary of Percent of Clinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Percent of Clinical Days with HSV-2 Viral Shedding

Period 1 n 5 16 0.406 Mean 30.4 52.4 -42% Median 20 50 SD 29.8 38 Min. 0 0 Max. 67 100 CONFIDENTIAL 134 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.25 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From P-value (N=52) (N=52) Placebo [1] ------Percent of Subclinical Days with HSV-2 Viral Shedding

Period 1 n 25 27 Mean 2.3 12.7 -82% Median 0 8.8 SD 4.2 16.7 Min. 0 0 Max. 17 68 CONFIDENTIAL Period 2 n 27 25 Mean 2.7 11.3 -76% Median 0 3.2 135 SD 6 15.9 Min. 0 0 Max. 27 51

Overall n 52 52 <0.001 Mean 2.5 12 -79% Median 0 5.3 SD 5.2 16.2 Min. 0 0 Max. 27 68

Test of Residual Effects 0.499

Test of Period Differences 0.476 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.26 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From P-value (N=35) (N=35) Placebo [1] ------Percent of Subclinical Days with HSV-2 Viral Shedding

Period 1 n 17 18 Mean 2.1 12.1 -82% Median 0 4.7 SD 3.4 17.8 Min. 0 0 Max. 12 68 CONFIDENTIAL Period 2 n 18 17 Mean 2.8 14.4 -81% Median 0 3.5 136 SD 6.8 17.8 Min. 0 0 Max. 27 51

Overall n 35 35 <0.001 Mean 2.5 13.2 -81% Median 0 3.5 SD 5.4 17.6 Min. 0 0 Max. 27 68

Test of Residual Effects 0.768

Test of Period Differences 0.818 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.27 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Percent of Subclinical Days w/HSV-2 Viral Shedding

Period 1 n 30 35 <0.001 Mean 2 12.9 -84% Median 0 6.1 SD 4 17 Min. 0 0 Max. 17 68 CONFIDENTIAL 137 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.28 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (ITTC)

Valtrex Placebo Change From P-value (N=13) (N=13) Placebo [1] ------Average Log DNA Copy Number Per Day on Subclinical Shedding Days

Period 1 n 7 6 Mean 3.8 4.9 -23% Median 3.7 4.9 SD 0.8 0.6 Min. 3 4 Max. 5 6 CONFIDENTIAL Period 2 n 6 7 Mean 4.2 4.4 -3% Median 4.1 4.7 138 SD 0.5 0.8 Min. 4 3 Max. 5 5

Overall n 13 13 0.078 Mean 4 4.6 -14% Median 4 4.8 SD 0.7 0.8 Min. 3 3 Max. 5 6

Test of Residual Effects 0.200

Test of Period Differences 0.834 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.29 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (PP)

Valtrex Placebo Change From P-value (N=8) (N=8) Placebo [1] ------Average Log DNA Copy Number Per Day on Subclinical Shedding Days

Period 1 n 5 3 Mean 3.6 4.9 -27% Median 3.3 4.9 SD 0.8 1 Min. 3 4 Max. 5 6 CONFIDENTIAL Period 2 n 3 5 Mean 4.3 4.3 -1% Median 4.3 4.7 139 SD 0.7 1 Min. 4 3 Max. 5 5

Overall n 8 8 0.272 Mean 3.9 4.6 -15% Median 3.6 4.7 SD 0.8 0.9 Min. 3 3 Max. 5 6

Test of Residual Effects 0.570

Test of Period Differences 0.570 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.30 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days In First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Average Log DNA Copy Number Per Day on Subclinical Shedding Days

Period 1 n 11 25 0.020 Mean 3.7 4.4 -15% Median 3.3 4.3 SD 0.7 0.8 Min. 3 3

Max. 5 6 CONFIDENTIAL 140 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Crossover Table 7.31 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (ITTC)

Valtrex Placebo Change From P-value (N=17) (N=17) Placebo [1] ------Average Log DNA Copy Number Per Day on All Shedding Days

Period 1 n 9 8 Mean 4.1 4.9 -17% Median 4 4.9 SD 0.6 0.5 Min. 3 4 Max. 5 6 CONFIDENTIAL Period 2 n 8 9 Mean 4 4.8 -17% Median 3.9 5.1 141 SD 0.7 0.9 Min. 3 3 Max. 5 6

Overall n 17 17 0.018 Mean 4 4.8 -17% Median 4 5 SD 0.6 0.8 Min. 3 3 Max. 5 6

Test of Residual Effects 0.962

Test of Period Differences 0.887 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: Per Protocol Table 7.32 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (PP)

Valtrex Placebo Change From P-value (N=12) (N=12) Placebo [1] ------Average Log DNA Copy Number Per Day on All Shedding Days

Period 1 n 7 5 Mean 4 4.9 -18% Median 4 4.9 SD 0.6 0.7 Min. 3 4 Max. 5 6 CONFIDENTIAL Period 2 n 5 7 Mean 3.8 4.9 -21% Median 3.7 5.2 142 SD 0.9 1 Min. 3 3 Max. 5 6

Overall n 12 12 0.030 Mean 3.9 4.9 -19% Median 3.8 5.1 SD 0.7 0.9 Min. 3 3 Max. 5 6

Test of Residual Effects 1.000

Test of Period Differences 0.876 RM2007/00260/00 VLX105832 VLX105832 [1]Nonparametric tests based on Wilcoxon Rank Sum. If the test of residuals is significant, both the Overall and the Test of Period Differences is biased. In this case, see the summary of this efficacy variable based on the first period data in the ITT Exposed population presented elsewhere in this report. Protocol: VLX105832 Page 1 of 1 Population: First Period Efficacy Table 7.33 Summary of Average Log DNA Copy Number Per Day on All Shedding Days in First Treatment Period (ITT)

Valtrex Placebo Change From P-value (N=33) (N=35) Placebo [1] ------Average Log DNA Copy Number Per Day on All Shedding Days

Period 1 n 13 26 0.002 Mean 3.9 4.7 -16% Median 4 4.9 SD 0.7 0.7 Min. 3 3 Max. 5 6 CONFIDENTIAL 143 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832

[1]Nonparametric test based on Wilcoxon Rank Sum Protocol: VLX105832 Page 1 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Female Period 1 n 18 21 Mean 2.7 15.5 -83% Median 0 6.1 SD 4 18.7 Min. 0 0 Max. 12 68

Period 2 n 21 18

Mean 3.4 12.5 -72% CONFIDENTIAL Median 0 4.1 SD 7.2 17.5 Min. 0 0 144 Max. 29 61

Overall n 39 39 Mean 3.1 14.1 -78% Median 0 5.4 SD 5.9 18 Min. 0 0 Max. 29 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Male Period 1 n 7 6 Mean 3.8 9.9 -61% Median 1.7 9.7 SD 6.1 2.3 Min. 0 7 Max. 17 13

Period 2 n 6 7

Mean 0.9 13 -93% CONFIDENTIAL Median 0 0 SD 1.5 18.7 Min. 0 0 145 Max. 4 48

Overall n 13 13 Mean 2.5 11.6 -78% Median 0 8.8 SD 4.7 13.4 Min. 0 0 Max. 17 48 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - <=30 Period 1 n 16 12 Mean 4 18.9 -79% Median 2.5 18.2 SD 5.3 14.3 Min. 0 2 Max. 17 53

Period 2 n 12 16

Mean 3.3 14.7 -77% CONFIDENTIAL Median 0 0 SD 8.3 21.1 Min. 0 0 146 Max. 29 61

Overall n 28 28 Mean 3.7 16.5 -77% Median 0 10.9 SD 6.6 18.3 Min. 0 0 Max. 29 61 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - >30 Period 1 n 9 15 Mean 1.2 10.6 -89% Median 0 5.4 SD 2.3 17.9 Min. 0 0 Max. 7 68

Period 2 n 15 9

Mean 2.5 8.9 -72% CONFIDENTIAL Median 0 8.5 SD 4.8 7.3 Min. 0 0 147 Max. 15 22

Overall n 24 24 Mean 2 10 -80% Median 0 5.7 SD 4.1 14.6 Min. 0 0 Max. 15 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Caucasian Period 1 n 14 15 Mean 1.9 19.1 -90% Median 0 13.3 SD 4.8 19.3 Min. 0 0 Max. 17 68

Period 2 n 15 14

Mean 2.1 8.1 -75% CONFIDENTIAL Median 0 1.6 SD 4.4 13.7 Min. 0 0 148 Max. 15 48

Overall n 29 29 Mean 2 13.8 -86% Median 0 8.5 SD 4.5 17.4 Min. 0 0 Max. 17 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Intent-to-Treat Crossover Table 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Non-Caucasian Period 1 n 11 12 Mean 4.4 8.2 -46% Median 3.3 4.8 SD 4.1 10.4 Min. 0 0 Max. 12 34

Period 2 n 12 11

Mean 3.9 18.4 -79% CONFIDENTIAL Median 0 17.5 SD 8.5 20.5 Min. 0 0 149 Max. 29 61

Overall n 23 23 Mean 4.2 13.1 -68% Median 1.8 5.4 SD 6.6 16.5 Min. 0 0 Max. 29 61 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Female Period 1 n 13 17 Mean 3.3 14.3 -77% Median 0 5.4 SD 4.6 18 Min. 0 0 Max. 12 68

Period 2 n 17 13

Mean 3.1 16 -81% CONFIDENTIAL Median 0 8.5 SD 7.4 19.3 Min. 0 0 150 Max. 29 61

Overall n 30 30 Mean 3.2 15.1 -79% Median 0 6.9 SD 6.2 18.3 Min. 0 0 Max. 29 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Male Period 1 n 4 1 Mean 2.5 8.5 -71% Median 2.6 8.5 SD 2.1 Min. 0 8 Max. 5 8

Period 2 n 1 4

Mean 1.8 16.4 -89% CONFIDENTIAL Median 1.8 8.7 SD 22.7 Min. 2 0 151 Max. 2 48

Overall n 5 5 Mean 2.4 14.8 -84% Median 1.8 8.5 SD 1.8 20 Min. 0 0 Max. 5 48 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - <=30 Period 1 n 11 8 Mean 4 16.1 -75% Median 3.3 18.2 SD 4.5 10.9 Min. 0 2 Max. 12 34

Period 2 n 8 11

Mean 3.9 19 -80% CONFIDENTIAL Median 0 1.6 SD 10.2 23.4 Min. 0 0 152 Max. 29 61

Overall n 19 19 Mean 3.9 17.8 -78% Median 0 17.9 SD 7.2 18.8 Min. 0 0 Max. 29 61 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - >30 Period 1 n 6 10 Mean 1.5 12.3 -88% Median 0 3 SD 2.8 21.8 Min. 0 0 Max. 7 68

Period 2 n 10 6

Mean 2.3 10.8 -79% CONFIDENTIAL Median 0 10.2 SD 4 7.8 Min. 0 2 153 Max. 11 22

Overall n 16 16 Mean 2 11.8 -83% Median 0 4.8 SD 3.5 17.5 Min. 0 0 Max. 11 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Caucasian Period 1 n 8 8 Mean 0.9 21.8 -96% Median 0 18.2 SD 2.6 21.2 Min. 0 0 Max. 7 68

Period 2 n 8 8

Mean 1.3 9 -85% CONFIDENTIAL Median 0 1.6 SD 3.1 16.5 Min. 0 0 154 Max. 9 48

Overall n 16 16 Mean 1.1 15.4 -93% Median 0 10.2 SD 2.8 19.5 Min. 0 0 Max. 9 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Per Protocol Table 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Non-Caucasian Period 1 n 9 10 Mean 5 7.7 -35% Median 3.5 3 SD 4.2 11.3 Min. 0 0 Max. 12 34

Period 2 n 10 9

Mean 4.3 22.5 -81% CONFIDENTIAL Median 0 21.7 SD 9.3 20.5 Min. 0 0 155 Max. 29 61

Overall n 19 19 Mean 4.7 14.7 -68% Median 1.8 5.4 SD 7.2 17.6 Min. 0 0 Max. 29 61 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Female Period 1 n 18 21 Mean 1.8 12.7 -86% Median 0 5 SD 3.3 18.4 Min. 0 0 Max. 12 68

Period 2 n 21 18

Mean 3 9.2 -67% CONFIDENTIAL Median 0 2.7 SD 6 12.5 Min. 0 0 156 Max. 24 39

Overall n 39 39 Mean 2.4 11.1 -78% Median 0 3.5 SD 4.9 15.9 Min. 0 0 Max. 24 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Male Period 1 n 7 6 Mean 3.6 9 -60% Median 0 9.7 SD 6.2 4 Min. 0 2 Max. 17 13

Period 2 n 6 7

Mean 0.6 12.2 -95% CONFIDENTIAL Median 0 0 SD 1.5 18.2 Min. 0 0 157 Max. 4 48

Overall n 13 13 Mean 2.2 10.8 -79% Median 0 8.8 SD 4.8 13.2 Min. 0 0 Max. 17 48 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - <=30 Period 1 n 16 12 Mean 3.5 15.4 -78% Median 1.7 9.9 SD 5 13.6 Min. 0 2 Max. 17 50

Period 2 n 12 16

Mean 2.7 11.8 -77% CONFIDENTIAL Median 0 0 SD 6.8 16.8 Min. 0 0 158 Max. 24 48

Overall n 28 28 Mean 3.1 13.3 -76% Median 0 8.6 SD 5.7 15.4 Min. 0 0 Max. 24 50 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - >30 Period 1 n 9 15 Mean 0.2 9.2 -98% Median 0 1.8 SD 0.6 18.2 Min. 0 0 Max. 2 68

Period 2 n 15 9

Mean 2.3 7.1 -68% CONFIDENTIAL Median 0 4.7 SD 4.2 6.3 Min. 0 0 159 Max. 11 17

Overall n 24 24 Mean 1.5 8.4 -82% Median 0 2.7 SD 3.5 14.7 Min. 0 0 Max. 11 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Caucasian Period 1 n 14 15 Mean 1.9 16.4 -89% Median 0 9.3 SD 4.8 19.7 Min. 0 0 Max. 17 68

Period 2 n 15 14

Mean 1.8 7 -74% CONFIDENTIAL Median 0 1.6 SD 3.7 13.2 Min. 0 0 160 Max. 11 48

Overall n 29 29 Mean 1.8 11.9 -85% Median 0 5 SD 4.2 17.3 Min. 0 0 Max. 17 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Intent-to-Treat Crossover Table 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Non-Caucasian Period 1 n 11 12 Mean 2.8 6.3 -55% Median 1.8 1.8 SD 3.6 8.7 Min. 0 0 Max. 12 30

Period 2 n 12 11

Mean 3.3 14 -76% CONFIDENTIAL Median 0 15 SD 7.1 14.5 Min. 0 0 161 Max. 24 39

Overall n 23 23 Mean 3.1 10 -69% Median 0 3.5 SD 5.6 12.2 Min. 0 0 Max. 24 39 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Female Period 1 n 13 17 Mean 2.1 11.3 -82% Median 0 3.4 SD 3.8 17.9 Min. 0 0 Max. 12 68

Period 2 n 17 13

Mean 2.8 11.6 -76% CONFIDENTIAL Median 0 3.5 SD 6.3 13.9 Min. 0 0 162 Max. 24 39

Overall n 30 30 Mean 2.5 11.4 -79% Median 0 3.4 SD 5.3 16 Min. 0 0 Max. 24 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Male Period 1 n 4 1 Mean 2.1 8.5 -76% Median 1.7 8.5 SD 2.5 Min. 0 8 Max. 5 8

Period 2 n 1 4

Mean 0 16.4 -100% CONFIDENTIAL Median 0 8.7 SD 22.7 Min. 0 0 163 Max. 0 48

Overall n 5 5 Mean 1.7 14.8 -89% Median 0 8.5 SD 2.3 20 Min. 0 0 Max. 5 48 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - <=30 Period 1 n 11 8 Mean 3.2 11.6 -73% Median 1.8 8.9 SD 3.9 9.6 Min. 0 2 Max. 12 30

Period 2 n 8 11

Mean 3 15.3 -81% CONFIDENTIAL Median 0 1.6 SD 8.4 18.7 Min. 0 0 164 Max. 24 48

Overall n 19 19 Mean 3.1 13.7 -78% Median 0 8.5 SD 6 15.3 Min. 0 0 Max. 24 48 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - >30 Period 1 n 6 10 Mean 0 10.7 -100% Median 0 0.9 SD 0 22.3 Min. 0 0 Max. 0 68

Period 2 n 10 6

Mean 2.3 8 -71% CONFIDENTIAL Median 0 6 SD 4 6.9 Min. 0 2 165 Max. 11 17

Overall n 16 16 Mean 1.4 9.7 -85% Median 0 1.9 SD 3.3 17.8 Min. 0 0 Max. 11 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Caucasian Period 1 n 8 8 Mean 0.9 18.3 -95% Median 0 8.2 SD 2.6 22.7 Min. 0 0 Max. 7 68

Period 2 n 8 8

Mean 1.3 7.7 -83% CONFIDENTIAL Median 0 1.6 SD 3.1 16.6 Min. 0 0 166 Max. 9 48

Overall n 16 16 Mean 1.1 13 -91% Median 0 4.2 SD 2.8 20 Min. 0 0 Max. 9 68 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Per Protocol Table 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Non-Caucasian Period 1 n 9 10 Mean 3.1 5.4 -43% Median 1.8 1.8 SD 3.9 9.3 Min. 0 0 Max. 12 30

Period 2 n 10 9

Mean 3.6 17.1 -79% CONFIDENTIAL Median 0 17.5 SD 7.8 14.3 Min. 0 0 167 Max. 24 39

Overall n 19 19 Mean 3.4 11 -69% Median 0 3.5 SD 6.1 13 Min. 0 0 Max. 24 39 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Female Period 1 n 18 21 Mean 0.9 2.8 -68% Median 0 0 SD 2.3 3.9 Min. 0 0 Max. 7 11

Period 2 n 21 18

Mean 0.4 3.2 -86% CONFIDENTIAL Median 0 0 SD 1.4 6 Min. 0 0 168 Max. 5 23

Overall n 39 39 Mean 0.6 3 -78% Median 0 0 SD 1.9 4.9 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Gender - Male Period 1 n 7 6 Mean 0.2 0.8 -71% Median 0 0 SD 0.6 2.1 Min. 0 0 Max. 2 5

Period 2 n 6 7

Mean 0.3 0.8 -62% CONFIDENTIAL Median 0 0 SD 0.7 2.1 Min. 0 0 169 Max. 2 5

Overall n 13 13 Mean 0.3 0.8 -67% Median 0 0 SD 0.7 2 Min. 0 0 Max. 2 5 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - <=30 Period 1 n 16 12 Mean 0.6 3.5 -84% Median 0 1.6 SD 1.8 4.4 Min. 0 0 Max. 7 11

Period 2 n 12 16

Mean 0.6 2.9 -79% CONFIDENTIAL Median 0 0 SD 1.6 6 Min. 0 0 170 Max. 5 23

Overall n 28 28 Mean 0.6 3.2 -82% Median 0 0 SD 1.7 5.3 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Age - >30 Period 1 n 9 15 Mean 1 1.4 -32% Median 0 0 SD 2.3 2.6 Min. 0 0 Max. 7 8

Period 2 n 15 9

Mean 0.3 1.9 -86% CONFIDENTIAL Median 0 0 SD 1 3.8 Min. 0 0 171 Max. 4 10

Overall n 24 24 Mean 0.5 1.6 -67% Median 0 0 SD 1.6 3 Min. 0 0 Max. 7 10 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Caucasian Period 1 n 14 15 Mean 0 2.7 -100% Median 0 0 SD 0 3.9 Min. 0 0 Max. 0 11

Period 2 n 15 14

Mean 0.3 1.1 -77% CONFIDENTIAL Median 0 0 SD 1 2.9 Min. 0 0 172 Max. 4 10

Overall n 29 29 Mean 0.1 1.9 -93% Median 0 0 SD 0.7 3.5 Min. 0 0 Max. 4 11 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Intent-to-Treat Crossover Table 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC)

Valtrex Placebo Change From (N=52) (N=52) Placebo ------Race - Non-Caucasian Period 1 n 11 12 Mean 1.6 1.9 -17% Median 0 0 SD 2.8 3.3 Min. 0 0 Max. 7 11

Period 2 n 12 11

Mean 0.6 4.4 -86% CONFIDENTIAL Median 0 0 SD 1.6 7 Min. 0 0 173 Max. 5 23

Overall n 23 23 Mean 1.1 3.1 -65% Median 0 0 SD 2.3 5.4 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Female Period 1 n 13 17 Mean 1.2 3 -60% Median 0 0 SD 2.7 4.2 Min. 0 0 Max. 7 11

Period 2 n 17 13

Mean 0.3 4.5 -93% CONFIDENTIAL Median 0 0 SD 1.3 6.7 Min. 0 0 174 Max. 5 23

Overall n 30 30 Mean 0.7 3.7 -80% Median 0 0 SD 2 5.3 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Gender - Male Period 1 n 4 1 Mean 0.4 0 Median 0 0 SD 0.8 Min. 0 0 Max. 2 0

Period 2 n 1 4

Mean 1.8 0 CONFIDENTIAL Median 1.8 0 SD 0 Min. 2 0 175 Max. 2 0

Overall n 5 5 Mean 0.7 0 Median 0 0 SD 1 0 Min. 0 0 Max. 2 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - <=30 Period 1 n 11 8 Mean 0.8 4.4 -82% Median 0 2.5 SD 2.2 5.1 Min. 0 0 Max. 7 11

Period 2 n 8 11

Mean 0.9 3.8 -76% CONFIDENTIAL Median 0 0 SD 1.9 7 Min. 0 0 176 Max. 5 23

Overall n 19 19 Mean 0.9 4 -79% Median 0 0 SD 2 6.1 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Age - >30 Period 1 n 6 10 Mean 1.5 1.6 -10% Median 0 0 SD 2.8 2.9 Min. 0 0 Max. 7 8

Period 2 n 10 6

Mean 0 2.8 -100% CONFIDENTIAL Median 0 0 SD 0 4.4 Min. 0 0 177 Max. 0 10

Overall n 16 16 Mean 0.5 2.1 -73% Median 0 0 SD 1.8 3.4 Min. 0 0 Max. 7 10 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Caucasian Period 1 n 8 8 Mean 0 3.5 -100% Median 0 0 SD 0 4.9 Min. 0 0 Max. 0 11

Period 2 n 8 8

Mean 0 1.3 -100% CONFIDENTIAL Median 0 0 SD 0 3.5 Min. 0 0 178 Max. 0 10

Overall n 16 16 Mean 0 2.4 -100% Median 0 0 SD 0 4.3 Min. 0 0 Max. 0 11 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 6 of 6 Population: Per Protocol Table 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP)

Valtrex Placebo Change From (N=35) (N=35) Placebo ------Race - Non-Caucasian Period 1 n 9 10 Mean 2 2.3 -16% Median 0 0 SD 3 3.5 Min. 0 0 Max. 7 11

Period 2 n 10 9

Mean 0.7 5.3 -86% CONFIDENTIAL Median 0 3.4 SD 1.8 7.4 Min. 0 0 179 Max. 5 23

Overall n 19 19 Mean 1.3 3.8 -65% Median 0 0 SD 2.5 5.7 Min. 0 0 Max. 7 23 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 3 Population: Intent-to-Treat Crossover Table 7.40 Summary by Subgroups of Proportion of Subjects With No Shedding (ITTC)

Valtrex Placebo (N=52) (N=52) ------Gender - Female Period 1 n 18 21 No 10 (56%) 5 (24%) Yes 8 (44%) 16 (76%)

Period 2 n 21 18 No 14 (67%) 6 (33%) Yes 7 (33%) 12 (67%)

Overall n 39 39 CONFIDENTIAL No 24 (62%) 11 (28%) Yes 15 (38%) 28 (72%)

180 Gender - Male Period 1 n 7 6 No 3 (43%) Yes 4 (57%) 6 (100%)

Period 2 n 6 7 No 4 (67%) 4 (57%) Yes 2 (33%) 3 (43%)

Overall n 13 13 No 7 (54%) 4 (31%) Yes 6 (46%) 9 (69%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 3 Population: Intent-to-Treat Crossover Table 7.40 Summary by Subgroups of Proportion of Subjects With No Shedding (ITTC)

Valtrex Placebo (N=52) (N=52) ------Age - <=30 Period 1 n 16 12 No 7 (44%) Yes 9 (56%) 12 (100%)

Period 2 n 12 16 No 8 (67%) 9 (56%) Yes 4 (33%) 7 (44%)

Overall n 28 28 CONFIDENTIAL No 15 (54%) 9 (32%) Yes 13 (46%) 19 (68%)

181 Age - >30 Period 1 n 9 15 No 6 (67%) 5 (33%) Yes 3 (33%) 10 (67%)

Period 2 n 15 9 No 10 (67%) 1 (11%) Yes 5 (33%) 8 (89%)

Overall n 24 24 No 16 (67%) 6 (25%) Yes 8 (33%) 18 (75%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 3 Population: Intent-to-Treat Crossover Table 7.40 Summary by Subgroups of Proportion of Subjects With No Shedding (ITTC)

Valtrex Placebo (N=52) (N=52) ------Race - Caucasian Period 1 n 14 15 No 11 (79%) 2 (13%) Yes 3 (21%) 13 (87%)

Period 2 n 15 14 No 11 (73%) 6 (43%) Yes 4 (27%) 8 (57%)

Overall n 29 29 CONFIDENTIAL No 22 (76%) 8 (28%) Yes 7 (24%) 21 (72%)

182 Race - Non-Caucasian Period 1 n 11 12 No 2 (18%) 3 (25%) Yes 9 (82%) 9 (75%)

Period 2 n 12 11 No 7 (58%) 4 (36%) Yes 5 (42%) 7 (64%)

Overall n 23 23 No 9 (39%) 7 (30%) Yes 14 (61%) 16 (70%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 3 Population: Per Protocol Table 7.41 Summary by Subgroups of Proportion of Subjects With No Shedding (PP)

Valtrex Placebo (N=35) (N=35) ------Gender - Female Period 1 n 13 17 No 7 (54%) 4 (24%) Yes 6 (46%) 13 (76%)

Period 2 n 17 13 No 12 (71%) 3 (23%) Yes 5 (29%) 10 (77%)

Overall n 30 30 CONFIDENTIAL No 19 (63%) 7 (23%) Yes 11 (37%) 23 (77%)

183 Gender - Male Period 1 n 4 1 No 1 (25%) Yes 3 (75%) 1 (100%)

Period 2 n 1 4 No 2 (50%) Yes 1 (100%) 2 (50%)

Overall n 5 5 No 1 (20%) 2 (40%) Yes 4 (80%) 3 (60%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 3 Population: Per Protocol Table 7.41 Summary by Subgroups of Proportion of Subjects With No Shedding (PP)

Valtrex Placebo (N=35) (N=35) ------Age - <=30 Period 1 n 11 8 No 4 (36%) Yes 7 (64%) 8 (100%)

Period 2 n 8 11 No 6 (75%) 5 (45%) Yes 2 (25%) 6 (55%)

Overall n 19 19 CONFIDENTIAL No 10 (53%) 5 (26%) Yes 9 (47%) 14 (74%)

184 Age - >30 Period 1 n 6 10 No 4 (67%) 4 (40%) Yes 2 (33%) 6 (60%)

Period 2 n 10 6 No 6 (60%) Yes 4 (40%) 6 (100%)

Overall n 16 16 No 10 (63%) 4 (25%) Yes 6 (38%) 12 (75%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 3 Population: Per Protocol Table 7.41 Summary by Subgroups of Proportion of Subjects With No Shedding (PP)

Valtrex Placebo (N=35) (N=35) ------Race - Caucasian Period 1 n 8 8 No 7 (88%) 1 (13%) Yes 1 (13%) 7 (88%)

Period 2 n 8 8 No 6 (75%) 3 (38%) Yes 2 (25%) 5 (63%)

Overall n 16 16 CONFIDENTIAL No 13 (81%) 4 (25%) Yes 3 (19%) 12 (75%)

185 Race - Non-Caucasian Period 1 n 9 10 No 1 (11%) 3 (30%) Yes 8 (89%) 7 (70%)

Period 2 n 10 9 No 6 (60%) 2 (22%) Yes 4 (40%) 7 (78%)

Overall n 19 19 No 7 (37%) 5 (26%) Yes 12 (63%) 14 (74%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 3 Population: Intent-to-Treat Crossover Table 7.42 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC)

Valtrex Placebo (N=52) (N=52) ------Gender - Female Period 1 n 18 21 No 15 (83%) 10 (48%) Yes 3 (17%) 11 (52%)

Period 2 n 21 18 No 17 (81%) 9 (50%) Yes 4 (19%) 9 (50%)

Overall n 39 39 CONFIDENTIAL No 32 (82%) 19 (49%) Yes 7 (18%) 20 (51%)

186 Gender - Male Period 1 n 7 6 No 5 (71%) 3 (50%) Yes 2 (29%) 3 (50%)

Period 2 n 6 7 No 4 (67%) 5 (71%) Yes 2 (33%) 2 (29%)

Overall n 13 13 No 9 (69%) 8 (62%) Yes 4 (31%) 5 (38%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 3 Population: Intent-to-Treat Crossover Table 7.42 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC)

Valtrex Placebo (N=52) (N=52) ------Age - <=30 Period 1 n 16 12 No 13 (81%) 4 (33%) Yes 3 (19%) 8 (67%)

Period 2 n 12 16 No 7 (58%) 8 (50%) Yes 5 (42%) 8 (50%)

Overall n 28 28 CONFIDENTIAL No 20 (71%) 12 (43%) Yes 8 (29%) 16 (57%)

187 Age - >30 Period 1 n 9 15 No 7 (78%) 9 (60%) Yes 2 (22%) 6 (40%)

Period 2 n 15 9 No 14 (93%) 6 (67%) Yes 1 (7%) 3 (33%)

Overall n 24 24 No 21 (88%) 15 (63%) Yes 3 (13%) 9 (38%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 3 Population: Intent-to-Treat Crossover Table 7.42 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC)

Valtrex Placebo (N=52) (N=52) ------Race - Caucasian Period 1 n 14 15 No 13 (93%) 7 (47%) Yes 1 (7%) 8 (53%)

Period 2 n 15 14 No 12 (80%) 9 (64%) Yes 3 (20%) 5 (36%)

Overall n 29 29 CONFIDENTIAL No 25 (86%) 16 (55%) Yes 4 (14%) 13 (45%)

188 Race - Non-Caucasian Period 1 n 11 12 No 7 (64%) 6 (50%) Yes 4 (36%) 6 (50%)

Period 2 n 12 11 No 9 (75%) 5 (45%) Yes 3 (25%) 6 (55%)

Overall n 23 23 No 16 (70%) 11 (48%) Yes 7 (30%) 12 (52%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 3 Population: Per Protocol Table 7.43 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP)

Valtrex Placebo (N=35) (N=35) ------Gender - Female Period 1 n 13 17 No 10 (77%) 8 (47%) Yes 3 (23%) 9 (53%)

Period 2 n 17 13 No 14 (82%) 6 (46%) Yes 3 (18%) 7 (54%)

Overall n 30 30 CONFIDENTIAL No 24 (80%) 14 (47%) Yes 6 (20%) 16 (53%)

189 Gender - Male Period 1 n 4 1 No 3 (75%) Yes 1 (25%) 1 (100%)

Period 2 n 1 4 No 4 (100%) Yes 1 (100%)

Overall n 5 5 No 3 (60%) 4 (80%) Yes 2 (40%) 1 (20%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 3 Population: Per Protocol Table 7.43 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP)

Valtrex Placebo (N=35) (N=35) ------Age - <=30 Period 1 n 11 8 No 9 (82%) 2 (25%) Yes 2 (18%) 6 (75%)

Period 2 n 8 11 No 4 (50%) 6 (55%) Yes 4 (50%) 5 (45%)

Overall n 19 19 CONFIDENTIAL No 13 (68%) 8 (42%) Yes 6 (32%) 11 (58%)

190 Age - >30 Period 1 n 6 10 No 4 (67%) 6 (60%) Yes 2 (33%) 4 (40%)

Period 2 n 10 6 No 10 (100%) 4 (67%) Yes 2 (33%)

Overall n 16 16 No 14 (88%) 10 (63%) Yes 2 (13%) 6 (38%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 3 Population: Per Protocol Table 7.43 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP)

Valtrex Placebo (N=35) (N=35) ------Race - Caucasian Period 1 n 8 8 No 8 (100%) 4 (50%) Yes 4 (50%)

Period 2 n 8 8 No 6 (75%) 6 (75%) Yes 2 (25%) 2 (25%)

Overall n 16 16 CONFIDENTIAL No 14 (88%) 10 (63%) Yes 2 (13%) 6 (38%)

191 Race - Non-Caucasian Period 1 n 9 10 No 5 (56%) 4 (40%) Yes 4 (44%) 6 (60%)

Period 2 n 10 9 No 8 (80%) 4 (44%) Yes 2 (20%) 5 (56%)

Overall n 19 19 No 13 (68%) 8 (42%) Yes 6 (32%) 11 (58%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 7.44 Summary of Percent of HSV-2 Isolates Resistant to Acyclovir Among Subjects Not Responding to 3 Days of Episodic Treatment

Percent of Positive Valtrex 1g QD Placebo Isolates (N=62) (N=62) ------

n 2 6 No 2 (100%) 6 (100%) CONFIDENTIAL 192 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 CONFIDENTIAL RM2007/00260/00 VLX105832

Safety Data Source Tables

Page Table 8.1 Summary of Exposure to Study Drug - Suppression Treatment (Intent-to-Treat Exposed Population) ...... 194 Table 8.2 Summary of Exposure to Study Drug - Open-Label Treatment (Intent-to-Treat Exposed Population) ...... 195 Table 8.3 Summary of Adverse Events (Intent-to-Treat Exposed Population) 196 Table 8.4 Summary of Drug Related Adverse Events (Intent-to-Treat Exposed Population) ...... 200 Table 8.5 Summary of Adverse Events Leading to Discontinuation (Intent-to-Treat Exposed Population) ...... 201 Table 8.6 Summary of Serious Adverse Events (Intent-to-Treat Exposed Population) ...... 202 Table 8.7 Summary of Adverse Events by Demographic Subgroups (Intent-to-Treat Exposed Population) ...... 203 Table 8.8 Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text (Intent-to-Treat Exposed Population) ...... 204 Table 8.9 Summary of Chemistry Data (Intent-to-Treat Exposed Population) 207 Table 8.10 Summary of Chemistry Data Outside the Reference Range (Intent-to-Treat Exposed Population) ...... 212 Table 8.11 Summary of Chemistry Data Outside the Threshold Values (Intent-to-Treat Exposed Population) ...... 224 Table 8.12 Summary of Haemotology Data (Intent-to-Treat Exposed Population) ...... 228 Table 8.13 Summary of Haemotology Data Outside the Reference Range (Intent-to-Treat Exposed Population) ...... 234 Table 8.14 Summary of Haemotology Data Outside the Threshold Values (Intent-to-Treat Exposed Population) ...... 248

193 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.1 Summary of Exposure to Study Drug - Suppression Treatment

Valtrex 1g QD Placebo (N=62) (N=62) ------Period 1 (Days) n 31 34 Mean 58.3 55.4 SD 7.87 16.66 Median 59.0 56.5 Min. 27 15 Max. 68 117

Period 2 (Days) n 27 27 Mean 54.1 55.9

SD 14.08 9.62 CONFIDENTIAL Median 58.0 59.0 Min. 9 22 Max. 75 69 194 Overall (Days) n 58 61 Mean 56.3 55.6 SD 11.29 13.89 Median 59.0 57.0 Min. 9 15 Max. 75 117 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.2 Summary of Exposure to Study Drug - Open-Label Treatment

Valtrex 1g QD Placebo (N=62) (N=62) ------Period 1 (Days) n 8 17 Mean 5.9 6.1 SD 3.09 3.47 Median 6.0 6.0 Min. 3 3 Max. 12 12

Period 2 (Days) n 6 11 Mean 5.5 7.7

SD 2.26 3.29 CONFIDENTIAL Median 6.0 8.0 Min. 3 3 Max. 9 13 195 Overall (Days) n 14 28 Mean 5.7 6.7 SD 2.67 3.44 Median 6.0 6.0 Min. 3 3 Max. 12 13 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 4 Population: Intent-to-Treat Exposed Table 8.3 Summary of Adverse Events

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------ANY EVENT 19 (31%) 26 (42%)

Infections and infestations Any event 15 (24%) 13 (21%) Fungal infection 3 (5%) 6 (10%) Upper respiratory tract infection 3 (5%) 1 (2%) Sinusitis 2 (3%) 1 (2%) Vaginitis bacterial 2 (3%) 1 (2%) Bronchitis 2 (3%) 0

Ear infection 2 (3%) 0 CONFIDENTIAL Folliculitis 1 (2%) 1 (2%) Urinary tract infection 1 (2%) 1 (2%) Vulvovaginal mycotic infection 2 (3%) 0 196 Vulvovaginitis trichomonal 0 2 (3%) Anogenital warts 0 1 (2%) Cervicitis human papilloma virus 0 1 (2%) Hordeolum 0 1 (2%) Labyrinthitis 1 (2%) 0 Onychomycosis 1 (2%) 0 Pelvic inflammatory disease 0 1 (2%) Sialoadenitis 0 1 (2%)

Injury, poisoning and procedural complications Any event 1 (2%) 5 (8%) Contusion 0 2 (3%) Concussion 0 1 (2%) RM2007/00260/00 Fall 0 1 (2%) Muscle strain 0 1 (2%)

Procedural pain 0 1 (2%) VLX105832 Tendon injury 1 (2%) 0 Protocol: VLX105832 Page 2 of 4 Population: Intent-to-Treat Exposed Table 8.3 Summary of Adverse Events

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------Gastrointestinal disorders Any event 1 (2%) 5 (8%) Diarrhoea 1 (2%) 2 (3%) Abdominal pain 0 1 (2%) Dental caries 0 1 (2%) Paraesthesia oral 0 1 (2%) Toothache 0 1 (2%)

Musculoskeletal and connective tissue

disorders CONFIDENTIAL Any event 0 5 (8%) Muscle spasms 0 2 (3%) Pain in extremity 0 2 (3%) 197 Back pain 0 1 (2%) Musculoskeletal pain 0 1 (2%) Neck pain 0 1 (2%)

Nervous system disorders Any event 1 (2%) 4 (6%) Headache 1 (2%) 2 (3%) Migraine 0 1 (2%) Paraesthesia 0 1 (2%)

Respiratory, thoracic and mediastinal disorders Any event 3 (5%) 2 (3%) Pharyngolaryngeal pain 1 (2%) 1 (2%) RM2007/00260/00 Sinus congestion 2 (3%) 0 Cough 0 1 (2%) VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 4 Population: Intent-to-Treat Exposed Table 8.3 Summary of Adverse Events

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------Investigations Any event 3 (5%) 0 Alanine aminotransferase increased 1 (2%) 0 Aspartate aminotransferase increased 1 (2%) 0 Blood pressure increased 1 (2%) 0 Smear cervix abnormal 1 (2%) 0

Metabolism and nutrition disorders Any event 0 2 (3%)

Anorexia 0 1 (2%) CONFIDENTIAL Hypercholesterolaemia 0 1 (2%)

Psychiatric disorders 198 Any event 0 2 (3%) Depression 0 2 (3%) Sleep disorder 0 1 (2%) Stress 0 1 (2%)

Renal and urinary disorders Any event 1 (2%) 1 (2%) Pollakiuria 1 (2%) 0 Urinary tract disorder 0 1 (2%)

Reproductive system and breast disorders Any event 1 (2%) 1 (2%) Vulvovaginal discomfort 0 1 (2%) Vulvovaginal dryness 1 (2%) 0 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 4 Population: Intent-to-Treat Exposed Table 8.3 Summary of Adverse Events

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------Eye disorders Any event 0 1 (2%) Abnormal sensation in eye 0 1 (2%)

Skin and subcutaneous tissue disorders Any event 0 1 (2%) Rash 0 1 (2%) CONFIDENTIAL 199 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.4 Summary of Drug Related Adverse Events

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------ANY EVENT 2 (3%) 3 (5%)

Gastrointestinal disorders Any event 1 (2%) 2 (3%) Diarrhoea 1 (2%) 1 (2%) Abdominal pain 0 1 (2%) Paraesthesia oral 0 1 (2%)

Nervous system disorders

Any event 0 3 (5%) CONFIDENTIAL Headache 0 2 (3%) Paraesthesia 0 1 (2%)

200 Eye disorders Any event 0 1 (2%) Abnormal sensation in eye 0 1 (2%)

Infections and infestations Any event 1 (2%) 0 Vulvovaginal mycotic infection 1 (2%) 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.5 Summary of Adverse Events Leading to Discontinuation

System Organ Class Valtrex 1g QD Placebo Preferred Term (N=62) (N=62) ------ANY EVENT 1 (2%) 1 (2%)

Investigations Any event 1 (2%) 0 Alanine aminotransferase increased 1 (2%) 0 Aspartate aminotransferase increased 1 (2%) 0

Nervous system disorders Any event 0 1 (2%)

Headache 0 1 (2%) CONFIDENTIAL 201 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.6 Summary of Serious Adverse Events

No data to report CONFIDENTIAL 202 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 1 Population: Intent-to-Treat Exposed Table 8.7 Summary of Adverse Events by Demographic Subgroups

Valtrex 1g QD Placebo (N=62) (N=62) ------ANY EVENT 19/62 (31%) 26/62 (42%)

Sex Female 16/43 (37%) 20/45 (44%) Male 3/19 (16%) 6/17 (35%)

Ethnicity Hispanic/Latino 1/ 5 (20%) 1/ 5 (20%) Not Hispanic/Latino 18/57 (32%) 25/57 (44%) CONFIDENTIAL Age Group Age<65 19/62 (31%) 26/62 (42%) 203 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 3 Population: Intent-to-Treat Exposed Table 8.8 Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ------Eye disorders Abnormal sensation in eye Tingling left eye

Gastrointestinal disorders Abdominal pain Abdominal Cramping Dental caries Tooth decay Diarrhoea Diarrhea diarrhea intermittent diarrhea Paraesthesia oral Tingling to left side of mouth/tongue Toothache toothache CONFIDENTIAL Infections and infestations Anogenital warts Genital Warts Bronchitis Bronchitis Cervicitis human papilloma Human Papilloma Virus (HPV) on 204 virus cervix Ear infection bilateral ear infection ear infection Folliculitis Folliculitis infected hair follicle Fungal infection Yeast Infection Yeast infection yeast infection Hordeolum right eye stye Labyrinthitis Labyrinthitis Onychomycosis Onychomychosis Right third toenail Pelvic inflammatory disease Pelvic Inflammatory Disease Sialoadenitis Submandibular Gland Infection RM2007/00260/00 Sinusitis Sinus Infection sinus infection

Upper respiratory tract Upper Respiratory Tract VLX105832 infection Infection upper respiratory infection Urinary tract infection Urinary Tract Infection Protocol: VLX105832 Page 2 of 3 Population: Intent-to-Treat Exposed Table 8.8 Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ------Infections and infestations Urinary tract infection urinary tract infection Vaginitis bacterial Bacterial Vaginosis Vulvovaginal mycotic infection Yeast vaginits vaginal yeast infection Vulvovaginitis trichomonal Trichomonas vaginitis wet prep positive trichomonas

Injury, poisoning and Concussion concussion procedural complications Contusion Contusion Left Shoulder

Right little toe contusion CONFIDENTIAL Fall Fall Muscle strain bilateral trapezius strain Procedural pain mouth pain from root canal 205 Tendon injury Severed tendon in R foot

Investigations Alanine aminotransferase elevated liver function test increased (SGPT) Aspartate aminotransferase elevated liver function SGOT increased Additional value 321, value 70, pen Blood pressure increased Elev Blood Pressure Smear cervix abnormal Abnormal PAP smear

Metabolism and nutrition Anorexia No appitite disorders Hypercholesterolaemia Hypercholesterolemia RM2007/00260/00

Musculoskeletal and Back pain Back Pain

connective tissue disorders VLX105832 Muscle spasms cramping right lower back radiating to right thigh low back muscle spasm Protocol: VLX105832 Page 3 of 3 Population: Intent-to-Treat Exposed Table 8.8 Relationship of Adverse Event System Organ Classes, Preferred Terms, and Verbatim Text

System Organ Class Preferred Term Verbatim Text ------Musculoskeletal and Musculoskeletal pain Left Shoulder Pain connective tissue disorders Neck pain Neck Pain Pain in extremity Leg pain bilateral leg pain

Nervous system disorders Headache Head Congestion Headache Increased frequency and intensity of headaches

Migraine Migraine CONFIDENTIAL Paraesthesia Tingling to left hand

Psychiatric disorders Depression Increased depression 206 Worsening Depression Sleep disorder Sleep problems Stress Increased Stress

Renal and urinary disorders Pollakiuria Urinary Frequency Urinary tract disorder Urinary Symptoms

Reproductive system and Vulvovaginal discomfort vag irritation breast disorders Vulvovaginal dryness vaginal dryness

Respiratory, thoracic and Cough Cough mediastinal disorders Pharyngolaryngeal pain Sore throat RM2007/00260/00 sore throat Sinus congestion Sinus congestion

sinus congestion VLX105832

Skin and subcutaneous tissue Rash Rash, bilateral legs, thigh disorders area Protocol: VLX105832 Page 1 of 5 Population: Intent-to-Treat Exposed Table 8.9 Summary of Chemistry Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Albumin (G/L) Screen 70 44.7 2.72 45.0 38 51

Valtrex 1g QD 62 Unsched., Period 1 6 43.5 1.64 44.0 41 45 End of Period 1 24 43.8 2.49 44.0 40 48 Unsched., Period 2 1 45.0 45.0 45 45 End of Study 27 43.8 3.00 44.0 37 50

Placebo 62 End of Period 1 27 43.9 2.60 45.0 38 48 Day 15, Period 2 2 44.0 7.07 44.0 39 49 Day 30, Period 2 1 48.0 48.0 48 48

End of Study 29 44.3 3.12 44.0 39 50 CONFIDENTIAL

Alkaline Phosphatase (IU/L) Screen 70 66.9 18.47 66.0 32 107 207 Valtrex 1g QD 62 Unsched., Period 1 6 52.8 16.90 46.0 43 87 End of Period 1 24 55.0 11.62 57.0 32 82 Unsched., Period 2 1 79.0 79.0 79 79 End of Study 27 64.7 14.75 64.0 37 87

Placebo 62 End of Period 1 27 63.7 17.81 61.0 33 97 Day 15, Period 2 2 105.5 13.44 105.5 96 115 Day 30, Period 2 1 107.0 107.0 107 107 End of Study 29 65.8 22.00 64.0 35 115

Alanine Amino Transferase Screen 70 19.4 12.75 15.0 6 75 (IU/L) RM2007/00260/00

Valtrex 1g QD 62 Unsched., Period 1 6 106.8 80.92 80.0 45 263

End of Period 1 24 33.1 78.90 15.0 8 401 VLX105832 Unsched., Period 2 1 9.0 9.0 9 9 End of Study 27 16.9 9.86 14.0 8 57 Protocol: VLX105832 Page 2 of 5 Population: Intent-to-Treat Exposed Table 8.9 Summary of Chemistry Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Alanine Amino Transferase Placebo 62 End of Period 1 27 18.1 10.30 16.0 6 54 (IU/L) Day 15, Period 2 2 53.0 46.67 53.0 20 86 Day 30, Period 2 1 19.0 19.0 19 19 End of Study 29 19.6 12.45 15.0 9 59

Aspartate Amino Transferase Screen 70 20.2 10.35 17.5 11 91 (IU/L)

Valtrex 1g QD 62 Unsched., Period 1 6 118.2 102.60 79.0 46 321 CONFIDENTIAL End of Period 1 24 28.5 46.58 19.0 11 246 Unsched., Period 2 1 14.0 14.0 14 14 End of Study 27 18.7 5.81 17.0 11 39 208 Placebo 62 End of Period 1 27 20.0 6.21 18.0 11 37 Day 15, Period 2 2 31.5 19.09 31.5 18 45 Day 30, Period 2 1 21.0 21.0 21 21 End of Study 29 21.8 7.12 20.0 13 43

Total Bilirubin (UMOL/L) Screen 70 8.4 3.63 8.0 4 24

Valtrex 1g QD 62 Unsched., Period 1 6 7.0 1.67 6.0 6 10 End of Period 1 24 8.1 3.41 6.0 4 16 Unsched., Period 2 1 8.0 8.0 8 8 End of Study 27 7.5 3.21 6.0 4 18 RM2007/00260/00 RM2007/00260/00 Placebo 62 End of Period 1 27 7.6 2.72 6.0 4 14 Day 15, Period 2 2 6.0 0.00 6.0 6 6

Day 30, Period 2 1 6.0 6.0 6 6 VLX105832 End of Study 29 8.1 3.91 6.0 4 18 Protocol: VLX105832 Page 3 of 5 Population: Intent-to-Treat Exposed Table 8.9 Summary of Chemistry Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Calcium (MMOL/L) Screen 70 2.4 0.08 2.4 2 3

Valtrex 1g QD 62 Unsched., Period 1 6 2.3 0.08 2.3 2 2 End of Period 1 24 2.3 0.06 2.3 2 2 Unsched., Period 2 1 2.3 2.3 2 2 End of Study 27 2.3 0.08 2.3 2 3

Placebo 62 End of Period 1 27 2.3 0.07 2.3 2 2 Day 15, Period 2 2 2.4 0.08 2.4 2 2 Day 30, Period 2 1 2.3 2.3 2 2

End of Study 29 2.3 0.08 2.3 2 3 CONFIDENTIAL

Chloride (MMOL/L) Screen 70 105.0 2.47 105.0 99 111 209 Valtrex 1g QD 62 Unsched., Period 1 6 105.5 1.05 105.5 104 107 End of Period 1 24 105.4 2.10 105.0 102 109 Unsched., Period 2 1 109.0 109.0 109 109 End of Study 27 105.5 2.31 105.0 101 111

Placebo 62 End of Period 1 27 105.9 2.03 106.0 101 109 Day 15, Period 2 2 105.5 3.54 105.5 103 108 Day 30, Period 2 1 107.0 107.0 107 107 End of Study 29 104.6 2.43 105.0 99 110

Creatinine (UMOL/L) Screen 70 88.2 16.74 88.0 53 133 RM2007/00260/00 RM2007/00260/00 Valtrex 1g QD 62 Unsched., Period 1 6 103.2 13.20 106.0 80 115 End of Period 1 24 80.0 17.13 80.0 62 124

Unsched., Period 2 1 71.0 71.0 71 71 VLX105832 End of Study 27 83.6 14.44 80.0 62 124

Placebo 62 End of Period 1 27 82.5 13.94 80.0 53 124 Protocol: VLX105832 Page 4 of 5 Population: Intent-to-Treat Exposed Table 8.9 Summary of Chemistry Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Creatinine (UMOL/L) Placebo 62 Day 15, Period 2 2 79.5 24.75 79.5 62 97 Day 30, Period 2 1 80.0 80.0 80 80 End of Study 29 77.2 13.62 80.0 53 115

Potassium (MMOL/L) Screen 70 4.2 0.32 4.1 3 5

Valtrex 1g QD 62 Unsched., Period 1 6 4.1 0.13 4.1 4 4 End of Period 1 24 4.4 0.42 4.3 4 6 Unsched., Period 2 1 4.0 4.0 4 4

End of Study 27 4.2 0.41 4.1 4 5 CONFIDENTIAL

Placebo 62 End of Period 1 27 4.2 0.29 4.2 4 5 Day 15, Period 2 2 4.2 0.28 4.2 4 4 210 Day 30, Period 2 1 4.0 4.0 4 4 End of Study 29 4.2 0.33 4.1 4 5

Sodium (MMOL/L) Screen 70 140.1 2.43 140.0 133 146

Valtrex 1g QD 62 Unsched., Period 1 6 140.7 0.82 140.5 140 142 End of Period 1 24 139.5 1.74 140.0 135 142 Unsched., Period 2 1 142.0 142.0 142 142 End of Study 27 140.7 1.83 141.0 137 144

Placebo 62 End of Period 1 27 140.9 1.95 141.0 138 146 Day 15, Period 2 2 140.0 2.83 140.0 138 142 Day 30, Period 2 1 144.0 144.0 144 144 RM2007/00260/00 End of Study 29 139.8 2.55 140.0 135 146 VLX105832 VLX105832 Phosphorus, Inorganic Screen 70 1.1 0.17 1.2 1 2 (MMOL/L) Protocol: VLX105832 Page 5 of 5 Population: Intent-to-Treat Exposed Table 8.9 Summary of Chemistry Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Phosphorus, Inorganic Valtrex 1g QD 62 Unsched., Period 1 6 1.1 0.19 1.1 1 1 (MMOL/L) End of Period 1 24 1.2 0.15 1.1 1 2 Unsched., Period 2 1 1.0 1.0 1 1 End of Study 27 1.1 0.21 1.1 1 1

Placebo 62 End of Period 1 27 1.1 0.16 1.2 1 1 Day 15, Period 2 2 1.2 0.32 1.2 1 1 Day 30, Period 2 1 1.4 1.4 1 1 End of Study 29 1.2 0.17 1.2 1 2 CONFIDENTIAL

Urea (MMOL/L) Screen 70 4.5 1.49 4.5 2 10

211 Valtrex 1g QD 62 Unsched., Period 1 6 8.5 2.86 8.3 5 13 End of Period 1 24 4.7 1.27 4.5 3 9 Unsched., Period 2 1 5.0 5.0 5 5 End of Study 27 4.6 1.43 4.5 2 9

Placebo 62 End of Period 1 27 4.7 1.43 4.5 2 8 Day 15, Period 2 2 4.3 0.35 4.3 4 5 Day 30, Period 2 1 4.5 4.5 5 5 End of Study 29 4.3 0.88 4.0 3 6 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Alanine Amino Transferase (IU/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 1 (50%) 0 Normal 1 (50%) 0

End of Period 1 n 24 27 High 2 (8%) 1 (4%) Normal 22 (92%) 26 (96%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

212 Day 15, Period 2 n 0 2 High 0 1 (50%) Normal 0 1 (50%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 1 (4%) 2 (7%) Normal 26 (96%) 27 (93%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Albumin (G/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 213 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 3 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Alkaline Phosphatase (IU/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 214 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 4 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Aspartate Amino Transferase (IU/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 2 (100%) 0 Normal 0 0

End of Period 1 n 24 27 High 1 (4%) 0 Normal 23 (96%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

215 Day 15, Period 2 n 0 2 High 0 1 (50%) Normal 0 1 (50%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 1 (3%) Normal 27 (100%) 28 (97%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Calcium (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 216 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 6 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Chloride (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 3 (13%) 2 (7%) Normal 21 (88%) 25 (93%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 1 (100%) 0 217 Normal 0 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 3 (11%) 1 (3%) Normal 24 (89%) 28 (97%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 7 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Creatinine (UMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 218 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 8 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Phosphorus, Inorganic (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 1 (4%) 0 Normal 23 (96%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 219 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 1 (3%) Normal 23 (85%) 28 (97%)

Low 4 (15%) 0 VLX105832 Protocol: VLX105832 Page 9 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Potassium (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 1 (4%) 0 Normal 23 (96%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 220 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 10 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Sodium (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 221 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 11 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Total Bilirubin (UMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

222 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 12 of 12 Population: Intent-to-Treat Exposed Table 8.10 Summary of Chemistry Data Outside the Reference Range

Lab Test: Urea (MMOL/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 1 (50%) 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 26 (96%)

Low 0 1 (4%) CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 223 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 26 (96%) 29 (100%)

Low 1 (4%) 0 VLX105832 Protocol: VLX105832 Page 1 of 4 Population: Intent-to-Treat Exposed Table 8.11 Summary of Chemistry Data Outside the Threshold Values

Lab Test: Alanine Amino Transferase (IU/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 1 (50%) 0 Normal 2 (100%) 0

End of Period 1 n 24 27 High 1 (4%) 0 Normal 23 (96%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

224 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 4 Population: Intent-to-Treat Exposed Table 8.11 Summary of Chemistry Data Outside the Threshold Values

Lab Test: Alkaline Phosphatase (IU/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

225 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 4 Population: Intent-to-Treat Exposed Table 8.11 Summary of Chemistry Data Outside the Threshold Values

Lab Test: Aspartate Amino Transferase (IU/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 1 (50%) 0 Normal 2 (100%) 0

End of Period 1 n 24 27 High 1 (4%) 0 Normal 23 (96%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

226 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 4 Population: Intent-to-Treat Exposed Table 8.11 Summary of Chemistry Data Outside the Threshold Values

Lab Test: Creatinine (UMOL/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 24 27 High 0 0 Normal 24 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

227 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Basophils (GI/L) Screen 70 0.0 0.02 0.0 0 0

Valtrex 1g QD 62 Unsched., Period 1 2 0.0 0.01 0.0 0 0 End of Period 1 23 0.0 0.01 0.0 0 0 Unsched., Period 2 1 0.0 0.0 0 0 End of Study 27 0.0 0.01 0.0 0 0

Placebo 62 End of Period 1 27 0.0 0.01 0.0 0 0 Day 15, Period 2 2 0.1 0.04 0.1 0 0 Day 30, Period 2 1 0.1 0.1 0 0

End of Study 29 0.0 0.02 0.0 0 0 CONFIDENTIAL

Basophils (percentage) (%) Screen 70 0.3 0.20 0.3 0 1 228 Valtrex 1g QD 62 Unsched., Period 1 2 0.4 0.14 0.4 0 1 End of Period 1 23 0.3 0.19 0.3 0 1 Unsched., Period 2 1 0.3 0.3 0 0 End of Study 27 0.3 0.13 0.3 0 1

Placebo 62 End of Period 1 27 0.3 0.20 0.3 0 1 Day 15, Period 2 2 0.8 0.42 0.8 1 1 Day 30, Period 2 1 0.6 0.6 1 1 End of Study 29 0.4 0.23 0.3 0 1

Eosinophils (GI/L) Screen 70 0.2 0.16 0.2 0 1 RM2007/00260/00 RM2007/00260/00 Valtrex 1g QD 62 Unsched., Period 1 2 0.2 0.11 0.2 0 0 End of Period 1 23 0.2 0.11 0.1 0 0

Unsched., Period 2 1 0.1 0.1 0 0 VLX105832 End of Study 27 0.2 0.12 0.2 0 0

Placebo 62 End of Period 1 27 0.2 0.13 0.2 0 0 Protocol: VLX105832 Page 2 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Eosinophils (GI/L) Placebo 62 Day 15, Period 2 2 0.4 0.33 0.4 0 1 Day 30, Period 2 1 0.2 0.2 0 0 End of Study 29 0.2 0.21 0.2 0 1

Eosinophils (percentage) (%) Screen 70 2.9 2.15 2.3 0 11

Valtrex 1g QD 62 Unsched., Period 1 2 3.9 2.05 3.9 2 5 End of Period 1 23 3.0 1.99 1.9 1 8 Unsched., Period 2 1 1.5 1.5 2 2

End of Study 27 2.5 1.46 2.2 0 6 CONFIDENTIAL

Placebo 62 End of Period 1 27 2.7 1.71 2.1 1 7 Day 15, Period 2 2 5.9 3.11 5.9 4 8 229 Day 30, Period 2 1 2.1 2.1 2 2 End of Study 29 3.1 2.52 2.6 0 14

Hemoglobin (G/L) Screen 70 136.5 14.82 137.5 108 174

Valtrex 1g QD 62 Unsched., Period 1 2 133.5 24.75 133.5 116 151 End of Period 1 23 132.9 14.61 128.0 115 161 Unsched., Period 2 1 124.0 124.0 124 124 End of Study 27 132.6 12.87 133.0 105 157

Placebo 62 End of Period 1 27 135.0 11.71 138.0 110 160 Day 15, Period 2 2 136.0 8.49 136.0 130 142 Day 30, Period 2 1 153.0 153.0 153 153 RM2007/00260/00 End of Study 29 133.6 12.14 132.0 115 160 VLX105832 VLX105832 Lymphocytes (GI/L) Screen 70 2.2 0.68 2.2 1 4

Valtrex 1g QD 62 Unsched., Period 1 2 2.2 0.26 2.2 2 2 Protocol: VLX105832 Page 3 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Lymphocytes (GI/L) Valtrex 1g QD 62 End of Period 1 23 2.0 0.40 1.9 1 3 Unsched., Period 2 1 3.3 3.3 3 3 End of Study 27 2.4 0.68 2.3 1 4

Placebo 62 End of Period 1 27 2.4 0.53 2.3 1 3 Day 15, Period 2 2 2.2 0.41 2.2 2 3 Day 30, Period 2 1 1.9 1.9 2 2 End of Study 29 2.0 0.37 2.0 1 3

Lymphocytes (percentage) (%) Screen 70 32.6 9.31 32.8 11 55 CONFIDENTIAL

Valtrex 1g QD 62 Unsched., Period 1 2 38.4 5.44 38.4 35 42 End of Period 1 23 33.3 8.40 33.3 14 51 230 Unsched., Period 2 1 57.2 57.2 57 57 End of Study 27 33.6 8.95 33.4 21 55

Placebo 62 End of Period 1 27 33.5 7.69 31.2 24 48 Day 15, Period 2 2 34.1 4.31 34.1 31 37 Day 30, Period 2 1 24.5 24.5 25 25 End of Study 29 32.9 8.10 31.3 22 55

Mean Corpuscle Volume (FL) Screen 70 90.4 5.37 91.0 73 101

Valtrex 1g QD 62 Unsched., Period 1 2 92.0 1.41 92.0 91 93 End of Period 1 23 93.5 5.51 94.0 82 102 Unsched., Period 2 1 96.0 96.0 96 96 RM2007/00260/00 End of Study 27 92.0 6.19 93.0 74 103

Placebo 62 End of Period 1 27 91.6 5.77 92.0 75 102 VLX105832 Day 15, Period 2 2 90.0 5.66 90.0 86 94 Day 30, Period 2 1 89.0 89.0 89 89 End of Study 29 91.7 5.11 92.0 81 102 Protocol: VLX105832 Page 4 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Monocytes (GI/L) Screen 70 0.4 0.16 0.4 0 1

Valtrex 1g QD 62 Unsched., Period 1 2 0.3 0.21 0.3 0 0 End of Period 1 23 0.3 0.14 0.3 0 1 Unsched., Period 2 1 0.2 0.2 0 0 End of Study 27 0.4 0.14 0.4 0 1

Placebo 62 End of Period 1 27 0.4 0.13 0.4 0 1 Day 15, Period 2 2 0.4 0.13 0.4 0 0 Day 30, Period 2 1 0.3 0.3 0 0

End of Study 29 0.4 0.17 0.3 0 1 CONFIDENTIAL

Monocytes (percentage) (%) Screen 70 5.6 2.34 5.6 0 13 231 Valtrex 1g QD 62 Unsched., Period 1 2 5.7 3.61 5.7 3 8 End of Period 1 23 5.4 2.18 5.1 2 11 Unsched., Period 2 1 3.8 3.8 4 4 End of Study 27 5.2 1.66 5.2 1 9

Placebo 62 End of Period 1 27 5.5 1.48 5.6 2 8 Day 15, Period 2 2 6.0 0.21 6.0 6 6 Day 30, Period 2 1 4.0 4.0 4 4 End of Study 29 5.7 2.31 5.6 2 13

Total Neutrophils (GI/L) Screen 70 4.2 1.92 3.7 1 12 RM2007/00260/00 RM2007/00260/00 Valtrex 1g QD 62 Unsched., Period 1 2 3.0 0.30 3.0 3 3 End of Period 1 23 3.7 1.42 3.5 2 7

Unsched., Period 2 1 2.2 2.2 2 2 VLX105832 End of Study 27 4.4 1.70 4.1 2 9

Placebo 62 End of Period 1 27 4.2 1.16 4.2 2 7 Protocol: VLX105832 Page 5 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------Total Neutrophils (GI/L) Placebo 62 Day 15, Period 2 2 3.6 1.13 3.6 3 4 Day 30, Period 2 1 5.4 5.4 5 5 End of Study 29 3.8 1.54 3.5 1 7

Total Neutrophils (percentage) Screen 70 58.5 9.67 58.0 37 79 (%)

Valtrex 1g QD 62 Unsched., Period 1 2 51.8 4.03 51.8 49 55 End of Period 1 23 58.0 10.08 57.9 40 81

Unsched., Period 2 1 37.2 37.2 37 37 CONFIDENTIAL End of Study 27 58.5 9.54 57.8 38 76

Placebo 62 End of Period 1 27 58.0 8.36 59.9 40 71 232 Day 15, Period 2 2 53.3 0.57 53.3 53 54 Day 30, Period 2 1 68.8 68.8 69 69 End of Study 29 57.8 9.76 59.3 36 73

Platelet count (GI/L) Screen 70 275.3 62.83 274.5 143 438

Valtrex 1g QD 62 Unsched., Period 1 2 287.5 33.23 287.5 264 311 End of Period 1 23 273.0 52.55 264.0 195 399 Unsched., Period 2 1 269.0 269.0 269 269 End of Study 27 264.4 52.59 269.0 182 366

Placebo 62 End of Period 1 27 268.4 65.12 283.0 155 378 Day 15, Period 2 2 327.5 62.93 327.5 283 372 RM2007/00260/00 Day 30, Period 2 1 343.0 343.0 343 343 End of Study 29 278.3 55.74 263.0 202 431 VLX105832 VLX105832

White Blood Cell Count (GI/L) Screen 70 7.0 2.28 6.6 4 16 Protocol: VLX105832 Page 6 of 6 Population: Intent-to-Treat Exposed Table 8.12 Summary of Haemotology Data

Lab Test Treatment N Visit n Mean SD Median Min. Max. ------White Blood Cell Count (GI/L) Valtrex 1g QD 62 Unsched., Period 1 2 5.8 0.14 5.8 6 6 End of Period 1 23 6.1 1.50 5.9 4 9 Unsched., Period 2 1 5.8 5.8 6 6 End of Study 27 7.3 2.15 7.1 4 13

Placebo 62 End of Period 1 27 7.1 1.37 7.1 5 11 Day 15, Period 2 2 6.7 2.05 6.7 5 8 Day 30, Period 2 1 7.8 7.8 8 8 End of Study 29 6.3 1.85 5.8 3 11 CONFIDENTIAL 233 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 1 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Basophils (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

234 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Basophils (percentage) (%) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

235 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 0 Normal 27 (100%) 29 (100%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Eosinophils (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 0 0 Normal 22 (96%) 26 (96%)

Low 1 (4%) 1 (4%) CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 236 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 1 (50%) Normal 0 1 (50%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 1 (3%) Normal 25 (93%) 25 (86%)

Low 2 (7%) 3 (10%) VLX105832 Protocol: VLX105832 Page 4 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Eosinophils (percentage) (%) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 23 27 High 2 (9%) 0 Normal 21 (91%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

237 Day 15, Period 2 n 0 2 High 0 1 (50%) Normal 0 1 (50%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 1 (3%) Normal 27 (100%) 28 (97%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 5 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Hemoglobin (G/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 1 (50%) 0 Low 1 (50%) 0

End of Period 1 n 23 27 High 0 0 Normal 18 (78%) 23 (85%)

Low 5 (22%) 4 (15%) CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 238 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 1 (50%) Low 0 1 (50%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 22 (81%) 24 (83%)

Low 5 (19%) 5 (17%) VLX105832 Protocol: VLX105832 Page 6 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Lymphocytes (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 239 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 27 (100%) 29 (100%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 7 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Lymphocytes (percentage) (%) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 2 (9%) 3 (11%) Normal 20 (87%) 24 (89%)

Low 1 (4%) 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 1 (100%) 0 240 Normal 0 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 2 (7%) 2 (7%) Normal 25 (93%) 27 (93%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 8 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Mean Corpuscle Volume (FL) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 1 (4%) 1 (4%) Normal 22 (96%) 25 (93%)

Low 0 1 (4%) CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 241 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 2 (7%) 1 (3%) Normal 24 (89%) 28 (97%)

Low 1 (4%) 0 VLX105832 Protocol: VLX105832 Page 9 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Monocytes (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 1 (50%) 0 Low 1 (50%) 0

End of Period 1 n 23 27 High 0 0 Normal 20 (87%) 26 (96%)

Low 3 (13%) 1 (4%) CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 242 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 0 Normal 25 (93%) 24 (83%)

Low 2 (7%) 5 (17%) VLX105832 Protocol: VLX105832 Page 10 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Monocytes (percentage) (%) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Unsched., Period 2 n 1 0 CONFIDENTIAL High 0 0 Normal 1 (100%) 0

243 Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%)

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%)

End of Study n 27 29 High 0 1 (3%) Normal 27 (100%) 28 (97%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 11 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Platelet count (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 244 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 0 1 (3%) Normal 27 (100%) 28 (97%)

Low 0 0 VLX105832 Protocol: VLX105832 Page 12 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Total Neutrophils (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 0 0 Normal 20 (87%) 27 (100%)

Low 3 (13%) 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 245 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 1 (4%) 0 Normal 25 (93%) 27 (93%)

Low 1 (4%) 2 (7%) VLX105832 Protocol: VLX105832 Page 13 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: Total Neutrophils (percentage) (%) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 1 (4%) 0 Normal 21 (91%) 27 (100%)

Low 1 (4%) 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 246 Normal 0 0 Low 1 (100%) 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 1 (4%) 0 Normal 25 (93%) 27 (93%)

Low 1 (4%) 2 (7%) VLX105832 Protocol: VLX105832 Page 14 of 14 Population: Intent-to-Treat Exposed Table 8.13 Summary of Haemotology Data Outside the Reference Range

Lab Test: White Blood Cell Count (GI/L) Normal Range Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 High 0 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 High 0 0 Normal 23 (100%) 27 (100%)

Low 0 0 CONFIDENTIAL

Unsched., Period 2 n 1 0 High 0 0 247 Normal 1 (100%) 0 Low 0 0

Day 15, Period 2 n 0 2 High 0 0 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 High 0 0 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 RM2007/00260/00 High 2 (7%) 0 Normal 25 (93%) 28 (97%)

Low 0 1 (3%) VLX105832 Protocol: VLX105832 Page 1 of 4 Population: Intent-to-Treat Exposed Table 8.14 Summary of Haemotology Data Outside the Threshold Values

Lab Test: Hemoglobin (G/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 Normal 23 (100%) 27 (100%) Low 0 0

Unsched., Period 2 n 1 0 CONFIDENTIAL Normal 1 (100%) 0 Low 0 0

248 Day 15, Period 2 n 0 2 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 Normal 27 (100%) 29 (100%) Low 0 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 2 of 4 Population: Intent-to-Treat Exposed Table 8.14 Summary of Haemotology Data Outside the Threshold Values

Lab Test: Platelet count (GI/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 Normal 23 (100%) 27 (100%) Low 0 0

Unsched., Period 2 n 1 0 CONFIDENTIAL Normal 1 (100%) 0 Low 0 0

249 Day 15, Period 2 n 0 2 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 Normal 27 (100%) 29 (100%) Low 0 0 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 3 of 4 Population: Intent-to-Treat Exposed Table 8.14 Summary of Haemotology Data Outside the Threshold Values

Lab Test: Total Neutrophils (GI/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 Normal 23 (100%) 27 (100%) Low 0 0

Unsched., Period 2 n 1 0 CONFIDENTIAL Normal 1 (100%) 0 Low 0 0

250 Day 15, Period 2 n 0 2 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 Normal 27 (100%) 27 (93%) Low 0 2 (7%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Protocol: VLX105832 Page 4 of 4 Population: Intent-to-Treat Exposed Table 8.14 Summary of Haemotology Data Outside the Threshold Values

Lab Test: White Blood Cell Count (GI/L) Clinical Concern Valtrex 1g QD Placebo Visit Category (N=62) (N=62) ------Unsched., Period 1 n 2 0 Normal 2 (100%) 0 Low 0 0

End of Period 1 n 23 27 Normal 23 (100%) 27 (100%) Low 0 0

Unsched., Period 2 n 1 0 CONFIDENTIAL Normal 1 (100%) 0 Low 0 0

251 Day 15, Period 2 n 0 2 Normal 0 2 (100%) Low 0 0

Day 30, Period 2 n 0 1 Normal 0 1 (100%) Low 0 0

End of Study n 27 29 Normal 27 (100%) 28 (97%) Low 0 1 (3%) RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 CONFIDENTIAL RM2007/00260/00 VLX105832 Flowchart to determine Subject Eligibility

HSV-2 seropositive at Screen

Documented GH signs and symptoms present at screen OR any time since initial diagnosis that occurred within 4 months of randomization*

YES NO

ENROLL DO NOT ENROLL

Subject must be:

HSV-2 seropositive at screen with documented clinical signs and symptoms consistent with genital herpes at screen

HSV-2 seropositive at screen with documented clinical signs and symptoms consistent with genital herpes within 4 months prior to randomization

* GH signs/symptoms must be observed and documented at some time between initial diagnosis and screen

Subjects may have received episodic therapy to treat the initial outbreak or a recurrence in accordance with the dosing regimen approved by local regulatory authorities. However, subjects must undergo a three day (72 hours) washout period PRIOR to randomization/initiation of study treatment, but must be randomized within 4 months of the initial diagnosis of GH to ensure only newly diagnosed subjects are randomized.

The presence or absence of HSV-2 culture/PCR results at initial diagnosis does not impact eligibility

252 CONFIDENTIAL RM2007/00260/00 VLX105832 Flowchart to determine Subject Eligibility (continued)

HSV-2 seronegative at Screen

Positive HSV-2 culture or PCR at screen OR at any time since initial diagnosis within 4 months of randomization*

YES NO

Documented clinical signs and symptoms consistent with genital herpes at screen or DO NOT ENROLL within 4 months prior to randomization

YES NO

ENROLL DO NOT ENROLL

Subject must be:

HSV-2 seronegative at screen, AND HSV-2 culture positive or HSV-2 PCR positive at screen or within 4 months prior to randomization, with:

documented clinical signs and symptoms consistent with genital herpes at screen

documented clinical signs and symptoms consistent with genital herpes within 4 months prior to randomization

* GH signs/symptoms must be observed and documented at some time between initial diagnosis and screen

253 CONFIDENTIAL RM2007/00260/00 VLX105832

CONFIDENTIAL RM2006/00617/00 The GlaxoSmithKline group of companies VLX105832

Division: World Wide Development Retention Category: GRS019 Information Type: Reporting and Analysis Plan

Title: Reporting and Analysis Plan for VLX105832: The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection

Compound Number: GW282358

Effective Date: 02-FEB-2007

Description: The purpose of this study is to determine the efficacy and safety of VALTREX™ 1g once daily in reducing viral shedding in immunocompetent subjects newly diagnosed with recurrent genital herpes.

This study is a randomized, double-blind, two-way cross-over study to compare the effect of VALTREX 1g vs. placebo administered once daily for 60 days on HSV-2 shedding in subjects newly diagnosed with HSV-2 infection.

The primary endpoint is the mean percent of days of total shedding as determined by type-specific PCR assay for HSV-2.

Eligible subjects will be male or female, aged 18 years or older and immunocompetent. Subjects must be randomized within 4 months of the initial diagnosis of GH, or be newly diagnosed with a first recognized episode of genital herpes at the screening visit.

During each 60-day Treatment Period and the 7-day washout period, the subject will collect swabs from the genital/anal-rectal area for HSV-2 detection. For each subject, each study day will be classified by PCR as 'shedding' or 'no shedding'; additionally each day will be classified as 'clinical' (i.e., presence of genital lesions) or 'subclinical" (i.e., no genital lesions).

Subjects will complete diaries to record relevant study information.

Identifier/Version Number: RM2006/00617/00

Subject: Valtrex, valacyclovir, 256U87, HSV (herpes simplex virus), PCR (polymerase chain reaction), recurrence, total shedding, newly diagnosed

Author’s Name, Title and Functional Area: Ph.D., MDC BDS, ID; MDC, ID, NA

254 CONFIDENTIAL RM2007/00260/00 VLX105832

CONFIDENTIAL RM2006/00617/00 VLX105832

TABLE OF CONTENTS

PAGE

ABBREVIATIONS ...... 4

1. INTRODUCTION...... 5

2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ...... 5 2.1. Study Objective(s) ...... 5 2.2. Study Endpoint(s) ...... 5 2.3. Statistical Hypotheses...... 6 2.4. Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses ...... 6

3. STUDY DESIGN ...... 6

4. PLANNED ANALYSES ...... 7 4.1. Interim Analyses ...... 7 4.2. Final Analysis ...... 7

5. SAMPLE SIZE CONSIDERATIONS...... 7

6. ANALYSIS POPULATIONS ...... 8

7. TREATMENT COMPARISONS...... 9 7.1. Data Display Treatment and Other Sub-group Descriptors ...... 9

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES...... 9 8.1. Multicentre Studies ...... 9 8.2. Other Strata and Covariates ...... 9 8.3. Examination of Subgroups...... 10 8.4. Multiple Comparisons and Multiplicity ...... 10

9. DATA HANDLING CONVENTIONS ...... 10 9.1. Premature Withdrawal and Missing Data ...... 10 9.2. Derived and Transformed Data...... 11 9.3. Assessment Windows...... 11 9.4. Values of Clinical Concern...... 11

10. STUDY POPULATION ...... 11 10.1. Disposition of Subjects...... 12 10.2. Protocol Deviations...... 12 10.3. Demographic and Baseline Characteristics...... 13 10.4. Treatment Compliance...... 13

11. EFFICACY ANALYSES...... 14 11.1. Primary Efficacy Analysis(es)...... 14 11.2. Secondary Efficacy Analysis(es)...... 15 11.3. Other Efficacy Analysis(es)...... 16

12. SAFETY ANALYSES ...... 17 12.1. Extent of Exposure ...... 17

255 CONFIDENTIAL RM2007/00260/00 VLX105832

CONFIDENTIAL RM2006/00617/00 VLX105832

12.2. Adverse Events...... 17 12.3. Deaths and Serious Adverse Events...... 17 12.4. Device Incidents and Near Incidents...... 17 12.5. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events...... 18 12.6. Pregnancies (as applicable)...... 18 12.7. Clinical Laboratory Evaluations...... 18 12.8. Other Safety Measures...... 19

13. HEALTH OUTCOMES ANALYSES...... 19 13.1. Humanistic Measures ...... 19 13.2. Resource Utilisation Measures ...... 19

14. CLINICAL PHARMACOLOGY DATA ANALYSES...... 19 14.1. Pharmacokinetic Analyses...... 19 14.2. Pharmacodynamic Analyses...... 19 14.3. Pharmacokinetic/Pharmacodynamic Analyses...... 19

15. BIOMARKER DATA ANALYSIS...... 19

16. PHARMACOGENETIC DATA ANALYSES...... 19

17. VIRAL GENOTYPING/PHENOTYPING ...... 20

18. REFERENCES...... 21

19. ATTACHMENTS ...... 22 19.1. Table of Contents for Data Display Specifications...... 22 19.2. Data Display Specifications ...... 25

256 CONFIDENTIAL RM2007/00260/00 VLX105832

CONFIDENTIAL RM2006/00617/00 VLX105832

ABBREVIATIONS

AE Adverse Event ALT Alanine Aminotransferase BID Twice Daily CIB Clinical Investigator Brochure CRF Case Report Form FDA Food & Drug Administration GCSP Global Clinical Safety and Pharmacovigilance GSK GlaxoSmithKline GW Glaxo Wellcome HSV Herpes Simplex Virus HSV-1 Herpes Simplex Virus Type 1 HSV-2 Herpes Simplex Virus Type 2 IEC International Ethics Committee IRB Institutional Review Board ITT Intent-to-Treat LLN Lower Limit of Normal NSS No Signs or Symptoms PCR Polymerase Chain Reaction PP Per Protocol QD Once Daily RAP Reporting and Analysis Plan SAE Serious Adverse Event SD Standard Deviation ULN Upper Limit of Normal

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies VALTREX

257 CONFIDENTIAL RM2007/00260/00 VLX105832

CONFIDENTIAL RM2006/00617/00 VLX105832

1. INTRODUCTION

This Reporting and Analysis Plan (RAP) is written for use by project team members within GlaxoSmithKline (GSK) only.

This RAP represents a plan for the analysis of data arising from study VLX105832 for the purposes of submission to the relevant regulatory authorities and for publication.

In this RAP, references are made to the following study document: Protocol VLX105832 (14 October 2005)

This RAP conforms to the following GSK international standard agreements:

Document Standard DS-WWD-4000 v03 Reporting and Analysis Plans 11November 2005

Standard Operating Procedure SOP-WWD-4000 v02 Development, Review and Approval of Reporting and Analysis Plans 24 August 2004

2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Study Objective(s)

Primary:

• To compare the effect of VALTREX™ 1g administered once daily for 60 days vs. placebo on total HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection.

Secondary:

• To compare the effect of VALTREX 1g administered once daily for 60 days vs. placebo on subclinical HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. To evaluate the safety of VALTREX 1g administered once daily for 60 days in immunocompetent HSV-2 seropositive subjects newly diagnosed with HSV-2 infection.

2.2. Study Endpoint(s)

Primary Endpoint:

• Mean percent of days with shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2

258 CONFIDENTIAL RM2007/00260/00 VLX105832

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Secondary Endpoints:

• Mean percent of days with subclinical HSV-2 shedding (shedding in the absence of genital lesions) • Mean percent of days with clinical HSV-2 shedding (shedding in the presence of genital lesions) • Proportion of subjects with no shedding • Proportion of subjects with at least one genital herpes recurrence • Time to first genital herpes recurrence

Other Endpoints:

• Time to first oral herpes recurrence Among subjects with a recurrence on study who do not respond to 3 days of episodic treatment (valacyclovir 500mg twice daily), the percent of HSV-2 isolates resistant to acyclovir will be tabulated.

2.3. Statistical Hypotheses

The primary endpoint is the percentage of days with HSV-2 viral shedding over 60 days, which will be compared between the VALTREX and placebo treatment groups. This study is designed to show superiority of VALTREX over placebo.

Ho: There is no difference in the percentage of days with HSV-2 shedding while taking suppressive Valtrex therapy compared to while taking placebo.

Ha: There is a reduction in the percentage of days with HSV-2 shedding while taking suppressive Valtrex therapy versus taking placebo.

Hypothesis tests of treatment differences will be conducted at the two–sided, 5% level of significance. Estimates of treatment difference and percent reduction will be calculated.

2.4. Pharmacokinetic (PK) and PK/Pharmacodynamic (PD) hypotheses

No pharmacokinetic or pharmacodynamic data are collected in this study.

3. STUDY DESIGN

This will be a randomized, double-blind, placebo-controlled, multicenter, two-way crossover study. Subjects will be randomized to receive VALTREX 1g or matching placebo once daily for 60 days in a two-way crossover design. There will be a washout period of seven days between Treatment Periods. Subjects will receive open-label Valtrex for treatment of an outbreak. Recurrences during the washout period will be treated the seven day washout period will be restarted.

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A central randomization will be employed.

4. PLANNED ANALYSES

4.1. Interim Analyses

There are no planned interim analyses.

4.2. Final Analysis

The final analysis will be carried out after database freeze (i.e., after the database has been authorized). Just prior to database freeze, the Project Statistician will be notified that there are no outstanding data clarification requests (DCRs) and that the data are considered fully “clean”. At this stage the Project Statistician will release the treatment plan (random allocation details for each subject) which will be merged with other treatment details, allowing the database to be authorized.

5. SAMPLE SIZE CONSIDERATIONS

ASSUMPTIONS:

In the shedding substudy of HS2AB3009, a suppression study of 500 mg QD VALTREX versus placebo, the mean percent days of total HSV-2 shedding in the 7 placebo subjects with less than one year duration of infection was 18.5%, considerably higher than the 9.6% in the 43 placebo subjects with one year or more duration of infection. However, given the small number of placebo subjects with less than one year duration of infection, the shedding rates for subjects with one year or longer duration of infection were conservatively used to design this study.

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In this crossover study, 47 completed subjects provide over 90% power to detect a reduction in the mean percent days of total HSV-2 shedding from 9.6% in the placebo treatment phase to 2.8% in the VALTREX treatment phase, assuming standard deviations of 9.8% and 5.6%, respectively, and a correlation of 0.4.

Subclinical shedding (shedding in the absence of genital lesions) is also of importance. Forty-seven completed subjects provide 90% power to detect a reduction in the mean percent days with subclinical HSV-2 shedding from 7.0% in the placebo treatment phase to 2.8% in the VALTREX treatment phase, assuming standard deviations of 9.3% and 5.4%, respectively, and a correlation of 0.4.

SENSITIVITY:

If the within subject correlation is reduced to 0.3, the standard deviation of treatment differences will increase. For the percent days of total HSV-2 shedding, the power to detect a reduction remains over 90%. For the percent days of subclinical shedding, the power is reduced to 86%.

If the assumed treatment difference is reduced by 0.5% but the assumptions regarding variability remain the same, the power to detect a reduction in percent days of total HSV- 2 shedding remains over 90% but the power to detect a reduction in the percent days of subclinical shedding is reduced to 81%.

If only 40 subjects complete the study, the power to detect a reduction in percent days of total HSV-2 shedding remains over 90% but the power to detect a reduction in the percent days of subclinical shedding is reduced to 84%.

If there is a significant residual effect in the cross-over analysis, only the first period data can be used to provide an unbiased test of the treatment difference. If only 50 patients complete the first period, the power to detect a reduction in percent days of total HSV-2 shedding with first period data is 84% but the power to detect a reduction in the percent days of subclinical shedding is reduced to 48%.

RE-ESTIMATION:

If the dropout rate is higher than anticipated then the enrollment size may be increased to ensure that 47 subjects complete the study.

6. ANALYSIS POPULATIONS

There will be three populations considered in the analysis:

1. Intent-to-Treat (ITT) Exposed Population: The ITT Exposed population is defined as consisting of all subjects with evidence of HSV-2 who received at least one dose of investigational product and at least one safety and/or efficacy evaluation. This will be the primary population for assessing safety and a secondary population for assessing efficacy in the first Treatment Period. Note that subjects inadvertently

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enrolled into the study who later are confirmed not to have HSV-2 will be excluded from the ITT population. 2. Intent-to-Treat Crossover (ITTC) Population: The ITT Crossover population is defined as consisting of all subjects in the ITT population who have at least one PCR swabbing result in each Treatment Period. This will be the primary population for assessing efficacy. 3. Per Protocol Population (PP): This population will include all subjects who completed the study without a major protocol violation and have PCR data on at least 85% of days on study. This will be the secondary population for assessing the primary and secondary efficacy endpoints.

7. TREATMENT COMPARISONS

The primary endpoint is the percentage of days with HSV-2 viral shedding. The objective of the study is to compare the effect of Valtrex 1g once daily for 60 days vs. placebo of the percentage of days with HSV-2 viral shedding. Thus the treatment comparison is daily suppressive Valtrex 1g QD versus placebo.

7.1. Data Display Treatment and Other Sub-group Descriptors

The daily suppressive Valtrex 1g arm will be denoted as “Valtrex 1g QD” in all tables and the daily Placebo arm will be denoted as “Placebo” in all tables.

For subgroups, they will be denoted as such:

• Gender – “Females” and “Males” • Age (<=30/>30) – “Age<=30” and “Age>30” • Race – “Caucasian” and “Non-Caucasian”

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES

8.1. Multicentre Studies

Formal examination of center (investigator) effects is not planned, unless a site enrolls more than 25% of subjects in the study.

8.2. Other Strata and Covariates

The randomization was not stratified by any covariate, and none of the analyses will be adjusted for any stratification factor.

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8.3. Examination of Subgroups

Subgroups of interest are: gender, age (<=30/>30), and race (caucasian/non-caucasian). The primary and secondary endpoint summaries will be provided for the following subgroups: gender, age (<=30/>30), and race (caucasian/non-caucasian).

8.4. Multiple Comparisons and Multiplicity

Multiplicity is not a major issue as there is one primary endpoint and two treatments.

There are multiple secondary endpoints and multiple subpopulations of interest, but each will be examined on its own in separate analyses and with respect to its effect on the endpoint, without adjustment for multiplicity.

9. DATA HANDLING CONVENTIONS

9.1. Premature Withdrawal and Missing Data

Premature Withdrawal:

Subjects who prematurely withdraw from the study will not be included in the Per Protocol Population. They will, however, be candidates for inclusion in the Intent-to- Treat Exposed Population, and the Intent-to-Treat Crossover Population.

Missing PCR Data:

In the primary analyses, missing PCR data (e.g., swabbing not done or assay result not available) will not be imputed, regardless of lesion status. If the swab is missing for any reason, then the subject’s shedding status will be missing for that day and will be excluded from both the numerator and denominator of percent days with shedding and mean average log HSV-2 DNA copy number calculations.

However, if swabbing results are present but the date the swabbing was performed is missing, and if a subject has only one missing date within the genital swab data, then the PCR data with the missing date can be inferred with certainty to belong to that date. If a subject has more than one date missing, but there is documentation that the subject did not have a recurrence during the time period the swab was collected, then those swabbing results will be used. In any other situation, no dates will be inferred and the PCR data with the missing dates will be ignored.

Missing Lesion Status Data:

The lesion status (clinical/subclinical) of each day is determined by two dates, the clinically confirmed “recurrence onset” and “heal" dates captured in the CRF.

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If no recurrence onset date is present for the entire study, then all days on study are considered subclinical.

If at least one recurrence onset date is present, then all days prior to the first onset date are considered subclinical. If a heal date is missing, then the official heal date for this recurrence will be imputed to be the earliest of the following: 6 days after the onset, the date of withdrawal, the date the subject completes the study, or the date of a subsequent recurrence. Six days after the onset date (a duration of 7 days) is used conservatively based on the median durations of episode from past studies of 3-day episodic therapy, which generally ranged 4 to 4.5 days.

All days from and including onset date through the corresponding official heal date inclusive will be considered clinical and all days after the corresponding official heal date until the next recurrence onset date or the subject completes or withdraws from the study, will be considered subclinical.

9.2. Derived and Transformed Data

The derived and transformed endpoints will be discussed in detail in the Efficacy Analyses section.

9.3. Assessment Windows

PCR measurements will be taken every day for the entire duration of the study (approximately 127 days). There will be eight routine study visits, at days 15, 30, 45, and 60 during each of the two Treatment Periods, to collect and/or dispense additional drug, and to review e-Diary data. There will be a +/- 5 day window for these eight visits. If a subject experiences an outbreak, (s)he must return to the clinic within 24 hours of experiencing signs/symptoms of a GH outbreak, for confirmation of the outbreak. At the end-of-treatment period visits (day 60 of each Treatment Period), hematology, clinical chemistry and urinalysis evaluations will be conducted. The end-of-study visit (day 60 of Treatment Period 2) will also be used to review remaining e-Diary data, collect unused study medications, and record end-of-study results.

9.4. Values of Clinical Concern

Threshold laboratory values of clinical concern are listed in Section 12.7.

10. STUDY POPULATION

The study population will consist of male and female subjects > 18 years of age, immunocompetent and in general good health. Subjects must be randomized within 4 months of the initial diagnosis of GH, or be newly diagnosed with a first recognized episode of genital herpes at the screening visit.

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10.1. Disposition of Subjects

The following summaries will be prepared:

Summary of Populations: For each treatment sequence and total, the number of subjects randomized, the number of subjects in the Intent-to-Treat Exposed Population, the number of subjects in the Intent-to-Treat Crossover Population, and the number of subjects in the Per Protocol Population.

Summary of Enrollment: For each treatment sequence and total, the number of subjects enrolled by each investigator

Summary of Investigational Product Status: For each treatment sequence and total, the number of subjects who completed study on investigational product, prematurely discontinued investigational product and the number of subjects by reasons for discontinuing investigational product. Subjects will be summarized based upon the treatment that the subject was taking at the time of discontinuation. A similar summary for each Treatment Period will also be prepared.

Summary of Subject Disposition: For each treatment sequence and total, the number of subjects who completed the study, the number of subjects who withdraw from the study, and the number of subjects by reason for these discontinuations. A listing of subjects for whom the treatment blind was broken during the study will be presented. Subjects will be summarized based upon the treatment that the subject was taking at the time of withdrawal. A similar summary for each Treatment Period will also be prepared.

Listings of the Investigational Product Discontinuation Record and Premature Withdrawals will also be presented.

10.2. Protocol Deviations

A summary of the number of subjects who entered the study but deviated from the inclusion or exclusion criteria will be prepared. A summary of major protocol deviations leading to exclusion from the Per Protocol population will also be prepared. A listing of the inclusion/exclusion criteria deviation record for all subjects with deviations will be presented.

Any unforeseen circumstance occurring during the study period will be reviewed in a blinded fashion to determine whether it constitutes a major protocol deviation. In particular the database will be examined to check for the following deviations:

• Evidence of failure to satisfy inclusion/exclusion criteria as recorded by the investigator. • Failure to visit doctor for on-treatment visits (Visits 3-5 and 7-9) within the desired window, or failure to return for end-of-treatment period visits (Visits 6 and 10). • PCR data on less than 85% of swabbing days

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• Failure to comply with dosing regimen. Compliance of less than 80% will be considered a major deviation. • Subject took at least one of the unapproved drugs listed in the protocol.

10.3. Demographic and Baseline Characteristics

Demographics

For each treatment sequence and total, continuous variables, including age, height and weight, will be summarized by mean, standard deviation (SD), median, minimum (min), and maximum (max).

For each treatment sequence and total, categorical variables, including sex, ethnicity, and race, will be summarized by the number and percentage in each possible category on the CRF.

Demographics will be summarized for the three analysis populations defined in Section 6.

A by-subject listing of demographic characteristics will be presented.

Current medical conditions

For each treatment sequence and total, the number and percentage of subjects with concurrent medical conditions will summarized by MedDRA System Organ Class.

Concomitant medications

For each treatment group, concomitant medications will be coded using GSK Drug. The number and percentage of subjects taking concomitant medications will be summarized by GSK-Drug Anatomical Therapeutic Chemical (ATC) classification level 1 (Body System) and ingredient. Concomitant medications started prior to randomization that continued post-randomization will be assigned to the treatment(s) of each period in which the subjects continued to take them.

Acyclovir Resistance

Pre-and post-treatment isolates from subjects not responding to three days of episodic treatment will be analyzed for sensitivity to acyclovir, and the percent of isolates resistant to acyclovir will be presented.

10.4. Treatment Compliance

Treatment compliance will be summarized for both the suppressive (blinded) treatment and the open-label treatment, if applicable. Compliance for each treatment will be calculated as such regarding caplet numbers:

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(number dispensed – number returned)/(number should have taken for treatment) where ‘number should have taken for treatment’ is determined by the number of days on the treatment and the number of caplets per day required for each treatment.

11. EFFICACY ANALYSES

Each subject’s study day will be classified by PCR as either ‘shedding’ (i.e., positive HSV-2 result from the daily swab(s)), ‘no shedding’ (i.e., negative HSV-2 result from the daily swab(s)), or ‘unknown’ (swabbing not done or assay result not available). If either the daily genital swab or a lesion swab are positive, the day will be classified as ‘shedding’. In addition, each study day will be classified as either ‘clinical’ (i.e., investigator-confirmed presence of genital lesions) or ‘subclinical’ (i.e. no genital lesions) by the investigator during recurrence visits.

11.1. Primary Efficacy Analysis(es)

Percent of days with HSV-2 shedding will be defined for each subject as the percent of days with PCR data for which HSV-2 shedding was detected by a positive PCR result, i.e., the number of days with HSV-2 PCR shedding divided by total number of days with PCR data, multiplied by 100.

The objective of the study is to compare the effect of VALTREX 1 g QD for 60 days vs. placebo on total HSV-2 shedding. The primary endpoint is the percent of days with HSV-2 viral shedding over 60 days. This comparison will be tested using a Wilcoxon rank-sum test at the 5% level of significance in the ITT Crossover population, after first testing for the equality of residual effects using a Wilcoxon rank-sum test at the 5% level of significance [Koch, 1972]. Mean percent of days with HSV-2 shedding will be the statistic used to summarize this endpoint for each treatment group.

To test for equality of residual effects, first calculate the sum of the mean percent of days with HSV-2 viral shedding across both Treatment Periods for each subject. The subjects’ sums are then compared between each treatment sequence using a Wilcoxon rank-sum test. If this test is not significant, then the treatment comparison is tested on the difference between each subject’s pair of treatment period measurements for percent of days with HSV-2 viral shedding. The test of period differences will also be carried out with a Wilcoxon rank-sum test.

If the test for equality of residual effects is significant, then treatment differences can only be assessed using the Treatment Period 1 data of the ITT Exposed population as if the study were a one-period parallel design. The percent of days with HSV-2 viral shedding in Treatment Period 1 would be compared between treatments using a Wilcoxon rank-sum test at the 5% level of significance. This analysis will be carried out as a supporting analysis in any case.

Summaries of the primary endpoint will also be provided for the following subgroups: gender, age (<=30/>30), and race (caucasian/non-caucasian).

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11.2. Secondary Efficacy Analysis(es)

Each day subjects took one combined swab of the genital area and the anal/rectal areas. During a recurrence, a swab of the lesion was also collected in the clinic. If there are multiple swabs for a day (e.g. a subject mistakenly collected multiple swabs on a day or if there is a clinic-collected swab in addition to a subject-collected swab), the maximum of the multiple PCR measurements for the day will be used. If low-quantity positive DNA copy numbers are present that are unable to be typed (HSV-1 or HSV-2) by the lab, it will be considered to be no shedding.

• Percent of days with subclinical HSV-2 shedding - The percent of days with subclinical HSV-2 shedding is defined as the percent of all days with PCR data for which subclinical HSV-2 shedding was detected (shedding in the absence of a genital lesion). Mean percent of days with subclinical HSV-2 shedding will be the statistic used to summarize this endpoint for each treatment group. • Percent of days with clinical HSV-2 shedding - The percent of days with clinical HSV-2 shedding is defined as the percent of all days with PCR data for which clinical HSV-2 shedding was detected (shedding in the presence of a genital lesion). Mean percent of days with clinical HSV-2 shedding will be the statistic used to summarize this endpoint for each treatment group. • Proportion of subjects with no shedding – The proportion of subjects with no shedding is defined as the number of subjects with no HSV-2 shedding detected by PCR divided by the total number of subjects with PCR data in the Treatment Period. • Proportion of subjects with at least one genital herpes recurrence – The proportion of subjects with at least one genital herpes recurrence is defined as the number of subjects with at least one investigator-confirmed genital herpes recurrence divided by the total number of subjects with at least one clinic visit in the Treatment Period. • Time to first genital herpes recurrence will be evaluated in the ITT-Exposed population with the Treatment Period 1 data using Kaplan-Meier estimates of investigator-confirmed genital herpes recurrences censoring the data from subjects who prematurely discontinue the study at the time of discontinuation. Percent of days with subclinical HSV-2 shedding and percent of days with clinical shedding will be compared using a Wilcoxon rank-sum test, after first testing for the equality of residual effects as described in Section 11.1. Treatment differences in the proportion of subjects with no shedding and the proportion of subjects with at least one genital herpes recurrence will be tested using a Fisher’s exact test and Prescott’s method [Senn, 2002]. Time to first genital herpes recurrence will be tested using the log rank test.

Summaries of the secondary endpoints will also be provided for the following subgroups: gender, age (<=30/>30), and race (caucasian/non-caucasian).

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11.3. Other Efficacy Analysis(es)

All primary and secondary endpoints will also be analyzed in the Per Protocol population. Analyses of the primary and secondary endpoints using the first Treatment Period data of the Intent-to-Treat Exposed population will also be carried out as supporting analyses.

Time to first oral herpes recurrence will be evaluated in the ITT-Exposed population and the Per Protocol population with the Treatment Period 1 data using Kaplan-Meier estimates of all investigator-confirmed oral herpes recurrences censoring the data from subjects who prematurely discontinue the study at the time of discontinuation.

Among subjects not responding to 3 days of episodic treatment, the percent of HSV-2 isolates resistant to acyclovir will be tabulated.

Four additional ad hoc endpoints will be analyzed in both the ITTC and the PP populations:

• Percent of clinical days with HSV-2 shedding - The percent of clinical days with HSV-2 shedding is defined as the percent of clinical days with PCR data for which HSV-2 shedding was detected. Mean percent of clinical days with HSV- 2 shedding will be the statistic used to summarize this endpoint for each treatment group. Note that only subjects with clinical days are evaluable for this endpoint. • Percent of subclinical days with HSV-2 shedding - The percent of subclinical days with HSV-2 shedding is defined as the percent of subclinical days with PCR data for which HSV-2 shedding was detected. Mean percent of subclinical days with HSV-2 shedding will be the statistic used to summarize this endpoint for each treatment group. Note that only subjects with subclinical days are evaluable for this endpoint. • Average log HSV-2 DNA copy number per day on days with subclinical shedding - The daily maximum HSV-2 DNA copy number will be log transformed and averaged over all subclinical shedding days. Note that only subjects with subclinical shedding are evaluable for this endpoint. • Average log HSV-2 DNA copy number per day on days with shedding (clinical and subclinical) - The daily maximum HSV-2 DNA copy number will be log transformed and averaged over all shedding days. Note that only subjects with shedding are evaluable for this endpoint. Mean average log HSV-2 DNA copy number per day will be the statistic used to summarize the two HSV-2 DNA copy number endpoints above for each treatment group.

Percent of days with total shedding, percent of clinical days with HSV-2 shedding, percent of subclinical days with HSV-2 shedding, average log HSV-2 DNA copy number per day on days with subclinical shedding, and average log HSV-2 DNA copy number per day on days with total shedding will be compared using a Wilcoxon rank-sum test, after first testing for the equality of residual effects as described in Section 11.1.

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For any subjects who received VALTREX in Treatment Period 1 and inadvertently skip Washout and progress directly to Treatment Period 2, a sensitivity analysis of the primary endpoint will be carried out, ignoring the first 7 days of Treatment Period 2. The primary analysis for which Treatment Period 2 begins with the initiation of study medication in Treatment Period 2 is conservative because it provides the benefit of the residual effect of 7 days of VALTREX to a Treatment Period 2 placebo treatment. Thus any bias created should favor placebo.

12. SAFETY ANALYSES

12.1. Extent of Exposure

Extent of exposure to randomised treatment will be calculated as the sum of the times from the start to the end of each Treatment Period, less any periods of open-label treatment for HSV recurrences.

The number of subjects taking any double-blind treatment and the number of days of double-blind treatment taken (as calculated above) will be summarised by treatment group. Similarly, the number of subjects taking any open-label treatment and the number of days of open-label treatment taken will be summarised by treatment group. In addition, the cumulative dose during the study will be summarized. Exposure data will also be listed.

12.2. Adverse Events

Full details of all adverse events will be listed. Adverse events will be coded using the MedDRA dictionary and grouped by MedDRA System Organ Classes (SOC) and preferred term. The summary of the number and percent of subjects with all adverse events, drug-related adverse events, and adverse events leading to the discontinuation of study drug will be displayed by body system and preferred term for each treatment arm. Additionally, summaries by subgroups (age≤=30/age>30, gender, and race) will be provided.

A listing of the hierarchical relationship between MedDRA SOCs, preferred terms and verbatim text of the adverse events in this study will be provided. A listing of which subjects reported individual adverse events grouped by preferred term and sorted by SOC will be provided.

12.3. Deaths and Serious Adverse Events

All serious adverse events (SAEs) will be summarized as described in Section 12.2. All deaths during the study will be listed. In addition, by-subject listings of all fatal adverse events and all non-fatal serious adverse events will be presented.

12.4. Device Incidents and Near Incidents

This study does not include a medical device.

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12.5. Adverse Events Leading to Discontinuation of Investigational Product and/or Withdrawal from the Study and Other Significant Adverse Events

Adverse events leading to discontinuation of study drug and/or withdrawal from the study will listed and summarized as described in Section 12.2. In addition, by-subjects listings of adverse events leading to premature discontinuation from the study, treatment-limiting adverse events, and adverse events that were marked laboratory abnormalities will be presented.

12.6. Pregnancies (as applicable)

Pregnancies will be listed individually in the study report.

12.7. Clinical Laboratory Evaluations

Summary statistics will be produced for Clinical Chemistry and Hematology laboratory values at baseline, at the post treatment visit and for change from baseline. Laboratory values will be converted to standard international (SI) units and summarized by mean, SD, median, min, and max. Full Chemistry and Hematology panels were analyzed and will be evaluated.

Clinical laboratory values will be assessed for post-dose changes from baseline to values outside these pre-defined threshold values.

Threshold limits:

Measure Change Category

CLINICAL CHEMISTRY Alkaline phosphatase To >1.50xULN ALT To >2.00xULN AST To >2.00xULN Creatinine To >1.50xULN

HEMATOLOGY Hemoglobin To <0.8xLLN Neutrophils To <0.8xLLN Platelets < 100,000/mm**3 WBC To <0.75xLLN

Shifts will be taken to the worst post-treatment value. The number of subjects counted as having a change to a threshold value will include subjects outside the threshold at baseline who got worse by any degree during the trial but not those who improved.

In addition, shifts relative to the normal range will also be calculated. The number of subjects calculated as shifting to high will consist of those subjects with a normal or low

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A listing of laboratory data for subjects with laboratory values outside the threshold limits of clinical concern at any time during the study will be presented.

12.8. Other Safety Measures

No other safety measures were collected.

13. HEALTH OUTCOMES ANALYSES

13.1. Humanistic Measures

No health outcomes measures were collected.

13.2. Resource Utilisation Measures

No health outcomes measures were collected.

14. CLINICAL PHARMACOLOGY DATA ANALYSES

14.1. Pharmacokinetic Analyses

No clinical pharmacology data were collected.

14.2. Pharmacodynamic Analyses

No clinical pharmacology data were collected.

14.3. Pharmacokinetic/Pharmacodynamic Analyses

No clinical pharmacology data were collected.

15. BIOMARKER DATA ANALYSIS

No biomarker data were collected.

16. PHARMACOGENETIC DATA ANALYSES

No pharmacogenetics data were collected.

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17. VIRAL GENOTYPING/PHENOTYPING

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18. REFERENCES

Koch G. The Use of Non-parametric Methods in the Statistical Analysis of the Two- Period Change-Over Design. Biometrics. 1972;328:579-584.

Senn S. Crossover Trials in Clinical Trial Research. 2nd ed. England:John Wiley and Sons; 2002.

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19. ATTACHMENTS

19.1. Table of Contents for Data Display Specifications

Study Population and Baseline Characteristics

6.1 Summary of Subjects Randomized by Investigator 6.2 Summary of Study Populations 6.3 Summary of Subject Disposition 6.4 Summary of Subject Disposition by Period 6.5 Summary of Investigational Product Status 6.6 Summary of Investigational Product Status by Period 6.7 Summary of Inclusion/Exclusion Criteria Deviations 6.8 Summary of Major Protocol Deviations Leading to Exclusion from the Per Protocol Population 6.9 Summary of Demographic Characteristics (ITT) 6.10 Summary of Race and Racial Combinations (ITT) 6.11 Summary of Demographic Characteristics (ITTC) 6.12 Summary of Race and Racial Combinations (ITTC) 6.13 Summary of Demographic Characteristics (PP) 6.14 Summary of Race and Racial Combinations (PP) 6.15 Summary of Current Medical Conditions 6.16 Summary of Concomitant Medications by Ingredient ATC Level 1 6.17 Relationship Between ATC Level 1, Ingredient and Verbatin Text 6.18 Summary of Treatment Compliance – Suppression Treatment 6.19 Summary of Treatment Compliance – Open-Label Treatment

Efficacy

7.1 Summary of Percent of Days with HSV-2 Viral Shedding (ITTC) 7.2 Summary of Percent of Days with HSV-2 Viral Shedding (PP) 7.3 Summary of Percent of Days with HSV-2 Viral Shedding in First Treatment Period (ITT) 7.4 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC) 7.5 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding (PP) 7.6 Summary of Percent of Days with Subclinical HSV-2 Viral Shedding in First Treatment Period (ITT)

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7.7 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC) 7.8 Summary of Percent of Days with Clinical HSV-2 Viral Shedding (PP) 7.9 Summary of Percent of Days with Clinical HSV-2 Viral Shedding in First Treatment Period (ITT) 7.10 Summary of Proportion of Subjects With No Shedding (ITTC) 7.11 Test of Proportion of Subjects With No Shedding (ITTC) 7.12 Summary of Proportion of Subjects With No Shedding (PP) 7.13 Test of Proportion of Subjects With No Shedding (PP) 7.14 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) 7.15 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) 7.16 Summary of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) 7.17 Test of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) 7.18 Summary of Time to First Genital Herpes Recurrence (ITT) 7.19 Summary of Time to First Genital Herpes Recurrence (PP) 7.20 Summary of Time to First Oral Herpes Recurrence (ITT) 7.21 Summary of Time to First Oral Herpes Recurrence (PP) 7.22 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (ITTC) 7.23 Summary of Percent of Clinical Days with HSV-2 Viral Shedding (PP) 7.24 Summary of Percent of Clinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT) 7.25 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (ITTC) 7.26 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding (PP) 7.27 Summary of Percent of Subclinical Days with HSV-2 Viral Shedding in First Treatment Period (ITT) 7.28 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (ITTC) 7.29 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days (PP) 7.30 Summary of Average Log DNA Copy Number Per Day on Subclinical Shedding Days in First Treatment Period (ITT) 7.31 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (ITTC) 7.32 Summary of Average Log DNA Copy Number Per Day on All Shedding Days (PP)

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7.33 Summary of Average Log DNA Copy Number Per Day on All Shedding Days in First Treatment Period (ITT) 7.34 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (ITTC) 7.35 Summary by Subgroups of Percent of Days with HSV-2 Viral Shedding (PP) 7.36 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (ITTC) 7.37 Summary by Subgroups of Percent of Days with Subclinical HSV-2 Viral Shedding (PP) 7.38 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (ITTC) 7.39 Summary by Subgroups of Percent of Days with Clinical HSV-2 Viral Shedding (PP) 7.40 Summary by Subgroups of Proportion of Subjects With No Shedding (ITTC) 7.41 Summary by Subgroups of Proportion of Subjects With No Shedding (PP) 7.42 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (ITTC) 7.43 Summary by Subgroups of Proportion of Subjects With At Least One Genital Herpes Recurrence (PP) 7.44 Summary by Subgroups of Time to First Genital Herpes Recurrence (ITT) 7.45 Summary by Subgroups of Time to First Genital Herpes Recurrence (PP) 7.46 Percent of HSV-2 Isolates Resistant to Acyclovir Among Subjects Not Responding to 3 Days of Episodic Treatment

Safety and Exposure

8.1 Summary of Exposure to Study Drug – Suppression Treatment 8.2 Summary of Exposure to Study Drug – Open-label Treatment 8.3 Summary of All Adverse Events 8.4 Summary of Drug-Related Adverse Events 8.5 Summary of Adverse Events Leading to Permanent Discontinuation of Study Drug or Withdrawal from Study 8.6 Summary of Serious Adverse Events 8.7 Summary of Adverse Events by Demographic Subgroups 8.8 Relationship of Adverse Event Body Systems, Preferred Terms, and Verbatim Text 8.9 Summary of Clinical Chemistry Data 8.10 Summary of Clinical Chemistry Data Outside the Reference Range 8.11 Summary of Clinical Chemistry Data Outside the Threshold Values

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8.12 Summary of Hematology Data Outside the Reference Range 8.13 Summary of Hematology Data Outside the Threshold Values

Data Listings

1. Listing of End of Study Record 2. Listing of Subjects for Whom the Treatment Blind was Broken During the Study 3. Listing of Inclusion/Exclusion Criteria Deviation Records 4. Listing of Subjects Excluded from Primary Efficacy Analysis 5. Listing of Demographic Characteristics 6. Listing of Concomitant Medications 7. Listing of Genital Herpes Recurrences 8. Listing of Exposure Data 9. Listing of Investigational Product Compliance 10. Listing of Investigational Product Discontinuation Record 11. Listing of Shedding Data 12. Listing of Subject Numbers for Individual Adverse Events 13. Listing of All Adverse Events 14. Listing of Drug-Related Adverse Events 15. Listing of Fatal Adverse Events 16. Listing of Non-Fatal Serious Adverse Events 17. Listing of Other Significant Adverse Events 18. Listing of HSV-2 Inhibition Assay Data 19. Listing of Clinical Laboratory Data for Subjects with Abnormalities of Clinical Concern 20. Listing of Databased e-Diary Data

Figures

7.1 Time to First Genital Herpes Recurrence (ITT) 7.2 Time to First Genital Herpes Recurrence (PP) 7.3 Time to First Oral Herpes Recurrence (ITT) 7.4 Time to First Oral Herpes Recurrence (PP)

19.2. Data Display Specifications

The VLX105832 data display specifications will be located in separate documents, RAP table shells and RAP listing shells on the Valtrex Clinical Trials Lotus Notes Database.

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Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol

Title: The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection

Compound Number: GW282358

Effective Date: 14-OCT-2005 Description:

The primary endpoint is the mean percent of days of total shedding as determined by type-specific PCR assay for HSV-2.

Subjects will complete diaries to record relevant study information.

Subject: Genital herpes, viral shedding

Author(s): A, Medicine Development Center, Infectious Diseases, North America, Medicine Development Center, Infectious Diseases, North America, Biomedical Data Sciences, US Medical Affairs

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SPONSOR INFORMATION PAGE

Clinical Study Identifier: VLX105832

GlaxoSmithKline Five Moore Drive P.O. 13398 Research Triangle Park, NC 27709-3398, USA Telephone:

Sponsor Contact Information:

Senior Study MD, Medical Monitor Manager Telephone:

Telephone:

Regulatory Agency Identifying Number(s): IND 34,526

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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

Investigator Name: ______

Investigator Signature Date

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TABLE OF CONTENTS

Page ABBREVIATIONS ...... 8 PROTOCOL SUMMARY ...... 9 1. INTRODUCTION ...... 13 1.1. BACKGROUND ...... 13 1.2. RATIONALE ...... 14 2. OBJECTIVE(S) ...... 15 2.1. PRIMARY ...... 15 2.2. SECONDARY ...... 15 3. ENDPOINT(S) ...... 15 3.1. PRIMARY ...... 15 3.2. SECONDARY ...... 15 3.3. OTHER ENDPOINTS ...... 15 4. STUDY DESIGN ...... 15 5. STUDY POPULATION...... 17 5.1. NUMBER OF SUBJECTS ...... 18 5.2. ELIGIBILITY CRITERIA ...... 18 5.2.1. Inclusion Criteria ...... 18 5.2.2. Exclusion Criteria ...... 19 5.2.3. Other Eligibility Criteria Considerations ...... 19 6. STUDY ASSESSMENTS AND PROCEDURES ...... 20 6.1. SCREENING VISIT ...... 20 6.2. RANDOMIZATION VISIT ...... 21 6.3. ROUTINE STUDY VISITS ...... 21 6.4. WASHOUT PERIOD ...... 22 6.4.1. Rationale for 7-day Washout Period ...... 22 6.4.2. Washout Period Procedures ...... 22 6.5. RECURRENCE VISIT ...... 22 7. SAFETY...... 23 7.1. PREGNANCY ...... 24 7.1.1. Time period for collecting pregnancy information ...... 24 7.1.2. Action to be taken if pregnancy occurs ...... 24 8. EFFICACY ...... 24 9. INVESTIGATIONAL PRODUCT(S) ...... 25 9.1. DESCRIPTION OF INVESTIGATIONAL PRODUCT...... 25

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9.2. DOSAGE AND ADMINISTRATION ...... 26 9.2.1. Double-Blind Treatment Periods 1 and 2 ...... 26 9.2.2. Open-label Treatment of Genital Herpes Recurrences ...... 26 9.3. DOSAGE ADJUSTMENTS ...... 26 9.4. DOSE RATIONALE ...... 27 9.5. BLINDING ...... 27 9.6. TREATMENT ASSIGNMENT ...... 28 9.7. PACKAGING AND LABELING ...... 28 9.8. HANDLING AND STORAGE ...... 28 9.9. PRODUCT ACCOUNTABILITY ...... 29 9.10. ASSESSMENT OF COMPLIANCE ...... 29 9.11. TREATMENT OF INVESTIGATIONAL PRODUCT OVERDOSE ...... 30 9.12. OCCUPATIONAL SAFETY ...... 30 10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ...... 31 10.1. PERMITTED MEDICATIONS ...... 31 10.2. PROHIBITED MEDICATIONS ...... 31 10.2.1. Pre-Study Prohibited Medications ...... 31 10.2.2. On-Study Prohibited Medications ...... 31 11. SUBJECT COMPLETION AND WITHDRAWAL ...... 31 11.1. SUBJECT COMPLETION ...... 31 11.2. SUBJECT WITHDRAWAL ...... 31 11.2.1. Subject Withdrawal from Study ...... 31 11.2.2. Subject Withdrawal from Investigational Product ...... 32 11.3. TREATMENT AFTER THE END OF THE STUDY ...... 32 12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) ...... 32 12.1. DEFINITION OF AN AE ...... 33 12.2. DEFINITION OF A SAE ...... 33 12.3. DISEASE-RELATED EVENTS ...... 34 12.4. SAES OF SPECIAL INTEREST ...... 35 12.5. CLINICAL LABORATORY ABNORMALITIES AND OTHER ABNORMAL ASSESSMENTS AS AES AND SAES ...... 35 12.6. TIME PERIOD, AND FREQUENCY OF DETECTING AES AND SAES . . 36 12.7. PROMPT REPORTING OF SAES TO GSK ...... 36 12.7.1. Timeframes for Submitting SAE Reports to GSK ...... 36 12.8. AE AND SAE DOCUMENTATION AND FOLLOW-UP PROCEDURES . . 36 13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...... 37 13.1. HYPOTHESES ...... 37 13.2. STUDY DESIGN CONSIDERATIONS ...... 37 13.2.1. Sample Size Assumptions ...... 37 13.2.2. Sample Size Sensitivity ...... 37

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13.2.3. Sample Size Re-estimation ...... 38 13.3. DATA ANALYSIS CONSIDERATIONS ...... 38 13.3.1. Analysis Populations ...... 38 13.3.2. Analysis Data Sets ...... 38 13.3.3. Treatment Comparisons ...... 38 13.3.4. Interim Analysis ...... 39 13.3.5. Key Elements of Analysis Plan ...... 39 14. STUDY CONDUCT CONSIDERATIONS ...... 40 14.1. REGULATORY AND ETHICAL CONSIDERATIONS, INCLUDING THE INFORMED CONSENT PROCESS ...... 40 14.2. QUALITY CONTROL (STUDY MONITORING) ...... 41 14.3. QUALITY ASSURANCE ...... 41 14.4. STUDY AND SITE CLOSURE ...... 42 14.5. RECORDS RETENTION ...... 42 14.6. PROVISION OF STUDY RESULTS AND INFORMATION TO INVESTIGATORS ...... 43 14.7. DATA MANAGEMENT...... 43 15. REFERENCES ...... 44 Appendices ...... 46 Appendix 1 Time and Events ...... 47 Appendix 2 Study Schematic Figure ...... 48 Appendix 3 Flowchart to Determine Subject Eligibility ...... 49 Appendix 4 Genital Herpes Lesion Stages ...... 51 Appendix 5 Decision Tree for Suspected TMA ...... 52 Appendix 6 Country Specific Requirements ...... 53

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ABBREVIATIONS

AE Adverse Event ALT (SGPT) Alanine Transaminase CrCl Creatinine Clearance CRF Case Report Form DNA Deoxyribonucleic acid FDA US Food and Drug Administration GCP Good Clinical Practice GH Genital Herpes GSK GlaxoSmithKline hCG Human Chorionic Gonadotropin HIV Human Immunodeficiency Virus HSV-2 Herpes Simplex Virus Type 2 HUS Hemolytic Uremic Syndrome ICF Informed Consent Form IEC Independent Ethics Committee IND Investigational New Drug Application IRB Institutional Review Board IUD Intrauterine Device MedDRA Medical Dictionary for Regulatory Activities mg milligram MSDS Material Safety Data Sheet PCR Polymerase chain reaction QD Once daily SAE Serious Adverse Event SrCr Serum Creatinine SRM Study Reference Manual STD Sexually Transmitted Disease TMA Thrombotic Microangiopathy TTP Thrombotic Thrombocytopenic Purpura VAL VALTREX, valacyclovir hydrochloride, valaciclovir

Trademarks

GSK Trademarks VALTREX

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PROTOCOL SUMMARY

Rationale

Genital herpes (GH) is most commonly caused by infection with herpes simplex virus type 2 (HSV-2) and is the most prevalent sexually transmitted disease (STD) in the United States [Cates, 1999; CDC, 2000]. Calculations based on recent survey data presented by Xu et. al. estimate 1 in 5 Americans, or approximately 45 million individuals, over the age of 14 years are infected with HSV-2 [Xu, 2004]. Up to 70% of genital herpes transmission occurs during periods of asymptomatic viral shedding, and asymptomatic shedding is considered to be the primary means of transmitting HSV to sexual partners and neonates [Mertz, 1992; Brown, 1991].

VALTREX™ (valacyclovir hydrochloride, valaciclovir) significantly reduces the frequency of total and asymptomatic viral shedding in subjects with recognized genital herpes infection [Barton, 1996; Patel, 1997; Gupta, 2004; Diaz-Mitoma, 1996; Wald, 1997; Straus, 1996] and has recently been approved for reduction in the risk of transmission of genital herpes in HSV-2 infected monogamous heterosexual couples [Corey, 2004]. Because recurrences are more frequent during the first year after initial HSV-2 infection [Benedetti, 1999], and there are no data available on the effect of VALTREX on viral shedding in subjects newly diagnosed with recurrent genital herpes, it is important to evaluate shedding patterns in this patient population.

The purpose of this study is to determine the efficacy and safety of VALTREX 1g once daily in reducing viral shedding in immunocompetent subjects newly diagnosed with recurrent genital herpes.

Objective(s)

Primary:

• To compare the effect of VALTREX 1g administered once daily for 60 days vs. placebo on total HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. Secondary:

• To compare the effect of VALTREX 1g administered once daily for 60 days vs. placebo on subclinical HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. • To evaluate the safety of VALTREX 1g administered once daily for 60 days in immunocompetent HSV-2 seropositive subjects newly diagnosed with HSV-2 infection.

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Endpoint(s)

Primary Endpoint

• Mean percent days of total shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2 Secondary Endpoint

• Mean % days subclinical shedding (no genital lesions present) • Mean % days clinical shedding (presence of genital lesions) • Proportion of subjects with no shedding • Proportion of subjects with at least one genital herpes recurrence • Time to first genital herpes recurrence Other Endpoints

• Time to first oral herpes recurrence • Among subjects with a recurrence on study who do not respond to 3 days of episodic treatment (valacyclovir 500mg twice daily), the percent of HSV-2 isolates resistant to acyclovir will be tabulated.

Study Design

This will be a randomized, double-blind, placebo-controlled, multicenter, two-way crossover study. Subjects will be randomized to receive VALTREX 1g or matching placebo once daily for 60 days in each of two Treatment Periods in a two-way crossover design. There will be a washout period of seven days between Treatment Periods.

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21 days 60 days 7 days 60 days

Washout Valtrex 1g QD Valtrex 1g QD

Placebo QD Placebo QD

Screening Visit Clinic Visits Clinic Visits 15 days apart 15 days apart

Randomization

Visit

Study Population

Approximately 66 subjects will be randomized at sites in North America to obtain a total of at least 47 subjects who complete the study.

Eligible subjects will be male or female, aged 18 years or older, immunocompetent and in general good health. Subjects must be randomized into the study within 4 months of the initial diagnosis of genital herpes, or be newly diagnosed with a first recognized episode of genital herpes at the screening visit. Subjects must have documented clinical signs and symptoms of genital HSV-2 infection, as well as laboratory confirmation of genital HSV- 2 infection to be eligible for the study (see Appendix 3).

Study Assessments

A typical subject’s total participation in this study will be approximately 148 days and will include the following: a screening evaluation (to be performed within 21 days of randomization), a randomization visit, and eight study visits (four visits per Treatment Period, with a 15-day interval between each visit). Once randomized, subjects will be required to attend the clinic for additional visits if they suspect they have a genital herpes recurrence. Upon confirmation of these recurrences, open-label study medication will be dispensed.

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During each 60-day Treatment Period and during washout, study subjects will be required to collect a daily swab from their genital/anal-rectal area for HSV-2 detection by polymerase chain reaction (PCR). During a genital herpes recurrence, swabs of the lesion also will be collected in the clinic for HSV-2 detection by culture and PCR.

Regardless of Treatment Period, subjects who experience a genital herpes recurrence during the study will temporarily discontinue their blinded study medication and receive open-label episodic treatment with VALTREX 500mg twice daily for 3 days, after which double-blind therapy will resume. All genital herpes recurrences must be at least at the macular/papular (erythema or elevation of skin without fluid) stage of development before open-label episodic treatment is initiated.

A genital examination must be conducted at the screening visit for subjects who present with genital herpes signs or symptoms. Genital exams also must be conducted at the randomization and genital herpes recurrence visits for all subjects. Adverse event and concomitant medication data will be collected throughout the study. HSV-1 and HSV-2 serology testing will occur at the screening visit. Hematology, clinical chemistry and urinalysis tests will be performed at the screening visit and at the end of each Treatment Period. Pregnancy (serum or urine hCG) tests will be performed at the start of the study and at the end of each Treatment Period.

Subjects will complete diaries to record study-related information.

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1. INTRODUCTION

1.1. Background

Genital herpes (GH) is most commonly caused by infection with herpes simplex virus type 2 (HSV-2) and is the most prevalent sexually transmitted disease (STD) in the United States [Corey, 2000; CDC, 2000]. The annual incidence rate of new infections is 1 million cases per year in the United States [Cates, 1999]. Genital herpes is characterized classically by painful, recurrent genital ulcers, although episodes may also manifest as blisters, erythema, swelling, excoriation or other similar clinical signs. It is estimated one in five Americans, approximately 45 million individuals, over the age of 14 years are infected with HSV-2 [Xu, 2004; GSK, Data on File]. Ninety percent (90%) of these individuals are unaware of their diagnosis, either because they do not have symptoms or, more often, because they have symptoms which go unrecognized [Fleming, 1997].

Although HSV is most contagious during active (visible) outbreaks, asymptomatic viral shedding is considered to be the primary means of transmitting HSV to sexual partners and neonates [Mertz, 1992; Brown, 1991]. Indeed, studies in couples discordant for HSV-2 infection have shown that transmission can occur even among partners who abstain from sexual contact during genital herpes recurrences (i.e., transmission occurs during a time when subjects are asymptomatic) and that 70% of transmission events took place when the source partner was asymptomatic [Mertz, 1988; Mertz, 1992]. Therefore, some experts now believe that the management of genital herpes and its transmission should focus on safer sex practices, including the use of condoms, in conjunction with antiviral therapy to reduce the number of genital herpes recurrences and reduce viral shedding. This approach potentially is applicable to any subject who has HSV-2 infection, independent of how long the subject has been infected, frequency of recurrences, or whether the subject has overt clinical signs and symptoms.

Viral shedding that occurs during the presence of genital herpes lesions is referred to as clinical shedding, while shedding that occurs in the absence of lesions is referred to as subclinical shedding. The terms, “subclinical” and “asymptomatic”, are sometimes used interchangeably however, subclinical shedding includes days with symptoms (e.g., prodrome) but no lesions, whereas asymptomatic shedding includes only days when no signs or symptoms are present.

More than 85% of people who have HSV-2 antibodies but do not report lesions shed virus from the genital tract [Langenberg, 1999; Wald, 2000]. In immunocompetent young adults studied within the first few years after infection, HSV-2 can typically be isolated by culture from genital or perianal swabs on 1% to 5% of days, and HSV-2 DNA can be detected by PCR testing on 15% to 20% of days [Wald, 1995; Wald, 1997; Corey, 2000]. Asymptomatic shedding occurs at a similar rate in individuals with one to twelve recurrences annually compared to those who report no symptoms [Wald, 1995]. Furthermore, up to one half of subclinical HSV-2 shedding episodes occur more than seven days before or after a symptomatic recurrence [Wald, 1995]. It has also been

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determined that both viral shedding and recurrences are more frequent in the first year after initial HSV-2 infection [Wald, 1995, Benedetti, 1999].

Suppressive antiviral therapy with nucleoside analogues significantly reduces the frequency of total and asymptomatic shedding [Barton, 1996; Patel, 1997; Gupta, 2004; Diaz-Mitoma, 1996; Wald, 1997; Straus, 1996]. A recent large randomized clinical trial in monogamous, heterosexual couples discordant for HSV-2 infection demonstrated that an antiviral medication, VALTREX (valacyclovir hydrochloride, valaciclovir) 500mg, used once a day by the infected source partner with nine or fewer recurrences per year, in combination with safer sex practices, reduced transmission of symptomatic HSV-2 infection by 75% and overall HSV-2 infection by 48% [Corey, 2004]. Of note, a viral shedding sub-study of 89 patients studied for 60 days demonstrated a 73% reduction in total days of viral shedding and a 64% reduction in days of subclinical viral shedding in infected source partners receiving VALTREX compared to those receiving placebo.

In a recently completed study (HS2100273) of VALTREX 1g once daily for the reduction of HSV-2 viral shedding in subjects with a history of ≥6 genital herpes recurrences per year, the mean percent of days with HSV-2 shedding was 9.3% in the placebo group, and 2.7% in the VALTREX group (p<0.001), representing a 71% reduction in total days of viral shedding compared to placebo. The mean percent of days with subclinical HSV-2 shedding was 6.4% on placebo and 2.7% in the VALTREX group (p<0.001), a 58% reduction compared to placebo [GSK Document Number RM2005/00245/00].

Since viral shedding (both clinical and subclinical) is an important source of transmissible virus, medical management of shedding is important from both a scientific and public health perspective [Corey, 2004]. Since newly diagnosed individuals are at high risk for frequent shedding, management becomes particularly important in this patient population. This study will provide additional natural history data in this population and will also provide the first robust evaluation of the efficacy of valacyclovir to reduce HSV-2 shedding in individuals who have been given a new diagnosis of genital herpes.

1.2. Rationale

There is a gap in our understanding of the impact of suppressive therapy on viral shedding in subjects newly diagnosed with recurrent genital herpes.

The recently completed study of VALTREX 1g once daily for the reducing HSV-2 viral shedding was conducted in subjects with a history of ≥6 recurrences per year. One ongoing study (HS2100275) is evaluating VALTREX for the suppression of genital herpes recurrences in newly diagnosed subjects. Yet, no data are available on the effect of VALTREX in reducing HSV-2 viral shedding in newly diagnosed subjects. This study will explore the value of daily suppressive therapy with VALTREX 1g QD in reducing clinical and subclinical viral shedding in this little-studied population.

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2. OBJECTIVE(S)

2.1. Primary

• To compare the effect of VALTREX 1g administered once daily for 60 days vs. placebo on total HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. Total shedding includes both clinical (genital lesion present) and subclinical (no genital lesions present) shedding.

2.2. Secondary

• To compare the effect of VALTREX 1g administered once daily for 60 days vs. placebo on subclinical HSV-2 shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. • To evaluate the safety of VALTREX 1g administered once daily for 60 days in immunocompetent HSV-2 seropositive subjects newly diagnosed with HSV-2 infection

3. ENDPOINT(S)

3.1. Primary

• Mean percent days of total shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2

3.2. Secondary

3.3. Other Endpoints

4. STUDY DESIGN

This will be a randomized, double-blind, placebo-controlled, multicenter, two-way crossover study. Subjects will be randomized to receive VALTREX 1g or matching

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placebo once daily for 60 days in each of two Treatment Periods in a two-way crossover design. There will be a washout period of seven days between Treatment Periods.

21 days 60 days 7 days 60 days

Washout Valtrex 1g QD Valtrex 1g QD

Placebo QD Placebo QD

Screening Visit Clinic Visits Clinic Visits 15 days apart 15 days apart

Randomization

Visit A typical subject’s total participation in this study will be approximately 148 days and will include the following: a screening evaluation (to be performed within 21 days of randomization), a randomization visit, and eight study visits (four visits per Treatment Period, with a 15-day interval between each visit). See Section 6 for additional information on Study Assessments and Procedures.

Subjects may have received episodic therapy to treat the initial outbreak or a recurrence in accordance with the dosing regimen approved by local regulatory authorities. However, they must undergo a three day (72 hours) washout period PRIOR to randomization/initiation of study treatment, but must be randomized within 4 months of the initial diagnosis of GH to ensure only newly diagnosed subjects are randomized.

In the event a subject experiences a genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, the subject should be provided a prescription for antiherpetic therapy. Once healed, and following at least a 72 hour washout period, the subject may resume the schedule of assessments and proceed to the randomization visit. For subjects who present with a genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, swabs of the lesion will be collected in the clinic for baseline HSV culture and PCR.

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During each 60-day Treatment Period and during washout, subjects will be required to collect a daily swab from their genital/anal-rectal area for HSV-2 detection by PCR. During a recurrence, swabs of the lesion also will be collected in the clinic for HSV-2 detection by culture and PCR.

Once randomized into the study, subjects who experience a genital herpes recurrence will be required to attend the clinic for an additional visit(s), as necessary, to allow the investigator to confirm that the genital lesion(s) are consistent with a genital herpes recurrence. Regardless of Treatment Period, a subject whom the investigator deems is experiencing a genital herpes recurrence will temporarily discontinue blinded study medication to receive open-label episodic treatment with VALTREX 500mg twice daily for 3 days, after which double-blind therapy will resume. The investigator/designated clinician must confirm all genital herpes recurrences by the presence of at least the macular/papular (erythema or elevation of skin without fluid) lesion stage of development, before open-label episodic treatment is initiated. The presence of symptoms alone (e.g., pain, tingling, burning, itching) are not sufficient to initiate open-label episodic treatment.

A swab for HSV culture also will be collected in the clinic on Day 1 of a genital herpes recurrence. For any subjects who receive an additional course of open-label VALTREX, an additional swab for HSV culture will be obtained at that time. HSV-2 isolates from subjects not responding to 3 days of episodic treatment will be sent to a designated central laboratory at the end of the study for antiviral sensitivity testing.

5. STUDY POPULATION

Subjects must be randomized within 4 months of the initial diagnosis of genital herpes, or be newly diagnosed with a first recognized episode of genital herpes at the screening visit. Subjects must have documented signs and symptoms of genital HSV-2 infection, as well as laboratory confirmation of genital HSV-2 infection to be eligible for the study (see Appendix 3).

Subjects must have documented signs (e.g., ulcer, blister, erythema, swelling, excoriation) of genital HSV-2 infection at the time of the screening visit or within 4 months prior to the randomization visit. Symptoms alone (e.g., pain, tingling, burning, itching) do not meet eligibility criteria. Signs and symptoms of genital herpes infection must be documented in the medical record. If a subject is referred from another healthcare provider, the subject’s clinical diagnosis documentation must be obtained to provide such documentation. Such documents must be made available to the investigator prior to randomization.

NOTE: For the purposes of this clinical study, the terms “lesion”, “genital herpes outbreak, and “genital herpes recurrence” as used in this protocol may encompass a number of clinical manifestations such as, but not limited to, ulcers, blisters, erythema, swelling, or excoriations. See Appendix 4 for information on Genital Herpes Lesion Stages.

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5.1. Number of Subjects

Approximately 66 subjects will be randomized at sites in North America to obtain a total of at least 47 subjects who complete the study.

5.2. Eligibility Criteria

5.2.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Subject is in overall general good health. 2. Subject is a male or female and aged 18 years or older. 3. If female, subject must be of: a. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is pre-menarchial or post-menopausal or surgically sterile); or b. Childbearing potential, but must have a negative pregnancy test at randomization, and must be compliant with one of the following: • Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period of 1 week after study completion or premature discontinuation from the study (to account for elimination of the drug) • Have a male partner who is confirmed to be sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject • Use of contraceptive(s) with a documented failure rate of less than 1% per year, including but not limited to: implants of levonorgestrel, use of injectable progestogen, oral contraceptives (either combined or progestogen only), an intrauterine device (IUD) or spermacide plus a mechanical barrier (condom/diaphragm) 4. Subjects must be newly diagnosed with a first recognized episode of genital herpes as described in (a) or (b) below (See Appendix 3): a. HSV-2 seropositive at screen, with documented clinical signs and symptoms consistent with genital herpes at screen or within 4 months prior to randomization OR

b. HSV-2 seronegative at screen, AND HSV-2 culture positive or HSV-2 PCR positive with documented clinical signs and symptoms consistent with genital herpes at screen or within 4 months prior to randomization.

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5. Subject must be willing and able to provide written informed consent and comply with the protocol.

5.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Subject is known or suspected to be immunocompromised (e.g., subjects receiving immunosuppressive therapy or chemotherapy for malignancy, or are seropositive for HIV). 2. Subject received an investigational drug in the 30 days prior to the randomization visit. 3. Subject is receiving systemic antiviral or immunomodulatory treatments. Subjects must not have received systemic antiherpetic treatments (e.g., valacyclovir, acyclovir, ganciclovir, famciclovir) within 3 days of starting study drug, nor immunomodulatory treatments in the 30 days before starting study drug. 4. Subject has clinically significantly impaired renal function as defined by creatinine clearance less than 50ml/min (calculated using the Cockcroft-Gault formula). 5. Subjects with a history or evidence of decompensated liver disease, or clinically significantly impaired hepatic function defined as an ALT (alanine transaminase) level >3 times the normal upper limit. 6. Subject is known to be hypersensitive to valacyclovir, acyclovir, ganciclovir or famciclovir. 7. Subject has malabsorption or vomiting syndrome or other gastrointestional dysfunction that may impair drug pharmacokinetics. 8. Female subject who is contemplating pregnancy within the duration of the study drug dosing period. 9. Female subject who is pregnant and/or nursing. 10. Subject with current alcohol or drug abuse. 11. Subjects who have received suppressive (daily) therapy for genital herpes prior to randomization. Suppressive therapy is defined as daily antiherpetic therapy of at least 4 weeks duration. 12. Subjects with a history of ocular HSV infection.

5.2.3. Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: VALTREX Clinical Investigator’s Brochure [GSK Document Number RM2001/00020/01], and the approved product label for VALTREX.

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6. STUDY ASSESSMENTS AND PROCEDURES

See Appendix 1 for a detailed Time and Events Table.

Written informed consent will be obtained before any study-specific procedures are performed.

The investigator must ensure the diagnosis of genital herpes (based on the presence of clinical signs and laboratory confirmation) is documented in the subject’s medical records before a subject is randomized into the study.

Subjects will be seen for a screening evaluation, a randomization visit, 8 study visits (15 days between visits) and genital herpes recurrence visits. Subjects will be randomized to either VALTREX 1g once daily or placebo. Subjects with genital herpes recurrences during the study will receive open-label episodic treatment with VALTREX 500 mg twice daily for 3 days for treatment of recurrences. Blinded study drug will be temporarily interrupted during treatment of recurrences, and will resume after completion of open-label episodic treatment. All visits will be conducted at the study site.

6.1. Screening Visit

The screening visit will be performed within 21 days of the randomization visit. Subjects will be assessed for their eligibility to enter the study at this visit. The following procedures will be performed:

• Review eligibility criteria • Obtain written informed consent for study participation • Obtain blood sample for HSV-1 and HSV-2 • Obtain blood and serum sample for evaluation of hematology and clinical chemistry • Height and weight measurements • Serum hCG pregnancy (females of child-bearing potential only) • A genital examination must be conducted at the screening visit for subjects who present with genital herpes signs or symptoms. For subjects who present with a genital herpes outbreak (initial or recurrent) at the screening visit, a swab of the lesion will be collected in the clinic for baseline HSV-2 viral culture and PCR. In the event a subject experiences a suspected genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, the subject should be provided a prescription for antiherpetic therapy. Open-label study medication for episodic management of genital herpes recurrences should not be dispensed prior to randomization. Once healed, and following at least a 72 hour washout, the subject may resume the schedule of assessments and proceed to the randomization visit. For subjects who present with a genital HSV-2 outbreak (initial or recurrent) at the screening visit, or between screen and randomization, swabs of the lesion will be collected in the clinic for baseline HSV culture and PCR.

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6.2. Randomization Visit

After HSV serology and clinical chemistry results are obtained from the screening visit and eligibility of the subject is confirmed, the following items and procedures will be recorded or conducted:

• Demographic data • Urine hCG pregnancy test (females of child-bearing potential only) • Genital examination • Current medical conditions • Concomitant medications • Central randomization of subject to either VALTREX 1g once daily or matching placebo once daily for 60 days in a two-way crossover design • Dispense double-blind medication • Issue a diary to the subject for recording study-related information • Instruct subject in how to complete the subject diary and how to administer blinded study drug. • Dispense swab kits to the subject with instructions on how to collect and store the daily genital/anal-rectal swab samples at home until they are returned to the study site. • Instruct the subject to contact the study center and return to it within 24 hours of experiencing signs/symptoms of a genital herpes recurrence. • Provide education and counselling on genital herpes.

6.3. Routine Study Visits

There will be eight routine study visits [four visits per Treatment Period, with a 15-day (±5 day) interval between each study visit]. At each routine visit, the following items and procedures will be recorded or conducted:

• Study drug accountability by counting and recording the number of caplets returned by the subject. • Adverse experiences since the last visit, after review of the subject diary and discussion with the subject. • Concomitant medications since the last visit, after review of the subject diary and discussion with the subject. • HSV recurrences since the last visit will be assessed after review of the subject diary and discussion with the subject. • The subject’s swab samples that were previously collected and stored at home will be returned to the study site; additional swab kits will be issued to the subject at each visit. Subjects are to return all swab samples to the study site at each routine visit.

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• Urine hCG pregnancy test (females only) at any time pregnancy is suspected. • Dispense another 15-day supply of blinded study drug (except at the End of Study visit). • Provide education and counselling on genital herpes.

6.4. Washout Period

6.4.1. Rationale for 7-day Washout Period

There will be a washout period of seven days between Treatment Periods.

The one week washout period was selected based on the design of an earlier 3-period crossover study that investigated the effect of valacyclovir and acyclovir for suppression of genital HSV shedding [Gupta, 2004]. In that study, a one week washout period of placebo followed the first 2 treatment arms. With the initiation of valacyclovir or acyclovir, 5 days of therapy were needed to achieve suppression of genital HSV shedding. After the discontinuation of therapy, viral shedding consistently reappeared in 5 days.

In all studies of VALTREX in volunteers with normal renal function, the plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours. Following the oral administration of a single 1 gram dose of radiolabeled valacylcovir to 4 healthy subjects, 45.60% and 47.12% of administered radioactivity was recovered in urine and feces over 96 hours, respectively (VALTREX Package Insert).

For these reasons, a 7-day washout period was selected in this study, and was considered sufficient time for adequate clearance of study medication.

6.4.2. Washout Period Procedures

No clinic visit is required during the washout period. The subject will continue with daily swabbing and diary completion during the washout period.

In the event the subject experiences a genital herpes recurrence during the washout period, the start of the 7-day washout clock will be re-set upon completion of episodic therapy to allow a full 7-day washout prior to the initiation of Treatment Period 2.

Study coordinators will telephone the subject at the end of the washout period, as a reminder to begin double-blind medication for the start of Treatment Period 2.

6.5. Recurrence Visit

The following items and procedures will be recorded or performed during visits for genital HSV recurrences:

• Genital examination and verification of lesion status. Lesion must be at least at the macular/papular (erythema or elevation of skin without fluid; clinical signs

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consistent with genital herpes) stage of development before episodic treatment is initiated. • Collect viral swab for HSV culture. • If subject has not performed already, collect genital/anal-rectal swab sample for HSV-2 PCR analysis • Collect swab sample from the lesion for HSV-2 PCR analysis. • Dispense 3-day open-label episodic treatment course of VALTREX 500mg twice daily. Double-blind suppressive therapy will be temporarily discontinued during the open-label episodic treatment of the recurrence; the subject will resume double-blind therapy following completion of the 3-day open-label episodic treatment course. • Instruct subject to return to the study site if there is no improvement or progress toward healing after completion of 3-day open-label therapy. Subjects who have not healed by Day 3 will be managed as deemed appropriate by the investigator, and may be offered an additional 3-day course of open-label episodic study medication with VALTREX. Collect a viral swab sample for HSV culture for any subjects who receive an additional course of open-label VALTREX. • Drug accountability of the open-label treatment is to occur routinely. • Adverse experiences since the last visit after review of the subject diary and discussion with the subject. • Concomitant medications since the last visit will be recorded after review of the subject diary and discussion with the subject. • Provide education and counselling on genital herpes. Upon completion of open-label episodic treatment, the subject will resume double-blind therapy.

7. SAFETY

A blood and urine sample will be collected for hematology, clinical chemistry and urinalysis at the screening visit and at the end of each Treatment Period. The following laboratory parameters will be evaluated: • Hematology: Hemoglobin, MCV, platelets, WBC, neutrophils, lymphocytes, monocytes, eosinophils, basophils. • Clinical Chemistry: calcium, phosphorous, sodium, potassium, chloride, AST (SGOT), total bilirubin, ALT (SGPT), alkaline phosphatase, albumin, BUN, creatinine. • Urinalysis: hematuria, proteinuria. A central laboratory will be used for evaluation of blood and urine samples, HSV cultures, and for PCR testing.

The safety and tolerability of VALTREX will be assessed by evaluation of changes in serum chemistry and hematology, and adverse event reporting.

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7.1. Pregnancy

A serum or urine sample will be collected for hCG pregnancy testing (female subjects of child-bearing potential only) at the screening visit, randomization visit, Day 60 of Treatment Period 1, the End of Study visit at Day 60 of Treatment Period 2, and at any time pregnancy is suspected.

7.1.1. Time period for collecting pregnancy information

Pregnancy information on female subjects who unexpectedly become pregnant after study drug initiation until the End of Study visit at Day 60 of Treatment Period 2 will be collected. Any pregnancy reported or occurring during this timeframe should be reported to GSK according to the guidelines provided in Section 7.1.2.

7.1.2. Action to be taken if pregnancy occurs

Subjects who become pregnant during the study will be instructed to immediately discontinue study medication.

The investigator will collect pregnancy information on any female subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see Section 12 of the protocol and the AE/SAE section of the SRM for definitions and a description of follow-up).

A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in section entitled, "Post-study AEs and SAEs" of the SRM. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

8. EFFICACY

Recent studies have used polymerase chain reaction (PCR) analysis in addition to or instead of viral culture to measure viral shedding in the presence of lesions as well as between outbreaks [Corey, 2004; Wald, 2000]. PCR analysis is a more sensitive test for HSV detection compared to culture [Ryncarz, 1999; Ramaswamy, 2004].

The primary endpoint of the study is mean percent days of total shedding (clinical and subclinical) as determined by type-specific PCR assay for HSV-2.

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Daily swab samples will be collected and stored properly by subjects at home during the study, and will be used to evaluate HSV-2 viral shedding by type-specific PCR methodology. For each subject, each study day will be classified by PCR as 'shedding' or 'no shedding' and by 'clinical' (i.e., presence of genital lesions) or ‘subclinical’ (i.e., no genital lesions). The site will ship all swab samples to the central laboratory designated for PCR analysis.

Secondary endpoints to be evaluated include mean percent days of subclinical HSV-2 shedding, mean percent days of clinical HSV-2 shedding, the proportion of subjects with no shedding, the proportion of subjects with at least one genital herpes recurrence during the study period, and the time to first genital herpes recurrence.

The time to first oral herpes recurrence also will be evaluated. In addition, HSV-2 isolates from subjects not responding to 3 days of open-label episodic treatment will be sent to a designated central laboratory at the end of the study for antiviral sensitivity testing by plaque reduction assay [Collins, 1986].

9. INVESTIGATIONAL PRODUCT(S)

GlaxoSmithKline will provide valacyclovir and matching placebo in accordance with established standards. Valacyclovir will be supplied as blue film coated caplets containing 500mg base valacyclovir as the hydrochloride salt plus excipients. Placebo will be supplied as blue caplets to match the valacyclovir 500mg caplets. Opadry blue placebo caplets will contain dibasic calcium phosphate, microcrystalline cellulose, magnesium stearate, Opadry blue, purified water and carnauba wax.

9.1. Description of Investigational Product

All study medication will be taken orally. The daily dosing regimen for each phase of the study is summarized in the following table.

Study Phase Drug Daily Dosage Dosing Period Double-blind VALTREX 1 gram once daily Treatment Period 1 = (2 x 500mg caplets) 60 days Treatment Period 1 or or and Treatment Period 2 = Treatment Period 2 Placebo Matching Placebo 60 days (2 caplets) Washout Period None None 7-day washout Open-label Episodic VALTREX 500mg twice daily 3 days Treatment

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9.2. Dosage and Administration

9.2.1. Double-Blind Treatment Periods 1 and 2

Double-blind dosing is 1 gram once daily, to be taken as two 500mg caplets once daily. During the two double-blind Treatment Periods, subjects will be provided with investigational product (valacyclovir 500mg caplets or matching placebo). Subjects will be instructed to take two caplets once daily at approximately the same time of day each day, without regard to meals. If a dose is missed, the subject will take the dose later that day provided they take it at least 2 hours before their next scheduled dose; otherwise the dose will be omitted.

9.2.2. Open-label Treatment of Genital Herpes Recurrences

Open-label dosing is 500mg twice daily. Subjects will temporarily discontinue double- blind suppressive therapy if they experience a genital HSV recurrence and will receive open-label treatment. To treat a recurrence, subjects will be instructed to take one VALTREX 500mg caplet twice daily at approximately the same time of day each day. If a dose is missed, the subject will take the dose later that day provided they take it at least 2 hours before their next scheduled dose; otherwise the dose will be omitted. Subjects will resume double-blind study medication following completion of the open-label treatment. Subjects whose lesions have not healed following completion of the initial 3- day open-label treatment course may be given an additional 3-day course of valacyclovir as deemed appropriate by the clinical investigator.

Open-label study medication is not to be used to treat genital herpes recurrences that occur between the screen and randomization visit.

Open-label episodic therapy must not be dispensed in advance to enable a subject to self-initiate treatment of a genital herpes recurrence at home.

9.3. Dosage Adjustments

Dose adjustments are not permitted.

Temporary discontinuation of double-blind medication for treatment of recurrences is required.

A subject may temporarily discontinue study drug at the discretion of the investigator in the event of an untoward or serious adverse event (SAE) or concomitant illness. The subject may resume study drug as directed by the investigator. The investigator may choose to discontinue study drug permanently for subjects who are unable to tolerate study drug at any point during the study. Subjects who permanently discontinue study drug before the end of the study period should be managed as outlined in Section 11.

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9.4. Dose Rationale

The recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 1g once daily in patients with normal immune function (in subjects with a history of nine or fewer recurrences per year, an approved alternative dose is 500mg once daily). A study (HS2100273) to investigate the effect of VALTREX 1g once daily on total and subclinical viral shedding in subjects with a history of frequent recurrences (6 or more per year) has been recently completed. The present study will utilize the same dose of VALTREX; however, the new study will evaluate shedding rates in a population with no established recurrence pattern, i.e., in newly diagnosed subjects. Dose selection was based on several factors: i) HSV-2 seropositive subjects with no symptoms shed virus at similar rates as do those with one to twelve annual recurrences [Wald, 1995]; ii) no recurrence history is available in this study population, therefore VALTREX 1g once daily, which is approved for all HSV-2 infected patients, is the most appropriate dose, and iii) the ability to contrast results from this study with those from the recently completed study of VALTREX 1g once daily on viral shedding in subjects with ≥6 recurrent genital herpes infections per year.

For this study in subjects newly diagnosed with genital herpes infection, subjects will receive the following two treatments in a two-way crossover design: VALTREX 1g once daily or matching placebo once daily for 60 days on each Treatment Period.

Subjects who experience genital herpes recurrences during the study will receive episodic treatment with open-label VALTREX 500mg twice daily for 3 days. This is the approved treatment regimen in the United States (US); the rationale for this dose of VALTREX for the treatment of genital herpes recurrences is found in the VALTREX Clinical Investigator’s Brochure [GSK Document Number RM2001/00020/01] and US PRODUCT INSERT [VALTREX Package insert, 2005].

9.5. Blinding

The study will be double-blinded.

Only in the case of an emergency, when knowledge of the investigational product is essential for the clinical management or welfare of the subject, the investigator may unblind a subject’s treatment assignment. The investigator will, whenever possible, discuss options with the Medical Monitor, on-call physician, or appropriate GSK study personnel before unblinding. If the blind is broken for any reason and the investigator is unable to contact GSK prior to unblinding, the investigator must notify GSK as soon as possible following the unblinding incident without revealing the subject’s study treatment assignment, unless the information is important to the safety of subjects remaining in the study. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate data collection tool (as defined in Section 14.7).

If a serious adverse event (SAE; as defined in Section 12.2, "Definition of an SAE") is reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for the individual subject. If an expedited regulatory

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report to one or more regulatory agencies is required, the report will identify the subject’s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GSK policy, or both.

9.6. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization schedule. Central randomization procedures will be used. The randomization schedule will be computer-generated by GSK. The investigator will contact a central randomization organization for allocation of treatment assignment.

9.7. Packaging and Labeling

All subjects will begin the trial with double-blind therapy. Double-blind study drug will be packaged, labeled, and numerically coded for each treatment according to a computer- generated random code by GlaxoSmithKline, Research Triangle Park, North Carolina, USA. The contents of the label will be in accordance with all applicable regulatory requirements. The following components may be included in the label:

• Investigational Use statement • Sponsor’s address • Protocol number • Space for subject number and date dispensed • Quantity • Directions for use • Storage conditions • Container number Double-blind dosing is 1 gram once daily, to be taken as two 500mg caplets. Double- blind therapy will be supplied in bottles containing 40 VALTREX 500mg caplets or 40 placebo caplets. Each bottle is packaged as a 15 day supply of study drug, plus 5 extra days of therapy, in the event a subject must delay a scheduled clinic visit.

Open-label dosing is 500mg twice daily. Open-label episodic therapy for the treatment of a genital herpes recurrence will be supplied in bottles containing 6 VALTREX 500mg caplets. The contents of the label will be in accordance with all applicable regulatory requirements. Each bottle is packaged with a 3-day open-label treatment regimen.

9.8. Handling and Storage

Investigational product must be dispensed or administered according to procedures described herein. Only subjects randomized in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must

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be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements.

Study medication must be stored in a secure area, free of environmental extremes and in accordance with the instructions printed on the medication labels. Investigational products will be stored according to product specifications (store at 15° to 25°C / 59° to 77°F). Protect from light. Prior to delivery of the study medication, the drug storage area may be inspected.

9.9. Product Accountability

The investigator, institution, or the head of the medical institution (where applicable) is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or the head of the medical institution (where applicable), or designated site staff (e.g., storage manager, where applicable) must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from and returned to GSK (when applicable), the amount supplied and/or administered to and returned by subjects, if applicable.

Bottles of double-blind therapy will be dispensed at the scheduled clinic visits (every 15 days). Site personnel are required to record the subject number and date dispensed on the label of each bottle prior to dispensing to the subject. The subject will be requested to return containers of study medication to site personnel at each clinic visit for accountability.

If a subject returns to the clinic with a genital herpes recurrence, a bottle of open-label episodic therapy will be dispensed upon confirmation by the clinician that the lesion is at least at the macular/papular genital lesion stage. Open-label episodic therapy must not be dispensed in advance to enable a subject to self-initiate treatment of a genital herpes recurrence at home. Site personnel are required to record the subject number and date dispensed on the label of each bottle prior to dispensing to the subject. The subject will be requested to return containers of open-label study medication to site personnel for accountability.

Investigational product will be accounted for by counting and recording the number of returned caplets on a dispensing record. Designated study site personnel are responsible for reconciling or resolving any discrepancies in the dispensing record. Empty containers will be discarded on site after review by GSK, and unused or partly used study medication will be returned to GSK for final disposition.

9.10. Assessment of Compliance

The investigator or designee will be responsible for study medication accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or designee will maintain study medication accountability records throughout the course of the study, and document the amount of study drug

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received from the sponsor, and the amount supplied and/or administered to and returned by subjects, as applicable.

All subjects will be instructed to return containers of study medication at each clinic visit. The investigator or designee will assess study medication compliance by counting and recording the number of returned caplets in the dispensing record. Subjects will also record any missed doses of study medication in their diary card. Following drug accountability and diary card review, the start and stop dates of each subject’s study treatment will be recorded in the CRF. Non-compliance with investigational product will be defined as failure to take study medication for at least 80% of the time on double-blind therapy.

Subjects will be instructed to return daily swabs to the clinic at scheduled visits. Non- compliance with swabbing will be defined as failure to swab on at least 85% of days on study.

9.11. Treatment of Investigational Product Overdose

For the purpose of this protocol, an overdose is defined as a single oral valacyclovir dose of 3 grams or greater. Subjects should be observed closely for signs of toxicity. Caution should be exercised to prevent inadvertent overdose. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored.

9.12. Occupational Safety

VALTREX is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure notify the medical monitor.

Precaution will be taken to avoid direct contact with the investigational product. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

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10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES

10.1. Permitted Medications

All concomitant medications taken during the study will be recorded in the CRF. The minimum requirement is that drug name and the dates of administration are to be recorded.

10.2. Prohibited Medications

10.2.1. Pre-Study Prohibited Medications

Subjects must not have received systemic antiherpetic treatments (e.g., valacyclovir, famciclovir, acyclovir, ganciclovir) within 3 days of starting study drug, nor systemic immunomodulatory treatments in the 30 days before starting study drug.

10.2.2. On-Study Prohibited Medications

Open-label episodic therapy that is supplied to the investigational sites for treatment of genital herpes recurrences must not be dispensed for the treatment of oral herpes outbreaks; the use of systemic anti-herpetics is not allowed during the study period the treatment of oral herpes outbreaks.

The use of systemic immunomodulatory treatments is not allowed during the study period.

11. SUBJECT COMPLETION AND WITHDRAWAL

11.1. Subject Completion

The duration of the study is approximately 148 days. A subject will complete the study at the End of Study visit at Day 60 of Treatment Period 2.

11.2. Subject Withdrawal

11.2.1. Subject Withdrawal from Study

A subject may voluntarily discontinue participation in this study at any time. The investigator may also, at his or her discretion, discontinue the subject from participating in this study at any time. If a subject is prematurely discontinued from participation in the study for any reason, the investigator must make every effort to perform the assessments and procedures as described for the End of Study Visit.

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These data should be recorded, as they comprise an essential evaluation that should be done prior to discharging any subject from the study. In the event that a subject is prematurely discontinued from the study at any time due to an AE or SAE, the procedures stated in Section 11.2.2 must be followed.

11.2.2. Subject Withdrawal from Investigational Product

11.2.2.1. Premature Discontinuation of Study Drug

Premature discontinuation of study drug is defined as complete discontinuation of study drug, with no intention of restarting medication, at any point before the full course of medication has been taken as prescribed. The investigator may choose to discontinue study drug permanently for subjects who are unable to tolerate study drug at any point during the study. All subjects who prematurely discontinue study drug will be required to complete the End of Study procedures, unless consent to be followed in the study is specifically withdrawn.

11.2.2.2. Temporary Discontinuation of Study Drug

Temporary discontinuation of double-blind medication for treatment of recurrences is required.

A subject may temporarily stop study drug at the discretion of the investigator in the event of an untoward or serious adverse event (SAE) or concomitant illness. The subject may resume study drug as directed by the investigator.

11.3. Treatment After the End of the Study

A subject will complete the study at the End of Study visit at Day 60 of Treatment Period 2. The subject’s participation in the study formally ends at that time. Subjects will not receive investigational product after the end of the study. The sponsor will not provide post-study medication to research subjects.

12. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)

The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the investigator or site staff will be responsible for detecting, documenting and reporting AEs and SAEs, as detailed in both this section of the protocol and in the AE/SAE section of the Study Reference Manual (SRM).

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12.1. Definition of an AE

Any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

Examples of an AE includes: a. Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. b. New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study. c. Signs, symptoms, or the clinical sequelae of a suspected interaction. d. Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concurrent medication (overdose per se should not be reported as an AE/SAE). e. “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an AE or SAE. However, the signs and symptoms and /or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE. Examples of an AE does not include a/an: a. Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE. b. Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). c. Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen. d. The disease/disorder being studied, or expected progression, signs, or symptoms of the disease/disorder being studied, unless more severe than expected for the subject’s condition.

12.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death

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b. Is life-threatening NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. c. Requires hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. d. Results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption. e. Is a congenital anomaly/birth defect f. Medical or scientific judgment should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse.

12.3. Disease-Related Events

Signs or symptoms of HSV recurrence (genital or oral) should not be reported to GSK as AEs. However, these individual events, as well as any sign, symptom, diagnosis, illness, and/or clinical laboratory abnormality that can be linked to any of these events, may be reported to GSK as AEs if the following conditions apply:

• the investigator determines that the event or outcome qualifies as an SAE under part “f” of the SAE definition, or • the event or outcome is, in the investigator’s opinion, of greater intensity, frequency or duration than expected for the individual subject, or

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• death occurring for any reason during a study, including death due to a disease- related event, will always be reported as a SAE.

12.4. SAEs of Special Interest

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are a part of a spectrum of diseases collectively known as thrombotic microangiopathies (TMA). TMA related SAEs have been reported in immunocompromised subjects with advanced HIV disease and also in bone marrow transplant and renal transplant recipients participating in clinical trials of valacyclovir. TMA related SAEs such as TTP/HUS have not been reported in immunocompetent subjects receiving valacyclovir in clinical trials. TMA should be considered in any subject who has:

1. microangiopathic hemolytic anemia, defined as the presence of schistocytosis (fragmented red blood cells on peripheral blood film) and anemia (Hb <13.5 g/dL in males or Hb <11.5 g/dL in females) AND

3 2. thrombocytopenia (platelets <150,000/mm ) AND

3. EITHER i. renal abnormality (either hematuria > trace, proteinuria >1+, or serum creatinine > upper limits of normal) OR ii. neurologic abnormality and fever ( 38°C)

A decision tree for suspected TMA is provided in Appendix 3. The investigator should complete the decision tree for any subject in which TMA is suspected. The investigator will complete the SAE section of the CRF (including supplemental pages designed to collect relevant information on TMA) for subjects meeting the above case definition or for subjects in which a serious case of TMA is suspected.

12.5. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs

Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other abnormal assessments that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE or SAE. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the

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subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

12.6. Time Period, and Frequency of Detecting AEs and SAEs

The investigator is responsible for recording AEs observed after study drug initiation (Randomization Visit) until the End of Study Visit on Day 60 of Treatment Period 2.

From the time a subject consents to participate in the study until he or she has completed the study (including any follow-up period), all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be reported promptly to GSK.

12.7. Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.

12.7.1. Timeframes for Submitting SAE Reports to GSK

Initial SAE Reports Follow-up Information on a Previously Reported SAE Type of SAE Time Frame Documents Time Frame Documents All SAEs 24 hrs "SAE" data 24 hrs Updated "SAE" collection tool data collection tool

12.8. AE and SAE Documentation and Follow-up Procedures

The investigator will review and adhere to the following procedures, which are outlined in detail in the AE/SAE section of the SRM:

• Method of Detecting AEs and SAEs • Recording of AEs and SAEs • Evaluating of AEs and SAEs • Completion and Transmission of SAE Reports to GSK • Follow-up of AEs and SAEs

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• Post-study AEs and SAEs • Regulatory Reporting Requirements for SAEs

13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

13.1. Hypotheses

The primary endpoint is the percent of days with total HSV-2 viral shedding over 60 days, which will be compared between the VALTREX and placebo treatment groups. The null hypothesis is that there is no difference between the two treatment groups with respect to the primary endpoint and the alternative hypothesis is that the two treatment groups are different. This study is designed to show superiority of VALTREX over placebo.

13.2. Study Design Considerations

13.2.1. Sample Size Assumptions

13.2.2. Sample Size Sensitivity

If the assumed treatment difference is reduced by 0.5% but the assumptions regarding variability remain the same, the power to detect a reduction in percent days of total HSV-

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2 shedding remains over 90% but the power to detect a reduction in the percent days of subclinical shedding is reduced to 81%.

13.2.3. Sample Size Re-estimation

If the dropout rate is higher than anticipated then the enrollment size may be increased to ensure that 47 subjects complete the study.

13.3. Data Analysis Considerations

13.3.1. Analysis Populations

There will be two populations considered in the analysis:

• Intent-to-Treat (ITT) Exposed Population: The ITT Exposed population is defined as consisting of all subjects who received at least one dose of investigational product. This will be the primary population for assessing efficacy as well as safety. • Per Protocol Population: This population will include all subjects who completed the study without a major protocol violation and have PCR data on at least 85% of days on study. This will be the secondary population for assessing the primary and secondary efficacy endpoints.

13.3.2. Analysis Data Sets

All data collected following start of treatment will be included in the analysis.

13.3.3. Treatment Comparisons

13.3.3.1. Primary Comparisons of Interest

The objective of the study is to compare the effect of VALTREX 1 g administered once daily for 60 days vs. placebo on the percent of days with total HSV-2 viral shedding in immunocompetent subjects newly diagnosed with HSV-2 infection. The comparison will be conducted in the ITT Exposed population and results will be tested at the two-sided 5% level.

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Subclinical shedding (shedding in the absence of genital lesions) is also of importance. If statistical significance is achieved in the total HSV-2 shedding treatment comparison, then the comparison of VALTREX vs. placebo on the percent of days with subclinical HSV-2 viral shedding will be carried out at the two-sided 5% level.

13.3.3.2. Other Comparisons of Interest

Treatment differences in each of the following secondary endpoints will be tested at the two-sided 5% level of significance:

Among subjects with a recurrence on study who do not respond to 3 days of episodic treatment, the percent of HSV-2 isolates resistant to acyclovir will be tabulated.

13.3.4. Interim Analysis

No interim analyses will be conducted.

13.3.5. Key Elements of Analysis Plan

13.3.5.1. Efficacy Analyses

For each subject, each study day will be classified by PCR as either ‘shedding’ (i.e. positive result), or ‘no shedding’ (i.e. negative result), or ‘unknown’; each study day will be classified as either ‘clinical’ (i.e. presence of genital lesions), or ‘subclinical’ (i.e. no genital lesions), or ‘unknown’.

The percent of days with total HSV-2 viral shedding is defined for each subject as the number of days with positive HSV-2 PCR shedding divided by the total number of days with PCR data. The percent of days with subclinical HSV-2 viral shedding is defined for each subject as the number of subclinical days with positive HSV-2 PCR shedding divided by the total number of days with PCR data.

Treatment differences will be tested using a Wilcoxon rank-sum test after first testing for the equality of residual effects using a Wilcoxon rank-sum test at the 5% level of significance [Koch, 1972].

All primary and secondary endpoints will be analyzed using the ITT Exposed population. An analysis using the Per Protocol population will also be carried out.

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13.3.5.2. Safety Analyses

All safety reporting will be based on the ITT Exposed population and will be summarized descriptively.

13.3.5.2.1. Extent of Exposure

Extent of exposure to randomized treatment will be calculated as time from start of randomized treatment to stop date of randomized treatment less any periods of open-label treatment for HSV recurrences.

13.3.5.2.2. Adverse Events

The proportion of subjects reporting adverse events will be tabulated by treatment group.

Adverse events will be coded using MedDRA and summarized by body system for:

• the overall incidence of adverse events • the incidence of adverse events considered to be related to study treatment • the incidence of adverse events leading to discontinuation of study drug • SAEs and deaths Full details of all adverse events will be listed.

13.3.5.2.3. Clinical Laboratory Evaluations

All clinical laboratory data will be listed, flagging values outside the normal range.

Clinical laboratory values will be summarized based on changes from baseline values.

14. STUDY CONDUCT CONSIDERATIONS

14.1. Regulatory and Ethical Considerations, Including the Informed Consent Process

GSK will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

The study will be conducted in accordance with all applicable regulatory requirements, including an U.S. IND.

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The study will also be conducted in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following:

• IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents • Subject informed consent • Investigator reporting requirements GSK will provide full details of the above either verbally, in writing or both.

Written informed consent will be obtained for each subject before he or she can participate in the study.

14.2. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRF will serve as the source document.

GSK will monitor the study consistent with the demands of the study and site activity to verify that the:

• Data are authentic, accurate, and complete. • Safety and rights of subjects are being protected. • Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements. The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

14.3. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

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14.4. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and GSK procedures.

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with the investigator or the head of the medical institution (where applicable), including the reasons for taking such action, at that time. When feasible, GSK will provide advance notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.

GSK will promptly inform all other investigators or the head of the medical institution (where applicable), and/or institutions conducting the study if the study is suspended or terminated for safety reasons. GSK will also promptly inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IEC/IRB promptly and provide the reason for the suspension or termination.

14.5. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

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The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.

14.6. Provision of Study Results and Information to Investigators

When required by applicable regulations, the investigator signatory for the clinical study report will be determined at the time the report is written. When the clinical study report is completed, GSK will provide the investigator with a full summary of the study results. The investigator is encouraged to share the summary results with the subjects, as appropriate. In addition, the investigator will be given reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the results for the entire study at a GSK site or other mutually agreeable location.

GSK will provide the investigator with the randomization codes for their site after the statistical analysis for the entire study has been completed.

14.7. Data Management

The data collection tool for this study will be GSK-defined case report forms (CRFs). Diary data will be collected. A central laboratory will be used. In all cases, subject initials will not be collected nor transmitted to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures. Original CRFs will be retained by GSK, while the investigator will retain a copy.

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15. REFERENCES

Barton S, Munday P, Patel R. Asymptomatic shedding of herpes simplex virus from the gential tract: uncertainty and its consequences for patient management. Int J STD AIDS 1996;7:229-232.

Benedetti JK, Zeh J and Corey L. Clinical reactivation of genital herpes simplex virus infection decreases in frequency over time. Ann Int Med 1999; 131:14-20.

Brown Z, Benedetti J, Ashley R, et al., Neonatal herpes simplex virus infection in relation to asymptomatic maternal infection at the time of labor. N Engl J Med 1991;324:1247-1252.

Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Transm Dis 1999; 26 (suppl); S2-S7.

Centers for Disease Control (CDC) and Prevention. Tracking the Hidden Epidemics: Trends in STDs in the United States. 2000.

Collins P, Oliver NM. Sensitivity monitoring of herpes simplex virus isolates from patients receiving acyclovir. J Antimicrob Chemother 1986;18 (Suppl B):103-12.

Corey L, Handsfield H. Genital herpes and public health. JAMA 2000;283:791-794.

Corey L, Wald A, Patel R, et al. Once-daily valacyclovir to reduce the risk of transmission of genital herpes. N Engl J Med 2004;350:11-20.

Diaz-Mitoma F, Ruben M, Sacks S, McPherson P, Caisse G. Detection of viral DNA to evaluate outcome of antiviral treatment of patients with recurrent genital herpes. J Clin Microbiol 1996;34:657-663.

Fleming D, McQuillan G, Johnson R, et al. Herpes simplex virus type 2 in the United States, 1976 to 1994. N Engl J Med 1997;337:1105-1111.

GlaxoSmithKline Document Number RM2005/00245/00, VALTREX study HS2100273, A Randomized, Double-Blind, Placebo-Controlled, Multicenter 60-Day Study Comparing the Efficacy of VALTREX 1 Gram Once Daily vs. Placebo Once Daily in Reducing Viral Shedding in Immunocompetent Subjects with Recurrent HSV-2 Genital Herpes. 2005.

GlaxoSmithKline Document Number RM2001/00020/01, International Clinical Investigator's Brochure - VALTREX (Valacyclovir). 2003.

Gupta R, Wald A, Krantz E, et.al, Valacyclovir and acyclovir for suppression of shedding of herpes simplex virus in the genital tract. J Infect Dis 2004;190:1374-1381.

Koch, G. The Use of Non-Parametric Methods in the Statistical Analysis of the Two- Period Change-Over Design. Biometrics 1972;328:579-584.

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Langenberg A, Corey L, Ashley R, et al. A prospective study of new infections with HSV-1 and HSV-2. N Engl J Med 1999;341:1432-1438.

Mertz G, Coombs R, Ashley R, et al. Transmission of genital herpes in couples with one symptomatic and one asymptomatic partner: a prospective study. J.Infect Dis 1988;157:1169-1177.

Mertz G, Benedetti J, Ashley R, Selke S, Corey L. Risk factors for the sexual transmission of genital herpes. Ann Intern Med 1992;116:197-202.

Nahmias AJ, Lee FK, Beckman-Nahmais S. Seroepidemiological and sociological patterns of herpes simplex virus infection in the world. Scan J Infect Dis Suppl 1990;69:19-36.

Ramaswamy M, McDonald C, Smith M, Thomas D, Maxwell S, Tenant-Flowers M, Geretti AM. Diagnosis of genital herpes by real time PCR in routine clinical practice. Sex Transm Infect 2004;80:406-410.

Patel R, Cowan F, Barton S. Advising patients with genital herpes. BMJ 1997;314:85-86.

Straus S, Rooney J, Hallahan C. Acyclovir suppresses subclinical shedding of herpes simplex virus. Ann Intern Med 1996;125:776-777.

VALTREX (valacyclovir hydrochloride) Product Information. June 2005.

Wald A, Barnum G, Selke S, Davis G, Zeh J, Corey L. Acyclovir suppresses asymptomatic shedding of HSV-2 in the genital tract. Abstract, 34th ICAAC, Orlando, FL, 1994.

Wald A, Zeh J, Selke S, et al. Virologic characteristics of subclinical and symptomatic genital herpes infections. N Engl J Med 1995;333:770-775.

Wald A, Corey L, Cone R, Hobson A, Davis G, Zeh J. Frequent genital herpes simplex virus 2 shedding in immunocompetent women: effect of acyclovir treatment. J Clin Invest 1997;99:1092-1097.

Wald A, Zeh J, Selke S, Warren T, et al. Reactivation of genital herpes virus type 2 infection in asymptomatic seropositive persons. N Engl J Med 2000;342:844-850.

Wald A, Zeh J, Selke S, Warren T, Ashley R, Corey L. Genital shedding of herpes simplex virus among men. J Infect Dis 2002;186:S34-S39.

Xu, F. Trends in Herpes Simplex Virus Type 2 infection in the United States. CDC. NHANES 1999-2002. 42nd annual meeting of Infectious Diseases Society of America. Oral Presentation, Boston 2004.

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Appendices

Appendix 1 Time and Events RM2005/00481/00 Screen Randomization Treatment Arm 1 Washout Treatment Arm 2 GH [15 days between visits] [15 days between visits] Recurrence Visit No. 1 2 3 4 5 6 7 8 9 10 Within 21 days of Day 1 Day Day Day Day 7 days Day Day Day Day 60 Recurrence Description of Activity randomization 15 30 45 60 15 30 45 End of Study Visit Clinic Visit X X X X X X X X X X X Written Informed Consent X HSV-1 and HSV-2 Serology X Hematology and Clinical Chemistry X X X Urinalysis X X X Pregnancy Test1 X X X X Demographic Data X Current Medical Conditions X CONFIDENTIAL Genital Examination X2 X X Investigational product Dispensed X X X X X X X X Investigational product Accountability X X X X X X X X X 47 Diary Dispensed X Diary Review X X X X X X X X X Education/Counseling on Genital Herpes X X X X X X X X X X Telephone Contact to Subject X Dispense and/or Collect Genital/Anal-rectal Swabs for X X X X X X X X X X X HSV-2 PCR Analysis3 Collect Lesion Swab for HSV-2 PCR Analysis X4 X Collect Viral Swab for HSV culture X5 X Open-label VALTREX Dispensed for treatment of GH X recurrence Adverse Events6 X X X X X X X X X X X X Concomitant Medications X X X X X X X X X X X RM2007/00260/00 1. A pregnancy test (serum hCG at screen; urine hCG at randomization) will be performed at the visits indicated and at any other time pregnancy is suspected. 2. A genital examination must be conducted at the screening visit for subjects who present with genital herpes signs or symptoms VLX105832 3. The subject will collect viral swabs daily during each entire 60-day treatment period, and the washout period. 4. Viral swab for HSV-2 PCR will be obtained at screen for subjects who present with a genital herpes lesion at screen. 5. Viral swab for HSV culture will be obtained at screen for subjects who present with a genital herpes lesion at screen. 6. SAEs due to study participation will be collected between the screening and randomization visit.

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Appendix 2 Study Schematic Figure

21 days 60 days 7 days 60 days

Washout Valtrex 1g QD Valtrex 1g QD

Placebo QD Placebo QD

Screening Visit Clinic Visits Clinic Visits 15 days apart 15 days apart

Randomization

Visit

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Appendix 3 Flowchart to Determine Subject Eligibility

HSV-2 seropositive at Screen

Documented GH signs and symptoms present at screen OR any time since initial diagnosis that occurred within 4 months of randomization*

YES NO

ENROLL DO NOT ENROLL

Subject must be: HSV-2 seropositive at screen with documented clinical signs and symptoms consistent with genital herpes at screen OR HSV-2 seropositive at screen with documented clinical signs and symptoms consistent with genital herpes within 4 months prior to randomization

* GH signs/symptoms must be observed and documented at some time between initial diagnosis and screen

FLOWCHART CONTINUED ON NEXT PAGE

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Appendix 3 Flowchart to determine Subject Eligibility (Continued)

HSV-2 seronegative at Screen

Positive HSV-2 culture or PCR at screen OR at any time since initial diagnosis within 4 months of randomization*

YES NO

Documented clinical signs and symptoms consistent with genital herpes at screen or DO NOT ENROLL within 4 months prior to randomization

YES NO

ENROLL DO NOT ENROLL

Subject must be: HSV-2 seronegative at screen, AND HSV-2 culture positive or HSV-2 PCR positive at screen or within 4 months prior to randomization, with: documented clinical signs and symptoms consistent with genital herpes at screen OR documented clinical signs and symptoms consistent with genital herpes within 4 months prior to randomization

* GH signs/symptoms must be observed and documented at some time between initial diagnosis and screen

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Appendix 4 Genital Herpes Lesion Stages

Prodrome: ‘warning symptoms’; sensations such as localized itching, tingling, burning, or vague discomfort. Also leg/buttock pain, headache, cold/flu-like feeling

Macule/papule: erythema (redness) or elevation of skin without fluid (swelling)

Vesicle/pustule/ulcer: blister, fluid-filled or collapsed

Crust: wet then dry

Healed: re-epithelialization, no crust, swelling, or ulceration. Eythema or flat residual scar tissue may be present

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Appendix 5 Decision Tree for Suspected TMA

1. Was hemoglobin <13.5g/dL (if subject is male) or <11.5g/dL (if subject is female)? Yes No (Subject does not have TMA) 2. Was platelet count <150,000/mm3 (<150 x 109/L)? Yes No (Subject does not have TMA) 3. Did subject have fragmented red cells (schistocytes) on peripheral smear? Yes No (Subject does not have TMA) 4. Did subject have a renal abnormality (hematuria >trace, proteinuria >1+, or serum creatinine > upper limits of the references range)? Yes No 5. Did subject have both a neurological abnormality AND fever (≥38°C)? Yes No 6. Were the answers to questions 1, 2, 3, and 4, or the answers to 1, 2, 3 and 5 ALL yes?

If Yes: If No: The diagnosis of TMA should be Subject does not meet all criteria for TMA. considered in this subject if the above events occurred at In your medical opinion, do you suspect this event to approximately the same time. be a serious case of TMA? Submit SAE Report Form (including TMA Supplemental pages) to sponsor within 48 Yes hours. No If Yes, submit SAE Report Form and If No, do you consider any of the above TMA Supplemental pages to sponsor events, in and of themselves, to be within 48 hours adverse events? Yes No If Yes, report the If No, no further event as AEs or action required SAEs, accordingly

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Appendix 6 Country Specific Requirements

There are no country-specific requirements.

53 Annotated Trial Design Page 1 of 62

GSK

Annotated Design For Trial 'vlx105832_yz705'

Protocol: VLX105832

Generated By InForm Architect®

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1 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 2 of 48

Time and Events Schedule For Trial 'vlx105832_yz705'

Assessment CRF SCREENING SUBJECT END OF Conflict RANDOMIZATION TREATMENT TREATMENT TREATMENT TREATMENT TREATMENT TREATMENT TREATMENT TMA - SERIOUS (Screening) LOGS STUDY (Conflict) (Random) ARM 1- DAY 15 ARM 1- DAY 30 ARM 1 - DAY 45 ARM 1 - DAY 60 ARM 2 - DAY 15 ARM 2 - DAY 30 ARM 2 - DAY 45 ADVERSE [ S ] (LOGS) (END) [ U/R/D ] [ S/D ] (VISIT 3) (VISIT 4) (VISIT 5) (VISIT 6) (VISIT 7) (VISIT 8) (VISIT 9) EVENTS [ S ] [ S ] [ S/D ] [ S/D ] [ S/D ] [ S/D ] [ S/D ] [ S/D ] [ S/D ] (TMA SAE) [ S/D ] 1 DATE OF VISIT/ASSESSMENT DOV 1 1 1 1 1 1 1 1 1 1 1 1 2 SUBJECT IDENTIFICATION SUB ID 2 3 ELIGIBILITY QUESTION ELIG 3 4 DEMOGRAPHY DEMOG 4 5 SCREEN FAILURE SCRNFAIL 5 6 GENITAL EXAM GENEXAM 6-DF 4 7 NON-SERIOUS ADVERSE AE 2-C-RF-DF EVENT 8 SERIOUS ADVERSE EVENTS SAE 3-C-RF 9 CONCOMITANT CONMEDS 4-C-RF-DF MEDICATIONS 10 INVESTIGATIONAL PRODUCT IP 5-RF-DF 11 INVESTIGATIONAL PRODUCT IPCOMP 6-RF-DF COMPLIANCE 12 GENITAL HERPES HERP_RECUR 7-RF-DF RECURRENCES 13 CLINICAL VISIT ASSESSMENT HERP_ASMT 2-DF 2 2 2 2 2 2 2 14 PREGNANCY INFORMATION PREG 3-DF

15 STATUS OF TREATMENT BLIND 4-DF CONFIDENTIAL BLIND 16 INVESTIGATIONAL PRODUCT IP DISC 5-DF DISCONTINUATION 17 STUDY CONCLUSION CONC 6-DF 2 18 INVESTIGATOR SIGNATURE SIGN 7 19 VITAL SIGNS VS 2 20 MEDICAL CONDITIONS MEDHX 3 21 INITIAL DIAGNOSIS OF HERPES_DIAG 5 GENITAL HERPES 22 ORAL HERPES/COLD SORE ORAL_HERP 6 RECURRENCE HISTORY HX 23 RANDOMISATION NUMBER RAND 7 24 INVESTIGATIONAL PRODUCT PACK 8 3 3 3 3 3 3 3 CONTAINER NUMBER 25 SUPPLEMENTAL PAGES FOR TMA SAE1 2 TMA SAEs 26 SUPPLEMENTAL PAGES FOR TMA SAE2 3 TMA SAEs (Continued) 27 LOCAL LABORATORY - CHEM 4 CLINICAL CHEMISTRY

28 LOCAL LABORATORY - HAEMA 5 RM2007/00260/00 HAEMATOLOGY

Key: [S] = Scheduled Visit [O] = Optional Visit [D] = Dynamic Visit [U] = Unscheduled Visit [R] = Repeating Visit C = Common Form DF = Dynamic Form RF = Repeating Form

VLX105832

6/14/2007 Annotated Trial Design Page 4 of 62

FORM: INFORM SCREENING (SCREEN) TRIAL: vlx105832_yz705

INFORM SCREENING 1.* Subject initials [hidden] A3 (MAPPINGS1:t_SCREEN.txtScrSINIT)

2. Date of birth Req / Req / Req (1900-2005) (MAPPINGS1:t_SCREEN.BIRTHDT)

3. What is the primary method that prompted the subject's interest in the study? (MAPPINGS1:t_SCREEN.rdcMETHOD) [1] Clinic patient (site actively reviews patient charts and/or databases and initiates contact with patient). [2] Physician referral (e.g., lunch-n-learn, letter to colleagues, etc.) [4] Referred by study participant [17] Referred by other individual [5] Subject-initiated internet search (e.g. discovered findclinicalstudy.com) [7] Information in clinic (e.g., posters, brochure, etc.) [8] Community outreach (e.g., healthfair, advocacy groups, support groups, etc.) [9] Local newspaper advertisement [10] Local radio advertisement [11] Other local paid advertisement (e.g., local television, local direct mail, etc.) [OT] Other, specify (MAPPINGS1:t_SCREEN.METHODOTH) A200 CONFIDENTIAL

* Item is not required

Form Design Note:

IDSL Version 02.01B - 01 DEC 05 Trial designers must use this form as specified here. Allowed changes are mentioned in the particular item level notes.

Item Design Notes:

Item Design Note No.

1. This item is hidden to all users and will be autopopulated by the system as "---"

2. Will be automatically mapped to demography form RM2007/00260/00

3. This item is optional. Select only choices that are applicable to the study. Study-specific criteria may be added as needed. More than one study-specific criterion may be added if needed, however it must be a unique reason not already listed.

VLX105832

CDD: MAPPINGS1 Table: t_SCREEN Key Type: PATIENTVISIT Column Name Column Data Type Design Note txtScrSINIT STRING(3) - A3 BIRTHDT DATE - DDMONYYYY Annotated Trial Design Page 5 of 62

rdcMETHOD STRING(2) METHODOTH STRING(200) - A200

CONFIDENTIAL 4 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 6 of 62

FORM: INFORM ENROLLMENT (ENROL) TRIAL: vlx105832_yz705

SUBJECT NUMBER 1. Subject number A6 (MAPPINGS1:t_ENROL.mtxtSubjectNumber)

Form Design Note:

IDSL Version 01.01B - 13 JUN 05

Item Design Notes:

Item No. Design Note

1. Subject number will be entered on the ENROL form and will be mapped to the SUBID form, where it can be changed if needed.

CDD: MAPPINGS1 Table: t_ENROL Key Type: PATIENTVISIT CONFIDENTIAL Column Name Column Data Type Design Note mtxtSubjectNumber STRING(6) - A6 5

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 7 of 62

FORM: DATE OF VISIT/ASSESSMENT (DOV) TRIAL: vlx105832_yz705

Record details of any new adverse event observed or reported by the subject or any changes to ongoing adverse events in the appropriate Non-Serious Adverse Event/Serious Adverse Event eCRF form in the LOG visit.

Record any changes to the subject's concomitant medication or any new medication taken since the last visit in the appropriate Concomitant Medication eCRF form in the LOG visit. DATE OF VISIT/ASSESSMENT 1. Date of visit/assessment Req / Req / Req (2006-2007) (MAPPINGS1:t_DOV.DOV)

2.* 100% Random Sample SDV Performed on this Subject Visit [hidden] (MAPPINGS1:t_DOV.chkSDVYes) [Y] Yes * Item is not required

Form Design Note:

IDSL Version 02.01A - 01 DEC 05

CONFIDENTIAL CDD: MAPPINGS1 Table: t_DOV Key Type: PATIENTVISIT Column Name Column Data Type Design Note DOV DATE - DDMONYYYY 6 chkSDVYes STRING(255)

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 8 of 62

FORM: SUBJECT IDENTIFICATION (SUB ID) TRIAL: vlx105832_yz705

SUBJECT IDENTIFICATION If Subject number was entered incorrectly, please correct and submit; otherwise disregard

1. Subject number A6 (MAPPINGS1:t_SUBID.mtxtSubjectNumber)

Form Design Note:

IDSL Version 01.00B - 13 JUN 05

Item Design Notes:

Item No. Design Note

1. Subject number will be entered on the ENROL form and will be mapped to the SUBID form, where it can be changed if needed.

CONFIDENTIAL CDD: MAPPINGS1 Table: t_SUBID Key Type: PATIENTVISIT Column Name Column Data Type Design Note 7 mtxtSubjectNumber STRING(6) - A6

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 9 of 62

FORM: ELIGIBILITY QUESTION (ELIG) TRIAL: vlx105832_yz705

ELIGIBILITY QUESTION 1. Did the subject meet all the entry criteria? (MAPPINGS1:t_ELIG.IEELIG) [Y] Yes [N] No, please select all boxes corresponding to violations of any inclusion/exclusion criteria

Inclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUMI01) [I01] Inclusion Criteria 1 (MAPPINGS1:t_ELIG.IECRTNUMI02) [I02] Inclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUMI03) [I03] Inclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUMI04) [I04] Inclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUMI05) [I05] Inclusion Criteria 5

Exclusion Criteria

(MAPPINGS1:t_ELIG.IECRTNUME01) [E01] Exclusion Criteria 1 CONFIDENTIAL (MAPPINGS1:t_ELIG.IECRTNUME02) [E02] Exclusion Criteria 2 (MAPPINGS1:t_ELIG.IECRTNUME03) 8 [E03] Exclusion Criteria 3 (MAPPINGS1:t_ELIG.IECRTNUME04) [E04] Exclusion Criteria 4 (MAPPINGS1:t_ELIG.IECRTNUME05) [E05] Exclusion Criteria 5 (MAPPINGS1:t_ELIG.IECRTNUME06) [E06] Exclusion Criteria 6 (MAPPINGS1:t_ELIG.IECRTNUME07) [E07] Exclusion Criteria 7 (MAPPINGS1:t_ELIG.IECRTNUME08) [E08] Exclusion Criteria 8 (MAPPINGS1:t_ELIG.IECRTNUME09) [E09] Exclusion Criteria 9 (MAPPINGS1:t_ELIG.IECRTNUME10) [E10] Exclusion Criteria 10 (MAPPINGS1:t_ELIG.IECRTNUME11)

[E11] Exclusion Criteria 11 RM2007/00260/00 (MAPPINGS1:t_ELIG.IECRTNUME12) [E12] Exclusion Criteria 12 Do not admit the subject into this study if any Inclusion / Exclusion criteria is checked unless an exception has (MAPPINGS1:t_ELIG.txtEligExempt)

been granted by the GSK Medical Monitor and subject is continuing in the study. Please clarify the exemption(s) VLX105832 below A200

Annotated Trial Design Page 10 of 62

CDD: MAPPINGS1 Table: t_ELIG Key Type: PATIENTVISIT Column Name Column Data Type Design Note IEELIG STRING(1) IECRTNUMI01 STRING(255) IECRTNUMI02 STRING(255) IECRTNUMI03 STRING(255) IECRTNUMI04 STRING(255) IECRTNUMI05 STRING(255) IECRTNUME01 STRING(255) IECRTNUME02 STRING(255) IECRTNUME03 STRING(255) IECRTNUME04 STRING(255) IECRTNUME05 STRING(255) IECRTNUME06 STRING(255) IECRTNUME07 STRING(255) CONFIDENTIAL IECRTNUME08 STRING(255) IECRTNUME09 STRING(255)

9 IECRTNUME10 STRING(255) IECRTNUME11 STRING(255) IECRTNUME12 STRING(255) txtEligExempt STRING(200) - A200

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 11 of 62

FORM: DEMOGRAPHY (DEMOG) TRIAL: vlx105832_yz705

DEMOGRAPHY 1. Date of birth Req / Req / Req (1900-2005) (MAPPINGS1:t_DEMO.BIRTHDT)

2. Sex (MAPPINGS1:t_DEMO.SEX1) [M] Male [F] Female 3. Ethnicity (MAPPINGS1:t_DEMO.ETHNICCD) [1] Hispanic or Latino [2] Not Hispanic or Latino 4. Geographic Ancestry Check all that apply (MAPPINGS1:t_DEMO.RACECCD11) [11] African American/African Heritage (MAPPINGS1:t_DEMO.RACECCD12) [12] American Indian or Alaskan Native (MAPPINGS1:t_DEMO.RACECCD13) [13] Asian - Central/South Asian Heritage (MAPPINGS1:t_DEMO.RACECCD14) [14] Asian - East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD15)

[15] Asian - Japanese Heritage CONFIDENTIAL (MAPPINGS1:t_DEMO.RACECCD16) [16] Asian - South East Asian Heritage (MAPPINGS1:t_DEMO.RACECCD17)

10 [17] Native Hawaiian or Other Pacific Islander (MAPPINGS1:t_DEMO.RACECCD18) [18] White - Arabic/North African Heritage (MAPPINGS1:t_DEMO.RACECCD19) [19] White - White/Caucasian/European Heritage

Form Design Note:

IDSL Version 01.01B - 01 DEC 05

Item Design Notes:

Item No. Design Note RM2007/00260/00

1. Will be automatically mapped to demography form

2. This item is conditional; Use it if you DO NOT need to collect childbearing potential information; Remove the other Sex item VLX105832

CDD: MAPPINGS1 Table: t_DEMO Key Type: PATIENTVISIT Column Name Column Data Type Design Note BIRTHDT DATE - DDMONYYYY Annotated Trial Design Page 12 of 62

SEX1 STRING(1) ETHNICCD STRING(1) RACECCD11 STRING(255) RACECCD12 STRING(255) RACECCD13 STRING(255) RACECCD14 STRING(255) RACECCD15 STRING(255) RACECCD16 STRING(255) RACECCD17 STRING(255) RACECCD18 STRING(255) RACECCD19 STRING(255)

CONFIDENTIAL 11 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 13 of 62

FORM: SCREEN FAILURE (SCRNFAIL) TRIAL: vlx105832_yz705

SCREEN FAILURE 1. Was this subject a screen failure? (MAPPINGS1:t_SCRNFAIL.SFFAIL) [N] No [Y] Yes, complete the following:

Date of screen failure Req / Req / Req (2006-2007) (MAPPINGS1:t_SCRNFAIL.SFDT) (MAPPINGS1:t_SCRNFAIL.SFREASCD)

Select primary reason [1] Adverse Event Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate. [2] Lost to follow-up [3] Protocol violation [4] Subject decided to withdraw from the study [6] Did not fulfill eligibility criteria [OT] Other, specify (MAPPINGS1:t_SCRNFAIL.SFRSOTH) A200 CONFIDENTIAL

Form Design Note:

IDSL Version 02.00A - 22AUG05 The terms 'run-in failure', 'screen failure' & 'subject not randomised' are optional - select the term required for your study. All the reasons for withdrawal are optional - select the reasons as per the protocol.

Section Design Notes:

Title Design Note

SCREEN FAILURE The terms 'Run-In Failure', 'Screen Failure' & 'Subject Not Randomised' are optional - select the term required for your study.

RM2007/00260/00 Item Design Notes:

Item No. Design Note VLX105832

1. This item is conditional. Additional reason codes from codelist to be added by study team as required.

CDD: MAPPINGS1 Table: t_SCRNFAIL Key Type: PATIENTVISIT Column Name Column Data Type Design Note Annotated Trial Design Page 14 of 62

SFFAIL STRING(1) SFDT DATE - DDMONYYYY SFREASCD STRING(2) SFRSOTH STRING(200) - A200

CONFIDENTIAL 13 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 15 of 62

FORM: GENITAL EXAM (GENEXAM) TRIAL: vlx105832_yz705

GENITAL EXAM 1. Was a genital examination performed on the (MAPPINGS1:t_GENEXAM.GENEXM) subject? [N] No [Y] Yes If Yes, complete the following.

(MAPPINGS1:t_GENEXAM.LSPRES) Were any herpes lesions present? [N] No [Y] Yes (MAPPINGS1:t_GENEXAM.GENABN) Were any other abnormal findings present? [N] No [Y] Yes, specify A200 (MAPPINGS1:t_GENEXAM.GENABNSP)

CDD: MAPPINGS1 Table: t_GENEXAM Key Type: PATIENTVISIT Column Name Column Data Type Design Note CONFIDENTIAL GENEXM STRING(1) LSPRES STRING(1)

14 GENABN STRING(1) GENABNSP STRING(200) - A200

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 16 of 62

FORM: NON-SERIOUS ADVERSE EVENT (AE) TRIAL: vlx105832_yz705 New

# Event Start Date Outcome Maximum Intensity Action Taken Subject Withdrawn? Relationship 1

NON-SERIOUS ADVERSE EVENT 1.* Sequence Number [hidden] A5 (MAPPINGS1:t_AE.AESEQ)

2. Event A100 (MAPPINGS1:t_AE.AETERM) Diagnosis Only (if known) Otherwise Sign/Symptom

* Modified term [hidden] (MAPPINGS1:t_AE.AEMODIFY) 3. A100 (AE_CODE:0.CommonCRF.AE.sctAE.0.itmAELLTCD.AELLTCD) (AE_SYNONYM:0.CommonCRF.AE.sctAE.0.itmAEMEDSYN.AEMEDSYN) (AE_FAILED:0.CommonCRF.AE.sctAE.0.itmAE_FAILED.calAE_FAILED)

MedDRA synonym [hidden] (MAPPINGS1:t_AE.AEMEDSYN) MedDRA lower level term code [hidden] (MAPPINGS1:t_AE.AELLTCD) Failed coding [hidden] (MAPPINGS1:t_AE.calAE_FAILED) CONFIDENTIAL 4. Start Date Req / Req / Req (2006-2007) (MAPPINGS1:t_AE.AESTDTTM)

5. Outcome / End Date (MAPPINGS1:t_AE.AEOUTCD) 15 [1] Recovered/Resolved, provide End Date Req / Req / Req (2006-2007) (MAPPINGS1:t_AE.AEENDTTM1) [2] Recovering/Resolving [3] Not recovered/Not resolved [4] Recovered/Resolved with sequelae, provide End Date Req / Req / Req (2006-2007) (MAPPINGS1:t_AE.AEENDTTM2)

6. Maximum Intensity (MAPPINGS1:t_AE.AESEVCD) [1] Mild [2] Moderate [3] Severe [X] Not applicable

7.* Maximum Toxicity [hidden] (MAPPINGS1:t_AE.AETOXCD) [1] Grade 1 [2] Grade 2 RM2007/00260/00 RM2007/00260/00 [3] Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable VLX105832 VLX105832 8.* Maximum Toxicity or Intensity [hidden] (MAPPINGS1:t_AE.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable 9. Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE.AEACTRCD) Annotated Trial Design Page 17 of 62

[1] Investigational product(s) withdrawn [4] Dose not changed [5] Dose interrupted [X] Not applicable 10. Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE.AEWD) [Y] Yes [N] No 11. Is there a reasonable possibility that the AE may have been caused by the (MAPPINGS1:t_AE.AEREL) investigational product? [Y] Yes [N] No

12.* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 ) (MAPPINGS1:t_AE.AEDURHR) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE.AEDURMIN) Hr(s) Min(s)

13.* Time to Onset Since Last Dose [hidden] xx (MAPPINGS1:t_AE.AEONLDSH) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE.AEONLDSM) Hr(s) Min(s) * Item is not required

Form Design Note: CONFIDENTIAL IDSL Version 03.01A - 16 NOV 2005

16 Item Design Notes:

Item No. Design Note

4. Start Time is optional

5. End Time is optional

6. Optional item: This item may be hidden if either the "Maximum Toxicity" or "Maximum Toxicity or Intensity" item has been used. Grade 5 is optional.

7. Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity or Intensity" item has been used Grade 5 is optional.

8. Optional item: RM2007/00260/00 This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity" item has been used Grade 5 is optional.

12. If AE start and end time are used this item must be hidden. VLX105832

13. This item is optional

CDD: MAPPINGS1 Table: t_AE Key Type: PATIENTVISIT Column Name Column Data Type Design Note Annotated Trial Design Page 18 of 62

AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY AEOUTCD STRING(1) AEENDTTM1 DATE - DDMONYYYY AEENDTTM2 DATE - DDMONYYYY AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) AEWD STRING(1) CONFIDENTIAL AEREL STRING(1) AEDURHR NUMERIC - N2

17 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 19 of 62

FORM: SERIOUS ADVERSE EVENTS (SAE) TRIAL: vlx105832_yz705 New

If Investigational Relevant product(s) stopped, Did SAE occur RELEVANT Follow- SERIOUS RELEVANT Medical RELEVANT Relevant did the reported event General Initial after initiation MEDICAL # Up ADVERSE Serious? CONCOMITANT/TREATMENT History / DIAGNOSTIC diagnostic (s) recur after further narrative Report of study CONDITIONS/RISK Report EVENT MEDICATIONS Risk RESULTS results investigational comments medication? FACTORS Factors product(s) were administered? 1

If you wish to record a new SAE please determine if the new SAE is clinically or temporally related to an SAE previously entered on this form. If yes, please record details below. If no, please create a new SAE form for this subject. Do not record pre and post randomisation events on the same form. TYPE OF REPORT 1.* Initial Report [read-only] (MAPPINGS1:t_AE_SER.chkSAE) [1] Initial

2.* Follow-Up Report [read-only] (MAPPINGS1:t_AE_SER.chkFU) [2] Follow-Up CONFIDENTIAL RANDOMISATION 3. Did SAE occur after initiation of study medication? (MAPPINGS1:t_AE_SER.rdcSAERAND) [N] No 18 [Y] Yes MedDRA Maximum Duration Was SAE lower Was the Modified MedDRA Failed Start Maximum Maximum Toxicity Action Subject of AE if Time to SAE Sequence Event level Outcome Relationship event term synonym coding Date Intensity Toxicity or Taken Withdrawn? < 24 Onset study Number term serious? Intensity hours related? code 4. [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden] [hidden]

SERIOUS ADVERSE EVENT Entry Add Entry

4.a* SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESEQ)

4.b Serious Adverse Event A100 (MAPPINGS1:t_AE_SER.AETERM) Diagnosis Only (if known) Otherwise Sign/Symptom RM2007/00260/00 RM2007/00260/00 * Modified term [hidden] (AE_FAILED1:0.CommonCRF.AE_SER.sctSAE.itsSAE.itmAE_FAILED.calAE_FAILED) 4.c A100 (AE_CODE1:0.CommonCRF.AE_SER.sctSAE.itsSAE.itmAELLTCD.AELLTCD) (AE_SYNONYM1:0.CommonCRF.AE_SER.sctSAE.itsSAE.itmAEMEDSYN.AEMEDSYN) (MAPPINGS1:t_AE_SER.AEMODIFY)

(MAPPINGS1:t_AE_SER.AEMEDSYN)

MedDRA synonym [hidden] VLX105832 MedDRA lower level term code [hidden] (MAPPINGS1:t_AE_SER.AELLTCD) Failed coding [hidden] (MAPPINGS1:t_AE_SER.calAE_FAILED)

4.d Start Date Req / Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AESTDTTM)

4.e Outcome / End Date (MAPPINGS1:t_AE_SER.AEOUTCD1) [1] Recovered/Resolved, provide End Date Annotated Trial Design Page 20 of 62

Req / Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AEENDTTM1) [2] Recovering/Resolving [3] Not recovered/Not resolved [4] Recovered/Resolved with sequelae, provide End Date Req / Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AEENDTTM2) [5] Fatal, record Date of Death Req / Req / Req (2006-2007) (MAPPINGS1:t_AE_SER.AEENDTTM3)

4.f Maximum Intensity (MAPPINGS1:t_AE_SER.AESEVCD) [1] Mild [2] Moderate [3] Severe [X] Not applicable

4.g* Maximum Toxicity [hidden] (MAPPINGS1:t_AE_SER.AETOXCD) [1] Grade 1 [2] Grade 2 [3] Grade 3 [4] Grade 4 [5] Grade 5 [X] Not applicable

4.h* Maximum Toxicity or Intensity [hidden] (MAPPINGS1:t_AE_SER.AETXHVCD) [1] Mild or Grade 1 [2] Moderate or Grade 2 CONFIDENTIAL [3] Severe or Grade 3 [4] Grade 4 [5] Grade 5 19 [X] Not applicable 4.i Action Taken with Investigational Product(s) as a Result of the AE (MAPPINGS1:t_AE_SER.AEACTRCD) [1] Investigational product(s) withdrawn [4] Dose not changed [5] Dose interrupted [X] Not applicable 4.j Did the subject withdraw from study as a result of this AE? (MAPPINGS1:t_AE_SER.AEWD) [Y] Yes [N] No 4.k Is there a reasonable possibility that the AE may have been caused (MAPPINGS1:t_AE_SER.AEREL) by the investigational product? [Y] Yes [N] No

4.l* Duration of AE if < 24 hours [hidden] xx ( 0 =< n <= 23 ) (MAPPINGS1:t_AE_SER.AEDURHR) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE_SER.AEDURMIN) Hr(s) Min(s) RM2007/00260/00

4.m* Time to Onset Since Last Dose [hidden] xx (MAPPINGS1:t_AE_SER.AEONLDSH) xx ( 0 =< n <= 59 ) (MAPPINGS1:t_AE_SER.AEONLDSM) Hr(s) Min(s) VLX105832 VLX105832 4.n Was SAE caused by activities related to study participation (e.g. (MAPPINGS1:t_AE_SER.rdcAESREL) procedures)? [Y] Yes [N] No

4.o* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESER) [Y] Yes [N] No SERIOUSNESS Annotated Trial Design Page 21 of 62

Specify the reason for considering this an SAE. Check all that apply. 5. Seriousness? (MAPPINGS1:t_AE_SER.AESERDTH) [A] Results in death (MAPPINGS1:t_AE_SER.AESERLIF) [B] Is life-threatening (MAPPINGS1:t_AE_SER.AESERHOS) [C] Requires hospitalisation or prolongation of existing hospitalisation (MAPPINGS1:t_AE_SER.AESERDIS) [D] Results in disability/incapacity (MAPPINGS1:t_AE_SER.AESERCON) [E] Congenital anomaly/birth defect (MAPPINGS1:t_AE_SER.AESEROTH) [F] Other, specify within general narrative comment Drug Name CM Sequence Primary Dose Unit Frequency Route Start Date Ongoing? Drug Type Number (Trade Name Indication preferred) 6. [hidden]

RELEVANT CONCOMITANT/TREATMENT MEDICATIONS Entry Add Entry

Include details of any medication that may have contributed to the SAE or was used to treat the SAE. 6.a* CM Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAECMSEQ) CONFIDENTIAL

6.b Drug Name A100 (MAPPINGS1:t_AE_SER.txtCMTERM)

20 (Trade Name preferred)

6.c* Dose xxxxxxxxx. (MAPPINGS1:t_AE_SER.txtSAECMDOS)

6.d* Unit Pulldown List 1 (MAPPINGS1:t_AE_SER.pdcCMUNIT)

6.e* Frequency Pulldown List 2 (MAPPINGS1:t_AE_SER.pdcSAECMFRQ)

6.f* Route Pulldown List 3 (MAPPINGS1:t_AE_SER.pdcCMROUTCD)

6.g* Start Date Req/Unk / Req/Unk / Req/Unk (1970-2010) (MAPPINGS1:t_AE_SER.dtmSAECMSTD)

6.h* Ongoing? (MAPPINGS1:t_AE_SER.rdcSAECMONG) [Y] Yes [N] No, specify End Date (1970-2010) (MAPPINGS1:t_AE_SER.dtmSAECMEND) Req/Unk / Req/Unk / Req/Unk RM2007/00260/00

6.i* Primary Indication A50 (MAPPINGS1:t_AE_SER.txtCMIND)

(MAPPINGS1:t_AE_SER.pdcCMDRGTYP) 6.j Drug Type Pulldown List 4 VLX105832

MHx Sequence Number Specific Condition Name Date of onset Continuing? 7. [hidden]

RELEVANT MEDICAL CONDITIONS/RISK FACTORS Entry Add Entry

Specify past or current medical disorders, allergies, surgeries, family or social history that may help explain the SAE Annotated Trial Design Page 22 of 62

7.a* MHx Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtMHXSEQ)

7.b Specific Condition Name A100 (MAPPINGS1:t_AE_SER.txtSAEMHTRM)

7.c* Date of onset Req/Unk / Req/Unk / Req (1970-2010) (MAPPINGS1:t_AE_SER.dtmMHSTDTM)

7.d* Continuing? (MAPPINGS1:t_AE_SER.rdcMHCONT) [Y] Yes [N] No, specify date of last occurrence Req/Unk / Req/Unk / Req (1970-2010) (MAPPINGS1:t_AE_SER.dtmMHLSTOC) [U] Unknown

8.* Relevant Medical History / Risk Factors not noted above A1000

Lab Sequence Number Test Name Test Date Test Result Test Units Normal Low Range Normal High Range 9. [hidden]

RELEVANT DIAGNOSTIC RESULTS Entry Add Entry CONFIDENTIAL

Provide details of any tests or procedures carried out to diagnose the SAE. 9.a* Lab Sequence Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAELBSEQ) 21

9.b Test Name Pulldown List 5 (MAPPINGS1:t_AE_SER.pdcLBTST)

9.c Test Date Req/Unk / Req/Unk / Req (2003-2010) (MAPPINGS1:t_AE_SER.dtmLABDTM)

9.d Test Result A50 (MAPPINGS1:t_AE_SER.txtLABRES)

9.e* Test Units A35 (MAPPINGS1:t_AE_SER.txtLABUNIT)

9.f* Normal Low Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNLR)

9.g* Normal High Range xxxxxxx. (MAPPINGS1:t_AE_SER.txtLABNHR)

10.* Relevant diagnostic results not noted above A1000 RM2007/00260/00 RM2007/00260/00

A1000 VLX105832 VLX105832

INVESTIGATIONAL PRODUCTS 11.* If Investigational product(s) stopped, did the reported event(s) recur after further investigational product (MAPPINGS1:t_AE_SER.rdcSAEIP) (s) were administered? [N] No Annotated Trial Design Page 23 of 62

[Y] Yes [U] Unknown at this time [X] Not applicable GENERAL NARRATIVE COMMENTS Provide a brief narrative description of SAE, possible other causes of the event (e.g. lack of efficacy, withdrawal of investigational product, the disease under study or other medical conditions) and details of the treatment. 12. General narrative comments A1000

A1000

NON CLINICAL 13.* Send incomplete SAE data to GSK Safety [hidden] (MAPPINGS1:t_AE_SER.chkSAESENDI) [3] Incomplete SAE

* (2004-2010) (MAPPINGS1:t_AE_SER.dtmSAEDTM) 14. Receipt by GSK date [hidden] Req / Req / Req CONFIDENTIAL Req : Req

15.* Was the event serious? [hidden] (MAPPINGS1:t_AE_SER.AESE1) 22 [Y] Yes [N] No

16.* SAE Sequence Number [hidden] A5 (MAPPINGS1:t_AE_SER.AESE2)

17.* Version Number [hidden] A4 (MAPPINGS1:t_AE_SER.txtSAEVERSION)

18.* Case ID [hidden] A20 (MAPPINGS1:t_AE_SER.txtSAEID)

19.* Randomisation Number [hidden] A255 (MAPPINGS1:t_AE_SER.txtSAERNDNO)

20.* OCEANS Code [hidden] A12 (MAPPINGS1:t_AE_SER.txtOCEANSCD)

Email Flag [hidden] (MAPPINGS1:t_AE_SER.calSAEEmailFlag) * Item is not required

RM2007/00260/00

Form Design Note: VLX105832 VLX105832 Version 05.00A - 08 DEC 2005

Item Design Notes:

Item No. Design Note Annotated Trial Design Page 24 of 62

4.d Start Time is optional

4.e End Time is optional

4.f Optional item: This item may be hidden if either the "Maximum Toxicity" or "Maximum Toxicity or Intensity" item has been used. Grade 5 is optional.

4.g Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity or Intensity" item has been used Grade 5 is optional.

4.h Optional item: This item may be hidden if either the "Maximum Intensity" or "Maximum Toxicity" item has been used Grade 5 is optional.

4.l If AE start and end time are used this item must be hidden.

4.m This item is optional

5. Optional Criterion G is an optional criterion and may be removed

13. This item is optional

CONFIDENTIAL

Pulldown List 1: 23 RefName Display Text Value Design Note estrSaeUnitACTU Actuation ACTU estrSaeUnitAMP Ampoule AMP estrSaeUnitAPP Application AP estrSaeUnitBOT Bottle BT estrSaeUnitCAP Capsule CAP estrSaeUnitCC Cubic centimeter CC estrSaeUnitGTT Drops 031 estrSaeUnitGM Gram 002 estrSaeUnitIU International units 025 RM2007/00260/00 RM2007/00260/00 estrSaeUnitIUKG International units per kilogram 028 estrSaeUnitIUML International units per millilitre IUML

estrSaeUnitL Litre 011 VLX105832 estrSaeUnitLPM Litre per minute LM estrSaeUnitLOZ Lozenge LOZ estrSaeUnitMU Megaunits (million units) MEGU estrSaeUnitMCG Microgram (MCG) 004 estrSaeUnitUG Microgram (UG) 004 Annotated Trial Design Page 25 of 62

estrSaeUnitMCGKG Microgram/kilogram 008 estrSaeUnitMCGKGMIN Microgram/kilogram per minute MCG/KG/MIN estrSaeUnitMCGMIN Micrograms per minute MCG/MIN estrSaeUnitMCL Microlitre 013 estrSaeUnitMEQ Milliequivalent 029 estrSaeUnitMEQ24HR Milliequivalent per 24 hours MEQ24 estrSaeUnitMG Milligram 003 estrSaeUnitMGPER Milligrams percent MGPER estrSaeUnitMGHR Milligram per hour MGH estrSaeUnitMGKG Milligram/kilogram 007 estrSaeUnitMGKGHR Milligram/kilogram per hour MGKH estrSaeUnitMGKGMIN Milligram/kilogram per minute MGKM estrSaeUnitMGM2 Milligram/metre squared 009 estrSaeUnitMGML Milligram/millilitre MGML estrSaeUnitML Millilitre 012 CONFIDENTIAL estrSaeUnitMLHR Millilitre per hour MLH estrSaeUnitMLMIN Millilitre per minute MLM

24 estrSaeUnitMMOL Millimole 023 estrSaeUnitMIU Million international units 027 estrSaeUnitMAC Minimum alveolar concentration MAC estrSaeUnitNEB Nebule NEB estrSaeUnitPATCH Patch PAT estrSaeUnitPer Percent 030 estrSaeUnitPUFF Puff PUFF estrSaeUnitSACH Sachet SAC estrSaeUnitSP Spray SPR estrSaeUnitSUPP Suppository SUP RM2007/00260/00 RM2007/00260/00 estrSaeUnitTBSP Tablespoon TBS estrSaeUnitTAB Tablet TAB

estrSaeUnitTSP Teaspoon TSP VLX105832 estrSaeUnitUNIT Units UNT estrSaeUnitUNK Unknown U estrSaeUnitVIAL Vial VIA

Annotated Trial Design Page 26 of 62

Pulldown List 2: RefName Display Text Value Design Note estrSaeFreq2XWK 2 times per week 2W estrSaeFreq3XWK 3 times per week 3W estrSaeFreq4XWK 4 times per week 4W estrSaeFreq5XD 5 times per day 5D estrSaeFreq5XWK 5 times per week 5W estrSaeFreqAC AC AC estrSaeFreqBID BID 2D estrSaeFreqCINF Continuous infusion CO estrSaeFreqQ2WK Every 2 weeks FO estrSaeFreqQ3WK Every 3 weeks Q3WK estrSaeFreqQ3M Every 3 months Q3M estrSaeFreqQOD Every other day AD estrSaeFreqHS At Bedtime 1N CONFIDENTIAL estrSaeFreqQM Once a month MO estrSaeFreqQWK Once a week WE

25 estrSaeFreqQD Once daily 1D estrSaeFreqONE Once only 1S estrSaeFreqPC PC PC estrSaeFreqPRN PRN PRN estrSaeFreqQ2H Q2H 12D estrSaeFreqQ3D Q3D Q3D estrSaeFreqQ4D Q4D Q4D estrSaeFreqQ4H Q4H 6D estrSaeFreqQ6H Q6H 4D estrSaeFreqQ8H Q8H 3D RM2007/00260/00 RM2007/00260/00 estrSaeFreqQ12H Q12H 2D estrSaeFreqQAM QAM 1M

estrSaeFreqQH QH 24D VLX105832 estrSaeFreqQID QID 4D estrSaeFreqQPM QPM 1N estrSaeFreqTID TID 3D estrSaeFreqUNK Unknown U

Annotated Trial Design Page 27 of 62

Pulldown List 3: RefName Display Text Value Design Note estrSaeRouteOU Both eyes 047 estrSaeRouteEP Epidural 008 estrSaeRouteGTT Gastrostomy tube GT estrSaeRouteIH Inhalation 055 estrSaeRouteINJ Injection INJ estrSaeRouteIA Intra-arterial 013 estrSaeRouteIB Intra-bursa IBU estrSaeRouteIL Intralesional 026 estrSaeRouteIM Intramuscular 030 estrSaeRouteIN Intranasal 045 estrSaeRouteIO Intraocular 031 estrSaeRouteIOS Intraosteal IOS CONFIDENTIAL estrSaeRouteIP Intraperitoneal 033 estrSaeRouteIT Intrathecal 037

26 estrSaeRouteIU Intrauterine 015 estrSaeRouteIV Intravenous 042 estrSaeRouteNS Nasal 045 estrSaeRoutePO Oral 048 estrSaeRoutePR Rectal 054 estrSaeRouteSC Subcutaneous 058 estrSaeRouteSL Sublingual 060 estrSaeRouteTP Topical 061 estrSaeRouteTD Transdermal 062 estrSaeRouteUNK Unknown 065

estrSaeRouteVG Vaginal 067 RM2007/00260/00

Pulldown List 4: VLX105832 RefName Display Text Value Design Note estrDRUGTYPE01 Concomitant 2 estrDRUGTYPE02 Treatment T estrDRUGTYPE03 Cause of SAE 1

Annotated Trial Design Page 28 of 62

Pulldown List 5: RefName Display Text Value Design Note estrSAELBTST01 Activated partial thromboplastin time Activated partial thromboplastin time estrSAELBTST02 Albumin Albumin estrSAELBTST03 Alkaline phosphatase Alkaline phosphatase estrSAELBTST04 Amylase Amylase estrSAELBTST05 Basophils Basophils estrSAELBTST06 Bicarbonate Bicarbonate estrSAELBTST07 Bilirubin Bilirubin estrSAELBTST08 Bilirubin direct Bilirubin direct estrSAELBTST09 Bilirubin total Bilirubin total estrSAELBTST10 Blood myoglobin Blood myoglobin estrSAELBTST11 Blood pH Blood pH estrSAELBTST12 Blood pressure Blood pressure CONFIDENTIAL estrSAELBTST13 Blood urea nitrogen Blood urea nitrogen estrSAELBTST14 Body temperature Body temperature

27 estrSAELBTST15 Calcium Calcium estrSAELBTST16 CD4 lymphocytes CD4 lymphocytes estrSAELBTST17 CD8 lymphocytes CD8 lymphocytes estrSAELBTST18 Chloride Chloride estrSAELBTST19 Cholesterol total Cholesterol total estrSAELBTST20 C-reactive protein C-reactive protein estrSAELBTST21 Creatine Creatine estrSAELBTST22 Creatine phosphokinase Creatine phosphokinase estrSAELBTST23 Creatine phosphokinase MB Creatine phosphokinase MB estrSAELBTST24 Creatinine Creatinine

estrSAELBTST25 Creatinine clearance Creatinine clearance RM2007/00260/00 estrSAELBTST26 Diastolic blood pressure Diastolic blood pressure estrSAELBTST27 Eosinophils Eosinophils VLX105832 VLX105832 estrSAELBTST28 Erythrocyte sedimentation rate Erythrocyte sedimentation rate estrSAELBTST29 Fasting blood glucose Fasting blood glucose estrSAELBTST30 FEV 1 FEV 1 estrSAELBTST31 Gamma-glutamyltransferase Gamma-glutamyltransferase estrSAELBTST32 Glutamic-oxaloacetic transferase Glutamic-oxaloacetic transferase Annotated Trial Design Page 29 of 62

estrSAELBTST33 Glutamic-pyruvate transaminase Glutamic-pyruvate transaminase estrSAELBTST34 HbA1c HbA1c estrSAELBTST35 HBV-DNA decreased HBV-DNA decreased estrSAELBTST36 HBV-DNA increased HBV-DNA increased estrSAELBTST37 Heart rate Heart rate estrSAELBTST38 Hematocrit Hematocrit estrSAELBTST39 Hemoglobin Hemoglobin estrSAELBTST40 High density lipoprotein High density lipoprotein estrSAELBTST41 HIV viral load HIV viral load estrSAELBTST42 INR INR estrSAELBTST43 Lactic dehydrogenase Lactic dehydrogenase estrSAELBTST44 Lipase Lipase estrSAELBTST45 Low density lipoprotein Low density lipoprotein estrSAELBTST46 Lymphocytes Lymphocytes estrSAELBTST47 Magnesium Magnesium CONFIDENTIAL estrSAELBTST48 Mean cell hemoglobin concentration Mean cell hemoglobin concentration estrSAELBTST49 Mean corpuscular hemoglobin Mean corpuscular hemoglobin

28 estrSAELBTST50 Mean corpuscular volume Mean corpuscular volume estrSAELBTST51 Monocytes Monocytes estrSAELBTST52 Neutrophils Neutrophils estrSAELBTST53 Oxygen saturation Oxygen saturation estrSAELBTST54 pCO2 pCO2 estrSAELBTST55 pH pH estrSAELBTST56 Phosphate Phosphate estrSAELBTST57 Platelet count Platelet count estrSAELBTST58 pO2 pO2 estrSAELBTST59 Potassium Potassium RM2007/00260/00 RM2007/00260/00 estrSAELBTST60 Protein total Protein total estrSAELBTST61 Prothrombin time Prothrombin time

estrSAELBTST62 Red blood cell count Red blood cell count VLX105832 estrSAELBTST63 Respiratory rate Respiratory rate estrSAELBTST64 Reticulocyte count Reticulocyte count estrSAELBTST65 Serum glucose Serum glucose estrSAELBTST66 Serum uric acid Serum uric acid estrSAELBTST67 Sodium Sodium Annotated Trial Design Page 30 of 62

estrSAELBTST68 Systolic blood pressure Systolic blood pressure estrSAELBTST69 Thrombin time Thrombin time estrSAELBTST70 Total lung capacity Total lung capacity estrSAELBTST71 Triglycerides Triglycerides estrSAELBTST72 Troponin Troponin estrSAELBTST73 Troponin I Troponin I estrSAELBTST74 Troponin T Troponin T estrSAELBTST75 Urine myoglobin Urine myoglobin estrSAELBTST76 Urine pH Urine pH estrSAELBTST77 Vital capacity Vital capacity estrSAELBTST78 White blood cell count White blood cell count

CDD: MAPPINGS1 Table: t_AE_SER Key Type: PATIENTVISIT Column Name Column Data Type Design Note

chkSAE STRING(255) CONFIDENTIAL chkFU STRING(255) rdcSAERAND STRING(1) 29 AESEQ STRING(5) - A5 AETERM STRING(100) - A100 AEREL STRING(1) AEDURHR NUMERIC - N2 AEDURMIN NUMERIC - N2 AEONLDSH NUMERIC - N2 AEONLDSM NUMERIC - N2 rdcAESREL STRING(1) AESER STRING(1)

AESERDTH STRING(255) RM2007/00260/00 AESERLIF STRING(255) AESERHOS STRING(255)

AESERDIS STRING(255) VLX105832 AESERCON STRING(255) AESEROTH STRING(255) txtSAECMSEQ STRING(4) - A4 txtCMTERM STRING(100) - A100 Annotated Trial Design Page 31 of 62

AEMODIFY STRING(100) - A100 AEMEDSYN STRING(255) AELLTCD STRING(255) dtmMHLSTOC DATE - DDMONYYYY txtSAELBSEQ STRING(4) - A4 pdcLBTST STRING(255) - Activated partial thromboplastin time, Albumin, Alkaline phosphatase, Amylase, Basophils, Bicarbonate, Bilirubin, Bilirubin direct, Bilirubin total, Blood myoglobin, Blood pH, Blood pressure, Blood urea nitrogen, Body temperature, Calcium, CD4 lymphocytes, CD8 lymphocytes, Chloride, Cholesterol total, C-reactive protein, Creatine, Creatine phosphokinase, Creatine phosphokinase MB, Creatinine, Creatinine clearance, Diastolic blood pressure, Eosinophils, Erythrocyte sedimentation rate, Fasting blood glucose, FEV 1, Gamma-glutamyltransferase, Glutamic-oxaloacetic transferase, Glutamic-pyruvate transaminase, HbA1c, HBV-DNA decreased, HBV-DNA increased, Heart rate, Hematocrit, Hemoglobin, High density lipoprotein, HIV viral load, INR, Lactic dehydrogenase, Lipase, Low density lipoprotein, Lymphocytes, Magnesium, Mean cell hemoglobin concentration, Mean corpuscular hemoglobin, Mean corpuscular volume, Monocytes, Neutrophils, Oxygen saturation, pCO2, pH, Phosphate, Platelet count, pO2, Potassium, Protein total, Prothrombin time, Red blood cell count, Respiratory rate, Reticulocyte count, Serum glucose, Serum uric acid, Sodium, Systolic blood pressure, Thrombin time, Total lung capacity, Triglycerides, Troponin, Troponin I, Troponin T, Urine myoglobin, Urine pH, Vital capacity, White blood cell count dtmLABDTM DATE - DDMONYYYY txtLABRES STRING(50) - A50 txtLABUNIT STRING(35) - A35 txtLABNLR FLOAT - F8.0

txtLABNHR FLOAT - F8.0 CONFIDENTIAL rdcSAEIP STRING(1) chkSAESENDI STRING(255) 30 dtmSAEDTM DATE - DDMONYYYY HHMM AESE1 STRING(1) AESE2 STRING(5) - A5 txtSAEVERSION STRING(4) - A4 txtSAEID STRING(20) - A20 txtSAERNDNO STRING(255) - A255 txtOCEANSCD STRING(12) - A12 calSAEEmailFlag STRING(255) calAE_FAILED STRING(255) AESTDTTM DATE - DDMONYYYY RM2007/00260/00 RM2007/00260/00 AEOUTCD1 STRING(1) AEENDTTM1 DATE - DDMONYYYY

AEENDTTM2 DATE - DDMONYYYY VLX105832 AEENDTTM3 DATE - DDMONYYYY AESEVCD STRING(1) AETOXCD STRING(1) AETXHVCD STRING(1) AEACTRCD STRING(1) Annotated Trial Design Page 32 of 62

AEWD STRING(1) txtSAECMDOS FLOAT - F10.0 pdcCMUNIT STRING(255) - ACTU, AMP, AP, BT, CAP, CC, 031, 002, 025, 028, IUML, 011, LM, LOZ, MEGU, 004, 004, 008, MCG/KG/MIN , MCG/MIN , 013, 029, MEQ24, 003, MGPER, MGH, 007, MGKH, MGKM, 009, MGML, 012, MLH, MLM, 023, 027, MAC, NEB, PAT, 030, PUFF, SAC, SPR, SUP, TBS, TAB, TSP, UNT, U, VIA pdcSAECMFRQ STRING(255) - 2W, 3W, 4W, 5D, 5W, AC, 2D, CO, FO, Q3WK, Q3M, AD, 1N, MO, WE, 1D, 1S, PC, PRN, 12D, Q3D , Q4D, 6D, 4D, 3D, 2D, 1M, 24D, 4D, 1N, 3D, U pdcCMROUTCD STRING(255) - 047, 008, GT, 055, INJ, 013, IBU, 026, 030, 045, 031, IOS, 033, 037, 015, 042, 045, 048, 054, 058, 060, 061, 062, 065, 067 dtmSAECMSTD DATE - DDMONYYYY rdcSAECMONG STRING(1) dtmSAECMEND DATE - DDMONYYYY txtCMIND STRING(50) - A50 pdcCMDRGTYP STRING(255) - 2, T, 1 txtMHXSEQ STRING(4) - A4 txtSAEMHTRM STRING(100) - A100 dtmMHSTDTM DATE - DDMONYYYY rdcMHCONT STRING(1)

CONFIDENTIAL

31 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 33 of 62

FORM: CONCOMITANT MEDICATIONS (CONMEDS) TRIAL: vlx105832_yz705 New

Drug Name # Reason for Medication Start Date Taken Prior to Study? Ongoing? (Trade Name preferred) 1

CONCOMITANT MEDICATIONS Sequence Number [hidden] (MAPPINGS1:t_CONMEDS.CMSEQ)

1. Drug Name A100 (MAPPINGS1:t_CONMEDS.CMTERM)

(Trade Name preferred) * Modified reported term [hidden] (CM_SYNONYM:0.CommonCRF.CONMEDS.sctCM.0.itmCMDRGSYN.CMDRGSYN) 2. A100 (MAPPINGS1:t_CONMEDS.CMMODIFY) (CM_CODE:0.CommonCRF.CONMEDS.sctCM.0.itmCMDRGCOL.CMDRGCOL) (CM_FAILED:0.CommonCRF.CONMEDS.sctCM.0.itmCM_FAILED.calCM_FAILED)

GSK Drug synonym [hidden] (MAPPINGS1:t_CONMEDS.CMDRGSYN) GSK Drug Collection code [hidden] (MAPPINGS1:t_CONMEDS.CMDRGCOL) CONFIDENTIAL Failed coding [hidden] (MAPPINGS1:t_CONMEDS.calCM_FAILED)

3. Reason for Medication A70 (MAPPINGS1:t_CONMEDS.CMREAS) 32

4. Start Date Req/Unk / Req/Unk / Req (1985-2007) (MAPPINGS1:t_CONMEDS.CMSTDTTM)

5. Taken Prior to Study? (MAPPINGS1:t_CONMEDS.CMPRIOR) [Y] Yes [N] No 6. Ongoing? (MAPPINGS1:t_CONMEDS.CMONGO) [Y] Yes [N] No, specify End Date Req / Req / Req (2006-2007) (MAPPINGS1:t_CONMEDS.CMENDTTM)

Medication Type [hidden] (MAPPINGS1:t_CONMEDS.CMTYPCD) * Item is not required

RM2007/00260/00

Form Design Note:

IDSL Version 03.03A - 01 DEC 05. This form can be used for disease specific conmeds or as a generic conmed form. If both are required in the trial, copy this form and adjust the form title and section titles VLX105832

Section Design Notes:

Title Design Note Annotated Trial Design Page 34 of 62

CONCOMITANT MEDICATIONS The following items can be added and made hidden: CMCAT, CMSCAT.

sctCMTYPCD This section is required and should be the last section on this form.

Item Design Notes:

Item No. Design Note

3. This item is optional

4. Time is optional

5. This item is optional

6. Time is optional

itmCMTYPCD This item will be calculated by InForm

CDD: MAPPINGS1 Table: t_CONMEDS Key Type: PATIENTVISIT

Column Name Column Data Type Design Note CONFIDENTIAL CMSEQ STRING(255) CMTERM STRING(100) - A100 33 CMMODIFY STRING(100) - A100 CMDRGSYN STRING(255) CMDRGCOL STRING(255) calCM_FAILED STRING(255) CMREAS STRING(70) - A70 CMSTDTTM DATE - DDMONYYYY CMPRIOR STRING(1) CMONGO STRING(1) CMENDTTM DATE - DDMONYYYY

CMTYPCD STRING(255) RM2007/00260/00

VLX105832 VLX105832 Annotated Trial Design Page 35 of 62

FORM: INVESTIGATIONAL PRODUCT (IP) TRIAL: vlx105832_yz705 New

# Sequence Number IP Start Date Stop Date 1

INVESTIGATIONAL PRODUCT Sequence Number (MAPPINGS1:t_EXPOSURE_IP.EXSEQ) 1. Investigational Product (MAPPINGS1:t_EXPOSURE_IP.EXINVPCD) [23] Double-Blind Therapy [24] Open-Label Treatment

2. Start Date Req / Req / Req (2006-2007) (MAPPINGS1:t_EXPOSURE_IP.EXSTDTTM)

3. Stop Date Req/Unk / Req/Unk / Req (2006-2007) (MAPPINGS1:t_EXPOSURE_IP.EXENDTTM)

Form Design Note: CONFIDENTIAL This form is required when IP is administered. If Planned Timepoint is not used, but repeats are needed, make this form repeating. Use this form for: Multiple assessments (per visit) running log (per study))

34 Item Design Notes:

Item No. Design Note

1. This item is optional and should be modified according to the trial design

2. Time is optional

3. Time is optional

CDD: MAPPINGS1 Table: t_EXPOSURE_IP Key Type: PATIENTVISIT Column Name Column Data Type Design Note RM2007/00260/00 RM2007/00260/00 EXSEQ STRING(255) EXINVPCD STRING(2)

EXSTDTTM DATE - DDMONYYYY VLX105832 EXENDTTM DATE - DDMONYYYY

Annotated Trial Design Page 36 of 62

FORM: INVESTIGATIONAL PRODUCT COMPLIANCE (IPCOMP) TRIAL: vlx105832_yz705 New

# Sequence Number IP Date IP Dispensed Num Dispensed Date IP Returned Num Returned 1

INVESTIGATIONAL PRODUCT COMPLIANCE Sequence Number (MAPPINGS1:t_INVPCOMP.SEQ) 1. Investigational Product (MAPPINGS1:t_INVPCOMP.AVINVPCD) [23] Double-Blind therapy [24] Open-label treatment

2. Date Investigational Product Dispensed Req / Req / Req (2006-2007) (MAPPINGS1:t_INVPCOMP.IPDISDT)

3. Number of Tablets/Caplets Dispensed xxx (MAPPINGS1:t_INVPCOMP.DISPNUM)

4. Date Investigational Product Returned Req/Unk / Req/Unk / Req/Unk (2006-2007) (MAPPINGS1:t_INVPCOMP.IPRTRNDT)

5. Number of Tablets/Caplets Returned xxx (MAPPINGS1:t_INVPCOMP.RETRNNUM) CONFIDENTIAL

CDD: MAPPINGS1 Table: t_INVPCOMP Key Type: PATIENTVISIT 35 Column Name Column Data Type Design Note SEQ STRING(255) AVINVPCD STRING(2) IPDISDT DATE - DDMONYYYY DISPNUM NUMERIC - N3 IPRTRNDT DATE - DDMONYYYY RETRNNUM NUMERIC - N3

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 37 of 62

FORM: GENITAL HERPES RECURRENCES (HERP_RECUR) TRIAL: vlx105832_yz705 New

Additional Open- Open-Label Sequence Prodrome Onset Onset of Confirmed by Exam Date Date Clinic Culture Was there a Day 3 Label # Valaciclovir Number Date Recurrence Exam Date Healed Collected Visit? Valaciclovir Dispensed Dispensed 1

GENITAL HERPES RECURRENCES Sequence Number (MAPPINGS1:t_GNHSVREC.SEQ)

1.* Prodrome Onset Date NReq / NReq / NReq (2006-2007) (MAPPINGS1:t_GNHSVREC.SYMPSTDT)

2. Date of Onset of Genital HSV Recurrence Req / Req / Req (2006-2007) (MAPPINGS1:t_GNHSVREC.RECONDT)

3. Was the herpes recurrence confirmed by examination? (MAPPINGS1:t_GNHSVREC.HSVRCCFM) [N] No [Y] Yes

4.* If examined, date of exam Req / Req / Req (2006-2007) (MAPPINGS1:t_GNHSVREC.EXAMDT) CONFIDENTIAL

5. Date Healed Req / Req / Req (2006-2007) (MAPPINGS1:t_GNHSVREC.HEALDT)

6. Date Clinic Culture Collected / / (2006-2007) (MAPPINGS1:t_GNHSVREC.CLNCULDT)

36 Req Req Req

7. Was a 3 day course of Open-Label Valaciclovir dispensed? (MAPPINGS1:t_GNHSVREC.DRGDISP) [N] No If Yes, record Open-Label Valaciclovir on Investigational Product page. [Y] Yes 8. Was there a Day 3 Visit? (MAPPINGS1:t_GNHSVREC.RECVS) [N] No [Y] Yes, provide culture date. Req / Req / Req (2005-2007) (MAPPINGS1:t_GNHSVREC.RECVSDT)

9. Was an additional 3 day course of Open-Label Valaciclovir dispensed? (MAPPINGS1:t_GNHSVREC.ADRGDISP) [N] No If Yes, record Open-Label Valaciclovir on Investigational Product page. [Y] Yes * Item is not required

RM2007/00260/00 CDD: MAPPINGS1 Table: t_GNHSVREC Key Type: PATIENTVISIT Column Name Column Data Type Design Note VLX105832 VLX105832 ADRGDISP STRING(1) SEQ STRING(255) SYMPSTDT DATE - DDMONYYYY RECONDT DATE - DDMONYYYY HSVRCCFM STRING(1) Annotated Trial Design Page 38 of 62

EXAMDT DATE - DDMONYYYY HEALDT DATE - DDMONYYYY CLNCULDT DATE - DDMONYYYY DRGDISP STRING(1) RECVS STRING(1) RECVSDT DATE - DDMONYYYY

CONFIDENTIAL 37 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 39 of 62

FORM: CLINICAL VISIT ASSESSMENT (HERP_ASMT) TRIAL: vlx105832_yz705

CLINICAL VISIT ASSESSMENT 1. Has the subject had a recurrence(s) of genital herpes since the last visit? (MAPPINGS1:t_CLINVS.GENHSVRC) [Y] Yes If Yes, complete the Genital Herpes Recurrences page. [N] No 2. Has the subject had an oral herpes recurrence since the last visit? (MAPPINGS1:t_CLINVS.ORHSVRC) [Y] Yes [N] No Notes: If the subject took any anti-herpetic medication other than open-label Valaciclovir to treat herpes recurrences since the last visit, record details on the (MAPPINGS1:t_CLINVS.ccDummy) Concomitant Medications Page. [read-only]

CDD: MAPPINGS1 Table: t_CLINVS Key Type: PATIENTVISIT Column Name Column Data Type Design Note GENHSVRC STRING(1)

ORHSVRC STRING(1) CONFIDENTIAL ccDummy STRING(255)

38 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 40 of 62

FORM: PREGNANCY INFORMATION (PREG) TRIAL: vlx105832_yz705

PREGNANCY INFORMATION 1. Did the subject become pregnant during the study? (MAPPINGS1:t_STATUS_PREG_F.PGYN) If Yes, complete the paper Pregnancy Notification form [N] No [Y] Yes

Form Design Note:

This is an optional form but is conditional upon females in the trial; This form will be dynamically generated to appear at the End visit if Female is selected on the Demographics form

CDD: MAPPINGS1 Table: t_STATUS_PREG_F Key Type: PATIENTVISIT Column Name Column Data Type Design Note PGYN STRING(1)

CONFIDENTIAL 39 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 41 of 62

FORM: STATUS OF TREATMENT BLIND (BLIND) TRIAL: vlx105832_yz705

STATUS OF TREATMENT BLIND 1. Was the treatment blind broken during the study? (MAPPINGS1:t_BLIND.BLBRK) If yes, complete the Adverse Event form and/or Investigational Product forms as appropriate [N] No [Y] Yes, complete the following : Date blind broken Req / Req / Req (2006-2007) (MAPPINGS1:t_BLIND.BLDTTM) (MAPPINGS1:t_BLIND.BLREASCD) Reason blind broken [1] Medical emergency requiring identification of investigational product for further treatment [Z] Other, specify (MAPPINGS1:t_BLIND.BLRSOTH) A200

Item Design Notes: CONFIDENTIAL Item No. Design Note

1. Time blind broken is optional

CDD: MAPPINGS1 Table: t_BLIND Key Type: PATIENTVISIT Column Name Column Data Type Design Note BLBRK STRING(1) BLDTTM DATE - DDMONYYYY BLREASCD STRING(1) BLRSOTH STRING(200) - A200

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FORM: INVESTIGATIONAL PRODUCT DISCONTINUATION (IP DISC) TRIAL: vlx105832_yz705

INVESTIGATIONAL PRODUCT DISCONTINUATION 1. Was the investigational product stopped permanently before (MAPPINGS1:t_STOPDRUG.SDSTOP) the end of the scheduled treatment period? [N] No [Y] (MAPPINGS1:t_STOPDRUG.SDREASCD) Yes, specify the primary reason the investigational product was stopped: [1] Adverse event, Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate. [2] Lost to follow-up [3] Protocol violation [4] Subject decided to withdraw from the study [Z] Other, specify (MAPPINGS1:t_STOPDRUG.SDRSOTH) A200

Form Design Note:

IDSL Version 01.01A - 01 Feb 2005 A unique form must be created for each IP in the study. This form is optional and should be used if the subject is allowed to stop IP but continue on in the study CONFIDENTIAL

41 Item Design Notes:

Item No. Design Note

1. All choices after Subject decided to withdraw from the study are optional choices. Other is required.

CDD: MAPPINGS1 Table: t_STOPDRUG Key Type: PATIENTVISIT Column Name Column Data Type Design Note SDSTOP STRING(1) SDREASCD STRING(1) SDRSOTH STRING(200) - A200 RM2007/00260/00 RM2007/00260/00

VLX105832 VLX105832 Annotated Trial Design Page 43 of 62

FORM: STUDY CONCLUSION (CONC) TRIAL: vlx105832_yz705

STUDY CONCLUSION 1. Date of subject completion or withdrawal Req / Req / Req (2006-2007) (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSDTTM)

2. Was the subject withdrawn from the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSWD) [N] No [Y] (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSREASCD1) Yes, select primary reason for withdrawal [1] Adverse Event Record details on the Non-Serious Adverse Events or Serious Adverse Events forms as appropriate. [2] Lost to follow-up [3] Protocol violation [4] Subject decided to withdraw from the study [Z] Other, specify (MAPPINGS1:t_DISPOSIT_CONCLUSION.DSRSOTH) A200

LOG STATUS

3. Did the subject experience any non-serious adverse events during the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcAEAny) CONFIDENTIAL [N] No [Y] Yes

42 4. Did the subject experience any serious adverse events during the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcSAEAny) [N] No [Y] Yes 5. Were any concomitant medications taken by the subject prior to screening and/or during the study? (MAPPINGS1:t_DISPOSIT_CONCLUSION.rdcConcCMAny) [N] No [Y] Yes

6.* Case book ready for signature [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.chkReadyForSig) [Y] Yes CRA should check the box when data cleaning is complete

7.* Q1 [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.AXCOMPLETERADIO) [Y] Yes [N] No

8.* Q2 [hidden] (MAPPINGS1:t_DISPOSIT_CONCLUSION.REASONRADIO) [?] PF_SC_LOST RM2007/00260/00 RM2007/00260/00 [?] PF_SC_DEATH [?] PF_SC_SPONSORDECISION [?] PF_SC_PHYSICIANDECISION [?] PF_SC_PATIENTDECISION [?] PF_SC_AE VLX105832 [?] PF_SC_ALE [?] PF_SC_CRITERIA [?] PF_SC_OTHER * Item is not required

Annotated Trial Design Page 44 of 62

Form Design Note:

IDSL Version 02.01A - 30 JUN 05

Item Design Notes:

Item No. Design Note

1. Time is optional

2. Choices after Subject decided to withdraw from the study are optional choices. Other is required

3. This item is not part of the SI datasets

4. This item is not part of the SI datasets

5. This item is not part of the SI datasets

6. This item is used for Phase I trials only. Remove for Phase II-IV

CDD: MAPPINGS1 Table: t_DISPOSIT_CONCLUSION Key Type: PATIENTVISIT CONFIDENTIAL Column Name Column Data Type Design Note

43 DSDTTM DATE - DDMONYYYY DSWD STRING(1) DSREASCD1 STRING(1) DSRSOTH STRING(200) - A200 rdcConcAEAny STRING(1) rdcConcSAEAny STRING(1) rdcConcCMAny STRING(1) chkReadyForSig STRING(255) AXCOMPLETERADIO STRING(1) REASONRADIO STRING(42)

RM2007/00260/00

VLX105832 VLX105832 Annotated Trial Design Page 45 of 62

FORM: INVESTIGATOR SIGNATURE (SIGN) TRIAL: vlx105832_yz705

INVESTIGATOR SIGNATURE 1. Is this casebook ready to sign? (MAPPINGS1:t_INVSIGN.INVSIGN) If not, click on the RETURN button below [Y] Yes

Form Design Note:

IDSL Version 02.00A - 01 DEC 05

CDD: MAPPINGS1 Table: t_INVSIGN Key Type: PATIENTVISIT Column Name Column Data Type Design Note INVSIGN STRING(1)

CONFIDENTIAL 44 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 46 of 62

FORM: VITAL SIGNS (VS) TRIAL: vlx105832_yz705

VITAL SIGNS 1. Height xxx cm (MAPPINGS1:t_VITALS.HEIGHT)

2. Weight xxx.x kg (MAPPINGS1:t_VITALS.WEIGHT)

Form Design Note:

This form is optional. This form is to be used when one Vitals is taken at a visit.

Section Design Notes:

Title Design Note

VITAL SIGNS All items are optional

CONFIDENTIAL

CDD: MAPPINGS1 Table: t_VITALS Key Type: PATIENTVISIT

45 Column Name Column Data Type Design Note HEIGHT NUMERIC - N3 WEIGHT FLOAT - F5.1

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 47 of 62

FORM: MEDICAL CONDITIONS (MEDHX) TRIAL: vlx105832_yz705

MEDICAL CONDITIONS Check only one response for each MedDRA System Organ Class 1. Blood and lymphatic system disorders (MAPPINGS1:t_MEDHIST_C.MHSTATCD) [1] Current [5] No Medical Condition 2. Cardiac disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC1) [1] Current [5] No Medical Condition 3. Ear and labyrinth disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC2) [1] Current [5] No Medical Condition 4. Endocrine disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC3) [1] Current [5] No Medical Condition 5. Eye disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC4) [1] Current [5] No Medical Condition CONFIDENTIAL 6. Gastrointestinal disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC5) [1] Current [5] No Medical Condition

46 7. Hepatobiliary disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC6) [1] Current [5] No Medical Condition 8. Immune system disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC7) [1] Current [5] No Medical Condition 9. Metabolism and nutrition disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC8) [1] Current [5] No Medical Condition 10. Musculoskeletal and connective tissue disorders (MAPPINGS1:t_MEDHIST_C.MHSTATC9) [1] Current [5] No Medical Condition 11. Neoplasms benign, malignant and unspecified (including cysts and polyps) (MAPPINGS1:t_MEDHIST_C.MHSTAT10)

[1] Current RM2007/00260/00 [5] No Medical Condition 12. Nervous system disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT11) [1] Current

[5] No Medical Condition VLX105832 13. Psychiatric disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT12) [1] Current [5] No Medical Condition 14. Renal and urinary disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT13) [1] Current [5] No Medical Condition Annotated Trial Design Page 48 of 62

15. Reproductive system and breast disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT14) [1] Current [5] No Medical Condition 16. Respiratory, thoracic and mediastinal disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT15) [1] Current [5] No Medical Condition 17. Skin and subcutaneous tissue disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT16) [1] Current [5] No Medical Condition 18. Vascular disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT17) [1] Current [5] No Medical Condition 19. Infections and infestations (MAPPINGS1:t_MEDHIST_C.MHSTAT18) [1] Current [5] No Medical Condition 20. Congenital, familial and genetic disorders (MAPPINGS1:t_MEDHIST_C.MHSTAT19) [1] Current [5] No Medical Condition 21. General disorders and administration site conditions (MAPPINGS1:t_MEDHIST_C.MHSTAT20) [1] Current [5] No Medical Condition CONFIDENTIAL 22. Injury, poisoning and procedural complications (MAPPINGS1:t_MEDHIST_C.MHSTAT21) [1] Current

47 [5] No Medical Condition

Form Design Note:

This form is optional

Section Design Notes:

Title Design Note

MEDICAL The following combinations are acceptable: 1. Current+No Medical Condition;2. Current+Past+No Medical Condition;3. Past+No Medical History. Not Assessed is optional for all CONDITIONS combinations. Combinations must be consistent for all terms specified RM2007/00260/00 RM2007/00260/00

CDD: MAPPINGS1 Table: t_MEDHIST_C Key Type: PATIENTVISIT VLX105832 VLX105832 Column Name Column Data Type Design Note MHSTATCD STRING(1) MHSTATC1 STRING(1) MHSTATC2 STRING(1) MHSTATC3 STRING(1) Annotated Trial Design Page 49 of 62

MHSTATC4 STRING(1) MHSTATC5 STRING(1) MHSTATC6 STRING(1) MHSTATC7 STRING(1) MHSTATC8 STRING(1) MHSTATC9 STRING(1) MHSTAT10 STRING(1) MHSTAT11 STRING(1) MHSTAT12 STRING(1) MHSTAT13 STRING(1) MHSTAT14 STRING(1) MHSTAT15 STRING(1) MHSTAT16 STRING(1) MHSTAT17 STRING(1) MHSTAT18 STRING(1) CONFIDENTIAL MHSTAT19 STRING(1) MHSTAT20 STRING(1)

48 MHSTAT21 STRING(1)

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 50 of 62

FORM: INITIAL DIAGNOSIS OF GENITAL HERPES (HERPES_DIAG) TRIAL: vlx105832_yz705

INITIAL DIAGNOSIS OF GENITAL HERPES 1. Date of initial diagnosis of genital herpes Req / Req / Req (2005-2007) (MAPPINGS1:t_HSVHX_DIAG.HSVDGDT)

2. Number of genital herpes recurrences since initial diagnosis? xxx (MAPPINGS1:t_HSVHX_DIAG.RECNO1)

CDD: MAPPINGS1 Table: t_HSVHX_DIAG Key Type: PATIENTVISIT Column Name Column Data Type Design Note HSVDGDT DATE - DDMONYYYY RECNO1 NUMERIC - N3

CONFIDENTIAL 49 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 51 of 62

FORM: ORAL HERPES/COLD SORE RECURRENCE HISTORY (ORAL_HERP HX) TRIAL: vlx105832_yz705

ORAL HERPES/COLD SORE RECURRENCE HISTORY 1. Has the subject ever had herpes infections/cold sores in the oral area? (MAPPINGS1:t_HSVHX.HSVORAL) [N] No [Y] Yes (MAPPINGS1:t_HSVHX.RECNO) If Yes, how many oral herpes/cold sore outbreaks has the subject had over the past 12 months? xxx

CDD: MAPPINGS1 Table: t_HSVHX Key Type: PATIENTVISIT Column Name Column Data Type Design Note HSVORAL STRING(1) RECNO NUMERIC - N3

CONFIDENTIAL 50 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 52 of 62

FORM: RANDOMISATION NUMBER (RAND) TRIAL: vlx105832_yz705

RANDOMISATION NUMBER 1. Was the subject able to be randomised? (MAPPINGS1:t_RAND.rdcRandYN) [N] No [Y] Yes, provide: Randomisation number (MAPPINGS1:t_RAND.RANDNUM) xxxxxx Date of randomisation Req / Req / Req (2006-2007) (MAPPINGS1:t_RAND.RANDDTTM)

Form Design Note:

IDSL Version 03.00B - 27 JUL 05

Item Design Notes:

Item No. Design Note CONFIDENTIAL

1. Date and time of Randomisation are optional. Randomisation number should be changed to match RAMOS.

CDD: MAPPINGS1 Table: t_RAND Key Type: PATIENTVISIT Column Name Column Data Type Design Note rdcRandYN STRING(1) RANDNUM NUMERIC - N6 RANDDTTM DATE - DDMONYYYY

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FORM: INVESTIGATIONAL PRODUCT CONTAINER NUMBER (PACK) TRIAL: vlx105832_yz705

INVESTIGATIONAL PRODUCT CONTAINER NUMBER Record the identifying number from the investigational product container dispensed at this visit

1. Investigational product container number A6 (MAPPINGS1:t_EXPOSURE_CONTAINER.EXINVNUM)

Form Design Note:

IDSL Version 01.00A - 01 DEC 04 This form is conditional on RAMOS being used in the trial. If additional container numbers are needed, copy the first item as needed, or change the repeating property on this form to True

CDD: MAPPINGS1 Table: t_EXPOSURE_CONTAINER Key Type: PATIENTVISIT Column Name Column Data Type Design Note EXINVNUM STRING(6) - A6

CONFIDENTIAL 52 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 54 of 62

FORM: SUPPLEMENTAL PAGES FOR TMA SAEs (TMA SAE1) TRIAL: vlx105832_yz705

SUPPLEMENTAL PAGES FOR TMA SAEs Sequence Number [read-only] (MAPPINGS1:t_TMASAE1.SEQ) 1. Was the subject's haemoglobin <13.5 g/dL (if subject is male) or <11.5 g/dL (if subject is female)? (MAPPINGS1:t_TMASAE1.DCHG) [N] No If No, the subject does not have TMA. [Y] Yes

2. Was the subject's platelet count <150,000/mm3 (<150 x 109/L)? (MAPPINGS1:t_TMASAE1.DCPLT) [N] No If No, the subject does not have TMA. [Y] Yes 3. Did the subject have fragmented red cells (schistocytes) on peripheral smear? (MAPPINGS1:t_TMASAE1.SCHIPRES) [N] No If No, the subject does not have TMA. [Y] Yes 4. Did the subject have a renal abnormality (either haematuria >trace, proteinuria >1+, or serum creatinine >upper limits of normal)? (MAPPINGS1:t_TMASAE1.RENABN) [N] No [Y] Yes 5. Did the subject have both a neurological abnormality and fever (>38 C)? (MAPPINGS1:t_TMASAE1.NEUABNFV) [N] No [Y] Yes CONFIDENTIAL 6. Were the answers to questions 1, 2, 3 and either question 4 or 5 answered Yes? (MAPPINGS1:t_TMASAE1.PREVQYES) [N] No If Yes, and the above events all occurred at approximately the same time, the diagnosis of TMA should be considered in this subject. Submit Serious Adverse Event [Y] Yes

53 Report Form (including Supplemental pages for TMA SAEs) to GlaxoSmithKline within 24 hours. (Procedures for reporting of SAEs are listed in section 12.7. of the protocol). If Question 6 is No, the subject does not meet all criteria for TMA.

Only if Question 6 is No, complete the following: 7. In your medical opinion, do you suspect this event to be a serious case of TMA? (MAPPINGS1:t_TMASAE1.TMASER) [N] No If Yes, submit SAE Report Form and Supplemental pages for TMA SAEs to GlaxoSmithKline within 24 hours. (Procedures for reporting of Serious Adverse Event are [Y] Yes listed in section 10.7. of the protocol). If No, complete the following: 8. Do you consider any of the above events, in, and of themselves, to be adverse events? (MAPPINGS1:t_TMASAE1.TMAAE) [N] No If Yes, record the above events(s) as Adverse Events. [Y] Yes If No, no further action is required.

RM2007/00260/00

CDD: MAPPINGS1 Table: t_TMASAE1 Key Type: PATIENTVISIT

Column Name Column Data Type Design Note VLX105832 SEQ STRING(255) DCHG STRING(1) DCPLT STRING(1) SCHIPRES STRING(1) RENABN STRING(1) Annotated Trial Design Page 55 of 62

NEUABNFV STRING(1) PREVQYES STRING(1) TMASER STRING(1) TMAAE STRING(1)

CONFIDENTIAL 54 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 56 of 62

FORM: SUPPLEMENTAL PAGES FOR TMA SAEs (Continued) (TMA SAE2) TRIAL: vlx105832_yz705

SUPPLEMENTAL PAGES FOR TMA SAEs (Continued) 1. Was the subject treated for suspected TMA? (MAPPINGS1:t_TMASAE2.TRTTMA) [N] No [Y] Yes If Yes, was the subject treated with the following: 2. Corticosteriods (MAPPINGS1:t_TMASAE2.TRTREC) [N] No [Y] (MAPPINGS1:t_TMASAE2.TRTOUTCD) Yes If Yes, indicate treatment outcome: [1] Favourable [2] Not Favourable [U] Unknown 3. Plasma infusions (MAPPINGS1:t_TMASAE2.TRTRE1) [N] No [Y] (MAPPINGS1:t_TMASAE2.TRTOUTC1) Yes If Yes, indicate treatment outcome: [1] Favourable CONFIDENTIAL [2] Not Favourable [U] Unknown 4. Plasmapheresis/exchange (MAPPINGS1:t_TMASAE2.TRTRE2) 55 [N] No [Y] (MAPPINGS1:t_TMASAE2.TRTOUTC2) Yes If Yes, indicate treatment outcome: [1] Favourable [2] Not Favourable [U] Unknown 5. Other (MAPPINGS1:t_TMASAE2.TRTREC2) [N] No [Y] Yes specify: A200 (MAPPINGS1:t_TMASAE2.TMATRTSP) (MAPPINGS1:t_TMASAE2.TRTOUTCD2) If Yes, indicate treatment outcome: [1] Favourable [2] Not Favourable [U] Unknown RM2007/00260/00 RM2007/00260/00

CDD: MAPPINGS1 Table: t_TMASAE2 Key Type: PATIENTVISIT VLX105832 VLX105832 Column Name Column Data Type Design Note TRTREC STRING(1) TRTOUTCD STRING(1) TRTRE1 STRING(1) TRTOUTC1 STRING(1) Annotated Trial Design Page 57 of 62

TRTRE2 STRING(1) TRTOUTC2 STRING(1) TRTTMA STRING(1) TRTREC2 STRING(1) TMATRTSP STRING(200) - A200 TRTOUTCD2 STRING(1)

CONFIDENTIAL 56 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 58 of 62

FORM: LOCAL LABORATORY - CLINICAL CHEMISTRY (CHEM) TRIAL: vlx105832_yz705

If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. LOCAL LABORATORY - CLINICAL CHEMISTRY 1. Laboratory ID [hidden] A20 (MAPPINGS1:t_LAB_CHEM.LBIDCD)

2. Laboratory name A80 (MAPPINGS1:t_LAB_CHEM.LBNAME1)

3. Address A80 (MAPPINGS1:t_LAB_CHEM.LBADRS1)

4. Date sample taken Req / Req / Req (2005-2007) (MAPPINGS1:t_LAB_CHEM.LBDTTM)

5. Creatinine (MAPPINGS1:t_LAB_CHEM.rdcLBORRES) [-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_CHEM.LBORRESN) [-98] Character result: A20 (MAPPINGS1:t_LAB_CHEM.LBORRES) [-99] No result

CONFIDENTIAL Form Design Note:

57 This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Clinical Chemistry tests

Section Design Notes:

Title Design Note

LOCAL LABORATORY - CLINICAL CHEMISTRY Use separate items for Name and address for the first occurrence of this form, and use the combined item for subsequent visits.

Item Design Notes:

Item No. Design Note

1. This field will be entered by the Data Owner. Data Owner must be given enterable rights to this item RM2007/00260/00

4. Time is optional

VLX105832

CDD: MAPPINGS1 Table: t_LAB_CHEM Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBIDCD STRING(20) - A20 LBNAME1 STRING(80) - A80 Annotated Trial Design Page 59 of 62

LBADRS1 STRING(80) - A80 LBDTTM DATE - DDMONYYYY rdcLBORRES STRING(3) LBORRESN FLOAT - F13.0 LBORRES STRING(20) - A20

CONFIDENTIAL 58 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 60 of 62

FORM: LOCAL LABORATORY - HAEMATOLOGY (HAEMA) TRIAL: vlx105832_yz705

If the laboratory results meet the protocol definition of an adverse event, record the details on the Adverse Events page. LOCAL LABORATORY - HAEMATOLOGY 1. Laboratory ID [hidden] A20 (MAPPINGS1:t_LAB_HAEMA.LBIDCD)

2. Laboratory name A80 (MAPPINGS1:t_LAB_HAEMA.LBNAME1)

3. Address A80 (MAPPINGS1:t_LAB_HAEMA.LBADRS1)

4. Date sample taken Req / Req / Req (2005-2007) (MAPPINGS1:t_LAB_HAEMA.LBDTTM)

5. Haemoglobin (MAPPINGS1:t_LAB_HAEMA.rdcLBORRES) [-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA.LBORRESN) [-98] Character result: A20 (MAPPINGS1:t_LAB_HAEMA.LBORRES) [-99] No result 6. Platelets (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE1) [-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA.LBORRES1) CONFIDENTIAL [-98] Character result: A20 (MAPPINGS1:t_LAB_HAEMA.LBORRE1) [-99] No result 59 7. Schistocytes (MAPPINGS1:t_LAB_HAEMA.rdcLBORRE2) [-97] Numeric result: xxxxxxxxxxxx. (MAPPINGS1:t_LAB_HAEMA.LBORRES2) [-98] Character result: A20 (MAPPINGS1:t_LAB_HAEMA.LBORRE2) [-99] No result

Form Design Note:

This form is optional. This form is to be used when a single lab is collected at a visit. This is only used for the Haematology tests

Section Design Notes: RM2007/00260/00

Title Design Note

LOCAL LABORATORY - HAEMATOLOGY Use separate items for Name and address for the first occurance of this form, and use the combined item for subsequent visits. VLX105832 VLX105832

Item Design Notes:

Item No. Design Note

1. This field will be entered by the Data Owner. Data Owner must be given enterable rights to this item Annotated Trial Design Page 61 of 62

4. Time is optional

CDD: MAPPINGS1 Table: t_LAB_HAEMA Key Type: PATIENTVISIT Column Name Column Data Type Design Note LBNAME1 STRING(80) - A80 LBADRS1 STRING(80) - A80 LBDTTM DATE - DDMONYYYY rdcLBORRES STRING(3) LBORRESN FLOAT - F13.0 LBORRES STRING(20) - A20 rdcLBORRE1 STRING(3) LBORRES1 FLOAT - F13.0 LBORRE1 STRING(20) - A20 rdcLBORRE2 STRING(3) LBORRES2 FLOAT - F13.0 CONFIDENTIAL LBORRE2 STRING(20) - A20

60 LBIDCD STRING(20) - A20

RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 Annotated Trial Design Page 62 of 62

CRB Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that all case report form pages accurately display the results of the examinations, tests, evaluations and treatments performed on this patient.

Pursuant to Section 11.100 of Title 21 of the Code of Federal Regulations, this is to certify that I intend that this electronic signature is to be the legally binding equivalent of my handwritten signature.

To this I do attest by supplying my password and clicking the button marked Submit below.

CRF Electronic Signature Affidavit By my dated signature below, I, [First Name] [Last Name], verify that this case report form accurately displays the results of the examinations, tests, evaluations and treatments noted within.

To this I do attest by supplying my password and clicking the button marked Submit below.

CONFIDENTIAL 61 RM2007/00260/00 RM2007/00260/00 VLX105832 VLX105832 CONFIDENTIAL RM2007/00260/00 VLX105832

62 CONFIDENTIAL RM2007/00260/00 VLX105832

63 CONFIDENTIAL RM2007/00260/00 VLX105832

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65 CONFIDENTIAL RM2007/00260/00 VLX105832

66 CONFIDENTIAL RM2007/00260/00 VLX105832

67 CONFIDENTIAL RM2007/00260/00 VLX105832

68 CONFIDENTIAL RM2007/00260/00 VLX105832

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72 CONFIDENTIAL RM2007/00260/00

LIST OF INVESTIGATORS AND IECS/IRBS FOR VLX105832

Investigator Investigator/ Hospital/ Institution and Address IEC/IRB Committee Chair and Name of Site no. Committee MD

CONFIDENTIAL

1 JD

RM2007/00260/00 JD

VLX105832

1 CONFIDENTIAL RM2007/00260/00

Investigator Investigator/ Hospital/ Institution and Address IEC/IRB Committee Chair and Name of Site no. Committee JD

CONFIDENTIAL

RM2007/00260/00 RM2007/00260/00

VLX105832

2 CONFIDENTIAL RM2007/00260/00

Investigator Investigator/ Hospital/ Institution and Address IEC/IRB Committee Chair and Name of Site no. Committee

CONFIDENTIAL MD, MSPH

RM2007/00260/00

VLX105832

3 CONFIDENTIAL RM2007/00260/00

Investigator Investigator/ Hospital/ Institution and Address IEC/IRB Committee Chair and Name of Site no. Committee

CONFIDENTIAL JD

* Did not randomize any subjects

** IRB Chairperson name not provided RM2007/00260/00 VLX105832 VLX105832

4 This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

CONFIDENTIAL RM2007/00260/00 VLX105832

SUBJECT INFORMATION AND CONSENT FORM

Study Title: The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection

Study Identification: VLX105832

Version Number: 01

Company Name: GlaxoSmithKline

Subject Identification: ______

Principal Investigator Name:

Research Site Address (es):

Daytime telephone number(s)

24-hour contact number(s)

Pager number(s) ______Purpose of this Subject Information and Consent Form This Subject Information and Consent Form may contain words you do not understand. Please ask the study doctor or the study staff to explain any words or procedures that you do not clearly understand.

The purpose of this form is to give you information about the research study and, if signed, will give your permission to take part in the study. The form describes the purpose, procedures, benefits, risks, discomforts and precautions of the research study. You should take part in the study only if you want to do so. You may refuse to take part or withdraw from this study at any time without penalty or loss of benefits to which you are otherwise entitled. Please read this Subject Information and Consent Form and ask as many questions as needed. You should not sign this form if you have any questions that have not been answered to your satisfaction.

Introduction Genital herpes (GH) is a commonly occurring sexually transmitted disease caused by herpes simplex virus (HSV). Two types of HSV, type 1 (HSV-1) and type 2 (HSV-2); can cause GH, although HSV-2 is much more likely to produce recurrent disease (signs and symptoms that repeat over and over as outbreaks). Signs and symptoms of genital herpes can vary widely and might include ulcers, blisters or sores (often called “lesions”) or less noticeable symptoms like redness or irritation.

A blood test can determine whether you have been infected with HSV regardless of whether or not you have symptoms. People with genital herpes are at risk of passing the infection to a sexual partner even when no symptoms are present. This can happen

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because HSV-2 is frequently released, or “shed,” in the genital area between genital herpes outbreaks. Shedding of infectious virus occurs in nearly all people infected with HSV-2. Laboratory tests can detect the presence of HSV-2 that is shed at genital sites.

VALTREX is approved by FDA for the treatment and suppression of genital herpes recurrences (signs and symptoms like genital lesions/outbreaks that appear again and again), as well as the treatment of herpes labialis (cold sores) and herpes zoster (shingles). However, there are no data available on how Valtrex effects the shedding of HSV-2 in people who are newly diagnosed with genital herpes infection. Therefore, use of Valtrex in this setting is considered experimental.

You have been asked to take part in a clinical research study testing whether VALTREX (taken by mouth once a day) decreases the amount of HSV-2 that is shed in the genital area. This study is being conducted in about 20 different centers (clinics) in the US and will involve approximately 66 subjects.

GlaxoSmithKline (GSK) is funding this research study, and the study doctor is paid to conduct this research study by GSK.

Purpose You are being asked to take part in this study because you have recently been diagnosed with genital herpes. The purpose of this trial is to study the effectiveness and safety of VALTREX 1g once a day compared with placebo (a pill that looks exactly like VALTREX but contains no active medication) in reducing herpes virus “shedding” (release of infectious virus) in healthy people who are infected with HSV-2.

To take part in this study you must: • Be in overall good health • Be at least 18 years old • Have been diagnosed with genital herpes type 2 (HSV-2) within 4 months prior to enrolling in the study. You will be required to provide documentation from the doctor who diagnosed you (if different than your study doctor) that provides information about your diagnosis. • Be willing to follow the requirements of the study protocol. Specifically, you will be asked to perform daily genital swabs, attend clinic visits and record daily herpes symptoms in a subject diary.

Women must have a negative pregnancy test to enter this study. If you are a woman who could become pregnant, you must agree to use suitable contraception throughout the study. The study doctor will discuss this information with you.

What Does The Study Involve? This study will make comparisons between 2 treatments: VALTREX and placebo. There will be two study periods in which you will participate. Each study period will last for 60 days. In one of these study periods you will receive VALTREX and in the other study period you will receive placebo. A computer will randomly decide the order in which you will receive these study pills. In between study periods there will be a 7-day break (washout period) so that the first study drug is cleared from your body before you start the other one. You will not take any study pills during the 7-day washout period.

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This study is also blinded, which means neither you nor your doctor will know which study pills you will receive in either test period. In addition, the order in which you will receive study pills is unknown. However, if your doctor needs to find out which study pills you are taking, he/she can do so quickly.

You will be asked to take two 500 mg caplets by mouth, either VALTREX or placebo, once every day for two 60-day Study Periods. You will also be asked to record your herpes symptoms in a daily study-related diary and to collect daily swabs of the genital/anal area. During the 7-day washout period you will still be required to complete your study-related diary and to collect your daily swabs even though you are not taking any study pills on those days.

If you experience symptoms that you think are due to a genital herpes recurrence/outbreak during the study, you will be asked to return to your study clinic so your study doctor can determine whether or not you are actually experiencing a genital herpes recurrence/outbreak. You will undergo a genital exam and receive VALTREX 500mg tablets to be taken twice daily for 3 days if your doctor decides you are experiencing a recurrence/outbreak.

You will need to visit the study clinic at least 10 times during this study. Your total time involvement in the study will be about 130-160 days.

You cannot take any other anti-herpes drugs during this study. You must tell the study doctor about all medications you are taking (including herbal, over-the-counter, and prescriptions), and not start any new drugs without first checking with the study doctor.

What Procedures will be done during the study? The study doctor and his/her staff will record information about your health, including any sicknesses you have or medicines that you are taking. Details will also be recorded of procedures performed before you start study drug and during the study. All regular medical care that your doctor thinks is necessary will still be available to you while you are taking part in this study.

You will have the following procedures performed at the Screening Visit:

• A blood sample (approximately 3 teaspoons) will be collected and tested to determine if you qualify to participate in the study. • A urine sample will be collected to test for protein and blood in your urine. • A genital exam will be performed if you are experiencing a genital herpes recurrence/outbreak. • A genital swab sample will be collected if you are experiencing a genital herpes recurrence/outbreak. • If you are a woman of childbearing potential you will have blood drawn for a pregnancy test at screening and be required to take a urine pregnancy test on study Days 1, 60 and 120. A blood or urine pregnancy test will also be done at any time you thing you may be pregnant. The pregnancy tests must be negative for you to participate in this study.

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The blood samples will be used for several purposes. Some will be tested in a laboratory to make sure that you meet specific requirements to enter the study, and some will be used to check your health before you enter and during your participation in the study. These include samples to determine whether you have been infected with HSV-2 and to check your blood cell counts, kidney and liver function.

After your study doctor has decided that you meet all the requirements for study entry, you will be asked to return for a “Randomization Visit”.

You will have the following procedures performed at the Randomization (Day 1) visit.

• Demographic information (date of birth, sex, race), current medical conditions, medications, and your height/weight will be collected. • Genital examination • Receive education on recognizing the signs/symptoms of genital herpes • Provide a urine sample for a pregnancy test (females only). • Receive study pills and instructions on how/when to take them • Receive instructions on how to record daily herpes symptoms in a study-related diary • Receive a swab collection kit and instructions on how to collect and store your swab samples.

After the Randomization Visit, you will be asked to return to the clinic every 15 days during each 60-day Study Period. As stated previously, you will need to visit the study site at least 10 times during this study. Your total time involvement in the study will be about 130-160 days.

Clinic Visits (every 15 days) During each clinic visit, you will be asked to return the swab samples you collected daily and stored at home and any unused study pills. You will receive a new swab kit and additional study pills at each clinic visit. In addition, the clinic staff will review your daily record of herpes symptoms, and ask about any new (different from last clinic visit) medical conditions you may have, or new (different from last clinic visit) medications you are taking. Blood and urine samples will be collected for laboratory testing at the end of each of the two 60-day Study Periods. If you are female, a urine sample will be obtained for pregnancy testing at the end of each 60-day Study Period.

Washout There will be a 7-day break between study periods so that the first study drug is cleared from your body before you start the other one. No clinic visit is required during the 7- day washout period. You will continue with daily swabbing and diary completion during the washout period, but will not take study medication. Once you complete your washout period, you will be asked to start taking your study pills for study period 2. You will not have a clinic visit during the washout period prior to starting study period 2.

Clinic Visit for Genital Herpes Recurrences You will be asked to return to the clinic within 24 hours of experiencing signs or symptoms of a genital herpes recurrence/outbreak. No matter which study period you are currently participating in, if you experience a genital herpes recurrence/outbreak (confirmed by your study doctor) during the study, you will receive VALTREX 500mg

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tablets to be taken twice daily for 3 days to treat the recurrence/outbreak. During the recurrence visit, the study doctor will perform a genital examination and collect genital swab samples. You will be instructed to stop taking double-blind study drug until you complete this treatment. If you continue to experience a genital recurrence/outbreak after the 3-day treatment, you will have to return to the clinic and your doctor will re-examine you and may provide additional VALTREX treatment. The study doctor will collect another genital swab at this visit. You should NOT start taking your study pills until you have completed treatment for your recurrence/outbreak. You will still be required to collect daily swab samples while you are experiencing a recurrence/outbreak or receiving treatment for the recurrence/outbreak.

Early Withdrawal If you decide to stop your participation in the study, you will be asked to return to the clinic for a final visit so that (if female), pregnancy testing can be performed. Swab kits, your daily record of herpes symptoms, and all study pills must be returned at this visit.

At the end of your study participation, the study doctor will discuss continued care needs with you.

What else will I have to do? You will need to take your study drugs everyday, collect daily genital swab samples and maintain a daily record of your herpes symptoms.

Possible ways to reduce risk of transmission to a partner include use of safer sex practices. Do not have sexual contact with your partner when you have any symptom or recurrence/outbreak of genital herpes. You should use safer sex practices, including condoms, during all sexual contacts (even if you do not have symptoms) since you could be shedding infectious HSV-2 at any time. Your doctor will discuss safer sex practices with you.

Because certain medicines may interact with your study drug, you must tell the study doctor about any medicines (either prescription or over the counter) or herbal remedies that you plan to take while you are on this study.

Are there any risks or discomforts involved? There may be risks or side effects of VALTREX that are not known at this time.

You should not take VALTREX if you are allergic to any of its ingredients or to acyclovir.

VALTREX may interact with other medications, causing side effects. Please inform the study doctor of all prescription, herbal, and over-the-counter medicine you are taking and do not start any new medications without asking the study doctor.

VALTREX does not cure herpes infections and it is necessary to follow the instructions given for safer sex practices.

Common side effects of VALTREX include: • headache

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• nausea • stomach pain • vomiting • dizziness

Taking VALTREX every day has been shown to reduce the risk of transmitting HSV-2 to a sexual partner. In this study you will be taking VALTREX for only one of the two 60- day study periods. For the other study period you will be taking placebo. You should know that it is possible for you to transmit HSV-2 to your partner even when you are taking active medication to treat or suppress genital herpes outbreaks. You can spread genital herpes to others even when you have no symptoms because you can “shed” (release) infectious virus in between outbreaks. If you are a male and transmit genital herpes to a partner who is pregnant or later becomes pregnant, she may go on to transmit virus to the baby and this could result in serious complications for the baby. Your doctor will counsel you on safer sex practices when you enter the study.

There have been rare reports of nervous system problems in patients with kidney or other health problems. Additional reports include poor kidney function and kidney failure; some of these cases have been fatal in patients with advanced HIV disease or with immune system problems. There have also been reports of an unusual blood disorder called microangiopathic hemolytic anemia leading to a decrease in the number of red blood cells. There are also reports of thrombocytopenia (a decrease in the number of platelets, which are cells involved in blood clotting) which is also sometimes fatal in patients with immune system problems. These events sometimes occurred in combination; a condition called Thrombotic Thrombocytopenia Purpura –Hemolytic Uremic Syndrome (TTP/HUS).

It should be noted that these events have been reported in severely immunocompromised patients (people with damaged immune systems or immune system diseases), particularly those with advanced HIV disease that received high doses (8g daily) of VALTREX for prolonged periods in clinical trials. It is of note that these findings have been observed in patients not treated with VALTREX who have the same underlying or concurrent conditions but who are severely immunocompromised. The current study that you are about to participate in does not allow subjects to enter the study with an abnormal immune system or kidney problems. The study pills are not to be taken by anyone other than you. Keep it away from children and others who cannot read or understand printed labels.

During this study you will have blood drawn. The risks of venipuncture (drawing blood from a vein in your arm) include temporary discomfort from the needle stick, possible bruising, and rarely, infection.

Reproductive Risks Because the effects of VALTREX on the unborn child or nursing baby are uncertain, you will not be allowed to enter this study if you are pregnant or breastfeeding. If you are a female who is able to have children and you choose to take part in this study, you must agree to one of the following: • Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period of 1 week after study

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completion or early discontinuation from the study (to allow time for the drug to be cleared from your body). • Have a male partner who is confirmed to be sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject. • Use birth control (a way to keep you from becoming pregnant) throughout the study and for 30 days after completion of study treatment. Ask your study doctor about appropriate birth control methods and which method might be best for you. Even when you use one of the allowed methods, there may be a small risk that you could become pregnant. If you become pregnant during the study, then you should stop taking all study drugs and inform your study doctor right away.

Are there any benefits? You may or may not benefit by participating in this study. Your participation in this study may add to the medical knowledge about the use of VALTREX in patients with genital herpes.

Are there alternatives to participating in this study? VALTREX is FDA-approved for the treatment of genital herpes. Other medications are also available (famciclovir, acyclovir). If you have any questions concerning alternative treatments, you should ask your study doctor for more information.

What happens if new information becomes available? During the course of the study, you will be informed of any new findings that may affect your willingness to continue participating in this study. You may contact the study doctor at any time after your withdrawal to find out if new information about this study has become available.

Is there compensation for study-related injuries? If, as part of participating in the study you are injured, seek medical care. GSK will pay for reasonable and necessary medical expenses if you are injured by the study drug or study-related procedures done to you in accordance with the study protocol that are not covered by your medical insurance. You must follow the directions of the study doctor to be eligible for this coverage.

Neither the study Sponsor, GlaxoSmithKline, nor the study doctor has a program in place to provide other compensation in the event of an injury.

Do I have Legal Rights? The above section does not restrict your right to seek legal assistance. You do not waive any legal rights by signing this Subject Information and Consent Form.

Is there a cost for participating in this study? You will receive all study drugs, study procedures, study-related materials (e.g. swab kit) and study visits at no cost. Medical costs of other treatment outside this study are your responsibility and will be charged to you, your health insurance company or your local health agency.

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Will I receive payment for participating? You will receive compensation while you take part in this study to cover expenses (e.g. parking and transportation expenses) brought upon yourself as a result of the study. You will be paid [X] for study visits (including genital herpes recurrence visits). You will not be paid for any study visits you do not attend.

What about voluntary participation or withdrawal from the study? Your participation in this study is voluntary. If you do decide to take part, you will be given this information to keep and be asked to sign this consent form. You may refuse to take part in this study, or once in the study you may decide to discontinue participation at any time. You must inform your study doctor if you decide to do this.

Your decision not to take part in the study or to stop participating in the study will not affect your current or future medical care, or any benefits to which you may otherwise be allowed. Contact your study doctor or clinic should you decide not to continue your participation in the study. He/she will explain the best way for you to stop your participation in the research study.

The US Food and Drug Administration (FDA), the study doctor, or GlaxoSmithKline may stop your participation in this study with or without your consent at any time. Your participation in the study may be stopped for any of the following reasons: • You fail to follow the study procedures outlined above; • You experience a serious side effect, which means you should no longer be in the study for safety reasons; • The study doctor decides that continuing the study would be harmful to you; • You have a change in your condition which requires medicines that are not allowed in this study; • You have a positive pregnancy test; • There are not enough subjects enrolled in the study; • GlaxoSmithKline, the study sponsor, stops enrolling new subjects into the study for any reason, and you are in the screening phase of the study and have not yet been assigned to a treatment group; • The study is stopped prematurely by GlaxoSmithKline or the FDA or another medicine control agency for other reasons not yet known.

WHO SHOULD I CONTACT IF I HAVE ANY QUESTIONS? If you have any questions about your participation in this research study, or if you feel you have experienced a research related injury or reaction to the study drug, or you are developing side effects from the study drugs, contact:

Principal Investigator: «FirstName» «MiddleName» «LastName» «Suffix»

Daytime telephone number(s): «Phone»

24-hour contact number(s): «Phone2»

Pager number(s): «Phone3»

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If you have questions about your rights as a research subject, you may contact the at (toll free). An Independent Review Board is a group of scientific and non-scientific individuals who perform the initial and ongoing ethical review of the research study with the study subject's safety and welfare in mind. If you have study-related comments, complaints or concerns, you should first contact the study investigator. Please call the IRB if you want to talk to someone other than the study investigator or have difficulty reaching the study investigator. For further information regarding the clinical trials process and your role as a research subject, you may visit the website at

What is Confidentiality? Maintaining confidentiality is important to GlaxoSmithKline. Your personal information, such as your gender, age, the details of your medical conditions, and other information or data collected by GlaxoSmithKline as part of the study, will be identified by a number. In other words it will be coded. Your name will not appear in any publications or reports produced from this study.

GlaxoSmithKline will keep the information and the results collected about you in this study. Your name and address are not included in the information kept by GlaxoSmithKline - only your study doctor will keep this information. GlaxoSmithKline has told your study doctor to keep the information about you in a secure place. GlaxoSmithKline will comply with internal procedures to protect personal and other information even in countries where data privacy laws are less strict than in Europe/US.

By agreeing to take part in this research study you will also be allowing certain persons to see the information about you, both personal, including your name, and other information held by the study doctor. Your information will be looked at to confirm that it is correct and that it is related to you. This will be done by selected people working for GlaxoSmithKline and organizations acting on behalf of GlaxoSmithKline, government regulatory authorities, and the These persons are required to maintain the confidentiality of your information.

Your information will be processed electronically (such as by a computer) or manually and analyzed to determine outcome of this study. GlaxoSmithKline may use your information for other medical/health care purposes related to development of this drug. For this purpose, only your coded information will be used.

Your information may/could be sent to regulatory authorities, to the CGIRB, to other doctors and/or organizations working with GlaxoSmithKline. It may also be sent to other GlaxoSmithKline sites in this country and in other countries where there may be different or lesser standards for looking after it. GlaxoSmithKline will apply the same standard in the protection of your information to the extent permitted by law.

As part of the study, medical information about you will be collected and analyzed. This medical information will include your HSV-2 status. By signing this document, you authorize the study doctor and staff to use this information in conducting the study, and to provide access to or copies of this information to the study sponsor or to others working with the sponsor to monitor the progress of the study or analyse the study data. Access to this information is necessary for the sponsor to check that the study is being done

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correctly, and to collect and analyse data about the safety and effectiveness of the study drug.

This authorization to use or disclose the information as described above is not time- limited (that is, will not automatically expire).

You have the right to ask the study doctor about the data being collected on you for the study and about the purpose of this data. You have the right to ask the study doctor to allow you to see your personal information and to have any needed corrections to it made.

However, you agree that, while the study is still in progress, you may not be given access to medical information about you that is related to the study. This may include, for example, information about whether you are receiving study drug or placebo, or any other information that is “blinded” (that is, kept secret during the study to prevent bias). While a request for access to medical information can be denied, the study doctor and staff will not automatically deny a request, but will consider whether it’s medically appropriate under the circumstances to allow access. Your agreement that you may be denied access to your study-related medical information during the study will not be used to deny you access to that information after the study is completed at all locations and study results are analyzed.

You may decide not to sign this authorization (by not signing this consent form), or you may revoke this authorization in writing at any time. However, you can only participate in the study if you authorize the use and disclosure of the information as described above. If you decide not to sign this authorization/consent form, you will not be enrolled in the study. If you sign this authorization and decide later to revoke this authorization, you will be dropped from the study at that time. Information collected up to the time you revoke this authorization will continue to be used as study data if it is scientifically appropriate to do so.

You may choose to withdraw this Authorization at any time, by notifying the study doctor in writing of your wishes.

If you withdraw from the study and withdraw your Authorization, no new information will be collected for study purposes unless the information concerns an adverse event (a bad effect) related to the study. If an adverse event occurs, your entire medical record may be reviewed. All information that has already been collected for study purposes, and any new information about an adverse event related to the study, will be sent to the study sponsor.

You should know that, once information is disclosed under this authorization to someone who is not a health care provider, the information is no longer protected by the federal privacy rules called the “HIPAA privacy regulations” and could be disclosed to others by the recipient, or by someone who is not a healthcare provider.

You will be given a copy of this authorization/consent after you have signed and dated it.

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GLA1-05-006

EXPERIMENTAL SUBJECT’S BILL OF RIGHTS

Any person who is requested to consent to participate as a subject in a research study involving a medical experiment, or who is requested to consent on behalf of another, has the right to:

1. Be informed of the nature and purpose of the experiment.

2. Be given an explanation of the procedures to be followed in the medical experiment, and any drug or device to be used.

3. Be given a description of any attendant discomforts and risks reasonably to be expected from the experiment.

4. Be given an explanation of any benefits to the subject reasonably to be expected from the experiment, if applicable.

5. Be given a disclosure of any appropriate alternative procedures, drugs or devices that might be advantageous to the subject, and their relative risks and benefits.

6. Be informed of the avenues of medical treatment, if any, available to the subject after the experiment if complications should arise.

7. Be given an opportunity to ask any questions concerning the experiment or the procedures involved.

8. Be instructed that consent to participate in the medical experiment may be withdrawn at any time, and the subject may discontinue participation in the medical experiment without prejudice.

9. Be given a copy of a signed and dated written consent form when one is required.

10. Be given the opportunity to decide to consent or not to consent to a medical experiment without the intervention of any element of force, fraud, deceit, duress, coercion, or undue influence on the subject’s decision.

______Signature of Subject

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GLA1-05-006

Subject’s Statement of Consent and Authorization

“The Effect of Valacyclovir 1g Once Daily on HSV-2 Viral Shedding in Subjects Newly Diagnosed with Genital Herpes Infection”

I confirm that I have read the statements in the informed consent form dated [ ______] for this study. I confirm that the study information and procedures have been explained to me by [ ______] on [ ______] during the consent process for this study.

I confirm that I have had the opportunity to ask questions about this study and I am satisfied with the answers and explanations that have been provided at this time.

I confirm that I have received counselling regarding the risks of HSV-2 transmission to a partner. I have also been given educational brochures for this study that describe genital herpes and the importance of using safer sex practices to reduce the risk of transmission.

I have been given time and opportunity to read the information carefully, to discuss it with others and to decide whether or not to take part in this study.

I agree to take part in this study. I have been told that I will receive a signed and dated copy of this Subject Information and Consent Form. Subject's Signature ______Date: ______

Printed name of ______Subject

*Signature of ______Date: ______Legally Acceptable Representative (as required by law)

*Printed name of ______Legally Acceptable Representative (as required by law)

*Signature of ______Date: ______Witness *Printed name of ______Witness

Signature of Person ______Date: conducting Consent Printed Name of ______Person conducting Consent

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Randomization Code

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1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Valtrex 1g QD Valtrex 1g QD RM2007/00260/00 2 Placebo Placebo

1 Valtrex 1g QD Valtrex 1g QD VLX105832 2 Placebo Placebo

1 Placebo Placebo Protocol: VLX105832 Page 2 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo CONFIDENTIAL

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo 3 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD RM2007/00260/00 RM2007/00260/00 1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo VLX105832 VLX105832 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD Protocol: VLX105832 Page 3 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo CONFIDENTIAL 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD

4 2 Placebo Placebo

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

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1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo Protocol: VLX105832 Page 4 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Placebo Placebo CONFIDENTIAL 2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo

5 2 Valtrex 1g QD Valtrex 1g QD

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

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1 Placebo Placebo

2 Valtrex 1g QD Valtrex 1g QD VLX105832

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD Protocol: VLX105832 Page 5 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Placebo Placebo

2 Valtrex 1g QD Valtrex 1g QD CONFIDENTIAL

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD 6 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo RM2007/00260/00 RM2007/00260/00 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD VLX105832 VLX105832 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD Protocol: VLX105832 Page 6 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD

2 Placebo Placebo CONFIDENTIAL

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo 7 1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo RM2007/00260/00 RM2007/00260/00

1 Valtrex 1g QD Valtrex 1g QD

2 Placebo Placebo VLX105832

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo Protocol: VLX105832 Page 7 of 7 Population: Randomized Listing 23 Listing of Random Codes

Randomized Actual Treatment Period Period Inv. Subj. Period Treatment Treatment ------

1 Placebo Placebo 2 Valtrex 1g QD Valtrex 1g QD

1 Valtrex 1g QD Valtrex 1g QD

2 Placebo Placebo CONFIDENTIAL

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo 8 1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

1 Valtrex 1g QD Valtrex 1g QD 2 Placebo Placebo

Table of Contents

Page Listing - ICH 1 Listing of End of Study Record (Intent-to-Treat Exposed Population) ...... 3 Listing - ICH 2 Listing of Subjects for Whom the Treatment Blind was Broken During the Study (Intent-to-Treat Exposed Population) ...... 6 Listing - ICH 3 Listing of Inclusion/Exclusion Criteria Deviation Records (Randomized Population) ...... 7 Listing - ICH 4 Listing of Subjects Excluded from Primary Efficacy Analysis (Randomized Population) ...... 8 Listing - ICH 5 Listing of Demographic Characteristics (Intent-to-Treat Exposed Population) ...... 12 Listing - ICH 6 Listing of Race (Intent-to-Treat Exposed Population) ...... 17 Listing - ICH 7 Listing of Current Medical Conditions (Intent-to-Treat Exposed Population) ...... 22 Listing - ICH 8 Listing of Concomitant Medications (Intent-to-Treat Exposed Population) ...... 28 Listing - ICH 9 Listing of Genital Herpes Recurrences (Intent-to-Treat Exposed Population) ...... 73 Listing - ICH 10 Listing of Exposure Data (Intent-to-Treat Exposed Population) ...... 81 Listing - ICH 11 Listing of Investigational Product Compliance (Intent-to-Treat Exposed Population) ...... 96 Listing - ICH 12 Listing of Investigational Product Discontinuation Record (Intent-to-Treat Exposed Population) ...... 121 Listing - ICH 13 Listing of Shedding Data (Intent-to-Treat Exposed Population) ...... 123 Listing - ICH 14 Listing of Subject Numbers for Individual Adverse Events (Intent-to-Treat Exposed Population) ...... 391 Listing - ICH 15 Listing of All Adverse Events (Intent-to-Treat Exposed Population) ...... 397 Listing - ICH 16 Listing of Drug-Related Adverse Events (Intent-to-Treat Exposed Population) ...... 415

1 CONFIDENTIAL RM2007/00260/00 VLX105832

Listing - ICH 17 Listing of Fatal Adverse Events (Intent-to-Treat Exposed Population) ...... 417 Listing - ICH 18 Listing of Non-Fatal Serious Adverse Events (Intent-to-Treat Exposed Population) ...... 418 Listing - ICH 19 Listing of Other Significant Adverse Events (Intent-to-Treat Exposed Population) ...... 419 Listing - ICH 20 Listing of HSV-2 Inhibition Assay (Intent-to-Treat Exposed Population) ...... 420 Listing - ICH 21 Listing of Laboratory Data for Subjects with Abnormalities of Clinical Concern (Intent-to-Treat Exposed Population)...... 421

2 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.