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In February 2013, Glaxosmithkline (GSK) Announced a Commitment

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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 - 1 1- CONFIDENTIAL RM2007/00260/00RM2007/00260/00 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies VLX105832VLX105832 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. Copyright 2007 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. - 2 2- CONFIDENTIAL RM2007/00260/00 VLX105832 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 3 CONFIDENTIAL RM2007/00260/00 VLX105832 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. 4 CONFIDENTIAL RM2007/00260/00 VLX105832 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
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