Version 1.0 + Amnd 1.0 Clinical Trial Protocol + Amnd 2.0, 3.0 + 4.0 AIC316-01-II-02 May 02, 2013

CLINICAL TRIAL PROTOCOL

A double-blind, double dummy, randomized cross-over trial to compare the effect of AIC316 100 mg once daily versus valacyclovir 500 mg once daily on genital HSV shedding in HSV-2 seropositive adults. Trial No./Trial Identification Code: AIC316-01-II-02

Sponsor AiCuris GmbH & Co. KG Friedrich-Ebert-Str. 475 / Building 302 42117 Wuppertal Germany Sponsor Contact Burkhard Timmler, MD Medical Director AiCuris GmbH & Co. KG Friedrich-Ebert-Str. 475 / Building 302 42117 Wuppertal Germany Phone: +49 202 31763 FAX: +49 202 31763 Contract Research Organization

Clinical Phase 2 Version Final 1.0 + Amendment 1.0 (September 24, 2012) + Amendment 2.0 (October 17, 2012) + Amendment 3.0 (December 18, 2012) + Amendment 4.0 (May 02, 2013) Date of Protocol July 05, 2012 Amendment 4.0 (May 02, 2013)

This document is strictly confidential. Disclosure of contents or any trial-related information to third parties other than applicable IEC(s)/IRB(s) and regulatory authorities is not permitted except by written consent of AiCuris GmbH & Co. KG.

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1.2 Declaration by the Principal Investigator

I have read this protocol and agree that it contains all the necessary details for carrying out this trial. I agree to personally conduct or supervise the trial-related activities at my investigative site as described in this protocol and will complete the trial-related activities for all enrolled subjects within the time designated for the trial. I verify that I am suitably qualified by my education, scientific medical training and experience to conduct the trial. Documentation of my qualifications and professional affiliations are contained in my signed and dated current curriculum vitae. I will provide the supplied copies of the protocol and all information relating to non-clinical and prior clinical experience (e.g., Investigator’s Brochure [IB]) to all staff in my unit who participates in this trial. I will discuss this material with them to ensure that they are fully conversant with the medical treatment in, and the conduct of, the trial, and that they will handle the data and information generated in the trial confidentially. I agree not to start enrolling subjects until a duly appointed Ethics Committee (EC)/Institutional Review Board (IRB) has issued a favorable opinion and the Competent Authorities (CA) have approved the trial. I will conduct the trial in accordance with Good Clinical Practice (GCP), the Declaration of Helsinki, and the moral, ethical and scientific principles that justify medical research. The trial will be conducted in accordance with the relevant laws and regulations relating to clinical trials and the protection of subjects in the country in which I will perform the trial. All subjects will be comprehensively informed about the nature of the trial, of its investigational nature and that they may withdraw from the trial at any time. They will give their written consent to participate before entry into the trial. I will only use the subject information sheet and informed consent form approved by AiCuris GmbH & Co. KG and the EC/IRB which has reviewed this trial. I will supply AiCuris GmbH & Co. KG any material written by myself (e.g., summary of trial, correspondence, etc.) which has been given to the EC/IRB in support of the application. I have read the current version of the IB, including the potential risks (especially the results of the pharmacological and toxicological examination) and adverse drug effects of the investigational medicinal product obtained in previous clinical trials and I agree to report all adverse events (AEs) that occur during the trial. Where applicable, the information contained in the electronic case report forms (eCRFs) will be transcribed from my records, reports and manuscripts. The eCRF may be the original source for certain items. Either I, or an appointed person, will attest to the authenticity of the data and accuracy and completeness of the transcriptions by providing an electronic signature in the eCRF. I agree to the audit and monitoring procedures described in the protocol which involve verification of trial records against the original records. I will make available additional background data from my records at the request of government regulatory agencies, if allowed by the hospital or institution where the trial is being conducted. I am aware of the requirements for the correct reporting of serious AEs, and I undertake to document and to report such events as requested. I understand that I am obliged to provide the complete results and all data generated during the trial to AiCuris GmbH & Co. KG for their unrestricted use. I understand and agree that such trial results, data,

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and all information concerning the investigational medicinal product(s) and AiCuris GmbH & Co. KG’s activities, such as patents, formulae, manufacturing procedures and basic, unpublished scientific data and information supplied by AiCuris GmbH & Co. KG or generated during the trial are confidential, and are the exclusive property of AiCuris GmbH & Co. KG. I undertake only to use this information plus the investigational medicinal product to conduct the trial and not to use it for any other purpose without the written agreement of AiCuris GmbH & Co. KG. I will supply AiCuris GmbH & Co. KG with the trial data in such a way that the subjects cannot be personally identified. As the Principal Investigator I will also adhere to the given detailed investigator responsibilities as specified in Appendix 20.1 of this protocol.

Investigator Signature date

Name and Address*

Telephone number*

* If the address or phone number of the Investigator changes during the course of the trial, written notification will be provided by the Investigator to the AiCuris GmbH & Co. KG and Inc. This will not require protocol amendment(s).

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1.3 Involved Parties

1. Sponsor’s Medical Burkhard Timmler, MD Director AiCuris GmbH & Co. KG Friedrich-Ebert-Straße 475 / Building 302 42117 Wuppertal, Germany Office phone: +49 (0) 202 31763 Office fax: +49 (0) 202 31763 Email: 2. Coordinating Investigator Anna Wald, MD, MPH University of Washington Virology Research Clinic 908 Jefferson St, Suite 11NJ-1166, Seattle, WA 98104, USA Office phone: Office fax:

3. Sponsor’s Clinical Trial Christiane Vank, PhD Manager AiCuris GmbH & Co. KG Friedrich-Ebert-Straße 475 42117 Wuppertal, Germany Office phone: 49 202 31763 Office fax: 49 202 31763 Email: 4. CRO’s Clinical Trial Manager

: 5. Statistical analysis

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6. Sponsor’s Dirk Kropeit, MD Pharmacokineticist AiCuris GmbH & Co. KG Friedrich-Ebert-Straße 475 42117 Wuppertal, Germany Office phone: 49 202 31763 Office fax: 49 202 31763 Email:

7. Bioanalysis of pharmacokinetic samples and samples for evaluation of potential drug metabolites

8. Analysis of routine blood and urine samples

9. Pharmacovigilance (SAE reporting)

10. HSV Western Blot, Anne Cent University of Washington, Virology Laboratory Children’s Hospital & Medical Center Room W8814 4800 Sand Point Way N. E. Seattle, WA 98105, USA Office phone: Email:

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11. HSV DNA PCR, Meei-Li Huang Sequencing University of Washington Molecular Diagnostic Laboratory 1616 Eastlake Ave E, Suite 320 Seattle, WA 98102, USA Office Phone: E-Mail: 12. Preparation and supply of Trial medication kits

13. Pharmacogenetic analysis

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2 PROTOCOL SYNOPSIS

Trial No. AIC-316-01-II-02 Title A double-blind, double dummy, randomized cross-over trial to compare the effect of AIC316 100 mg once daily versus valacyclovir 500 mg once daily on genital HSV shedding in HSV-2 seropositive adults.

Trial Identification AIC-316-01-II-02 Code Clinical Phase 2 Trial design Approximately ninety subjects with proven recurrent episodes of genital herpes will be randomized to receive an oral daily dose of either AIC316 100 mg or valacyclovir 500 mg for 28 days, then to undergo a 4 week washout period, followed by a second 28 day period receiving the corresponding other treatment (cross over design), and ending with a 28 day follow up period. Appropriate matching placebo will be administered in parallel to the verum. During both, the first and second treatment period, subjects will obtain swabs of the genital secretions 4 times a day and maintain a diary of genital signs and symptoms. Randomization will be stratified by gender and will be capped at no more than 2/3 for each gender.

valacyclovir valacyclovir 500 mg po 500 mg po qd x 28 days qd x 28 days HSV-2 28 days 14-21 seropositive wash 28 days Days adults: out Follow-up screening Randomize period AIC316 AIC316 100 mg po 100 mg po qd x 28 days qd x 28 days

Randomization and Randomization will be 1:1 into one of the 2 dosing arms starting with either AIC316 blinding or valacyclovir. Each dosing arm will include approximately 45 subjects. Blinding is accomplished by assigning drug kit (randomization) numbers, on the basis of a dynymic randomization via IVRS. Double dummy design including placebo tablets and placebo comparator capsules ensures consistency and blinding of the treatment regimes. Overall rationale HSV-2 is a significant human pathogen with several adverse health outcomes and continuing medical need for new therapeutic options for HSV therapy in many settings, e.g., HSV encephalitis, neonatal HSV, and prevention of HSV-2 transmission. In addition, a drug that could interrupt the synergy between HIV and HSV-2 by efficiently inhibiting HSV-2 has great potential as an HIV transmission prevention strategy.

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AIC316 - is a helicase-primase inhibitor representing a new class of drugs with high specificity for HSV. Preclinical studies show good antiviral activity in vitro, and animal models show that the compound is effective for skin, eye and genital infection. Phase 1 studies in healthy volunteers have shown high bioavailability, and a long half-life, facilitating once daily dosing. A proof of concept trial showed that AIC316 75mg daily reduced substantially and significantly genital viral shedding in comparison to placebo and genital lesions in a dose-dependent manner. The dose- response effect was observed for both genital shedding and lesions suggests that a further increase in the dose of AIC316 would result in abrogation of viral shedding (and thus lesions). While acyclovir and valacyclovir are effective therapies for many manifestations of HSV-related disease, recent detailed studies show that HSV replication on genital mucosa continues in the presence of standard suppressive therapy with valacyclovir 500 mg daily. Available data from a previous trial with AIC316 suggests that AIC316 may be a more efficacious inhibitor of HSV replication in the genital tract, and thus provide a greater virologic and clinical effect. Reactivation of HSV on the genital mucosa is characterized by intermittent shedding of the virus, which can be detected by HSV PCR from a swab of genital secretions. The frequency of shedding is highly variable between people, and fairly constant within persons, especially after the initial year since HSV-2 acquisition. Anna Wald’s group at the University of Washington has developed the use of viral shedding, obtained from self-collected genital swabs by subjects as a reliable and effective strategy to assess the efficacy of interventions. This approach is ideally suited to proof-of-concept studies and comparative studies as it can unequivocally demonstrate objective antiviral activity of the proposed intervention in vivo. Since shedding characteristics vary widely between subjects, but tend to remain stable within persons, cross-over trials present an advantage over parallel trials to show the distinctive efficacy of antiviral drugs. The treatment duration of 28 days has been used in trial AIC316-01-II-01 and has shown to be sufficient to show differences between treatment groups and placebo in regard to shedding and has therefore been chosen for this trial. Trial objective The objective of this trial is to compare the efficacy of AIC316 100 mg given perorally once daily to standard peroral dose valacyclovir 500 mg qd on genital mucocutaneous HSV shedding in immunocompetent HSV-2 seropositive women and men with a history of genital herpes. Shedding will be determined by HSV DNA PCR measurement of daily swabs taken from the anogenital region throughout the treatment. Primary objective: Comparison of HSV shedding rate under treatment with AIC316 100 mg daily versus valacyclovir 500 mg daily. Secondary objectives: Comparison between treatment groups of the following: x Mean HSV copy numbers on HSV DNA positive samples; x Mean HSV copy numbers on HSV DNA positive samples on days with

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lesion(s); x Mean HSV copy numbers on HSV DNA positive samples on days without lesion(s); x Overall shedding rate x Shedding rate on days with lesion(s); x Shedding rate on days without lesion(s); x Lesion rate; x Duration of pain; x HSV shedding episode rate; x Shedding episode duration; x Recurrence rate; x Recurrence duration; x Occurrence of molecular signals of resistance to AIC316; x Safety and tolerability of AIC316; x Predose blood concentrations for AIC316 and valacyclovir at steady-state x Pharmacogenetic evaluation x Evaluation of potential AIC316 drug metabolites

Trial period Start of trial conduct (first subject dosed): October 2012

Estimated enrollment period: 6 months Estimated end of trial (last subject out): September 2013 Period of time for subject in trial: 21 weeks (in total) as a maximum Screening period: Up to 21 days Treatment periods: 2 times 28 days Washout (in between the treatment phases) 28 days (+14 days) Follow up period: 28 days

Investigational sites Number of centers: 4 Number of countries: 1(US only)

Trial population Approximately ninety (90) subjects (male or female) with recurrent episodes of HSV-2 as defined by the inclusion and exclusion criteria. Treatment Trial medication AIC316 (unique compound identifier: AIC090093) will be supplied as mesylate monohydrate salt (AIC090016) immediate release tablets containing AIC316 100 mg. Valacyclovir 500 mg will be supplied in capsules.

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Matching placebo tablets and capsules. To maintain the blinding, subjects in both dosing arms will receive identical number of tablets and capsules, double dummy technique, so that every subject will receive an identical daily dose with respect to tablet/capsule number and appearance. Two dosing arms Dosing arm 1, AIC316 100 mg, once daily for 28 days, followed by a 28-day washout period, followed by valacyclovir 500 mg once daily for 28 days. On Day 1, the subject will take a loading dose of AIC316 400 mg (four 100 mg tablets). Following the loading dose, the subject will take AIC316 100 mg (one tablet) once daily for 27 consecutive days (Days 2-28). In addition, the subject will take one valacyclovir-placebo capsule daily from Day 1 to 28. There will be a 28 day (Days 29-56) washout period during which no trial medication will be taken. After the washout period, the subject will take valacyclovir 500 mg (one capsule) once daily for 28 consecutive days (Days 57-85). In addition, on Day 57, the subject will take a loading dose of AIC316-placebo (four tablets). Following the loading dose, the subject will take AIC316-placebo (one tablet) daily for 27 consecutive days (Days 57- 85). Dosing arm 2, valacyclovir 500 mg once daily for 28 days, followed by a washout period of 28 days, followed by AIC316 100 mg, once daily for 28 days. On Day 1, the subject will take valacyclovir 500 mg (one capsule) once daily for 28 consecutive days (Days 1-28). In addition, on Day 1, the subject will take a loading dose of AIC316-placebo (four tablets) followed by AIC316-placebo (one tablet) daily for 27 consecutive days (Days 2-28). There will be a 28 day (Days 29-56) washout period during which no trial medication will be taken. After the washout period, on Day 57, the subject will take a loading dose of AIC316 400 mg (four 100 mg tablets). Following the loading dose, the subject will take AIC316 100 mg (one tablet) once daily for 27 consecutive days (Days 58-85). In addition, the subject will take one valacyclovir-placebo capsule daily from Day 57 to 85.

Concomitant Due to their known effects to induce drug metabolizing enzymes and transporters therapy the following drugs are prohibited in this trial within a period of 14 days prior to the first dosing with IMP (Day1) until the final examination visit of the trial: carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, troglitazone Furthermore, the following should not be consumed for 14 days prior to the first dosing with IMP (Day1) until the final examination visit of the trial: o grapefruit, Seville oranges, pomelo, or any product containing grapefruit, Seville oranges, and/or pomelo o Quinine- and quinidine-containing drinks such as tonic water In addition, no topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence are allowed from screening until final examination.

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Inclusion Participating subjects have to fulfill the following inclusion criteria: criteria 1. Age greater or equal to 18 years 2. HSV-2 seropositive by the UW Western blot 3. History of recurrent genital herpes, defined as • 4 but ” 9 clinical recurrences in the last year or, if currently on suppressive therapy, prior to starting suppressive therapy (suppressive therapy has to be stopped at least 7 days prior to initiation of trial medication). 4. Negative results for human immunodeficiency virus antibody (HIV-Ab). 5. Willing to not use any topical genital therapy for the duration of the trial. 6. Willing to not use any systemic anti HSV therapy during Treatment Period 1 and 2, including 7 days prior to Treatment Period 1 and 7 days prior to start of Treatment Period 2. 7. Willing to obtain four (4) swabs per day from genital secretions (non-lesional as well as lesional, if appropriate) for the full duration of the 2 treatment phases (2 x 28 days) of the trial. 8. Willing to keep a daily trial diary during both treatment periods. 9. Negative serum E-HCG (beta-human chorionic gonadotropin) test for women at screening and a negative urine pregnancy test prior to randomization. 10. Willing to use effective birth control: Male subjects who are surgically sterile (e.g. after vasectomy) or who must agree to use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. An adequate method of contraception is defined as sexual abstinence or the use of a male condom combined with female contraception. Female subjects who are surgically sterile (e.g. 2-sided tubal ligation, resection or ovariectomy) or post-menopausal (defined as older than 50 years of age and who have a history of no menses for at least 24 months) or female subjects of childbearing potential who are sexual abstinence or use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. An adequate method of contraception is defined as a double-barrier method combining two of the following acceptable birth control methods: - the use of the copper-releasing intrauterine device (to have been in place for at least 2 months prior to screening) - the use of one of the following: diaphragm, Lea’s shield, FemCap, sponge, and - monogamous relationship with vasectomized partner - the use during each act of sexual intercourse of a male condom. 11. Subject must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the clinical trial protocol and procedures.

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12. Subject must give written informed consent.

Exclusion Any of the following will exclude a subject from the trial: criteria 1. Acute episode of genital herpes at randomization. 2. Serious medical conditions, such as diabetes, significant autoimmune disease, etc. 3. Clinically relevant acute or chronic infections (excluding HSV-2). 4. Known intolerance to valacyclovir, acyclovir, or any component of the formulation 5. Documented HSV resistance to acyclovir, valacyclovir, famciclovir or penciclovir 6. History or current evidence of malignancy except for a localized non-melanoma skin cancer 7. Subject known to be immunosuppressed 8. Treatment with systemic steroids or other immunomodulating agents 9. Participation in any clinical trial within 30 days prior to screening 10. Renal impairement (creatinine clearance < 30ml/min) and/or hepatic impairment (Child-Pugh stage B and C) 11. History or current evidence of gastrointestinal malabsorption which could interfere with absorption 12. Known to have other genital tract disorders or sexually transmitted diseases that may interfere with assessment of the trial medication efficacy 13. Medical history of acute or chronic pancreatitis 14. Medical history of macular or maculopapular skin reactions (exanthema or eruption) 15. Clinically relevant abnormalities in clinical chemical, hematological or any other laboratory variables 16. Electrocardiogram (ECG) abnormalities of clinical relevance (e.g.: QTc >450 ms) 17. Positive results in any of the serology tests for HCV-Ab or HBsAg 18. Pregnancy or breastfeeding 19. Evidence of active abuse of alcohol or drugs 20. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 21. Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial Criteria for Primary Endpoint evaluation Within-subject genital HSV mucocutaneous shedding rate: number of HSV positive

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swabs per subject relative to the total number of swabs collected per subject. Secondary endpoints EFFICACY x Mean log number of HSV DNA copies on all HSV DNA positive samples as detected by quantitative real-time PCR; x Mean log number of HSV DNA copies on HSV DNA positive samples on days with lesions as detected by quantitative real-time PCR; x Mean log number of HSV DNA copies on HSV DNA positive samples on days without lesions as detected by quantitative real-time PCR x Overall shedding rate: total number of HSV positive swabs per treatment group divided by the total number of swabs collected per treatment group; x Clinical (lesional) shedding rate: number of HSV positive swabs on days with lesion(s) divided by the total number of swabs collected on days with lesion(s); x Subclinical (non-lesional) shedding rate; number of HSV positive swabs on days without lesion(s) divided by the total number of swabs collected on days without lesions; x Lesion rate: number of days with lesion(s) reported divided by the total number of days with any report. x Mean pain duration: mean time with pain assessed from subject documentation (from the day/time of „When did you first notice new pain?“ to „the day/time of disappearance“) in diary; x HSV shedding episode rate: number of onsets of shedding episodes divided by the total number of days with swabs collected x HSV shedding episode duration: duration of a period with consecutive HSV- positive swab specimens starting at the chronological midpoint between the last HSV-negative and first HSV-positive swab specimens, and ending at the midpoint between the last HSV-positive and first HSV-negative swab specimens. x Recurrence rate: number of reappearances of lesion(s) (HSV score 2-7) divided by the total number of days with any report x Recurrence duration: consecutive days with the presence of HSV lesion(s) (lesion=HSV lesion score 2-7) and associated prodrome/paraesthesia or erythema. The recurrence begins on the day the subject first reports symptoms, including prodrome (paraesthesia) or erythema, if any, and ends on the day before the lesion is either reported as being healed (HSV lesion Score = 8) or reports no lesion present on any data obtained for the day. A day with missing lesion data in between two days of active lesion (HSV lesion Score 2-7, inclusive) is considered part of the same recurrence. “Recurrences” consisting only of prodromes/paraesthesia, erythema and/or healing (HSV lesion Score 0, 1 and 8), in any combination, will not be counted. x Occurrence of molecular signals of resistance to AIC316: detection of any potential resistance mediating mutation(s) in HSV positive swabs under AIC316

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treatment in the respective regions in the UL5 helicase gene and/or the UL52 primase gene known for helicase-primase inhibitor resistance mutations SAFETY and TOLERABILITY x Nature, frequency, duration, severity, seriousness and causality of adverse events (AEs) x Safety laboratory parameters x Physical examination x Vital signs (systolic and diastolic blood pressure, pulse rate,) x Standard 12-lead electrocardiogram (ECG) PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state x Evaluation of potential AIC316 drug metabolites PHAMACOGENETICS x Pharmacogenetics data to evaluate possible genetic influences on drug efficacy/safety.

Schedule and Recruitment course of the trial Patient recruitment will be performed from the clinic’s subject pool, by word of mouth, through referrals and advertisement, if applicable. Screening (within 21 days before Day 1) Screening visit will be performed within 21 days before randomization (Day 1), including: written informed consent, inclusion and exclusion criteria, demographics, medical history, adverse events, previous and concomitant medications, physical examination (incl. height and weight), vital signs, and a 12-lead electro-cardiogram (ECG). Blood samples for safety analyses (hematology, coagulation, serum chemistry), virology testing (HIV-Ab, HCV-Ab, HbsAg), HSV Type 2 by Western blot analysis (if HSV2 seropositivity not yet documented by Western blot) and for women of child-bearing potential for a serum E-HCG (beta human chorionic gonadotropin) test will be taken as well as a urine sample collected. Swabs of the anogenital region will be taken and the subjects will be trained accordingly. Day 1: Randomization and Treatment Period 1 Prior to randomization and first treatment the following examinations/ evaluations will be done: concomitant medications, adverse events (AEs), physical examination, weight measurements, vital signs, 12-lead ECG, laboratory measurements, inclusion/exclusion criteria, blood sampling for safety analyses, predose PK, and pharmacogenetics, urinalysis, urine pregnancy test (women of child-bearing potential only) and swabbing of the anogenital region. After randomization the subject starts treatment by taking the first (loading) dose. Swabbing kits, subject diary and trial medication will be provided.

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Day 2 until Day 28: Further Treatment Period 1 During this treatment period, subjects will: - take trial medication once daily - take anogenital swabs 4x daily and additional swabs from lesions (if lesions are developed) - complete their diary daily. - visit the clinical trial site weekly (Day 8, Day 15, Day 22) During the pre-scheduled weekly visits the following examinations/ evaluations and procedures will be done: concomitant medications, AEs, review and collection of subject’s diary, drug accountability, physical examination, vital signs, 12-lead ECG (Day 8), blood & urine sampling for safety analyses, predose blood sampling for PK analysis, swabbing of anogenital region, and collection of subject swabs. New trial medication and diary will be provided. If a subject develops a new HSV episode of prodromal symptoms and/or lesions, this needs to be documented in detail in the subject’s diary. Lesions must also be documented by the investigator. Therefore, any subject with a new episode of lesions (not required for prodromes only) needs to be seen at the investigational trial site as soon as possible (within 48 hrs at a maximum) after the onset of the lesions for an HSV recurrence visit. During an un-scheduled HSV recurrence visit the following examinations/ evaluations and procedures will be done: concomitant medications, AEs, review subject’s diary, drug accountability, physical examination, vital signs, swabbing of anogenital region and lesions, and collection of subject swabs. Day 29 through Day 56: Wash-out Period (28 +14 days) From the day following the last treatment dose (ie, Day 29), subjects will not take any medication for a total of 4 weeks (28 days +1 day). No swabs will be taken during this period. On day 29 subjects will visit the clinical trial site for a pre-scheduled visit. Same examinations and evaluations as described for the weekly visits will be done, including a 12-lead ECG, a blood and urine sample for evaluation of potential drug metabolites, and a urine pregnancy test for women of child-bearing potential. Pharmacogenetics sample may be taken at this visit if not already done on Day 1. Should subjects require HSV treatment during washout this must have been discontinued at least 7 days prior to start of the second treatment period. Should a HSV recurrence occur during wash-out the investigator needs to be informed immediately and an HSV Recurrence Visit has to be scheduled within 48 hours at maximum. Should the investigator feel the need to treat the HSV outbreak a 3 day course of valacyclovir can be prescribed. It has to be considered, that following valacyclovir treatment a wash-out period of at least 7 days must follow, before the subject may enter Treatment Period 2. Day 57: Start of Treatment Period 2 Same examinations and evaluations will be done as listed for Day 1. Pharmacogenetics sample may be taken at this visit if not already done at previous visits. Day 58 until Day 84: Further Treatment Period 2

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During this treatment period, subjects will: - take trial medication once daily - take anogenital swabs 4x daily and additional swabs from lesions (if lesions are developed) - complete their diary daily. - visit the clinical trial site weekly (Day 64, Day 71, Day 78). These pre-scheduled visits will be performed in accordance to the visits scheduled during treatment period 1. HSV-recurrence visits will be done if indicated as described for treatment period 1. Day 85 through Day 112: Follow-up Period (28r1days) From the day following the last treatment dose (ie, Day 85), no further swabs will be taken. On day 85 a pre-scheduled visit will be performed in accordance to the Day 29 visit scheduled after treatment period 1. In case of lesions an HSV recurrence visit must be done within 48 hrs at maximum after the onset of the lesions. Day 112(r1): Final Examination During the final examination visit, the following examinations and evaluations will be done: concomitant medications, AEs, physical examination, weight, vital signs, 12- lead ECG, swabbing of the anogenital region, blood & urine sampling for safety analyses, PK and pharmacogenetics (only if not already done), urine pregnancy test, collection of remaining trial medication. Premature Termination In case of premature termination, the subject should visit the investigational trial site for an Early Termination Visit. Same examinations and evaluations as for a Final Examination visit will be done.

Statistics Sample size : Approximately 90 subjects Justification for sample size The average shedding rate during treatment with AIC316 100 mg is anticipated to be 1-2% and during treatment with valacyclovir 500 mg will be approximately 5%. Using a cross-over design with 80% power and permitting a 5% type I error rate, a total of 82 subjects completing the trial is needed to detect superiority of AIC316 100 mg over valacyclovir 500 mg. To account for potential drop-outs (in trial AIC 316-01-II-01 the rate of discontinuation was 6%), the number of subjects to be randomized is approximately 90. Trial analysis populations Full-analysis-set population (FAS, Intention-to-treat population): All randomized subjects who took the trial medication at least once and provided at least one analyzable genital-perianal swab (not including the training swab) during the treatment period.

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Per-protocol-set population (PPS) Subset of the full analysis set (FAS) with exclusion of major protocol violators. Safety population All randomized subjects who received the trial medication at least once. Pharmacogenetic population All randomised subjects who consented to pharmacogenomic sampling. Primary efficacy analysis (FAS & PPS) The difference in shedding rate within subjects, between AIC316 100 mg vs valacyclovir 500 mg, will be tested using non-linear mixed effects models with a log link, similar to Poisson regression but with a random intercept for each subject, and including robust error estimation to account for extra-Poisson variability. Secondary efficacy analyses (FAS) Comparisons of secondary efficacy analyses will be tested between AIC316 100 mg od and valacyclovir 500 mg od using the following methods: The log number of HSV DNA copies will be compared between both treatment groups using generalized estimation equations (GEE) accounting for the correlation between repeated measures per subject and including terms for treatment, gender and investigational site. This analysis will be repeated including only days when lesions are present. Rates such as shedding rate, lesion rate, shedding episode rate and recurrence rate will be compared between both treatment groups using Poisson regression, if sufficient numbers of events, incorporating subject-level intercepts and account for extra-Poisson variability. For rarer events the non-parametric Wilcoxon signed-rank test may be employed. Duration outcomes will be rare and non-centrally distributed (most short and a few long). Therefore the comparison between treatment groups will be performed using the Wilcoxon signed ranke test, a paried non-parametric test. Or if few episodes occur in the same subjects on both treatments, the Wilcoxon rank sum test for independent samples. Safety analyses (Safety population) The results of safety measurements (clinical laboratory parameters, urinalysis, vital signs, ECGs) and adverse events will be listed by subject and treatment group and analyzed descriptively. Pharmacogenomic analysis (Pharmacogenetic population) The results of pharmacogenetic testing will be analyzed descriptively, listed by subject and treatment group and will be reported in a separate report.

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3 TABLE OF CONTENTS

1 SIGNATURES 2 1.1 Protocol Approval 2 1.2 Declaration by the Principal Investigator 3 1.3 Involved Parties 5

2 PROTOCOL SYNOPSIS 8

3 TABLE OF CONTENTS 19 3.1 List of in-text tables 24 3.2 List of in-text figures 24

4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 25 4.1 Abbreviations 25

5 AMENDMENT RATIONALE 30 5.1 Protocol amendment #1 30 5.2 Protocol amendment #2 30 5.3 Protocol amendment #3 31 5.4 Protocol amendment #4 31

6 ETHICS 32 6.1 Institutional Review Board 32 6.2 Ethical conduct of the trial 32 6.3 Subject information and consent 32 6.4 Point of contact 33

7 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE 33 7.1 Investigator 33 7.2 Sponsor 34 7.3 Contract Research Organization 34

8 INTRODUCTION 34 8.1 Background Information 34 8.2 Rationale of the trial 37 8.3 Rationale for the doses 39 8.3.1 AIC316 39 8.3.2 Valacyclovir 40

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8.3.3 Summary 41 8.4 Benefit/risk of trial medication 41 8.4.1 Expected clinical benefit of AIC316 41 8.4.2 Potential risks profile of AIC316 42 8.4.3 Known risks and benefit of valacyclovir 43 8.4.4 Conclusion 43

9 TRIAL OBJECTIVES AND ENDPOINT CRITERIA 43 9.1 Objectives 43 9.1.1 Primary objective 43 9.1.2 Secondary objectives 43 9.2 Endpoint criteria 44 9.2.1 Primary endpoint 44 9.2.2 Secondary endpoints 44

10 TRIAL DESIGN AND METHODOLOGY 46 10.1 Trial design 46 10.2 Discussion of trial design 46 10.3 Blinding 47 10.4 Unblinding 47 10.4.1 Scheduled unblinding: 47 10.4.2 Emergency unblinding: 47 10.5 Time schedule 47 10.6 End of trial 48

11 TRIAL POPULATION 48 11.1 Selection of trial population 48 11.1.1 Recruitment procedure 48 11.1.2 Screening log 48 11.1.3 Inclusion criteria 48 11.1.4 Exclusion criteria 49 11.2 Removal of subjects from the trial, trial assessments or investigational medicinal product(s) 50 11.2.1 Notification of discontinuations 52 11.3 Trial completion 52 11.3.1 Subject definitions and subject completion 52 11.3.2 Procedures for handling of replacements, withdrawals or drop-outs 52 11.3.3 Premature termination of the trial 52

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12 INVESTIGATIONAL MEDICINAL PRODUCT 53 12.1 Identity of investigational medicinal product and comparator 53 12.2 Packaging and labeling 54 12.3 Administration of investigational medicinal products 55 12.4 Dosing arms 56 12.5 Loading dose 56 12.6 Storage 56 12.7 Documentation of drug accountability 57 12.8 Delivery of investigational medicinal product(s) 57 12.9 Identification of investigational medicinal products in emergency situations – unblinding in case of medical emergency 57

13 TRIAL PROCEDURES 58 13.1 Course of the trial 58 13.1.1 Information of subjects and informed consent 58 13.1.2 Screening period 59 13.1.3 Treatment Period 1 60 13.1.4 Wash out period 62 13.1.5 Treatment Period 2 63 13.1.6 Follow-up period 64 13.1.7 Final Examination Visit - Day 112 ± 1 day 65 13.1.8 Unscheduled visit: HSV Recurrence Visit 66 13.1.9 Early Termination Visit 66 13.1.10 Examination hierarchy and time windows 67 13.2 Flow chart 68 13.3 Protocol compliance 70 13.4 Trial conditions and restrictions 70 13.4.1 Prohibited concomitant medication 70 13.4.2 Meals and fluid intake 70 13.4.3 Medical surveillance 70 13.4.4 Counseling of women and men of reproductive age 71 13.4.5 Precautions and emergencies 71 13.4.6 General restrictions 71 13.4.7 Trial cards 72 13.4.8 Provisions of any additional care of subjects after trial termination 72 13.4.9 Informing the subject’s general practitioner 72

14 TRIAL VARIABLES 72

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14.1 Demography 72 14.2 Vital signs 73 14.3 12-lead ECG 73 14.4 Physical examination 73 14.5 Laboratory monitoring 73 14.6 Prior and concomitant medication/treatment 75 14.7 HSV shedding evaluation 75 14.7.1 Assessment of HSV recurrence 76 14.8 Molecular signals of drug resistance 76 14.9 Appropriateness of assessments 76

15 ADVERSE EVENTS 77 15.1 Definition of adverse events (AEs) 77 15.2 Definition of adverse drug reaction (ADRs) 77 15.3 Definition of serious adverse events (SAEs) or serious adverse drug reactions (SARDs) 77 15.4 Definition of adverse events of special interest 78 15.5 Definition of adverse event severity 78 15.6 Definition of adverse event causality 78 15.7 Definition of adverse event outcome 79 15.8 Definition of expectedness 79 15.9 Adverse event recording and reporting 79 15.9.1 Period of recording 79 15.9.2 Follow-up of subjects with an adverse event 79 15.9.3 Adverse event recording 80 15.9.4 Adverse Event Reporting 80 15.9.5 Serious Adverse Event Reporting 80 15.9.6 Procedures in case of pregnancy 82 15.9.7 Suspected unexpected serious adverse reactions reporting (SUSARs) 82 15.9.8 Other safety issues altering the benefit-risk assessment of the trial medication 82 15.9.9 Development Safety Update Report (DSUR) 82

16 DOCUMENTATION AND ARCHIVING OF THE TRIAL DATA 83 16.1 Electronic Case Report Form (eCRF) 83 16.2 Subject’s diary 84 16.3 Source data 84 16.3.1 Source data at the investigational trial site 84 16.3.2 Subject’s reported outcome - Diary 85

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16.4 Data management 85 16.4.1 Coding 85 16.5 Data archiving 86

17 STATISTICAL METHODS 86 17.1 Determination of sample size 86 17.2 Randomization 87 17.3 Analysis of the trial 87 17.3.1 Subject populations 88 17.3.2 Analysis of demographic data 89 17.3.3 Efficacy Analysis 89 17.3.4 Safety analysis 90 17.3.5 Interim analysis 92 17.3.6 Further analysis 92

18 GENERAL CONDITIONS AND AGREEMENTS 93 18.1 Insurance 93 18.2 Interaction with regulatory authorities 94 18.3 Monitoring 94 18.4 Quality system, audit and inspection 94 18.4.1 Quality system 94 18.4.2 Audit 95 18.4.3 Inspection 95 18.5 Investigator’s site file (ISF) 95 18.6 Amendment of protocol 95 18.7 Subject data and data protection 96 18.8 Publication policy 96 18.9 Contracts 96 18.10 Final report 97 18.11 Confidentiality of trial results 97 18.12 Organization 97 18.12.1 Coordinating Investigator 97 18.12.2 Committees 97 18.12.3 Data flow to committees 97 18.12.4 Investigational site personnel 97

19 REFERENCES 98

20 APPENDICES 100

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20.1 Investigator responsibilities 101 20.2 Swabbing for HSV PCR 102 20.3 HSV lesion Score 103 20.4 List of medical concepts for consideration of seriousness stratified by system- organ class 104 20.5 DAIDS toxicity criteria 105 20.6 Valtrex® Summary of Product Characteristics 106 20.7 Protocol amendment #1 107 20.8 Protocol amendment #2 110 20.9 Protocol amendment #3 113 20.10 Protocol amendment #4 120

3.1 List of in-text tables Table 1: Sample size calculation 86

3.2 List of in-text figures Figure 1: Frequency histogram of shedding frequency under treatment with AIC316 compared with the nucleoside analogs acyclovir and famciclovir, respectively 38 Figure 2: Prediction of different AIC316 dosing regimens for suppression of genital shedding 40

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4 LIST OF ABBREVIATIONS AND DEFINITION OF TERMS

4.1 Abbreviations

Abbreviation Term AE Adverse event ADR Adverse drug reaction ALT Alanine aminotransferase ANOVA Analysis of variance AP Alkaline phosphatase APTT Activated Partial thromboplastin time AST Aspartate aminotransferase AT1 Angiotensin type-1 receptor ATP Adenosintriphosphate

AUC0-last Area under curve from administration to non-zero

AUCf Area under curve up to infinity

AUC24h Area under curve up to 24 hours E-HCG Beta human chorionic gonadotropin bid Twice daily (bis in die) BMI Body mass index CAP College of American Pathologists CA Competent authority CL/F Apparent oral clearance

Cmax Maximum drug concentration

Cmax,ss Maximum drug plasma concentration at steady state

Cmin Minimum drug concentration

Cmin,ss Minimum drug plasma concentration at steady state

Css av Average steady-state concentrations CRA Clinical Research Associate CRF Case report form

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Abbreviation Term CRO Contract research organization CV Curriculum Vitae CV Coefficient of Variation CYP2C9 Cytochrome P450 2C9 CYP3A4 Cytochrome P450 3A4 CYP450 Cytochrome P450 DAIDS The Division of AIDS DNA Deoxyribonucleic acid DMP Data Management Plan ECG Electrocardiogram

EC50 Half maximal effective concentration

EC90 Ninety percent effective concentration

EC90,HS Ninety percent effective concentration in human serum

EC90,u Ninety percent effective concentration unbound eCRF Electronic case report form EDTA Ethylenediaminetetraacetic acid EDC Electronic data capture ELISA Enzyme-linked immunosorbent assay FAS Full analysis set FDA U.S. Food and Drug Administration FHCRC Fred Hutchinson Cancer Research Center FRET Fluorescent resonance energy transfer GCP Good Clinical Practice GEE Generalized estimating equations g/dL Grams/deciliter Ȗ-GT Gamma-glutamyl transpeptidase g/L Grams/liter HBc-Ab Hepatitis B core antibody HBsAg Hepatitis B surface antigen HCV-Ab Hepatitis C antibody

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Abbreviation Term hERG Human ether-a-go-go related gene Hgb Hemoglobin HIV Human immunodeficiency virus HIV-Ab Human immunodeficiency virus antibody (HIV-Ab) HSV Herpes simplex virus Htc Hematocrit IB Investigator’s brochure ICF Informed consent form ICH International Conference on Harmonization (I)EC (Independent) ethics committee IMP Investigational medicinal product IRB Institutional review board ISF Investigator’s site file IVR Interactive voice response kg/h/L Kilogram per hour per liter LD Loading dose LDH Lactate dehydrogenase L/h/kg Liter per hour per kilogram L/kg Liter per kilogram LLN Lower limit of normal MCH Mean corpuscular hemoglobin MCHC Mean corpuscular hemoglobin concentration MedDRA“ The Medical Dictionary for Regulatory Activities mg/kg Milligrams per kilogram mmol/L Millimoles/liter NOAEL No observed adverse effect level NOEL No observed effect level OAT Organic anion transporters OCT Organic cation transporters PC Predefined changes

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Abbreviation Term PCA Predefined changes of abnormality PCR Polymerase chain reaction PD Pharmacodynamics PK Pharmacokinetic PPS Per-protocol set PQ PQ-interval: the time between the beginning of atrial depolarization and the beginning of ventricular depolarization. PR The period of time from the onset of the P wave to the beginning of the QRS complex qd Once daily (quaque die) QRS QRS-complex: the largest-amplitude portion of the ECG, caused by currents generated when the ventricles depolarize prior to their contraction. QT The duration of the QT-interval is a measure of the time required for depolarization and repolarization to occur. qwk Once weekly RBC Red blood cell SADR Serious adverse drug reaction SAE Serious adverse event SAP Statistical analysis plan SAR Serious adverse reaction SmPC Summary of Product Characteristics SOC System Organ Class SOP Standard Operating Procedure SUSAR Suspected unexpected serious adverse reaction TEAE Treatment emergent adverse event TEN Toxic epidermal necrolysis TK Thymidine kinase

tmax Time to reach maximum plasma concentration TPN Toxic parental nutrition U/L Units/liter

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Abbreviation Term ULN Upper limit of normal UW University of Washington WHO-DD The World Health Organization Drug Dictionary

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5 AMENDMENT RATIONALE

5.1 Protocol amendment #1 This protocol amendment dated 24 September 2012 was issued due to the feedback and comments given by the Quorum IRB on the final protocol AIC316-01-II-02 dated 05 July 2012: x Excluded concomitant drugs listed on page ten of the protocol have been specifically added to the exclusion criteria.

In addition, the following changes were made: x Update of AiCuris pharamacokineticist x Update of UW lab addresses x Addition of a reference to the AIC316 INN x Correction of minor formal issues like e.g. typos and missing spaces, etc.

A detailed list of all changes can be found in Appendix 20.7.

5.2 Protocol amendment #2 This protocol amendment dated 17 October 2012 was issued due to the feedback and comments given by the FDA on the final protocol AIC316-01-II-02 dated 05 July 2012. x “Medical history of acute or chronic pancreatitis” has been specifically added to the exclusion criteria. x Exclusion of subjects with known medical history of macular or maculopapular skin reactions (exanthema or eruption) has been added to the exclusion criteria. x Instructions to investigators were added in the protocol in regards to activities required in case of any skin disorder. x Withdrawal criteria were amended to withdraw any case of pancreatitis, grade 3 or 4 rash judged to be related to study treatment and any grade 2 rash accompanied by constitutional symptoms.

A detailed list of all changes can be found in Appendix 20.8.

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5.3 Protocol amendment #3 This protocol amendment dated 18 December 2012 was issued due to: x Inclusion of a sample for pharmacogenetic analysis x Correction of minor formal issues like e.g. typos and missing spaces, etc.

A detailed list of all changes can be found in Appendix 20.9.

5.4 Protocol amendment #4 This protocol amendment dated 02 May 2013 was issued due to: x Inclusion of interim results of a 39 week toxicology study in monkeys x Inclusion of an additional blood and urine sample at the end of each treatment period for evaluation of potential AIC316 drug metabolites. x Correction of minor formal issues like e.g. typos and missing spaces, etc.

A detailed list of all changes can be found in Appendix 20.10.

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6ETHICS

6.1 Institutional Review Board The institutional review boards (IRBs) will safeguard the rights, safety, and well-being of all trial subjects. The IRBs will be provided with the following documents: Trial protocol(s)/amendment(s), written information sheets and informed consent form(s) and updates, thereof, that the Investigator proposes for use in the trial, subject recruitment procedures (e.g. advertisements), written information to be provided to subjects, the subject diary, Investigator’s Brochure (IB), available safety information, information about payments and compensation available to subjects, the Investigator's current curriculum vitae (CV) and/or other documentation evidencing qualifications, and any other documents that the IRB may need to fulfill its responsibilities. The IRB will be requested by the Investigator, AiCuris GmbH & Co. KG, Inc., or regulatory authorities to provide its membership, voting lists and Federal Wide Assurance number (if applicable). The IRB will vote on the trial and will provide a written statement of their decision. The IRB should maintain written records of its activities and minutes of its meetings.

6.2 Ethical conduct of the trial This trial is to be conducted under the auspices of an IRB, as defined in the Code of Federal Regulations, title 21 parts 50 and 56, and according to the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and applicable regulatory requirement(s). ICH-GCP is a standard for the design, conduct, performance, monitoring, auditing, recording, analyses and reporting of clinical trials that provides assurance that the data and reported results are credible and accurate, and that the rights, integrity and confidentiality of the trial subjects are protected. The medical care given to, and medical decision made on behalf of subjects should always be the responsibility of a qualified physician. Each individual involved in conducting the trial should be qualified by education, training and experience to perform his or her respective task(s). The trial can only start at the Investigator’s site when the relevant IRBs have given signed and dated approval of the protocol, written informed consent forms and other written information to be provided to the subjects, and subject recruitment procedures (e.g., advertisements). All subjects will be informed that participation is voluntary and that they can cease participation at any time without necessarily giving a reason and without any penalty or loss of benefits to which they are entitled.

6.3 Subject information and consent With the help of the information sheet the subject will be informed about the investigational medicinal product(s) and anticipated effects. At the same time the subject will be informed of the reason, design and implication of the trial. The subject must give his/her consent to participate prior to any trial specific investigations which include the screening examination. This consent must be given in writing.

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The Investigator who conducted the informed consent discussion must also sign. With his/her consent the subject will confirm that his/her participation is voluntary and that he/she will follow the instructions of the Investigator and answer the questions that are asked of him/her. Signatures must be personally dated. Prior to participation in the trial, the subject should receive a copy of the signed and dated written informed consent form and any other pertinent written information. Neither the Investigator, nor the trial staff, should coerce or unduly influence a subject to participate or to continue to participate in the trial. The Investigator should not include him/herself, his/her relatives, and members of his/her clinical team or their relatives in the trial. Ample time, the length of which depends on local regulations, must be allowed for the subject to make his or her decision, and to make further enquiries about the trial. Copies of the signed consent forms will be kept by the investigator and provided to the subjects. Should new information become available during the course of the trial that may be relevant to the subject’s consent, the information sheet will be revised, and the revised version will be submitted for IRB approval before use. The subject must be informed as soon as possible if new information becomes available that may be relevant to the subject’s willingness to continue participation in the trial. The communication of this information should be documented. The subject should receive a copy of any updates and must provide written informed consent.

6.4 Point of contact As required by national regulations subjects will be provided with information where additional information can be obtained about the trial and the right of the subject and whom to contact in the event of trial-related injury. This source of information will also be specified in the information sheet and Informed consent form.

7 INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE

The trial is planned to be performed at approximately 4 investigational sites in the United States. Responsible team members will be detailed in the investigator’s site file.

7.1 Investigator The Investigator, in general, is the person responsible for the conduct of the trial at the investigational site. If the trial is conducted by a team of individuals at the investigational site, the Investigator is the responsible leader of the team and may be called the Principal Investigator (PI). A Sub-Investigator is any individual member of the clinical trial team designated and supervised by the PI at an investigational site to perform critical trial-related procedures and/or to make important trial- related decisions (e.g. associates, residents, research fellows). The Investigator must maintain a signed list of appropriately qualified persons to whom she/he has delegated significant trial-related duties which must be specified. A copy is held in the investigator site file and trial master file at Inc. during trial conduct, under the responsibility of AiCuris GmbH & Co. KG.

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Trial-related medical decisions are the responsibility of a qualified physician (the Investigator or delegate). Curriculum Vitae and/or other relevant documents confirming the qualifications of the Investigator and Sub-Investigators are required by AiCuris GmbH & Co. KG or Inc., respectively. When personnel changes are made, the relevant documentation has to be updated before a new member of the team can perform critical and/or significant trial-related activities and EC/IRB and CA have to be informed. The Investigator has to comply with the local legal requirements concerning reporting of information relevant for the trial conduct.

7.2 Sponsor AiCuris GmbH & Co. KG accepts the responsibilities of the sponsor.

7.3 Contract Research Organization A contract research organization - Inc. - will be employed by AiCuris GmbH & Co. KG to perform trial-related duties and functions. The extent of the delegation will be specified in a contract between the involved parties. Inc. will implement quality assurance and quality control but AiCuris GmbH & Co. KG will have the right to supervise the implementation of the methods for quality assurance and quality control.

8 INTRODUCTION

8.1 Background Information HSV-2 is the most frequent cause of genital ulcer disease and is one of the most common sexually transmitted infections in the world (1-12). It is a recurrent life-long infection characterized by high rates of clinical and sub-clinical reactivation in the genital mucosa and a high risk of sexual transmission (13, 14, 15, 16). Herpes infections can be sexually transmitted during symptomatic and asymptomatic reactivation of the virus (17, 18, 19, 20). Currently, there are three antiviral drugs (nucleoside analogs) approved for the treatment of genital herpes: acyclovir, famciclovir, and valacyclovir. However, they do not completely abrogate viral replication. There are still high titer (>104 HSV DNA copies) shedding episodes under therapy which can lead to recurrences and transmission of genital herpes (22, 24). This limitation can be attributed to two characteristics of the nucleoside analogs: the requirement to become activated by viral thymidine kinase (TK) and their short half-life. Therefore, a compound with a different mechanism of action is needed to provide an improved treatment option. One such potential drug is AIC316 which is currently being developed by AiCuris GmbH & Co. KG. The free base AIC316 (INN Pritelivir, synonym: AIC090093, BAY 57-1293) is a thiazolylamide belonging to a novel active class of non-nucleoside compounds against HSV-1 and 2. Due to favorable formulation properties for tablets, the mesylate monohydrate of AIC316, AIC090016, was selected for clinical development. Calculated drug amounts always refer to the amount of the free base.

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AIC316 is a helicase-primase inhibitor, and therefore has a mode of action that is distinct to that of other antiviral agents currently in use. In contrast to nucleoside analogs, AIC316 is immediately active after viral entry without the need for activation by a viral enzyme. Furthermore, due to its favourably long half-life of up to 80 h (see below), the likelihood that trough drug levels fall below the critical concentration for activity between dosing intervals is low. Therefore, AIC316 may offer sustained protection from viral replication. AIC316 is more potent in vitro and has greater efficacy in vivo in animal infection models compared with the nucleoside analogues against HSV. Results of mouse, rat, and guinea pig infection models show that AIC316 is efficiently: x abolishing the acute symptoms of HSV infections; x suppressing viral shedding; x reducing viral load in nervous tissue; x reducing lesion healing time; and x reducing the frequency of recurrent episodes.

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In a Phase 2 proof-of-concept and dose finding trial 156 HSV-2 positive subjects were randomized at seven US sites. The primary objective was to compare the efficacy of 4 different doses (5 mg, 25 mg, or 75 mg qd, as well as 400 mg qwk) of AIC316 and matching placebo with respect to the suppression of HSV mucocutaneous shedding, as measured by the shedding rate within the treatment period. Secondary objectives included log number of HSV DNA copies, lesion rate, and frequency of HSV recurrences, lesional and nonlesional shedding, PK, resistance development, and safety. Subjects in the qd groups received a loading dose on Day 1 to reach steady state quickly.

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In this trial, AIC316 was safe and well-tolerated, with no toxicities emerging during the trial. No serious TEAE were reported during the trial and the majority of reported TEAEs were mild to moderate in severity. One SAE, acute pancreatitis, was reported in the AIC316 25 mg qd group. This SAE occurred approximately 2 weeks after the last dose of trial medication in a subject with a previous history of pancreatitis and with possible alcohol use and was assessed by the investigator as not related to trial medication. No clinically relevant treatment-emergent changes in mean serum chemistry, hematology, or coagulation parameters were observed. Likewise, no trends emerged in shifts in laboratory results from baseline to the end of treatment or from screening to the end of the trial for serum chemistry, liver enzyme, hematology, coagulation, or urinalysis laboratory parameters. In addition, no differences between treatment groups were noted for any laboratory parameter in incidence of clinically significant laboratory results. No clinically important trends in vital signs, weight, or physical examination and no clinically relevant electrocardiographic effects of AIC316 were observed. With regard to efficacy both subjects treated with 75 mg qd AIC316 and those treated with 400 mg qwk AIC316 showed statistically significantly lower mean HSV shedding rates during the treatment period (2.0% and 5.2%, respectively) compared with placebo-treated subjects (16.5%) (P=0.0001 and P=0.0013, respectively); the mean shedding rate was also lower than placebo in the AIC316 25 mg qd group (9.2%), although this difference was not statistically significant after correcting for multiplicity (P=0.0478). The mean log number of HSV DNA copies on days when HSV was detected was lower during the treatment period in the 5, 25, and 75 mg qd AIC316 groups and 400 mg qwk AIC316 group (4.6, 4.0, 2.8, and 4.0, respectively) compared with placebo (5.1), with the lowest number occurring in the 75 mg qd AIC316 group. The proportion of days with lesions (mean lesion rate) was lower during the treatment period in the 25 and 75 mg qd AIC316 groups and 400 mg qwk AIC316 group (4.6%, 1.1%, and 1.3%, respectively) compared with placebo (9.1%), with the lowest frequencies seen in the 75 mg qd and 400 mg qwk AIC316 groups. There have been no signals for drug resistance detected so far. Overall, efficacy endpoints appeared to be related to exposure with AIC316. The majority of subjects in the 75 mg qd treatment group had no HSV DNA shedding during the treatment period and while shedding was not eliminated overall, viral DNA was no longer detectable for the majority of subjects with Ctrough levels >2,500 ng/mL. In swabs with detectable HSV DNA, copy numbers were generally lower in those swabs from subjects with higher daily AIC316 exposure. Most swabs in the 75 mg qd group exhibited less than 103 HSV genome copies which is below 105.9, an average copy number that was reported from swab specimens with identifiable lesions (21). This is in agreement with the observation that no HSV lesions were reported for subjects with Ctrough values above 2,800 ng/mL.

8.2 Rationale of the trial HSV is a significant human pathogen with several adverse health outcomes. The pipeline for new HSV drugs has been virtually empty in the last decade, despite continuing medical need for new therapeutic options for HSV therapy. New drugs for HSV are needed in many settings, e.g., HSV encephalitis, neonatal HSV, and prevention of HSV-2 transmission. In addition, a drug that could interrupt the synergy between HIV and HSV-2 by efficiently inhibiting HSV-2 has great potential as an HIV transmission prevention strategy. AIC316 is a helicase-primase inhibitor representing a new class of drugs with high specificity for HSV. Preclinical studies show good antiviral activity in vitro, and studies show that the compound is effective

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for skin, eye and genital infection in animal models. Phase 1 studies in healthy volunteers have shown high bioavailability, and a long half-life, facilitating once daily dosing. A proof of concept trial that evaluated the effect of AIC316 in various doses on HSV shedding showed that AIC316 75 mg daily reduced substantially and significantly genital viral shedding in comparison to placebo (Chapter 8.1). The dose-response effect which was observed for both genital shedding and lesions suggests that a further increase in the dose of AIC316 would result in fading or disappearance of viral shedding (and thus lesions). While acyclovir and valacyclovir are effective therapies for many manifestations of HSV-related disease, recent detailed studies show that HSV replication on genital mucosa continues in the presence of daily valacyclovir. In a trial of 70 persons who obtained genital swabs 4 times per day during administration of standard suppressive valacyclovir 500 mg daily, HSV was detected in 5% of the swabs. Comparing these results with available data from trial AIC316-01-II-01 in which the minimum shedding rate was 2% with once daily swabbing suggests that AIC316 may be a more potent inhibitor of HSV replication in the genital tract, and thus provide a greater antiviral effect and clinical benefit. Furthermore, a retrospective comparison of the shedding frequency under therapy with acyclovir/famciclovir in previous studies (24) with the results from treatment with 75 mg qd AIC316 in trial AIC316-01-II-01 by using frequency histograms showed that for both treatments most shedding episodes had peak HSV DNA copy numbers of 2-3 logs. However, in contrast to acyclovir/famciclovir the proportion of positive swabs with higher viral load is markedly reduced for AIC316, only very few swabs containing a peak HSV DNA copy numbers of more than 4 (Figure 1).

Figure 1: Frequency histogram of shedding frequency under treatment with AIC316 compared with data from previous studies with the nucleoside analogs acyclovir and famciclovir, respectively

2.0% Acyclovir/famciclovir

AIC316 75 mg QD 1.5%

1.0%

Percent of swabsPercent 0.5%

0.0% 2-3 3-4 4-5 5-6 6-7 7-8 8-9 >9 log 10 HSV DNA copy number / ml

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Results are from swabs performed in subjects who received either 400 mg of acyclovir orally twice daily or 250 mg of famciclovir orally twice daily (24) compared with results from subjects receiving 75 mg qd AIC316 in trial AIC316-01-II-01. Reactivation of HSV on the genital mucosa is characterized by intermittent shedding of the virus, which can be detected by HSV PCR from a swab of genital secretions. The frequency of shedding is highly variable between people, and fairly constant within persons, especially after the initial year since HSV-2 acquisition. Anna Wald’s group has developed the use of viral shedding, obtained from self-collected genital swabs by subjects as a reliable and effective strategy to assess the efficacy of interventions (25). This approach is ideally suited to proof-of-concept studies and comparative studies as it can unequivocally demonstrate objective antiviral activity of the proposed intervention in vivo. Since shedding characteristics vary widely between subjects, but tend to remain stable within persons, cross-over trials present an advantage over parallel trials to efficiently evaluate the efficacy of antiviral drugs. The treatment duration of 28 days was used in trial AIC316-01-II-01 and showed to be sufficient to show differences between treatment groups and placebo in regards to shedding and has therefore been also chosen for this trial.

8.3 Rationale for the doses 8.3.1 AIC316 As described in Section 8.1 treatment of HSV-2 positive subjects with AIC316 led to a significant suppression of viral shedding, the amount of virus shed, and clinical symptoms compared to placebo. The strongest effect on both primary and secondary endpoints was seen with 75 mg qd. Corresponding pharmacokinetics (PK) in trial AIC316-01-II-01 were in line with results from previous phase I studies. To determine if increasing the dose would lead to further reduction of shedding, a modeling approach was used based on mathematical description of HSV shedding episodes defined by frequency, pattern and duration of shedding events reported from clinical trials (22, 23). This approach has been validated based on its ability to reproduce detailed shedding datasets that were generated in persons on and off antiviral therapy (24). The model was applied to data derived from trial AIC316-01-II-01 to characterize the shedding patterns of subjects in the control arm compared to those in the 4 treatment arms [report in preparation]. By using the modeling parameters that were able to provide the most appropriate reflection of the actual study results simulations were performed to mimic the effect on shedding frequency and duration of different AIC316 doses and dosing frequencies. Figure 2 shows the simulated effect of 75 mg qd AIC316 compared to 100 mg qd, 150 mg qd, and 75 mg twice daily (bid) AIC316.

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Figure 2: Prediction of different AIC316 dosing regimens for suppression of genital shedding

0.8 75 mg qd 100 mg qd

0.6 150 mg qd 75 mg bid

0.4

Percent of swabsPercent 0.2

0 2-3 3-4 4-5 5-6 6-7 7-8 8-9 >9

log 10 HSV DNA copy number / mL

As shown for the shedding frequency/the proportion of swabs with higher viral load in Figure 2, an increase of the AIC316 dose is estimated to lead to a further reduction of the proportion of swabs with higher viral load as well as to a lower shedding rate (e.g. 40% further reduction with 100 mg qd compared to 75 mg qd). However, as depicted in the graph, the effect is asymptotical, i.e. doses >100 mg or more frequent administration will not lead to a further significant improvement, also with respect to shedding episode duration and frequency (data not shown). Therefore, the preferred AIC316 dose for future trials addressing the suppression of HSV genital shedding is 100 mg qd. In line with the modeled reduction of shedding is an expected further improvement of suppression of clinical lesions by increasing the dose. PK/pharmacodynamic (PD) assessment of trial AIC316-01-II-01 showed that a trough blood concentration of approximately 2800 ng/ml AIC316 in the 75 mg qd group defined a threshold for lesion development in this trial (26). As PK can be assumed to be proportional, it is expected that increasing the dose from 75 mg qd to 100 mg qd will lead to an increased number of subjects with trough blood levels above this threshold. Therefore, for trial AIC316-01-II-02 the selected AIC316 dose is 100 mg qd.

8.3.2 Valacyclovir The recommended dosage of valacyclovir according the label of Valtrex® for chronic suppressive therapy of recurrent genital herpes is 1000 mg qd in patients with normal immune function (27). However, in patients with a history of 9 or fewer recurrences per year, 500 mg qd valacyclovir is proposed as alternative dose as it also provides an adequate suppression. Since this dose is widely used for suppressive therapy and is also indicated for reduction of transmission, the selected valacyclovir dose is 500 mg qd for trial AIC316-01-II-02.

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8.3.3 Summary The following treatment groups will be included in the AIC316-01-II-02 trial: 1. A loading dose of AIC316 400 mg as first daily dose followed by AIC316 100 mg tablet qd 2. Valacyclovir 500 mg capsule qd Subjects will be asked to take the tablets and capsules in the morning (time range 06:00 AM until 12:00 AM) with or directly after intake of food.

8.4 Benefit/risk of trial medication

d.

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8.4.3 Known risks and benefit of valacyclovir For risks benefit profile, please refer to the package insert of Valtrex® in the Appendix 20.6. 8.4.4 Conclusion Overall, the benefit/risk ratio analysis results in a favorable justification to perform this comparative trial in the subject population defined by the inclusion and exclusion criteria aiming at comparing the efficacy on genital HSV shedding and safety of AIC316 and valacyclovir.

9 TRIAL OBJECTIVES AND ENDPOINT CRITERIA

9.1 Objectives The objective of this trial is to compare the efficacy of AIC316 100 mg given perorally once daily to standard peroral dose valacyclovir 500 mg qd on genital mucocutaneous HSV shedding in immunocompetent HSV-2 seropositive women and men with a history of genital herpes. Shedding will be determined by HSV DNA PCR measurement of daily swabs taken from the anogenital region throughout the treatment 9.1.1 Primary objective To compare the efficacy of AIC316 and valacyclovir, both administered for 28 days to immunocompetent HSV-2 seropositive subjects, on the genital mucocutaneous shedding rate at the end of the trial medication period. 9.1.2 Secondary objectives Comparison of the treatment groups: x Mean HSV copy numbers on HSV DNA positive samples; x Mean HSV copy numbers on swabs taken on days with lesion(s);

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x Mean HSV copy number on swabs taken on days without lesion(s); x Overall shedding rate; x Shedding rate on days with lesion(s); x Shedding rate on days without lesion(s); x Lesion rate; x Duration of pain; x HSV shedding episode rate; x Shedding episode duration; x Recurrence rate; x The recurrence duration. x The occurrence of molecular signals of resistance to AIC316; x Safety and tolerability of AIC316; x Predose blood concentrations for AIC316 and valacyclovir at steady state x Pharmacogenetic evaluation x Evaluation of potential AIC316 drug metabolites

9.2 Endpoint criteria 9.2.1 Primary endpoint Within-subject genital HSV mucocutaneous shedding rate: number of HSV positive swabs per subject relative to the total number of swabs collected per subject. NB: A swab is regarded as positive for HSV DNA if at least 3 HSV genome copies can be detected by quantitative PCR per reaction (equaling 150 copies per ml swab collection medium). When multiple swabs are available from the same time point (eg. genital and lesional swab), the swab with the highest copy number is retained for computation of the shedding rate. 9.2.2 Secondary endpoints EFFICACY x Mean log number of HSV DNA copies on all HSV DNA positive samples detected by quantitative real-time PCR x Mean log number of HSV DNA copies on HSV DNA positive samples on days with lesions detected by quantitative real-time PCR x Mean log number of HSV DNA copies on HSV DNA positive samples on days without lesions detected by quantitative real-time PCR

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NB: When multiple swabs are available from the same time point (eg. genital and lesional swab), the highest copy number is retained for computation of quantity. x Overall shedding rate: total number of HSV positive swabs per treatment group divided by the total number of swabs collected per treatment group; x Clinical (lesional) shedding rate: number of HSV positive swabs on days with lesion(s) divided by the total number of swabs collected on days with lesion(s); x Subclinical (non-lesional) shedding rate: number of HSV positive swabs on days without lesion(s) divided by the total number of swabs collected on days without lesions; x Lesion rate: number of days with lesion(s) reported divided by the total number of days with any report. NB: A lesion (HSV score 2-7) is reported by the subject or noted by the investigator. x Mean pain duration: mean time with pain assessed from subject documentation (from the day/time of „When did you first notice new pain?“ to „the day/time of disappearance“) in diary. x HSV shedding episode rate: number of onsets of shedding episodes divided by the total number of days with swabs collected x HSV shedding episode duration: duration of a period with consecutive HSV-positive swab specimens starting at the chronological midpoint between the last HSV-negative and first HSV- positive swab specimens, and ending at the midpoint between the last HSV-positive and first HSV-negative swab specimens. NB: A shedding episode may include no more than 1 missing or 1 HSV-negative swab specimen within the episode between the first and last HSV-positive swab specimens. x Recurrence rate: number of reappearances of lesion(s) (HSV score 2-7) divided by the total number of days with any report x Recurrence duration: consecutive days with the presence of HSV lesion(s) (lesion=HSV lesion score 2-7) and associated prodrome/paraesthesia or erythema. The recurrence begins on the day the subject first reports symptoms, including prodrome (paraesthesia) or erythema, if any, and ends on the day before the lesion is either reported as being healed (HSV lesion Score = 8) or reports no lesion present on any data obtained for the day. A day with missing lesion data in between two days of active lesion (HSV lesion Score 2-7, inclusive) is considered part of the same recurrence. “Recurrences” consisting only of prodrome/paraesthesia, erythema and/or healing (HSV lesion Score 0, 1 and 8), in any combination, will not be counted. x Occurrence of molecular signals of resistance to AIC316: detection of any potential resistance mediating mutation(s) in HSV positive swabs under AIC316 treatment in the respective regions in the UL5 helicase gene and/or the UL52 primase gene known for helicase-primase inhibitor resistance mutations SAFETY and TOLERABILITY x Nature, frequency, duration, severity, seriousness and causality of adverse events (AEs); x Safety laboratory parameters;

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x Physical examination; x Vital signs (systolic and diastolic blood pressure, pulse rate); x Standard 12-lead electrocardiogram (ECG). PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state, determined at each pre-scheduled visit starting from Day 1. x Evaluation of potential AIC316 drug metabolites in blood and urine samples taken at the end of each treatment period. PHARMACOGENETIC x Pharmacogenetic data to evaluate possible influences on drug metabolism.

10 TRIAL DESIGN AND METHODOLOGY

10.1 Trial design This is a double-blind, double dummy, randomized, active controlled cross-over designed trial to compare genital HSV shedding in HSV-2 seropositive adults treated with oral AIC316 100 mg qd versus oral valacyclovir 500 mg qd during 28 days. A total of approximately 90 male or female subjects with recurrent episodes of HSV-2 will be randomized to the trial. The planned number of subjects randomized is approximately 90. The planned number of participating investigational sites is 4. Randomization will be balanced across investigational sites and among gender per investigational site. Randomization is stratified by gender and will be capped at no more than 2/3 for each gender.

10.2 Discussion of trial design This trial follows a double-blind, double dummy, randomized, active controlled cross-over design in order to minimize potential bias. Randomization and allocation concealment by randomly allocating subjects to a treatment arm in strict chronological order following confirmation of the subject’s eligibility minimizes selection bias between active treatment and active comparator group. The trial population consists of HSV Type 2 positive subjects determined by HSV Western blot analysis and the subject’s medical history will assess the existing recurrent episodes. Reactivation of HSV on the genital mucosa is characterized by intermittent shedding of the virus, which can be detected by HSV PCR from a swab of genital secretions. The frequency of shedding is highly variable between people, and fairly constant within persons, especially after the initial year since HSV-2 acquisition. The duration of treatment is planned to be 4 weeks for each cross-over treatment period which is an appropriate length of time reflecting the power calculations which is the time required to have sufficient precision in establishing a person’s viral shedding rate to be able to compare AIC316 and valacyclovir. Due to the administration of a loading dose of AIC 316 steady state will be achieved after 1 day. The

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half-life of valacyclovir (prodrug of acyclovir) is approx. 3h. Therefore valacyclovir will be at steady state by Day 1. Relative exposures of AIC 316 and acyclovir will be assessed by measurement of trough concentration at steady-state.

10.3 Blinding Subjects and all trial personnel (sites, central laboratories, CRO, and the sponsor personnel, except for for packaging and labeling purposes, the randomization statistician at Inc. for randomization purposes and for assignment of PK analysis) will be blinded with respect to the order of treatment allocation (AIC316 or valacyclovir) of each subject. Treatment conditions differ in terms of appearance: AIC316 tablets and valacyclovir capsules. To maintain blinding for subjects and site staff, subjects will receive matching placebo tablets and capsules, respectively, so that all subjects will receive identical numbers of tablets and capsules resulting in the same appearance of both treatment regimens. This minimizes any bias that could be caused by knowledge of the treatment by either the investigator or subject. Dynamic randomization via IVRS will be used for this study (see Section 17.2.).

10.4 Unblinding 10.4.1 Scheduled unblinding: Unblinding of the trial will be carried out after entry of all clinical data and database closure at the end of the trial. Unblinding will be performed under the responsibility of the biostatistician. This scheduled unblinding will occur only after all clinical data have been entered, cleaned, and all data handling decisions (e.g. inclusion/exclusion into analysis populations) based on blinded data review have been made. The study biostatistician will request unblinding in accordance with procedures defined in Inc. SOPs and/or Work Instructions. 10.4.2 Emergency unblinding: Unscheduled unblinding should only be done in case of a medical emergency and if the further treatment of the subject depends on knowing whether the subject has received AIC316 or valacyclovir. In this case, procedures described in Section 12.9 will be followed.

10.5 Time schedule x Start of trial conduct (first subject dosed): October 2012 x Estimated enrollment period: 6months x Estimated end of trial (last subject out): September 2013 x Period of time for subject in trial: 21 weeks in total as a maximum x Screening period: Up to 21 days x Treatment periods (I & II): 2 times 28 days x Washout 28 days (+14 days) (in between Treatment Period 1 and 2) x Follow up period: 28 days

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10.6 End of trial The end of the trial is defined as the final examination visit of the last subject.

11 TRIAL POPULATION

11.1 Selection of trial population 11.1.1 Recruitment procedure Potential subjects will be identified from the clinic’s existing pool of subjects, by word of mouth, through referrals, or advertisements, if applicable. All advertising material has to be approved by AiCuris and the corresponding IRB prior to use. Prior to any trial specific examination or evaluations suitable subjects will be informed in detail about the trial and asked for their written informed consent for trial participation 11.1.2 Screening log Each participating investigational site will keep a log of all subjects screened for the clinical trial. In addition, all subjects who sign an informed consent form will be entered in the electronic data capture (EDC) system, which will be used for the trial. All screening evaluations performed will be recorded in the EDC system, even if the subject will not be randomized into the trial. If a subject is not randomized, the major reason for not being randomized will be recorded. 11.1.3 Inclusion criteria Participating subjects have to fulfil the following criteria at the day of randomization: 1. Age greater or equal to 18 years 2. HSV-2 seropositive by the UW Western blot 3. History of recurrent genital herpes defined as • 4 but ” 9 clinical recurrences in the last year or, if currently on suppressive therapy, prior to starting suppressive therapy (suppressive therapy has to be stopped at least 7 days prior to initiation of trial medication). 4. Negative results for human immunodeficiency virus antibody (HIV-Ab). 5. Willing to not use any topical genital therapy for the duration of the trial. 6. Willing to not use any systemic anti HSV therapy during Treatment Period 1 and 2, including 7 days prior to Treatment Period 1, and 7 days prior to start of Treatment Period 2. 7. Willing to obtain four (4) swabs per day from genital secretions (non-lesional as well as lesional, if appropriate) for the full duration of the 2 treatment phases (2x 28 days) of the trial. 8. Willing to keep a daily trial diary during both treatment periods. 9. Negative serum E-HCG (beta-human chorionic gonadotropin) test for women at screening and a negative urine pregnancy test at randomization. 10. Willing to use effective birth control:

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Male subjects who are surgically sterile (e.g. after vasectomy) or who must agree to use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. An adequate method of contraception is defined as sexual abstinence or the use of a male condom combined with female contraception. Female subjects who are surgically sterile (e.g. 2-sided tubal ligation, resection or ovariectomy) or post-menopausal (defined as older than 50 years of age and who have a history of no menses for at least 24 months) or female subjects of childbearing potential who are sexual abstinence or use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final dose of trial medication. An adequate method of contraception is defined as a double-barrier method combining two of the following acceptable birth control methods: - the use of the copper-releasing intrauterine device (to have been in place for at least 2 months prior to screening); - the use of one of the following: diaphragm, Lea’s shield, FemCap, sponge, and - monogamous relationship with vasectomized partner; - the use during each act of sexual intercourse of a male condom. 11. Subject must be willing and able (in the opinion of the investigator) to understand the subject information and informed consent form and to comply with the clinical trial protocol and procedures. 12. Subject must be willing to give written informed consent. 11.1.4 Exclusion criteria Any of the following will exclude a subject from the trial if criterion is correct or present at day of randomization: 1. Acute episode of genital herpes at randomization. 2. Serious medical conditions, such as diabetes, significant autoimmune disease, etc. 3. Clinically relevant acute or chronic infections (excluding HSV-2). 4. Known intolerance to valacyclovir, acyclovir, or any component of the formulation 5. Documented HSV resistance to acyclovir, valacyclovir, famciclovir or penciclovir. 6. History or current evidence of malignancy except for a localized non-melanoma skin cancer. 7. Subject known to be immunosuppressed. 8. Treatment with systemic steroids or other immunomodulating agents. 9. Participation in any clinical trial within 30 days prior to screening. 10. Renal impairment (creatinine clearance < 30ml/min)and/or hepatic impairment (Child-Pugh stage B and C). 11. History or current evidence of gastrointestinal malabsorption which could interfere with absorption.

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12. Known to have other genital tract disorders or sexually transmitted disease that may interfere with assessment of the trial medication efficacy. 13. Medical history of acute or chronic pancreatitis 14. Medical history of macular or maculopapular skin reactions (exanthema or eruption) 15. Clinically relevant abnormalities in clinical chemical, hematological or any other laboratory variables. 16. Electrocardiogram (ECG) abnormalities of clinical relevance (e.g.: QTc >450 ms). 17. Positive results in any of the serology tests for HCV-Ab or HBsAg. 18. Pregnancy or breastfeeding. 19. Evidence of active abuse of alcohol or drugs. 20. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 21. Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial.

11.2 Removal of subjects from the trial, trial assessments or investigational medicinal product(s) A subject may terminate participation in the trial at any time without providing a reason and without any personal disadvantage. Additionally, the Investigator can stop the participation of a subject after consideration of the benefit/risk ratio. In any case, the Investigator can discuss the removal of the subject with the AiCuris Medical Expert by contacting AiCuris GmbH & Co. KG at the following emergency number 24 hours 7 days a week: +49-(0)202-31763- . Subjects who discontinue early from the trial for any reason will not be allowed to re-enter at a later date. Possible reasons for the investigator to discontinue a subject’s trial medication or participation include: x Planned surgery. x Any relevant deterioration in the health of the subject possibly impacting the participation in the trial, including adverse events (irrespective of relationship to trial medication), laboratory parameters, vital signs or other safety parameters (e.g. ECG) at the discretion of the Investigator. x Intake of prohibited medication. x Technical reasons (e.g. subject moves away). x Failure to comply with trial requirements, e.g. non-compliance with the intake of trial medication and/or swabbing.

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x Subject desires to withdraw from the trial x Pregnancy. Reasons for discontinuation the subject’s trial participation and/or treatment will be clearly documented in the electronic case report form (eCRF). In addition, the investigator must prepare a detailed written explanation for AiCuris GmbH & Co. KG/ Inc. and the IRB where applicable. AiCuris GmbH & Co. KG/ Inc. will be informed as soon as possible about the withdrawal of a subject from the trial. The following different situations can occur and the following must be noticed: In all situations, the reasons for discontinuation of the trial treatment will be recorded and an Early Termination Visit will be performed. In addition, due to the long half-life of the drug a visit will be scheduled 28 days after last trial medication intake and all assessments of the Final Examination Visit will be performed. Consent withdrawn by subject: No further investigation and treatment will be performed; nevertheless an Early Termination Visit (and ideally a Final Examination Visit) will be done. Removal of subject from trial participation: All efforts will be performed by the Investigator to prevent this situation because information about the subject after stopping the trial treatment is very helpful for the drug development. However, if the situation cannot be avoided for good reasons no further investigations and treatment except the Early Termination Visit will be performed. Removal of a subject from trial treatment: No further investigation and treatment will be performed; nevertheless an Early Termination Visit will be done and ideally a Final Examination Visit 28 days after last trial medication intake. The Investigator has to remove a subject from the study treatment in the following situations: x occurrence of an adverse event or any other condition which in the opinion of the Investigator does not justify a safe continuation of the trial treatment in this subject x any case of pancreatitis, regardless of causality x any case of grade 3 or 4 rash judged to be related to study treatment x any grade 2 rash accompanied by constitutional symptoms x any serious adverse event considered to be possibly, probably or definitely related to trial medication and clinically relevant x any occurrence of hematologic, hepatic, and pancreatic clinically significant laboratory abnormalities on two consecutive samples that are considered drug related and show the following abnormal values: o hemoglobin concentration < 8 g/dL o erythrocytes < 2 x 10E6/μL

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o white blood count < 2 x 10E3/μL o neutrophils count < 1 x 10E3/μL o platelets count < 75 x 10E3/μL o ALT •[8/1and/or AST > 3 x ULN o indirect and direct bilirubin > 2.5 x ULN o amylase and/or lipase > 2.5 x ULN. 11.2.1 Notification of discontinuations Prior to unblinding or discontinuation of a subject, the Investigator should discuss circumstances with the AiCuris Medical Expert by contacting AiCuris GmbH & Co. KG at the following emergency number 24 hours 7 days a week: +49-(0)202-31763- . Inc. and AiCuris GmbH & Co. KG must be informed within 24 hours about any removal of a subject from the trial including the reason. The Investigator must prepare a detailed written explanation for Inc. and AiCuris GmbH & Co. KG and the IRB (where applicable).

11.3 Trial completion 11.3.1 Subject definitions and subject completion x Enrolled subjects are those on whom trial specific investigations are performed after informed consent is given. x Randomized subjects are those allocated to trial medication. x Treated subjects are those with at least 1 intake of trial medication. x A “drop-out” is an enrolled subject who stops prematurely due to non-observance of the protocol or to reasons unrelated to the trial, e.g., AE, death, “moved away” or who is otherwise lost before the final scheduled examination. A subject who simply wishes to terminate the trial should also be considered as a drop-out. x A “withdrawal” is an enrolled subject who stops prematurely or is withdrawn by the investigator for reasons related to the trial, e.g., an adverse event (AE). x A “completed” subject is one who has completed all measurements as scheduled in the trial protocol. In detail: completed all visits, treatments, the wash-out and follow-up period as scheduled in the trial protocol including the final examination at Day 112 (r 1 day) 11.3.2 Procedures for handling of replacements, withdrawals or drop-outs Randomized subjects who withdraw or drop out of the trial before completion or are lost to follow up may not re-enter the trial. Subjects who fail the screening process may not be re-screened. All subjects who terminate the trial prematurely will undergo an Early Termination Visit, and the Final Examination Visit 28 days after last medication intake whenever possible. 11.3.3 Premature termination of the trial The trial may be prematurely terminated, by the IRB, regulatory authorities, or AiCuris GmbH & Co. KG, e.g. if the perception of the benefit/risk ratio becomes unfavorable for the continuation of the trial.

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In addition, AiCuris GmbH & Co. KG may terminate the trial prematurely for administrative reasons. A decision to cease the trial is binding for all investigators. Inc. and the investigators must be informed immediately about the discontinuation of the trial. If the trial is prematurely terminated or suspended for any reason, the Investigator will promptly inform the subjects, will assure appropriate follow-up for the subjects, and inform the IRB and regulatory authorities (where appropriate) and the institution where the trial is being performed. Specifically, the trial will be stopped if the benefit/risk ratio becomes unfavorable for the continuation of the trial due to: x new toxicological or pharmacological findings or findings from parallel clinical trials or serious adverse events within the current trial invalidate the earlier positive benefit-risk-assessment x adverse events occur in an intensity and frequency that a continuation of the trial is no longer justified x the number of drop-outs is so high that proper completion of the trial cannot realistically be expected

12 INVESTIGATIONAL MEDICINAL PRODUCT

12.1 Identity of investigational medicinal product and comparator AIC316 film-coated tablets Manufacturer: , Germany Active ingredient: AIC090016 (AIC316 mesylate monohydrate) Substance name: 2-(4-{2-[[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl](methyl)amino]-2-oxoethyl}phenyl)-pyridinium methanesulfonate monohydrate International non-proprietary name: not applicable Pharmaceutical properties: Film-coated, white to off-white round biconvex tablets of 11 mm (0.43 inch) diameter. Strengths 100 mg (strength refers to the amount of AIC316 free base, the pharmaceutically active moiety). Placebo film-coated tablets Manufacturer: Germany Substance code: not applicable Substance name: not applicable International non-proprietary name: not applicable Pharmaceutical properties: Film-coated, white to off-white biconvex round tablets of 11mm (0.43 inch) diameter

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Valacyclovir capsules Each capsule contains one valacyclovir 500mg tablet Manufacturer: GSK Strength: 500 mg Substance name: L-valine, 2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethlyester, monohydrochloride Brand name: Valtrex® International non-proprietary name: valacyclovir hydrochloride Capsule properties: Size 00 opaque Swedish orange gelatin capsule Encapsulation by: , Germany Capsule properties: Size 00 opaque Swedish orange gelatin capsule. Placebo capsules Each capsule contains one placebo tablet Manufacturer: , Germany Substance name: not applicable International non-proprietary name: not applicable Capsule properties: Size 00 opaque Swedish orange gelatin capsule

12.2 Packaging and labeling Packaging, labeling and shipment of trial medication to the investigational sites will be done by . Trial medication will be provided as kits. Corresponding labels will be located on each package for identification and for allocation of a package to a subject. Each trial medication kit will contain 10 blister cards in the following way: x 2 blister cards, one per treatment period, each containing tablets and capsules for 7 treatment days including the loading dose for the first day of each treatment period, labelled according to the treatment period, week and day; x 6 weekly blister cards, each containing tablets and capsules for 7 treatment days, labelled according to the treatment period, week and day; x 2 blister cards, one per treatment period, each containing tablets and capsules for the first treatment day and 6 further treatment days as back up The kit number will be allocated by the IVRS/IWRS system at time of randomization. After the receipt of a kit number, site staff must immediately enter the unique subject number on the kit labels.

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The trial medication kit will contain tear off labels. One should be placed in the subject’s clinic file and one should be placed on the site’s Drug Accountability Log. Additional spare labels will be provided. Upon receipt of the trial medication kits, and again prior to administration a check for intactness of the packaging will be performed by the respective responsible person at the investigational site. The labeling of the trial medication will be performed in compliance with all applicable guidelines, laws, and regulations. Labels will include English and Spanish language and will contain the following (but not limited to): Name, address, phone number of the Sponsor Protocol No Number of tablets of AIC090016 or matching placebo and capsules of valacyclovir or matching placebo for oral use Treatment week / Extra package Direction for Use Storage condition Subject Number [5 digits, needs to be entered manually by the investigational site staff] Lot Number Kit Number KEEP OUT OF REACH OF CHILDREN Return any unused medication and empty boxes. Caution: New Drug – Limited by Federal (or United States) Law to Investigational use Any discrepancy in the packages should be communicated immediately to the Clinical Supplies Specialist at Clinical Services or his/her designee. All necessary trial medication related documents will be filed in the Trial Master File.

12.3 Administration of investigational medicinal products AIC090016 (AIC316 mesylate monohydrate) tablets with strengths of 100 mg and valacyclovir 500 mg encapsuled, as well as matching placebo tablets and capsules will be administered orally. All tablets/capsules are to be swallowed whole, without being crushed, chewed or opened (capsules) and need to be taken between 6:00 am and 12:00 noon, either with a meal or immediately after eating, ideally at the same time each day. Date and time of trial medication intake needs to be documented in the subject’s diary. If a subject vomits when taking the trial medication, the subject will NOT take another tablet/capsule to replace the one that could have been lost. Vomiting will be notified to the study doctor. Trial medication will be administered for each of the two 28 days treatment periods from trial Day 1 and Day 57, respectively, if the subject fulfills all inclusion criteria and does not meet any exclusion criteria. On days with visits at the investigational site, trial medication will be taken at the investigational site after blood has been drawn for pharmacokinetic analysis.

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12.4 Dosing arms There will be two dosing arms, each arm consisting of 45 subjects. One arm will start with AIC316 for the first treatment period and switch to valacyclovir for the second treatment period after the 28 days washout period. The other arm will start with valacyclovir and switch to AIC 316 after washout: x Dosing arm 1: Day 1: loading dose of 400 mg AIC316; Day 2 to Day 28: maintenance dose of AIC316 100 mg qd; Day 29 to 56: wash out Day 57 to 84: valacyclovir 500 mg qd x Dosing arm 2,: Day 1 to Day 28: valacyclovir 500 mg qd; Day 29 to 56: wash out Day 57: loading dose of 400 mg AIC316; Day 58 to Day 84: maintenance dose of AIC316 100 mg qd To maintain the blinding a double-blind double-dummy design was chosen. In addition to the active tablets or capsules, subjects in both groups will be given a matching amount of placebo tablets/capsules so that every subject will receive an identical daily treatment with respect to tablet/capsule number and appearance. Thus, the pill regimen is consistent across treatment arms and dosing is handled through the relative proportions of active vs. placebo pills.

12.5 Loading dose In order to reduce the time to steady-state for AIC316, an active loading dose of 4-times 100 mg will be administered on the first treatment day starting with AIC316 (Day 1 or Day 57). A loading dose of matching placebo will be administered for those subjects receiving valacyclovir at Day 1 and Day 57, respectively, to maintain the blind.

12.6 Storage At all storage locations during packaging, labeling and distribution temperature logs and documentation about the receipt and shipment of trial medication will be maintained. The trial medication kits will be stored in a secure location with restricted access. At each investigational site, the trial medication kits will be stored in a secure location with restricted access at room temperature between 59-86° F (15 and 30°C). The storage conditions at the investigational sites will be recorded daily and documentation about drug accountability (receipt and dispense) will be maintained. All subjects need to be instructed by the trial staff to meet the storage requirements as given on the labels.

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12.7 Documentation of drug accountability Full drug accountability will be done with the kit numbers assigned to each investigational site noted. An IMP Accountability Form will be developed for use on the trial which will allow the accurate and reliable tracking of all IMP. At each investigational site, the Investigator may assign some or all of the Investigator’s duties for drug accountability to an appropriate pharmacist or another appropriate individual who is under supervision of the Investigator. The Investigator or appropriate designee is obliged to keep documentation (e.g. site specific drug accountability log, trial medication dispensing log) of the delivery, use, and destruction or return of unused, used or partially used, packages of trial medication. The documentation must include dates, quantities, kit numbers, lot/batch/serial numbers or other identification numbers, and the means to identify the subject to whom a specific trial medication kit was dispensed, e.g. subject number. Before any trial medication is returned from the site to a central facility, the Investigator must allow the Clinical Research Associate to perform drug reconciliation. Entries in the eCRF and other accountability records will be compared with the returned and residual trial medication, with clarification of any discrepancies or inconsistencies.

12.8 Delivery of investigational medicinal product(s) Trial medication will be packaged and distributed by Clinical Services. Clinical Services will be responsible for supplying the Investigator with trial medication(s). These will not be delivered until a trial site is approved by EC/IRB and drug delivery to this site is released by AiCuris GmbH & Co based on the required documentation. The trial medication will not be destroyed at the investigational sites. All unused trial medication and packages will be sent back to Clinical Services.

12.9 Identification of investigational medicinal products in emergency situations – unblinding in case of medical emergency For medical emergencies, e.g. in situations in which the identification of the treatment group (either AIC316 or valacyclovir) would lead to the investigator treating the subject differently, the following precautionary measures are foreseen which will enable unblinding of single cases, e.g. by the Investigator, responsible persons at AiCuris GmbH & Co. and/or Inc. Individual sealed envelopes with log in data to the unblinding area of the IVRS/IWRS system at will be provided to the investigators for emergency unblinding in the event of medical need. x Investigators are aware that no specific antidote is known and available for AIC316 nor for valacyclovir for any emergency situation or in case of overdosing. x Investigators are obliged to contact AiCuris GmbH & Co. KG at the following emergency number: +49-(0)202-31763- , before the unblinding process may be initiated. x However, if it is not possible to reach AiCuris GmbH & Co. KG before the unblinding process has to be initiated, the investigator will alert and get in contact with AiCuris GmbH & Co. KG within one day.

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x In the case of an AE/SAE, the investigator will assess the relationship of the AE/SAE to the trial medication before the code is broken. The AE/SAE will be documented and reported according to Section 15. For every unblinded subject the following information will be tracked by the IVRS/IWRS: x Name of the person who did the unblinding x The reason for, and date and time of unblinding. In order to maintain the double blind nature of this trial, the actual treatment assignment must not be communicated further unless required for the surveillance of the subject or if necessary for urgent risk/benefit re-evaluation and/or measures for urgent risk minimization. CRAs will inspect the integrity of these envelopes at each monitoring visit. At the end of the trial the envelopes must be returned intact for filing in the TMF. Unblinded subjects will be withdrawn from trial treatment but will perform the Early Termination visit and the Final Examination Visit 28 days after last trial medication intake.

13 TRIAL PROCEDURES

13.1 Course of the trial 13.1.1 Information of subjects and informed consent The investigator or delegate will explain the trial to the subject, including why the subject may be eligible to participate, the planned assessments, possible risks and discomforts and any available alternative therapies. The subjects will have the opportunity to discuss the trial or think about it prior to decide about their participation. After taking time for consideration, clarifying open questions, and deciding to participate, the subject will sign and date the ICF to confirm the informed consent in writing. Written informed consent must be obtained from each potential subject to be enrolled in the trial prior to performing any trial specific procedures. A copy of the signed and dated informed consent document will be given to the subject. The information provided in the ICF will be given in language the potential subject can understand: colloquial, native language. The consent form and any subsequent revisions must be reviewed and approved by the IRB or EC overseeing the trial prior to use. Only ICF versions approved by the IRB/EC will be used. The consent administration process must be described in the subject’s source documents. A separate patient information and informed consent form will be available for pharmacokinetic sampling and tests. A subject’s refusal to participate the pharmacogenetic tests is NOT a reason for exclusion from the study.

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13.1.2 Screening period To be eligible for this trial, subjects must meet all inclusion criteria and none of the exclusion criteria as defined in Sections 11.1.3 and 11.1.4. The subject’s general practitioner will be informed of the subject’s participation in the trial, if applicable. Once the subject agrees to participate, a 5 digit subject number will be assigned: The first 2 digits will be the investigational site identification code and the 3 following digits will be the screening number sequentially assigned at the time of informed consent is given. 13.1.2.1 Screening visit (within 21 days before Day 1) The following procedures will be done and information will be assessed at the screening visit(s): x Written informed consents x Inclusion- and Exclusion Criteria x Demographics x Medical history x Adverse events x Previous and concomitant medications x Detailed general physical examination including: o Height, weight and physical examination of the whole body o Visual examination of the genital and perianal region x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position) x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters (see Section 14.5). x Blood sampling for virology testing: o Tests for human immunodeficiency virus antibody (HIV-Ab), hepatitis C virus antibody (HCV-Ab) and hepatitis B surface antigen (HBsAg). o HSV Type 2 Western blot evaluation by University of Washington (UW) if results are not available (see inclusion criteria No.2, Section 11.1.3) o For all female subjects: serum ȕ-HCG blood test. x Swabbing of the anogenital region for HSV DNA PCR measurement by the investigator x Swabbing of the anogenital region for HSV DNA PCR measurement by the subject for training purposes (see below). x Subject’s training on swabbing of the genital region: Both the investigator and subject will take anogenital swabs by rubbing a polyester fiber-tipped swab across the surface. o Men: penile, perianal and anal areas (in that order) o Women: Across the posterior cervical/vaginal, vulvar, perianal and anal areas (in that order)

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13.1.3 Treatment Period 1 13.1.3.1 Randomization visit (Day 1) Subjects will be randomized within 21 days after the screening visit took place. The randomization visit will only take place when all results from all screening assessments are available. The day of randomization will be Day 1 and trial medication will be started directly after randomization and blood draw for pharmacokinetic sampling on Day 1 at the investigational site. The following will be assessed on Day 1: Evaluations before randomization and treatment: x Confirmation of eligibility of subject regarding inclusion and exclusion criteria (For the assessment of the inclusion and exclusion criteria concerning blood and urine parameters screening values will be used) x Review of previous and concomitant medications x AEs x Detailed general physical examination including: o Weight and physical examination of the whole body o Visual examination of the genital and perianal region x Vital signs with supine blood pressure, pulse rate (after 5 minutes in the supine position x 12-lead ECG x Blood and urine sampling for safety laboratory analyses as baseline before trial treatment start (hematology, coagulation, serum chemistry, and urinalysis - parameters (see Section 14.5): x Virology: o Swabbing of the anogenital region (by Investigator and subject) for HSV DNA PCR measurement x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test x Blood draw for trial medication plasma level (blank value). x Preparation of sample for pharmacogenetic tests (if consented to by subject).

Once these procedures are completed and it is confirmed that the subject meets all the inclusion criteria and none of the exclusion criteria, the subject will be randomized to a treatment arm by requesting the assignment of a trial medication kit number at the IVR/IWR system. The subject number must be entered immediately onto the kit label. The link between kit number and subject number will be documented in the IVRS/IWRS and eCRF. Intake of first treatment: Under the observation of the Investigator the subject will take the first dose with food or after food intake before noon.

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Procedures after drug intake first dose: Site staff will instruct the subjects on the dosing regimen, the pre-scheduled visits at the investigational site and how to complete the subject diary (see Section 16.2), which also will be provided. Subjects will be reminded to contact the investigational site immediately if they experience an HSV recurrence with lesion(s). In addition, subjects will receive the blister card for the first weekly treatment as well as the back-up blister card along with all material needed for swabbing (kits, mirror etc.). Provision of all materials will be documented on the trial medication dispensing log and in the subject’s file on site, respectively. Subjects will be reminded of the 4-times daily swabbing requirement. 13.1.3.2 Activities and evaluations by the subject Trial medication intake: Subjects will receive a weekly blister card and a back-up blister card on Day 1. Thus it is guaranteed that subjects can self-administer the trial medication without interruptions until the next visit at the investigational site. Self-administration will be performed in the morning between 6:00 AM and 12:00 PM together with or directly after food intake. Trial medication at any visit day must not be taken at home, but only after blood draw for pharmacokinetic sampling at the site. Each dosing will be documented in the subject’s diary. Swabbing of the anogenital region: Presence or absence of genital lesions will be assessed by the subject. Swabbing of the genital region for HSV DNA PCR measurement as described for the screening visit (see Section 13.1.2.1) will be performed by the subjects 4 times daily: in the morning before the subject may take a shower or a bath, at lunch time, in late afternoon and before the subject goes to bed (but before taking a bath or shower). The time of each swabbing will be documented in the subject’s diary. Swabbing of lesion(s): In case of an HSV recurrence, an additional, separate swab will be obtained from the lesion(s) by the subject in parallel to each of the 4 times daily swabs. Furthermore subjects need to visit the investigational site for an unscheduled HSV recurrence visit (see Section 13.1.8) within 48 hours at the latest after the lesion(s) occurred. Swabbing of lesion(s) will be documented in the subject’s diary. Completion of subject’s diary: Subjects will receive a weekly diary for daily documentation of medication intake, time of each swabbing, duration and severity of pain (if any), and in case of an HSV recurrence, occurrence of lesion(s) and their morphology. 13.1.3.3 Treatment Period 1 visits on Day 8, Day 15, and Day 22 (each r1day) During treatment period 1, from Day 1 to 28, visits will occur on Days 8, 15 and 22. For all visits a visit window of ±1 day is acceptable. The following procedures will be performed during these visits: x Review of concomitant medications

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x Review of subject’s diary and hand out new diary for the next week x Drug accountability and hand out of blister cards for treatment during the next week x Collection of subject’s swabs x AEs/SAEs x Detailed general physical examination including: o Physical examination of the whole body o Visual examination of the genital and perianal region. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position). x 12-lead ECG (Day 8 only) x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (trough value) before intake of the daily dose. x Swabbing of the anogenital region and lesions if any, by Investigator for HSV DNA PCR measurement. 13.1.4 Wash out period Wash out will start on Day 29 and will last for 28 days. During wash out subjects will not take trial medication, and must not use prohibited concomitant medication. No daily swabs and no lesional swabs will be taken by the subject. In case of circumstances, which prevent that a subject can visit the site according to the preplanned schedule, the washout period may be prolonged by a maximum of 14 days. Should an HSV recurrence occur during wash-out, the investigator needs to be informed immediately and an HSV Recurrence Visit has to be scheduled within 48 hours at maximum. Should the investigator feel the need to treat the HSV outbreak a 3 day course of valacyclovir can be prescribed. It has to be considered, that following valacyclovir treatment a wash-out period of at least 7 days must follow, before the subject may enter Treatment Period 2. 13.1.4.1 Day 29r1 visit The Day 29 visit will be performed one day after the last medication of the first treatment period has been taken. The following procedures will be performed during this visit: x Review of concomitant medications x Review of subject’s diary x Drug accountability and collection of all trial medication not used during treatment period 1 x Collection of subject’s swabs x AEs/SAEs x Detailed general physical examination including: o Weight measurement and physical examination of the whole body o Visual examination of the genital and perianal region. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position).

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x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (through value). x Blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only, if not done at Day 1: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test.

13.1.5 Treatment Period 2 13.1.5.1 Start of second treatment period (Visit Day 57r1) The following will be assessed during the Day 57 Visit: Evaluations before re-start and intake of trial medication: x Confirmation of further eligibility of subject regarding inclusion and exclusion criteria x Review of concomitant medications x Hand out new diary for the next week x Hand out of blister cards for treatment during the next week x AEs/SAEs x Detailed general physical examination including: o Weight measurement and physical examination of the whole body o Visual examination of the anogenital region. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position) x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (blank value) x Only, if not done at Day 1 or Day 29: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesions, if any, by Investigator for HSV DNA PCR measurement. x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test. Intake of first medication of treatment period 2: Under the observation of the Investigator the subject will take the first dose of trial treatment for Treatment Period 2 with food or after food intake before noon.

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Procedures after drug intake of first dose: Site staff will re-instruct subjects on the dosing regimen and how to complete the subject diary (see section 16.2). In addition, subjects will receive the subject diary and blister cards for the weekly treatment along with all material needed for swabbing (kits, mirror etc.). Provision of all materials will be documented on the trial medication dispensing log and in the subject’s file on site, respectively. Subjects will be reminded of the 4-times daily swabbing requirement. Subjects will be reminded to contact the investigational site immediately if they experience an HSV recurrence with lesion(s). In addition subjects will be reminded that self-administration should be done in the morning between 6:00 AM and 12:00 PM together with or directly after food intake and that trial medication at any visit day must not be taken at home, but only after blood draw for pharmacokinetic sampling at the site. 13.1.5.2 Treatment visits Day 64, Day 71 and Day 78 (each r1 day) During Treatment Period 2, from Day 57 to 84, weekly visits will occur on Days 64, 71 and 78. For all visits a visit window of ±1 day is acceptable. The following procedures will be performed during these visits: x Review of concomitant medications x Review of subject’s diary and hand out new diary for the next week x Drug accountability and hand out of blister cards for treatment during the next week x Collection of subject’s swabs x AEs/SAEs x Detailed general physical examination including: o Physical examination of the whole body o Visual examination of the genital and perianal region. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position),. x 12-lead ECG (Day 64 only) x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (through value) before intake of daily dose. x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement 13.1.6 Follow-up period After completion of the second 28-day treatment period, all subjects will enter a 28-day (r1) follow-up period (Day 85-112). During this follow-up period subjects will not take trial medication and will not continue swabbing and diary recording. Subjects will inform investigational site if recurrences occur. The following scheduled visit at the beginning of the follow-up period has to be performed:

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13.1.6.1 Visit Day 85r1 day The Day 85 visit will be performed one day after the last medication of the second treatment period has been taken. The following procedures will be performed during the visit: x Review of concomitant medications x Review of subject’s diary x Drug accountability and collection of all trial medication not used during treatment period 2 x Returning of all blisters (used and unused) by the subject x Collection of subject’s swabs x AEs/SAEs x Detailed general physical examination: o Weight measurement and physical examination of the whole body o Visual examination of the genital and perianal region including. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position), x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (through value) x Blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only, if not done at Day 1, Day 29 or Day 57: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test. 13.1.7 Final Examination Visit - Day 112 ± 1 day A final examination will be performed at the end of the 28 days (±1 day) follow-up period. The following assessments will be performed: x Review of concomitant medications x Collection of all remaining material x AEs/SAEs x Detailed general physical examination including: o Weight measurement and physical examination of the whole body o Visual examination of the genital and perianal region x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position) x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5)

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x Blood draw for trial medication plasma level (through value) x Only, if not done at Day 1, Day 29, Day 57 or Day 85: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test. 13.1.8 Unscheduled visit: HSV Recurrence Visit In case a subject develops a new HSV recurrence during any of the 2 treatment periods or during wash-out the investigator needs to be informed immediately and an HSV Recurrence Visit will take place as soon as possible within 48 hours of lesion onset, to enable an assessment by the investigator. During the treatment periods, development of new lesions need to be documented in detail by the subject in the subject’s diary, and the subjects will take a separate swab from the lesion(s) from the anogenital region in addition to the 4 times daily regular swabs which should spare the lesion area. The following assessments will be performed at an unscheduled HSV recurrence visit: x Detailed general physical examination including: o Physical examination of the whole body o Detailed visual examination of the genital and perianal region with the HSV lesion(s). o Documentation of number of lesions, localization, and morphology of lesions according the HSV score in Appendix 20.3. x Swabbing of the anogenital region and separate swabbing of the lesion(s) by Investigator for HSV DNA PCR measurement. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position) x Review concomitant medications x Review of subject’s diary x Drug accountability x Collection of subject’s swabs x AEs/SAEs If the unscheduled HSV Recurrence Visit takes place at a regular scheduled visit or within the time window of the respective visit, evaluations and assessments must not be duplicated. All evaluations foreseen for the regular scheduled visit will be performed and in addition the lesion swabbing and documentation will be added as described above. 13.1.9 Early Termination Visit If a subject withdraws trial participation prematurely for any reason, an Early Termination Visit will be scheduled and the following assessments will be performed: x Review of concomitant medications

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x Review of subject’s diary x Collection of subject’s diary x Drug accountability x Returning of all blisters (used and unused) by the subject x Collection of subject’s swabs x Returning of all unused swabbing material x AEs/SAEs x Detailed general physical examination including: o Weight measurement and physical examination of the whole body o Visual examination of the genital and perianal region. x Vital signs with supine blood pressure and pulse rate (after 5 minutes in the supine position) x 12-lead ECG x Blood and urine sampling for safety laboratory analyses (hematology, coagulation, serum chemistry, and urinalysis - parameters see Section 14.5) x Blood draw for trial medication plasma level (through value) x In case of early termination of a treatment period: blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only, if not done at Day 1, Day 29, Day 57 or Day 85: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. x For all female subjects of child-bearing potential: urine (dipstick) pregnancy test. 13.1.10 Examination hierarchy and time windows All assessments and examinations (e.g. vital signs, ECGs, safety assessments) will be performed before trial treatment will be taken at all visits of the treatment periods. The following time windows for visits will be permitted during the trial: x Screening: within 21 days before Day 1 x Treatment period visits: Days 8, Day 15, Day 22, Day 64, Day 71, Day 78: each ±1 day x Day 57 visit: - 1/+14 days x Wash out period (Day 29), and Follow-up period (Day 85): each ±1 day, these visits must be performed one day after last trial medication intake, x Final Examination Visit (Day 112): ±1 day

Note: All trial visits must be conducted before noon.

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13.2 Flow chart

Screening Treatment period I Wash out Unscheduled Visits (treatment on 28 days: Day 1-28) (28 days) Procedure Any time Day 1 Day 8±1 Day 15±1 Day 22±1 Day Day HSV Early Day -21 to -1 29±1 30±1-56±1 recurrence terminationh) 9LVLW”K Written informed consent obtained X Evaluation of inclusion/exclusion criteria X X Randomization (only after confirmation of eligibility) X Demographics X Medical history X Detailed general physical examinationd) XXXXXX X X Vital signsa) XXXXXX X X 12-lead ECGb) XXX X X Safety laboratory measurementsc) XXXXXX X Blood sampling for PK (pre-dose) and drug metabolites l) X k) XX XXk) l) X k) l) ȕ-HCG blood test X Urine dipstick pregnancy test X X X Sampling for HSV Type 2 Western Blot X Blood sampling HIV-Ab, HCV-Ab, HBsAg X Swabbing anogenital region for HSV by subject X Swabs at home 4x daily Swabbing of lesions if present by subject Swabs at home if lesion present Swabbing of anogenital region for HSV by Investigator X Xe) XX XX X X Swabbing of lesions if present by Investigator X X X X X X Hand out blister cards X X X X At on-site visits (Day1, Day 8, 15 & 22) AFTER PK blood Intake of treatment sampling. At home daily between 6:00AM and 12:00PM together with or directly after food intake on Day 2 until Day 28. Self-assessment of HSV lesions by subject Daily until Day 28 Hand out Subject Diary X X X X Diary Completion by Subject Daily recording until Day 28 Collect and review subject diary X X X X Xf) X Collect unused trial medication/trial medication accountability XX XX X X Collect subject’s swabs XX XX X Xi) Pre- and concomitant medication X X X X AEs / SAEs X X X X Return of all study material from subject X Cont.

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Cont.

Treatment period II Follow-up period Unscheduled Visits (treatment on 28 days: Day 57-84) (28 days) Procedure Day 57 Day 64±1 Day 71±1 Day 78±1 Day Day Final HSV Early -1/ +14 85±1 86±1 to Examination recurrence terminationh) 111±1 Day 112±1 9LVLW”K Re-Evaluation of inclusion/exclusion criteria X Detailed general physical examinationd) XXXXX X X X Vital signsa) XXXXX X X X 12-lead ECGb) XX X X X Safety laboratory measurementsc) XXXXX X X Blood sampling for PK (pre-dose) and drug metabolites l) X k) XXXXk) l) X k) X k) l) Urine dipstick pregnancy test X X X X Swabbing anogenital region for HSV by subject Swabs at home 4x daily Swabbing of lesions if present by subject Swabs at home if lesion present Swabbing anogenital region for HSV by Investigator Xe) XXXX X X X Swabbing of lesions if present by Investigator X X X X X X X X Hand out blister cards X X X X At on-site visits (Day 57, 64, 71 & 78) AFTER PK blood sampling. Intake of treatment At home daily between 6:00AM and 12:00PM together with or directly after food intake on Day 58 until Day 84. Self-assessment of HSV lesions by subject Daily until Day 84 Hand out subject diary X X X X Diary completion by subject Daily recording until Day 84 Collect and review subject diary X X X X Xg) Xf) X Collect unused trial medication / trial medication X X X X Xg) XX Collect subject’s swabs X X X X Xg) XXi) Concomitant medication XXX AEs / SAEs XXX Return of all remaining study material from subject XX a) Supine blood pressure and pulse rate (after 5 minutes in a supine position). b) Supine position after at least 5 minutes’ rest; ECGs to be performed in duplicates. c) Hematology, Coagulation, Serum chemistry, Urinalysis – Urine sample for evaluation of potential AIC316 drug metabolites to be collected on Day 29 and Day 85, and/or at Early Termination, respectively. d) Physical examination of whole body and visual examination of genital & perianal region. Screening visit: in add. height & weight. Day 1, 29, 57, 85, Final Exam. & Early Termination: in add. weight. e) Hand out required swabbing kits to subjects. f) Review only. g) If not already done during the previous visit. h) As soon as possible after decision about withdrawal has been made. During treatment phases, this visit should be done on the day after last treatment intake. i) Required only if visit occurs during treatment phases. k) Pharmacogenetic sample to be prepared at one of these visits. Blood to be taken from pk sample. l) Blood sampling for evaluation of potential AIC316 drug metabolites on Day 29 and Day 85, and/or at Early Termination Visit, respectively. CONFIDENTIAL page 69 of 125

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13.3 Protocol compliance All randomized subjects will be asked to maintain a daily diary to record time of trial medication intake, time and type (non-lesional/lesional) of swabs obtained, symptoms, presence or absence of lesions, etc. Responses on the diary will be reviewed by site staff during clinic visits and inconsistencies or discrepancies will be clarified with the subject.

13.4 Trial conditions and restrictions 13.4.1 Prohibited concomitant medication During administration of the trial medication, concomitant use of other anti-HSV treatments or therapy is prohibited. This also includes all topical preparations to the genital area which might be used by subjects for the treatment of HSV or for the relief of symptoms. During the period of trial participation, the amount of concomitant use of other drugs and medication – also over-the-counter drugs - should be as low as possible. Due to their known effects to induce drug metabolizing enzymes and transporters which may influence the plasma levels of AIC316 the following drugs are prohibited in this trial within a period of 14 days prior to the first dosing until the final examination visit of the trial: x carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, troglitazone Subjects taking forbidden medication might be withdrawn after discussion with the Sponsor. 13.4.2 Meals and fluid intake During the trial, from 14 days before the first trial medication intake until the Final Examination Visit, all subjects need to avoid the consumption of x grapefruit, Seville oranges, and grapefruit and/or pomelo containing products or their respective juice, and x Quinine- and quinidine-containing drinks such as tonic water 13.4.3 Medical surveillance A physician or a medically trained delegate (as appropriate) will perform the medical examinations, physical examinations, and administration of trial medication at the investigational site. He/she will be available at the investigational site and be responsible for the medical surveillance and the safety of the subjects at that investigational site from the consent procedures and screening examinations until the last trial-related visit for each subject. All medical assessments and medical judgments will be performed by an experienced physician. Any additional safety assessments, including laboratory values, vital signs, ECG, and all other necessary examinations, may be performed at the discretion of the investigator at any time during the course of the trial. In respect of the deviations, safety laboratory measurements including hematology, coagulation, serum chemistry and urine parameters will be assessed at every pre scheduled clinic visit. Results will

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be provided to the investigator within 24 - 48 hours after blood sample was drawn. For allowing an immediate reaction in case of any findings the results have to be reviewed by the responsible physician upon receipt. All values will be uploaded into the EDC system. In addition AiCuris will perform an overall monitoring. Any deviation from the baseline of safety parameters including the hematology, liver, and pancreatic parameters of all randomized subjects by investigational sites will be reviewed by the medically qualified person or a deputy physician of AiCuris on a routine basis. 13.4.4 Counseling of women and men of reproductive age All women and men will be counseled on the need to practice adequate birth control and the importance of avoiding pregnancy once they start taking the trial medication. All females are considered to be of childbearing potential unless they are surgically sterile (e.g. 2-sided tubal ligation, resection or ovariectomy) or are post-menopausal (defined as older than 50 years of age and who have a history of no menses for at least 24 months). Females who are considered surgically sterile or who are post-menopausal are not required to use any contraception. Female subjects of childbearing potential must be sexual abstinent or must use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final trial visit and final examination. An adequate method of contraception is defined as a double-barrier method combining: x the use of the copper-releasing intrauterine device (to have been in place for at least 2 months prior to screening) or the use of one of the following: diaphragm, Lea’s shield, FemCap, sponge, and x monogamous relationship with vasectomized partner or the use of a male condom during each act of sexual intercourse. Male subjects must be either surgically sterile (e.g. after vasectomy), or must agree to use an adequate method of contraception during participation in the trial and for at least 1 complete month after the final trial visit and final examination. An adequate method of contraception is defined as sexual abstinence or the use of a male condom combined with female contraception. If a pregnancy is suspected during trial participation, either for a female trial subject or the female partner of a male trial subject, the Investigator or his/her staff has to be informed immediately. 13.4.5 Precautions and emergencies For any signs or symptoms or adverse events, a causal or symptomatic treatment according to standard medical practice will be performed, if deemed necessary by the Investigator. 13.4.6 General restrictions Topical applications of creams, lotions etc. at the area of swabbing are not allowed (see also inclusion criterion 6). Otherwise the subject will follow his/her usual habits. No restrictions on strenuous or unusual physical activities throughout the trial are given.

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13.4.7 Trial cards Subjects who entered the trial will receive a "subject’s trial card". The trial card provides the following information: x Name of the subject and a statement that he/she is currently participating in a clinical trial x Trial code x Dates of all individual visits (if not covered by the subject’s diary or other documentation provided to the subject by the investigational site staff) x Name of Investigator x Phone number of Investigator / investigational site which is engaged 7 days a week. The card will be collected at the last visit and stored in the Investigator’s site file. 13.4.8 Provisions of any additional care of subjects after trial termination After trial termination, the further subject care will be in the discretion of the subject’s physician. 13.4.9 Informing the subject’s general practitioner If the subject is usually treated by a general practitioner or other equivalent health care provider, this health care provider will be informed of the subject’s participation in the trial at trial entry if the subject agrees. The general practitioner/health care provider should be informed of the title of the trial, date of entry into the trial, and the dates of the outstanding visits as well as the restrictions regarding food and concomitant medications. The communication with the general practitioner will be documented in the subject’s medical record

14 TRIAL VARIABLES

14.1 Demography Demographic data to be collected for this trial include: gender, age, weight, height, and ethnic group. In addition, the following will also be recorded at screening: x Medical history and concomitant diseases, including data of initial HSV-2 acquisition and frequency of recurrences in the year prior to study entry or prior to starting therapy x HSV Type 2 status: written documentation of being seropositive for HSV Type 2 as assessed by University of Washington (UW) Western blot performed after 01st January 1990 x Hepatitis and HIV status: HIV-Ab, HCV-Ab and HBsAg, (blood sampling for serology testing at screening; see Section 14.5). x ȕ-HCG pregnancy test (see Section 14.5).

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14.2 Vital signs Systolic and diastolic blood pressure, pulse rate will be measured after 5 minutes in the supine position at each subject’s visit at the investigational site as specified in Section 13.1 and 13.2 (Flow Chart) using the investigational sites’ standard devices.

14.3 12-lead ECG 12-lead ECGs will be recorded at Screening, Day 1, 8, 29, 57, 64, 85 and Day 112 at the investigational site as specified in Section 13.2 (Flow Chart). Recordings will be performed in the supine position after at least 5 minutes rest. The ECGs will be recorded using investigational sites’ standard devices. The same machine will be used for all subjects and ECGs will be in duplicate using the same machine at the same time-point. The following ECG parameters will be analyzed: PR, QRS, QT, QTc, and heart rate. All ECGs will be evaluated by the investigator regarding clinically significant changes. Electrocardiogram duplicates will be sent to AiCuris GmbH & Co. KG and/or their delegate for potential further central evaluations.

14.4 Physical examination A complete physical examination will be performed at each visit at the investigational site from screening until the final examination. The physical examination will include assessment of the skin, head, eyes, ears, nose and throat, and the following body systems: musculoskeletal, cardiovascular, respiratory, gastrointestinal and neurological. Any other clinically relevant findings will be recorded. Special attention will be given to the visual physical examination of the genital region especially on HSV recurrence visits. Detailed documentation will be performed for HSV lesions (see Appendix 20.3).

14.5 Laboratory monitoring Laboratory monitoring for hematology, serum chemistry, coagulation and urinalysis will be performed at each subject’s visit during the trial as specified in Section 13.1 and 13.2 (Flow Chart). All laboratory tests will be performed by Inc. All ambient samples will be shipped on the day of collection to in an ambient box; frozen samples will be shipped batch wise in a frozen box (for details please refer to the laboratory manual). All required blood sampling tubes, urine dipstick tests, urine pregnancy tests and shipment material will be put on the sites disposal by A table of reference ranges for each laboratory parameter measured and a description of the analysis methods will be provided by the Central Laboratory Service prior to the trial start. Changes in reference ranges and/or in analysis methodology during the course of the trial will be communicated by Inc. to the Clinical Trial Manager at AiCuris GmbH & Co. Laboratory values outside the reference range require a comment by the Investigator regarding their clinical significance throughout the clinical part of the trial. The Investigator will indicate which laboratory values are clinically significant and, if required, record a corresponding AE in the eCRF.

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Hematology At all pre-scheduled subject visits at the investigational site and in case of premature termination, 3.0 mL of blood will be collected in an EDTA tube and the following parameters will be analyzed: Hb, Htc, erythrocytes, MCH, MCV, MCHC, white blood cell count, differential blood count, and platelets using the Beckman Coulter LH750 automated hematology systems. Coagulation At all pre-scheduled subject visits at the investigational site and in case of premature termination, 3.0 mL of blood will be collected in a citrate tube and the following parameter will be analyzed: APTT using Siemend BCS. Serum chemistry At all pre-scheduled subject visits at the investigational site and in case of premature termination, 7.0 mL blood will be collected in a serum separation tube and the following parameters will be analyzed$67$/7Ȗ-GT AP, indirect and direct bilirubin, cholesterol, creatine phosphokinase (CK- MB if needed), LDH, creatinine, urea, albumin, total protein, potassium, sodium, calcium, glucose, amylase, and lipase, using Beckman Coulter AU5400/back-up Beckman Coulter AU2700. Serology At Screening, 5.0 mL blood will be taken and placed in a serum separation tube for the analysis of the following parameters: HIV-Ab, HCV-Ab, and HBsAg by immunoassay. These samples will be analyzed with Siemens Centaur. If an evaluation of HSV Type 2 seropositivity is not available, a separate tube will be used for the analysis of HSV Type 2 by Western blot and will be analyzed at the Laboratory at the University of Washington, Institute for Vaccine and Infectious Diseases, Fred Hutchinson Cancer Research Center, Seattle, USA. Urinalysis At all pre-scheduled subject visits at the investigational site and in case of premature termination, a urine dipstick test will be performed. The following parameters will be determined: pH, ketones, protein, glucose, bilirubin, nitrite, urobilinogen, and blood. Should any abnormalities be identified, an urine sample should be send to to be further analyzed by microscopy. For women of child-bearing potential according to Section 13 urine pregnancy tests will be performed at the investigational site on Day 1, Day 29, Day 57, Day 85 and on Day 112 and in case of premature termination. E-HCG test At Screening blood samples provided by women only will be tested for E-HCG by immunoassay. Pharmacokinetics

Trough levels of AIC316 (C0h) and valacyclovir will be monitored to ensure compliance with drug intake.

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At all pre-scheduled visits and in case of premature termination 4.0 mL blood samples will be taken in a K3-EDTA collection tube prior to trial medication intake. Further details will be included in the Laboratory Manual. At the end of each treatment period (Day 29 and Day 85) an additional 4.0 mL blood sample will be taken in a K3-EDTA tube and a 5.0 mL urine sample will be separated from the urine sample collected for routine dipstick analysis for evaluation of potential AIC316 drug metabolites. Further details will be included in the Laboratory Manual. Pharmacogenetics One sample will be prepared for pharmacogenetics tests (will be reported separately). Preferably on Day 1 500μL of the blood volume collected for the PK sample preparation will be transferred into a separate tube. Further details will be included in the Laboratory Manual. This sample will only be prepared after subject has given written consent. A separate subject information and informed consent form will be available. Denying consent to collect this sample does not exclude the subject from participating in the study.

14.6 Prior and concomitant medication/treatment All medications being taken by the subjects on entry to the trial (Screening Visit) and at any time during the trial in addition to the trial medication are regarded as prior and concomitant medication, respectively, and must be documented in the appropriate parts of the eCRF (trade name and/or generic name together with indication, daily dose, route of administration, and date and time of administration).

14.7 HSV shedding evaluation Swabbing will be performed according to instructions for women and men as outlined in Appendix 20.2. To ensure that the procedure will be performed in a consistent manner by all investigational sites and all subjects: x all investigational sites and all site staff will have to be trained by the same Investigator who is experienced in the disease and the procedure; x all subjects will be trained on swabbing at the investigational site. Swabs by the subject and the investigator will be taken from the anogenital region and from lesions as specified in Section 13.1 and the Flow Chart 13.2. The central evaluation of HSV mucocutaneous shedding by HSV DNA quantification of viral load in the swabs will be performed by quantitative TaqManTM real-time PCR by the University of Washington (UW) at the central laboratory of the Vaccine and Infectious Diseases Institute, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington in accordance with UW's SOPs. Swabbing kits, labels and instructions will be provided by UW. An example of the labels can be found in the Laboratory Manual.

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14.7.1 Assessment of HSV recurrence A visual assessment and examination of an episode of HSV recurrence will be performed by the Investigator if an HSV recurrence occurs following randomization as specified in Section 13.1.8. The Investigator will perform a complete examination of all lesions which includes detailed descriptions on numbers of lesions and morphology including HSV scoring as outlined in Appendix 20.3.

14.8 Molecular signals of drug resistance Since this trial uses the detection of viral DNA in genital swabs by PCR as endpoint, these swabs can directly be used to address potential resistance development genotypically without intervening cell culture steps. Subject to an appropriate amount of DNA positive swabs under treatment with AIC316 will be subjected to sequence analysis of the regions within UL5 and UL52 known to carry resistance- mediating mutations from in vitro data (29). Sequence analysis by BigDyeTerminator cycle sequencing and comparison with reference sequence will be conducted by the University of Washington (UW) at the central laboratory of the Vaccine and Infectious Diseases Institute, Fred Hutchinson Cancer Research Center (FHCRC), Seattle, Washington in accordance with UW's SOPs. Subjects will be asked within the ICF to give consent for isolation of the virus DNA and potential future sequence analyses of their swabs. Extracted viral DNA will be kept accordingly.

14.9 Appropriateness of assessments Measuring the frequency of viral reactivation during daily suppressive therapy has been successful in defining differences in antiviral activity between different doses of AIC316 and between different drugs (30). More recently, the frequency of reactivation of subclinical shedding was shown to demonstrate differences between valacyclovir vs. famciclovir for suppressing reactivation of HSV-2 as demonstrated by total days of HSV reactivation or genital lesion reactivation over a defined course of therapy (31) and differences between doses for AIC316 in trial AIC316-01-II-01. As described in section 8.1 the mechanism of AIC316 is inhibition of viral replication and it is therefore reasonable to utilize markers of viral replication as a surrogate to define the dose and dosage regimen of the drug. The use of PCR technologies to assay the reduction in the titer duration and frequency of HSV-2 reactivation between subjects receiving AIC316 or valacyclovir should provide an objective and reliable endpoint for differentiating the efficacy of different treatments. In addition to the HSV PCR evaluations, the presence and absence of genital lesions will be assessed daily by the trial subjects and by the investigator at visits at the investigational site. This visual assessment includes a detailed evaluation of the morphology of lesions (see Section 13.1.8 and Appendix 20.3). The safety assessments planned for this trial are standard measures commonly used to ensure subject safety.

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15 ADVERSE EVENTS

15.1 Definition of adverse events (AEs) An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of an IMP, whether or not considered related to the IMP. [ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. CPMP/ICH/377/95, EMEA June 1995; Code of Federal Regulations, Title 21, Part 312.32 IND Safety Reporting] During a clinical trial, an AE can also occur at times when trial medication is not taken, e.g. during wash-out periods, follow-up or during a placebo run-in.

15.2 Definition of adverse drug reaction (ADRs) In the pre-approval clinical experience with a new medicinal product or its new usages, particularly as the therapeutic dose(s) may not be established, all noxious and unintended responses to a medicinal product related to any dose should be considered adverse drug reactions (ADRs). The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an AE is at least a reasonable possibility, i.e., the relationship cannot be ruled out [ICH E2A Clinical Safety Data Management: Definitions and Standards for Expedited Reporting. CPMP/ICH/377/95, EMEA June 1995; Code of Federal Regulations, Title 21, Part 312.32 IND Safety Reporting].

15.3 Definition of serious adverse events (SAEs) or serious adverse drug reactions (SARDs) An SAE (serious adverse event or experience) or serious adverse drug reaction (SADR) is any AE or ADR that: 1. Results in death 2. Is life-threatening* 3. Requires subject hospitalization or prolongation of an existing hospitalization 4. Results in persistent or significant disability/incapacity 5. Is a congenital anomaly/birth defect, or 6. Is another medically important event or reaction** *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 was more severe. **NOTE: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-

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threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the other outcomes listed in the definitions above. These should also be considered serious.

15.4 Definition of adverse events of special interest From the previous results of non-clinical and clinical trials no AEs of special interest have been identified.

15.5 Definition of adverse event severity The following categories will be used for the rating of severity: Mild: Causing no limitation of usual activities; the subject may experience slight discomfort Moderate: Causing some limitation of usual activities; the subject may experience annoying discomfort Severe: Causing inability to carry out usual activities; the subject may experience intolerable discomfort or pain

15.6 Definition of adverse event causality The relationship between an AE and the trial medication must be determined only after due consideration by the Investigator for each AE. The assessment of the relationship of an AE with the administration of trial medication is a clinical decision based on all available information at the time of and after the occurrence of an event. The factors which may be considered when evaluating the relationship of an AE with the trial medication include: time from exposure of trial medication until onset of the event; recovery or improvement following discontinuation of trial medication; availability of alternative explanations such as underlying or intercurrent diseases; concomitant medications or treatments; pharmacology of the trial medication; known response pattern for this class of drug; recurrence on reintroduction of the trial medication. The relationship of AEs with the trial medication will be assessed according to the following categories: x "definite": Any clinical event, including laboratory test abnormality, with a reasonable temporal to drug administration. The AE cannot be explained by concomitant diseases or other drugs or chemicals. Response on trial medication withdrawal must be clinically explicable. The AE must be pharmacologically or phenomenologically unambiguous; a satisfactory rechallenge procedure might be used. x "probable": Any clinical event, including laboratory test abnormality in a reasonable time sequence to administration of the drug. The AE is unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on withdrawal, information about rechallenge is not required.

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x "possible": Any clinical event, including laboratory test abnormality in a reasonable time sequence to administration of the drug, but the AE could also be explained by concurrent diseases or other drugs or chemicals; information on drug withdrawal may be lacking or unclear. x "unlikely": Any clinical event, including laboratory test abnormality, with a weak temporal relationship to drug administration. Other factors, such as the underlying concomitant diseases, concomitant medication, are plausible to have contributed to the event. x "not related": No relationship to administration of trial medication, i.e., there is a clear alternative explanation, an unreasonable temporal relationship between the drug and the event, or relationship is otherwise not plausible.

15.7 Definition of adverse event outcome The outcome of adverse events will be described according to the following 6 categories: 1. Resolved 2. Resolving 3. Not Resolved 4. Resolved with sequelae 5. Fatal 6. Unknown

15.8 Definition of expectedness If the nature and severity of an adverse reaction is consistent with the applicable product information (e.g. IB for an unapproved investigational medicinal product), this event is considered as expected. The current versions of the AIC316 IB and the Valtrex® SmPC will serve as the reference documents for the assessment on expectedness in this clinical trial.

15.9 Adverse event recording and reporting 15.9.1 Period of recording The period of recording of an AE or SAE will last from the time the subject signs the informed consent form to the last trial day. All AEs and SAE, regardless of the relationship to trial medication, will be documented. This also includes events that occur in time periods when trial medication is not taken, e.g. between screening and the first dosing, during wash-out, or during the follow-up period until the Final Examination Visit. 15.9.2 Follow-up of subjects with an adverse event AEs and SAEs have to be followed up until they are resolved, have become stable or can be explained by other causes (e.g. concomitant symptom or disease) and clinical judgment indicates that further follow-up is not warranted.

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In addition, all hematologic, pancreatic or hepatic laboratories abnormalities classified according the DAIDS toxicity criteria (see Appendix 20.5) as Grade 2 or higher have to be followed up until resolution. 15.9.3 Adverse event recording Each AE and SAE, either spontaneously revealed by the subject, or observed by the Investigator, and independent from the Investigator’s judgment on relationship to the trial medication, must be recorded on the AE information page of the eCRF and in the subject’s source data,. The following aspects of AE/SAEs will be documented by the investigator in the source data as well as on the eCRF: x If possible, diagnosis or syndrome graded according the DAIDS toxicity criteria (see Appendix 20.5), otherwise each single symptom graded according the DAIDS toxicity criteria (see Appendix 20.5) x Date and time of onset and end of AE/SAE x Seriousness (serious/non-serious) x Intensity (mild/moderate/severe) x Causal relationship with the trial medication (definite/probable/possible/unlikely/not related) x Outcome (resolved/resolving/not resolved/resolved with sequelae/fatal/unknown) x Treatment of event, if applicable (e.g. any concomitant medication as well as any other medical measures) x Actions taken regarding to trial medication intake (withdrawn, dose reduced, dose increased, dose not changed, unknown, not applicable). Increase of intensity of an AE should be recorded as a separate AE with a new onset. If an AE becomes serious, a new AE has to be recorded, documented as serious and additionally an SAE form has to be completed accordingly. 15.9.4 Adverse Event Reporting The investigator must report all AEs that occur during the clinical trial, regardless of their relationship to the trial medication by documentation in the eCRF. Recurrence of HSV episode that occur during the screening period (Day -21 to -1) will be documented as AE. HSV recurrences that occur during the treatment period will not be documented as AEs since they are captured in a separate section of the electronic data capture system in this trial. In case of any skin disorder; patients should be referred to a dermatologist for further diagnosis and qualified treatment. The diagnosis and the description of the skin disorder as well as the treatment, if any, shall be documented in the eCRF. This includes any concurrent viral and/or bacterial infection. 15.9.5 Serious Adverse Event Reporting SAEs will be reported by the Investigator to Pharmacovigilance within 24 hours after becoming aware of their occurrence. To report an SAE, the Adverse Events form in the electronic data capture (EDC) system for the study has to be completed. If an adverse event is marked as “serious”, entry of additional information

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regarding the SAE will be required. It has to be ensured that all other relevant information has been recorded on the appropriate forms (eg, medical history, concomitant medications, trial medication). The Investigator will generate an SAE report within the EDC system. This report will be signed and faxed to Pharmacovigilance. If the event meets serious criteria and it is not possible to access the Internet, contact Pharmacovigilance by phone or email, and fax the completed back-up paper SAE form to the number listed below within 24 hours of awareness. When the EDC system becomes available, the SAE information must be entered within 24 hours of system availability. Pharmacovigilance Fax: The contact details for Pharmacovigilance are: Pharmacovigilance

Phone: + Email: The following information will be available in the SAE report:: x Trial protocol number x Subject identification number x Subject demographics x Trial treatment: o kit number o start and end date, dose – if known x AE description x Date of onset x Intensity x Actions taken in regard to treat the event (concomitant medication or treatment, including hospitalization) x Action taken with respect to trial medication x Causal relationship to trial medication(s) in the opinion of the investigator x Unblinding performed by the investigator (if applicable) x Previous and concomitant diseases x Previous and concomitant medication x Outcome (if available) x Recovery date (if available) x In case of death, the cause and post-mortem findings

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In case of death, the investigator must provide Pharmacovigilance with all relevant follow-up information (anonymized, e.g. autopsy findings, clear photocopies of hospital records, consultant report(s)) by fax within 24 hours after becoming aware of this event. 15.9.6 Procedures in case of pregnancy All pregnancies that occur during the trial in female trial subjects as well as female partners of male trial subjects should be followed up. If such a pregnancy occurs, a Drug Exposure via Parent form has to be completed and sent to Pharmacovigilance within 24 hours after becoming aware of it. 15.9.7 Suspected unexpected serious adverse reactions reporting (SUSARs) Any AE that is serious, unexpected and associated with the use of the trial medication (a suspected unexpected serious adverse reaction [SUSAR]) will be notified to the investigators/investigational sites by Pharmacovigilance in a timely fashion. Follow-up information may be submitted if necessary. This information has to be filed in the Investigator site file and is regarded as an update to the IB. In case of occurrence of any new event or other safety issue relating to the conduct of the trial or the development of the trial medication indicating that the new event is likely to affect the safety of the clinical trial subjects, AiCuris GmbH & Co. KG and the Investigator must take appropriate urgent safety measures to protect the subjects against any immediate hazard. AiCuris GmbH & Co. KG/ Pharmacovigilance informs the concerned CAs and IRBs/ECs of those new events and the measures taken. 15.9.8 Other safety issues altering the benefit-risk assessment of the trial medication Other safety issues that might alter the current benefit-risk assessment of the trial medication or which would be sufficient to consider changes in the trial medication administration or in the overall conduct of the trial must be reported to the CA and the EC/IRB as soon as possible but no later than 15 calendar days after AiCuris GmbH & Co. KG/ Pharmacovigilance has first knowledge of them. Further relevant follow-up information should be given as soon as possible. Such safety issues may be: x An increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be clinically important, x Post-trial SUSARs that occur after a subject has completed a clinical trial and are reported by the investigator to AiCuris GmbH & Co. KG, x Events related to the conduct of the trial or the development of the IMP that are likely to affect the safety of the subjects. The investigators will be informed accordingly. 15.9.9 Development Safety Update Report (DSUR) AiCuris GmbH & Co. KG will provide annually DSURs throughout the clinical development of an investigational drug to the regulatory authorities and ECs/IRBs responsible for the trial(s), if applicable. These updates will include information on serious adverse reaction (including SUSAR) which occurred in the clinical trial(s) and other relevant safety findings.

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16 DOCUMENTATION AND ARCHIVING OF THE TRIAL DATA

16.1 Electronic Case Report Form (eCRF) A web based electronic data capture (EDC) system will be used to record all trial subject specific information required by the protocol. The system which will be used for the trial is using fully validated software that conforms to the US Electronic Records/Electronic Signature Rule 21 CFR Part 11 requirements. ClinTrack® System will be utilized for this trial’s eCRF. Inc. will supply the necessary system documentation and technical training to the investigator, trial site staff and sponsor, and will support the use of the eCRF through the establishment of a help-desk system throughout the trial. Subject data will be entered into the eCRF by the Investigator and/or authorized investigational trial site staff. The main objective is to obtain the data required by the trial protocol in a complete, accurate, and timely fashion. The Investigator is responsible for the correctness of the documented data. Consistency of the data entered in the eCRF with the relevant source documents will be confirmed by source data verification by Inc. Access to the eCRF is limited to the responsible persons involved in this trial and all users are provided with trial-specific user name and password and will not be given access to the eCRF until they have been trained. The Investigator will maintain a list of designated investigational site staff individuals who are authorized to enter or correct data. Only these persons are allowed to enter the system and their identity during use will be registered. Entries in the eCRF will be tracked electronically within the EDC system, recording the date, time, initial entry, new entry and person who made the entry and/or modification, respectively. Automatic validation programs will check for data discrepancies and, by generating appropriate error messages (queries), will allow the data to be confirmed or corrected by the Investigator or designee. Queries will be sent to the investigational site using an electronic data query process, and it is required to respond to these queries either by confirmation or correction of the data. The Investigator/designee must state his/her reasons for the correction of data. All electronic errors, confirmations and corrections will be captured by the audit trail. After completion of all entries, the Investigator must certify that the data entered into the eCRF are complete and accurate. The system will be secured to prevent unauthorized access to the data or system. All electronic data entered by the investigational site (including the electronic audit trail) as well as computer hardware and software (for accessing the data) will be maintained or made available at the site in compliance with applicable record retention regulations. The computerized system is able to generate accurate and complete copies of records in both human readable and electronic form for inspection, review and copying by regulatory authorities, the IEC/IRB, and/or the Sponsor representative. Site documentation will identify the software and hardware systems used to create, modify, maintain, archive, retrieve or transmit data. Data on subjects collected on eCRFs in the course of this trial will be documented in an anonymous fashion, i.e., the subject will be identified only by a subject identification number.

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16.2 Subject’s diary Subjects will be asked to maintain a daily diary to complete with the following information for each treatment period: x The date and time of trial medication intake. x If the trial medication has not been taken the reason why. x The date and time of swabs being taken (Morning swab, Noon swab, Afternoon swab, Evening swab), and if additional swabs have been taken from genital HSV lesion x Date and time of first notice of pain x Pain intensity (mild, moderate, severe) x Question on menstruation (for females only) x Date and time of first notice of lesion(s) with exact description of lesion(s) morphology x Any change of morphology during an episode x Date and time of stop of lesional pain and complete healing of lesion(s) Entries in the diary will be reviewed by investigational site staff and inconsistencies or discrepancies clarified with the subject. Diaries will cover one treatment week, each.

16.3 Source data 16.3.1 Source data at the investigational trial site Source data is all information in original records and certified copies of original records of clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Source data are contained in source documents which comprise clinical documentation, data and records (e.g. hospital records, clinical and office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing records, recorded data from automated instruments and data and records arising from other departments such as the pharmacy, laboratory and medico-technical departments). Clinical documentation relevant to the trial includes all records in any form (including, but not limited to, written, electronic, magnetic and optical records, and scans, X-rays and ECGs) that describe or record the methods, conduct and/or results of the trial, the factors affecting the trial and the actions taken. All clinical documentation and data arising from the trial are to be kept by the Investigator. There should be documentation in the subject’s clinical file of any recordings or data specifically obtained for the trial (e.g. date of investigations, scans or X-rays). The Investigator will permit monitors/clinical research associates (CRAs) of Inc. to inspect all relevant portions of the subjects’ source data at regular intervals throughout the trial to verifying adherence to the protocol and the completeness and accuracy of the data being entered in the eCRF (see also Section 18.3). Certain specific data will be allowed to be entered directly in the eCRF: e.g. blood sampling time- points. These data may not be recorded in other documents. In these cases the eCRF is considered to be the source document. For each investigational site a document signed by the responsible

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Investigator will be prepared listing all trial relevant data and their respective source documents, e.g. investigational site’s subject files, eCRF. For monitoring and auditing purposes, and to the greatest extent possible, all information recorded on eCRFs must be traceable back to the source documents, which are generally maintained in the subject’s file. The subject’s file should also indicate that the subject is participating in the clinical trial referring the trial number and the trial medication. Subjects’ diaries will also be monitored by the CRAs, but CRAs will not query any data in the diary other than header information and possibly date information since the diary is a self-reporting tool. 16.3.2 Subject’s reported outcome - Diary Subjects will use the diary to report the trial medication intake, presence or absence of lesion(s), date and time of swabs taken, etc. Diary data will be entered into the clinical database. The diaries will be maintained as source documents at the investigational site.

16.4 Data management Data Management will be handled by Inc. A data management plan (DMP) will be prepared outlining the processes that will be undertaken to clean and code the data, and to integrate external data sources into the backend datasets. Updates to the DMP will be made throughout the trial, as applicable. Trial data not recorded in the eCRF (e.g. safety laboratory data) will be transferred electronically using a secure method of Inc. at predefined intervals during the trial in a data structure suitable for integration into the clinical trial database. At the end of the trial all clinical data will be provided to AiCuris GmbH & Co. KG with a complete and clean data transfer, accompanied by a Quality Control statement, confirming that quality control has been performed on the final data. In addition to the automatic queries, the responsible data management associate reviews the data entered into the EDC system. Queries will be issued to the site staff to clarify missing data, inconsistencies, illegible data, incorrect values and items that are not clearly corrected. Resolutions of queries will be made by the investigational site staff directly in the EDC system. Subject diary data will be entered by double data entry with third party verification processes by Inc. data entry personnel. When all data are entered into the eCRF, all queries have been resolved, data checks and quality control checks have been performed, and a blind data review meeting has been held, the trial database is considered clean and will be locked. 16.4.1 Coding Medication names will be coded using the appropriate current version of the WHO Drug dictionary. Medical history and adverse events will be coded using the appropriate current version of the Medical Dictionary for Regulatory Activities (MedDRA). The version most currently implemented at Inc. will be used. Coding will be checked by the medically experienced coding specialists at Inc. before being sent to AiCuris for final approval.

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16.5 Data archiving The trial master file, the eCRFs, and other material supplied for the performance of the trial will be retained by AiCuris GmbH & Co. KG according to applicable regulations and laws after the trial has been finalized and the material has been transferred.

17 STATISTICAL METHODS

The statistical planning of the trial has been performed by Dr. Wald’s group at the University of Washington and the analysis will be done by Inc. A detailed statistical analysis plan (SAP) will be drafted at the beginning of the trial and finalized the latest prior to database lock.

17.1 Determination of sample size Approximately 90 subjects will be randomized in this trial. To ensure this, and based on experience in a previous trial (30% screening failures), about 120 subjects need to be screened. Justification for sample size The average shedding rate during treatment with AIC316 100 mg is anticipated to be 1-2%, and during treatment with valacyclovir 500 mg will be approximately 5%. Using a cross-over design with 80% power and permitting a 5% type I error rate, a total of 82 subjects completing the trial is needed to detect superiority of AIC316 100 mg over valacyclovir 500 mg (see Table 1). To account for potential drop-outs (in trial AIC 316-01-II-01 the rate of discontinuation was 6%), the number of subjects to be randomized is 90.

Table 1: Sample size calculation

Swabbing No. subjects No. subjects assuming frequency / assuming a a shedding rate per day shedding rate on AIC316 100 mg of on AIC316 100 mg 2% of 1%

1 51 100 2 47 91 4 43 82

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17.2 Randomization In this trial randomization will be centralized at the IVRS/IWRS and will follow a dynamic algorithm. Subjects will be randomly assigned to kit numbers balanced for treatment arms by investigational site and gender. Randomization is stratified by gender to ensure that both genders are represented in each investigational site and to ensure that at least 1/3 of each gender will be included in each treatment arm. Assignment to treatment arms will be balanced (1:1) within these strata. Dynamic randomization via IVRS will be used for this study. Separate sequences of kit numbers, one for each gender stratum, will be created. Treatment assignments for each kit number will be communicated to Clinical Services in a highly secure, confidential manner in accordance with the corresponding Inc. specifications. Clinical Services will then prepare treatment kits in strict accordance to the schedule. After a subject has been identified for the trial and signed the informed consent a consecutive subject number will be allocated to the subject (see Section 13.1.2). This subject number is unique for the subject’s identification and will be used throughout the trial. The subject number and details will be promptly transferred to the eCRF and the investigator will complete the screening data in the eCRF. It is required to enter key data in the eCRF before randomization. After a subject’s eligibility has been confirmed, the investigator will use the IVR/IWR system to randomize the subject. The IVR/IWR system will allocate the subject’s treatment and provide the site with the kit number. Only after all data are cleaned and the database is locked, the trial biostatistician will be given access to the randomization code.

17.3 Analysis of the trial Due to the cross-over design of this trial, the following definitions apply: x “Baseline” is defined as the last time point prior to first dosing, i.e. Day 1 (for Treatment Period 1) and Day 57 (for Treatment Period 2). If Day 1 values are missing then screening data will be defined as the last non-missing assessment before Day1; if Day 57 data are missing, Day 29 data will be defined as the last non-missing assessment before Day 57. x For substance specific analyses, the corresponding treatment periods of both dosing arms will be pooled, i.e. for AIC316 dosing arm 1 Treatment Period 1 and dosing arm 2 Treatment Period 2, and for valacyclovir dosing arm 1 Treatment Period 2 and dosing arm 2 Treatment Period 1. x “Treatment group” is defined as pooled data for AIC316 and valacyclovir respectively. All variables documented in the eCRF will be statistically described according to the data type as defined in the SAP. Continuous variables will be summarized using the number of non-missing observations, the mean, the standard deviation, the median, the first and third quartiles (Q1-Q3), the minimum value, and the maximum value. Categorical variables will be summarized using frequency counts and percentages.

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Missing values will be presented as a separate category. Tables with descriptive statistics will be given by treatment group and time point (where applicable). All data will be listed in data listings. All statistical tests will be given with 2-sided p-values. For descriptive purposes, two-sided 95% confidence intervals will be given. Significance levels and adjustment of test level for control of Type I error rate: To avoid inflation of the Type I error rate for the primary efficacy analysis, comparisons between treatment with AIC316 and valacyclovir will be evaluated at alpha=0.05, two-tailed. In addition to the 95% confidence intervals, 98.75% intervals will be calculated to be consistent to significance testing. The statistical report will provide caveats regarding interpretation of these results in the context of multiple analyses. All statistical output will be produced in SAS® version 8.2 (or a more recent version) or, for PK data, in WinNonLin version 5.2 (or a more recent version). Further details on the statistical analysis methodology will be provided in the SAP. If the final blinded data review suggests changes to the statistical analysis stated in the protocol, these will be documented and explained in the SAP. Only results from analyses described in the protocol (including amendments) can be regarded as inferential. Additional analyses, or analyses not performed strictly according to the protocol and forming part of the final report will be described in full in the SAP and in the final report. Analyses initiated/requested by AiCuris GmbH & Co. KG. for publications or for the purposes of a drug license application (e.g. safety summaries, clarification of subgroup responses) will be separately documented in the project files at AiCuris GmbH & Co. KG. 17.3.1 Subject populations 17.3.1.1 Full analysis set (FAS, intention-to-treat population) The Full analysis set (FAS, intention-to-treat population) is the primary analysis population and will consist of all randomized subjects who took trial medication at least once and provided at least one analyzable genital-perianal swab (not including the training swab). This is the primary population for demographics/baseline characteristics description and efficacy analysis (both primary and secondary endpoints). 17.3.1.2 Per-protocol set (PPS) The Per-protocol set (PPS) is the secondary supportive analysis population and will consist of a subset of the FAS with exclusion of major protocol violators, as determined at the blind-data review meeting and documented in the SAP. The PPS is used for sensitivity tests of the primary and secondary efficacy endpoints. Subjects will be excluded from the PPS if: x the trial medication was discontinued early x compliance with trial medication was less than 80% Further major protocol violations will be defined in the SAP.

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17.3.1.3 Safety set The Safety set will consist of all randomized subjects who took trial medication at least once. The Safety set will be used for the safety analyses. 17.3.2 Analysis of demographic data Demographic data, including anthropometrics and body mass index, will be summarized by treatment group and overall for each analysis population. For continuous variables such as age, weight, height, and BMI, descriptive statistics will be provided. For the categorical variables such as ethnic group, gender, medical history and concomitant diseases, HSV immune status and hepatitis and HIV status, absolute and relative frequencies will be tabulated. Previous and concomitant medications will also be tabulated. To evaluate investigational site differences, the demographic table will be repeated by investigational site within the FAS population. 17.3.3 Efficacy Analysis 17.3.3.1 Primary efficacy analysis Descriptive statistics will be given by treatment group separately for the treatment period only, FAS. All performed tests will be given with 2-sided p-values. For descriptive purposes, two-sided 95% confidence intervals will be given. The statistical report will provide caveats regarding interpretation of these results in the context of multiple analyses. The difference in shedding rate will be analyzed within subjects, AIC316 100 mg vs. valacyclovir 500 mg using non-linear mixed effects models with a log link, similar to Poisson regression but with a random intercept for each subject, and including robust error estimation to account for extra-Poisson variability. Mixed effects models appropriately handle the association between repeated measures on the same subject over time. Sensitivity analyses will test treatment x investigational site and treatment x gender interactions and will repeat the primary efficacy analysis for the Per-protocol set (PPS). A sensitivity analysis will repeat the primary analysis using subjects with a very high medication compliance (e.g. >=95%). Other sensitivity analyses (e.g. using only subjects with a minimum total number of analyzable swabs, e.g. 50%) will be specified in the SAP. 17.3.3.2 Secondary efficacy analyses Secondary efficacy analyses will be conducted in the FAS. The secondary efficacy endpoints will be inferentially described for the 2 treatment periods only. The methods are as follows: x The mean log number of HSV DNA copies at times when HSV is detected will be compared between both treatment groups using generalized estimation equations (GEE) accounting for the correlation between repeated measures per subject and including terms for treatment, gender and investigational site. This analysis will be repeated including only days when lesions are present. x Rates such as shedding rate, shedding episode rate, lesion rate and recurrence rate will be compared between both treatment groups using Poisson regression, if sufficient numbers of events. Similarly to the primary objective, subject-level intercepts and account for extra- Poisson variability will be incorporated. For rarer events like recurrences, numbers may not be

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sufficient to employ parametric methods; and therefore the non-parametric Wilcoxon signed- rank test may be employed. x Duration outcomes (shedding episode duration, pain duration) will be rare and non-centrally distributed (most short and a few long). Therefore the comparison between groups will be performed using the Wilcoxon signed rank test, a paired non-parametric test. Or if few episodes occur in the same subjects on both treatments, the Wilcoxon rank sum test for independent samples. Sensitivity analyses will test treatment x investigational site and treatment x gender interactions and will repeat the secondary efficacy analysis for the Per-protocol set (PPS). A sensitivity analysis will repeat the secondary analysis using subjects with a very high medication compliance (e.g. >=95%). Other sensitivity analyses (e.g. using only subjects with a minimum total number of analyzable swabs, e.g. 50%) will be specified in the SAP Exact or non-parametric methods may be substituted for some of the methods described above if the number of events is lower than anticipated. These decisions will be made and documented in the SAP prior to unblinding. 17.3.3.3 Additional sensitivity analyses All analyses for FAS and PPS will be repeated excluding data from the first week of each treatment period. 17.3.4 Safety analysis All safety and tolerability parameters (AEs, vital signs, 12-lead ECG, safety laboratory tests) will be listed by subject and treatment group. All analyses will be performed in the Safety set. Stratified analyses, if any, will be described in the SAP. Rates of AEs will be compared by dosing arm and treatment group. However, since very low rates are anticipated based on earlier studies, no formal statistical testing is planned. Denominators for percentages will not include subjects who do not have evaluable data for the parameter of interest (for example, did not have a serum chemistry blood draw). For any statistical tests, p-values will be reported on a per-test basis and will not be adjusted for multiple analyses. No inferential statistical analyses will be performed. Safety data will be statistically described by treatment group. Also, for the differences from baseline, descriptive statistics will be provided. All further details on the safety analysis as well as details on the analysis in respect of certain variables will be given in the SAP. 17.3.4.1 Adverse events The number and percentage of subjects with treatment-emergent AEs will be determined within both treatment groups. Treatment-emergent AEs are defined as AEs that start or worsen after onset of trial medication and/or those occurring within 28 days after the last dose of trial medication, respectively. Absolute and relative frequencies for subjects with a given AE will be listed with respect to the preferred term according to MedDRA. Furthermore, absolute and relative frequencies of the individual AEs will be determined and listed by system organ class according to MedDRA.

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Similarly, the frequencies of the degrees of intensity, causal relationship with the trial medication, and of the countermeasures taken for each AE will be tabulated for both treatment groups. The time of onset of AEs after the last dosing and their duration will be evaluated on a categorical basis. These categories will be agreed upon prior to database lock and breaking the blind. In case of multiple consecutive episodes of one AE, these episodes will be analyzed as one AE with the highest intensity, the worst relationship, the last outcome and all documented countermeasures. The time of onset will be the start time of the first episode of the AE and the duration will be the sum of the durations of all documentations, using an imputed end date if needed. Additional tables with respect to all categories of AEs will also include the numbers of subjects who experienced the respective AE. Separate listings will be provided for all subjects with SAEs and for all subjects who withdrew from the trial due to AEs. Adverse events with an onset prior to the start of trial medication will also be listed. 17.3.4.2 Vital signs Baseline values and change from baseline in systolic and diastolic blood pressure, pulse rate and will be summarized by each treatment group and overall. Summary statistics will be calculated for all vital signs, by visit, and changes from baseline will be presented separately by time windows. In addition, selected vital signs will be evaluated using extended normal ranges and on the basis of predefined changes abnormal (PCA) at different time windows on treatment. Details on the PCA will be given in the SAP. The number of subjects with at least one PCA will be summarized and presented by treatment group and compared between the two different treatment groups using Fisher’s exact tests. 17.3.4.3 12-lead ECG Summary statistics will be calculated for all quantitative data. Baseline values and changes from baseline for PR, PQ, QRS, QT, QTc and heart rate will be summarized by treatment and visit. Summary statistics will be calculated for QTc corrected with Bazett formulae and with Fridericia formulae for changes from baseline for treatment period 1 and from Day 57 for treatment period 2 and will be presented by time windows. The formula for the corrected QT value is: QTc=QT/RRa Bazett correction: a=0.5 / Fridericia correction: a=0.33 In addition, QTc will be evaluated using predefined changes (PC). Details on the PC will be given in the SAP. The proportion of subjects with at least one PC will be compared between the treatment groups using Fisher’s exact tests. Subjects with at least one clinically noteworthy abnormal ECG QTc finding will be listed by treatment group. If conduction system disorders of the heart (such as Torsades de pointes, ventricular tachycardia, ventricular fibrillation and flutter), sudden death, syncope and seizures are reported as AEs, a correlation between these events and QT values will be summarized by treatment group.

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17.3.4.4 Laboratory parameters All values of laboratory parameters will be listed by treatment and visit. Values of laboratory parameters outside the reference range will be flagged in the listings as H (high: above the reference range), or L (low: below the reference range), respectively. In addition, all values that satisfy PC and PCA as well as all abnormal laboratory values that are judged clinically significant will also be flagged in these listings. Descriptive statistics will be provided within each treatment group for the absolute values of all blood laboratory parameters before and after administration of trial medication (Day 1 & 29 and Day 57 & 85, respectively) and for the respective differences from pre-treatment, baseline (Day1) and Day 57, respectively. Blood laboratory values documented at screening and at the Final Examination Visit will be analyzed for all subjects in the same way. For the urinalysis parameters, absolute and relative frequencies will be tabulated at screening and at final examination for all subjects, and, before and after trial medication (Day 1 & 29 and Day 57 & 85, respectively) within each treatment group. Shift tables will be provided for changes with respect to reference range for the following groups of laboratory parameters: hematology, coagulation, serum chemistry and urinalysis. These shifts will be tabulated within each treatment group for the comparison between before and after administration of trial medication and additionally for all subjects for the comparison between screening and final examination. For selected parameters, clinically significant values are predefined and their occurrence will be compared between both treatment groups. The results of pregnancy tests will be listed. 17.3.5 Interim analysis No interim analysis is planned. 17.3.6 Further analysis 17.3.6.1 Pharmacokinetic analysis AIC316 and valacyclovir trough levels over time will be graphed by treatment group. Details regarding data analyses will be provided in the SAP. The results of the evaluation of potential AIC316 drug metabolites will be reported separately. 17.3.6.2 Molecular signals of drug resistance Descriptive statistics will summarize molecular signals of drug resistance monitoring by sequence analysis of every positive swab under AIC316 treatment with a sufficient amount of DNA 17.3.6.3 Compliance Descriptive statistics will summarize, by treatment group, the percentage of days in the treatment periods in which (a) all trial medication was taken and (b) partial trial medication was taken (e.g. some but not all complement of pills) based on pill count. This analysis will be conducted in the FAS population.

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17.3.6.4 Flow chart (population tree) An accounting of all enrolled subjects showing number screened, number and percentage of screened subjects who met inclusion and exclusion criteria and were randomized, and the number and percentage of randomized subjects being included in each of the trial populations, by treatment group where relevant, will be provided. 17.3.6.5 Final status Descriptive statistics will summarize, by treatment group and dosing arm, the percentage of subjects who completed the trial, were lost to follow up, or discontinued early (by reason for early discontinuation). The proportion of subjects completing the trial, stratifying by investigational site and gender, will be statistically compared across both treatment groups and dosing arms using an extended Cochran-Mantel-Haenszel test. This analysis will be conducted in the FAS population.

18 GENERAL CONDITIONS AND AGREEMENTS

18.1 Insurance Insurance for the subjects included in this trial will be arranged by AiCuris GmbH & Co. KG, as sponsor of the clinical trial according to country-specific requirements. If the maintenance of insurance is statutory and/or AiCuris GmbH & Co. KG provides such insurance the following shall apply: A copy of the insurance certification will be held in the investigator site file at the investigational sites and in the trial master file at AiCuris GmbH & Co. KG and Inc.. Subjects are to be informed by the Investigator of the existence of the insurance, and that they have the right to inspect the terms and conditions of said insurance. In any case the subject must be informed that they are required to immediately report any illness or other untoward event during the trial to the investigator and that they should only undergo treatment from another physician after consultation with the investigator. x During the trial, the subject is only allowed to undergo other therapeutic treatment and investigations after consultation with the investigator. This does not apply in the case of a medical emergency; the investigator is to be informed promptly about any emergency treatment. x Any 'injury' to the health of the subject that might be due to the clinical trial must be reported by the responsible person who is mentioned in the insurance’s conditions to the insurer promptly. x The subject must be willing to undergo any test or investigation that is deemed necessary to explain the cause of the 'injury', or to limit the extent of the 'injury'. x In the event of an 'injury', the subject will allow the investigator or physician appointed by the insurer to prepare a report about the 'injury'; furthermore, it is to be ensured that all other reports from the treating physician will be made available upon request. x In the event of a reported 'injury', the subject will allow the insurer to make further enquiries of the investigator or other physicians consulted, health insurance agencies, or other insurance companies.

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If the 'injury' results in death, the insurer must be informed by the responsible person who is mentioned in the insurance’s conditions immediately by telegram or fax, even when a report has already been made. The insurer reserves the right to have a post-mortem examination of the body by a physician of its choice. The insurance regulations will be provided to the subjects, if applicable according national regulations.

18.2 Interaction with regulatory authorities This trial will be carried out in compliance with legal regulations. Before initiating the trial AiCuris GmbH & Co. KG, Inc. and/or the Investigator, will submit any required application(s) to the appropriate authority(ies) for review, acceptance, and/or permission to begin the trial as required by the applicable regulatory requirement(s). A copy of the submission will be held in the trial master file at Inc. and AiCuris GmbH & Co. KG. Note: The Investigator should be informed when new information about the IMP and adverse events due to the administration of the IMP becomes available.

18.3 Monitoring Monitoring is the process of overseeing the progress of a clinical trial, and of ensuring that the rights and well-being of subjects are protected, that the trial is conducted, recorded, and reported in accordance with the protocol, SOPs, ICH-GCP and applicable regulatory requirements, and that the trial data are accurate, complete and verifiable from source data. Before the trial starts at an investigational site, the Clinical Research Associate (CRA) will ensure that the investigational site has sufficient capacity and equipment for performing the trial. Monitoring of the investigational site will be performed by Inc. CRA on a regular basis depending on the progress of the trial. The Investigator(s) will permit the CRA to check and verify the data entered into the eCRF against the on-site subject records (source data verification) and site’s trial documentation (e.g. ISF) and other information prepared for the trial. Corrections, amendments or clarifying statements will be made by the Investigator where necessary. A report will be written by the Clinical Research Associate after each visit. In addition, an ongoing review of timely data entry in the eCRFs will be performed by the CRAs. Monitoring of the trial will be conducted in accordance to Inc.SOPs. Additional information regarding monitoring activities will be contained in the Monitoring Plan of the trial.

18.4 Quality system, audit and inspection 18.4.1 Quality system Inc. is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs. Inc. is responsible for ensuring that all parties involved with the trial agree to direct access to all trial related investigational sites, source data and documents, and reports for the purposes of monitoring and auditing by AiCuris GmbH & Co. KG and inspection by domestic and foreign regulatory authorities.

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The documentation of the trial should be adequate for reconstruction of the course of events (audit trail). 18.4.2 Audit An audit is a systematic and independent examination of trial related activities and documents to determine whether these activities were conducted, and the data recorded, analyzed and reported according to the protocol, Inc. SOPs, SOPs of third parties or if applicable AiCuris GmbH & Co. KG SOPs, ICH-GCP and applicable regulatory requirements. On behalf of AiCuris GmbH & Co. KG, a qualified appointed person will perform on-site audits at the investigational sites. The Investigator will permit to audit the facilities and documentation at agreed dates. Auditors are independent of the clinical trial and its performance. 18.4.3 Inspection Inspection is the act by regulatory authorities of conducting an official review of the documents, facilities, records and other resources that are deemed by the authorities to be related to the clinical trial and that may be located at the investigational sites, at AiCuris GmbH & Co. KG, at Inc., or at other facilities deemed appropriate by the regulatory authorities. The Investigator is obliged to cooperate with any inspection.

18.5 Investigator’s site file (ISF) The Investigator will keep files of essential documents as defined by the ICH-GCP guidelines and local requirements. Inc. will provide a suitable structure for the Investigator’s site file. The Investigator’s site file must be updated on a regular basis and available at monitoring visits and during an audit or inspection. AiCuris GmbH & Co. KG will inform the Investigator in writing of the need for record retention, and will notify the Investigator when the trial related records are no longer required.

18.6 Amendment of protocol Changes of the protocol during the trial will be documented as amendments. The amended protocol will be signed by the relevant personnel at AiCuris GmbH & Co. KG and Inc., and by the Investigator(s). Depending on the content of the amendment and local legal requirements, the amendment will be submitted to the relevant IRBs/ECs and, where necessary, to the relevant competent authorities, for notification and/or approval. The Investigator should not implement any deviation from or changes of the protocol without agreement by AiCuris GmbH & Co. KG and Inc., nor prior to review and documented approval/favourable opinion of the appropriate IRB and, if legally required, competent authorities. The only exceptions are: the need to eliminate an immediate hazard to the subjects, or change(s) involving only logistical or administrative aspects of the trial. If an amendment substantially alters the trial design, increases the potential risk to the subjects or affects the treatment of the subject, then the subject information sheet and informed consent form

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must be revised and submitted to the relevant IRB/EC and, where necessary, to the relevant competent authorities, for review and approval. A subject currently undergoing trial procedures who is affected by the amendment must be asked to re-consent using the new informed consent form. The new informed consent form must be used to obtain consent from new subjects before enrolment.

18.7 Subject data and data protection Permission for direct access to subject’s data will be sought in writing by the Investigator and from the subject as part of the informed consent procedure. This gives permission to examine, analyze, verify and reproduce any records and reports that are important to the evaluation of the trial. Any party (e.g., domestic and foreign regulatory authorities, CRAs and auditors) with direct access to the source data must take all reasonable precautions within the constraints of the applicable regulatory requirement(s) to maintain the confidentiality of the subject’s identities and Sponsor’s proprietary information. It is the CRA’s responsibility to verify that each subject has consented, in writing, to direct access. It is to be ensured by the Investigator that documents provided to Inc. or AiCuris GmbH & Co. KG or its representatives do not contain the name or address of the subjects, nor other information that affect the anonymity of the subjects.

18.8 Publication policy Investigator shall have the right to publicly present or publish the results of the trial ("Public Disclosure"), provided that such Public Disclosure shall not contain Sponsor's Confidential Information without the written consent of the Sponsor. Investigator shall provide a draft manuscript of any Public Disclosure to Sponsor not less than sixty days before a presentation or submission for publication to enable Sponsor to review and comment. Upon notification by Sponsor that the draft manuscript contains Sponsor's Confidential Information, Investigator shall remove it from the manuscript prior to such Public Disclosure. If Sponsor does not respond to Investigator within such sixty-day period, then Investigator shall be free to make a Public Disclosure exactly as presented to Sponsor, provided, he has obtained a written permission for the publication in question from Sponsor. Notwithstanding the foregoing, Investigator acknowledges that its efforts in the trial are part of a multi- center trial, and that no Public Disclosure shall be made by Investigator until after Sponsor first releases the results of the multi-center trial to the general public. However, if no disclosure of the multi-center trial has been made by Sponsor within eighteen months after the completion of the trial at all centers, then Investigator will be free to make a Public Disclosure of their own results, subject to Sponsor's right to review and comment in accordance with this section.

18.9 Contracts Any remuneration for performing this clinical trial at the investigational sites and for acting as a clinical investigator in this clinical trial is exclusively part of (a) separate contract(s) between the relevant parties, i.e., between the Investigator/other parties at the investigational site/hospital/institution and AiCuris GmbH & Co. KG.

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In addition, responsibility for insurance or indemnity to cover any liability of the Investigator which may arise directly or indirectly from the Investigator’s participation in the trial will be specified in a contract between the Investigator and AiCuris GmbH & Co. KG.

18.10 Final report A final report integrating clinical, pharmacokinetic and statistical results will be prepared. At the end of the trial, AiCuris GmbH & Co. KG will provide the competent authority and IRBs/ECs with a summary of the clinical trial report within 1 year after trial completion, where required.

18.11 Confidentiality of trial results The results of this trial are confidential and are not to be transmitted to a third party in any form or fashion. All persons involved in the trial are bound by this confidentiality clause.

18.12 Organization 18.12.1 Coordinating Investigator As Coordinating Investigator, Anna Wald MD will be nominated to assist with the organization and development of the trial. The Coordinating Investigator reviewed this protocol to provide input into the trial design and to review and sign the final report on behalf of all the participating investigators. 18.12.2 Committees No committees are nominated. 18.12.3 Data flow to committees Not applicable due to the reason that no committees are nominated. 18.12.4 Investigational site personnel Inc. will provide the investigational sites with Staff Responsibility Logs which will be completed for each staff member working on this trial. The log will clearly delineate the responsibilities of each staff member that has been delegated to them by the Principal Investigator.

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19 REFERENCES

1. Smith J, Robinson NJ. Age-specific prevalence of infection with Herpes simplex virus type 2 and 1: a global review. J Infect Dis 2002;186:S3–S28. 2. Mertz KJ, Trees D, Levine WC, et al. Etiology of genital ulcers and prevalence of human immunodeficiency virus coinfection in 10 US cities. The Genital Ulcer Disease Surveillance Group. J Infect Dis 1998;178:1795–1798. 3. Ahmed HJ, Mbwana J, Gunnarson E, et al. Etiology of genital ulcer disease and association with human immunodeficiency virus infection in two Tanzanian cities. Sex Transm Dis 2003;30:114–119. 4. Chen CY, Ballard RC, Beck-Sague CM, et al. Human immunodeficiency virus infection and genital ulcer disease in South Africa: the herpetic connection. Sex Transm Dis 2000; 27:21–9. 5. Sanchez J, Volquez C, Totten PA, et al. The etiology and management of genital ulcers in the Dominican Republic and Peru. Sex Transm Dis 2002;29:559–567. 6. Beyrer C, Jitwatcharanan K, Natpratan C, et al. Molecular methods for diagnosis of genital ulcer disease in a sexually transmitted disease clinic population in northern Thailand: Predominance of herpes simples virus infection. J Infect Dis 1998;178:243–246. 7. Bruisten SM, Cairo I, Fennema H, et al. Diagnosing genital ulcer disease in a clinic for sexually transmitted diseases in Amsterdam, The Netherlands. J Clin Microbiol 2001; 39:601– 605. 8. Sasadeusz JJ, Silvers JE, Kent HE, et al. Prevalence of HSV-2 antibody in a Melbourne antenatal population attending a tertiary obstetric hospital. Aust N Z J Obstet Gynaeco 2008;48:266–272. 9. O’Farrell N, Morison L, Moodley, et al. Genital ulcers and concomitant complaints in men attending a sexually transmitted infections clinic: implications for sexually transmitted infections management. Sex Transm Dis 2008;35:545–549. 10. Schillinger JA, McKinney CM, Garg R, et al. Seroprevalence of herpes simplex virus type 2 and characteristics associated with undiagnosed infection: New York City, 2004. Sex Trans Dis 2008;35:599–606. 11. Clark JL, Konda KA, Munayco CV, et al. Prevalence of HIV, herpes simplex virus-2, and syphilis in male sex partners of pregnant women in Peru. BMC Public Health 2008;8:64. 12. Jennings JM, Louis TA, Ellen JM, et al. Geographic prevalence and multilevel determination of community-level factors associated with herpes simplex virus type 2 infection in Chennai, India. Am J Epidemiol 2008;167:1495–1503. 13. Corey L, Wald A, Genital herpes. In: Holmes KK, Mardh P-A, Sparling PF. Et al. ed. Sexually transmitted diseases. Third Edition. New York: McGraw-Hill, 1999:285–312. 14. Ashley R, Wald A. Genital herpes: review of the epidemic and potential uses of type-specific serology. Clin Microbiol Rev 1999;12:1–8.

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15. Benedetti J, Corey L, Ashley R. Recurrence rates of genital herpes after symptomatic first- episode infection. Ann Intern Med 1994;121:847–854. 16. 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. 17. Langenberg AGM, Corey L, Ashley R, et al. A prospective study of new infections with herpes simplex virus type 1 and type 2. N Engl J Med 1999;341:1432–1438. 18. Rooney JF, Felser JM, Ostrove JM, et al. Acquisition of genital herpes from an asymptomatic sexual partner. N Engl J Med 1986;314:1561–1564. 19. Mertz GJ, Coombs RW, Ashley RJ, et al. Transmission of genital herpes in couples with one asymptomatic and one asymptomatic partner: a prospective study. J Infect Dis 1988; 157:1169–1177. 20. Mertz GJ, Schmidt O, Jourden JL, et al. Frequency of acquisition of first-episode genital infection with herpes simplex virus from asymptomatic and asymptomatic source contacts. Sex Trans Dis 1985;12:33–39. 21. Mark KE, Wald A, Magaret AS, et al. Rapidly cleared episodes of herpes simplex virus reactivation in immunocompetent adults. J Infect Dis. 2008;198(8):1141-9 22. Schiffer JT, bu-Raddad L, Mark KE, et al. Frequent release of low amounts of herpes simplex virus from neurons: results of a mathematical model. Sci Transl Med. 2009;1:7ra16 23. Schiffer JT, Wald A, Selke S, Corey L, Magaret A. The kinetics of mucosal herpes simplex virus-2 infection in humans: evidence for rapid viral-host interactions. J Infect Dis. 2011; 204:554-561 24. Schiffer JT, Magaret A, Selke S, Corey L, Wald A. Detailed analysis of mucosal herpes simplex virus-2 replication kinetics with and without antiviral therapy. J Antimicrob Chemother. 2011;66:2593-2600 25. 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. 26. PK/PD Report Trial AIC316-01-II-01; 2012 27. Valtrex® prescribing information, March 2010 28. Xu F, Sternberg MR, Kottiri BJ, et al. Trends in herpes simplex virus type 1 and type 2 seroprevalence in the United States. JAMA. 2006;296:964-73 29. Field HJ, Biswas S. Antiviral drug resistance and helicase-primase inhibitors of herpes simplex virus. Drug Resist Updat. 2011; 14(1):45-51 30. Mindel A, Carney O, Freris M, Faherty A, Patou G, Williams P. Dosage and safety of long term suppressive acyclovir therapy for recurrent genital herpes. Lancet 1988;1:926-8. 31. Wald A, Selke S, Warren T, Aoki FY, Sacks S, Diaz-Mitoma F, et al. Comparative efficacy of famciclovir and valacyclovir for suppression of recurrent genital herpes and viral shedding. Sex Transm Dis 2006;33(9):529-33.

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20 APPENDICES

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20.1 Investigator responsibilities

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 Investigator responsibilities Per Good Clinical Practices 21CFR312.53 The Investigator: x Will conduct the trial in accordance with the relevant, current protocol and will only make changes in the protocol after notifying the Sponsor, except when necessary to protect the safety, the rights, or welfare of patients/subjects; x Will comply with all requirements regarding the obligations of clinical investigators and all other pertinent requirements; x Will personally conduct or supervise the described investigation; x Will inform any potential patients/subjects that the drugs are being used for investigational purposes and will ensure that the requirements relating to obtaining informed consent and institutional review board review and approval are met. x Will report to the Sponsor adverse experiences that occur in the course of the investigation in accordance with Section 312.64; x Has read and understands the information in the investigator’s brochure, including the potential risks and side effects of the drug; and x Will ensure that all associates, colleagues, and employees assisting in the conduct of the trial are informed about their obligations in meeting the above commitments. Per Good Clinical Practices 21CFR312.60 General responsibilities of Investigators: An Investigator is responsible for ensuring that an investigation is conducted according to the signed investigator statement, the investigational plan, and applicable regulations; for protecting the rights, safety, and welfare of patients/subjects under the Investigator’s care; and for the control of drugs under investigation. An Investigator shall, in accordance with the provisions of part 50, obtain the informed consent of each patient/subject to whom the drug is administered, except as provided in CFR50.23. Obligations of the Investigator The Investigator shall: x Maintain IRB approval to conduct the clinical trial and report to the IRB as required. The IRB must assume continued responsibility for the trial and review the research on at least an annual basis. x Maintain a file of all communications with the IRB on issues related to the clinical trial. x Complete, sign, and return to Inc. a Form FDA 1572 including a current CV for the Principal Investigator and Sub-Investigator(s), if listed. x Conduct the trial in strict adherence to the protocol. x Supervise the use of the trial medication as outlined in the protocol. The trial medication may only be provided by staff working under the supervision of the Investigator. x Store the trial medication in a secure and locked area with limited access. The storage and custody of the trial drug are the responsibilities of the Investigator.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 x Maintain adequate records of the receipt and disposition of all trial medication (including dates, quantities and use by trial subjects). x Inform each subject of the risks and benefits of participating in the trial and obtain a properly signed, dated and witnessed (if applicable) informed consent form for each subject before he or she begins any trial-related procedures. x Document all AEs on the eCRFs; document all Serious Adverse Events (SAEs) in the eCRF, print out the corresponding SAE report and send this to Pharmacovigilance/AiCuris GmbH & Co. KG via fax or e-mail (). x Report all SAEs to the IRB. x Maintain a master log of all subjects screened for the trial and establish a system to alert clinic staff of scheduled follow-up visits; provide clinic staff with a system for contacting trial subjects who do not return for scheduled follow-up. x Document and maintain accurate eCRFs for all subjects. As required, sign forms ascertaining the accuracy of data recorded. Storage and custody of all trial-related records are the responsibility of the Investigator. x Retain the copies of the eCRFs, the original informed consent forms and all trial-related documentation at the investigational site for a period of fifteen (15) years after termination of the trial unless Inc. or AiCuris authorizes, in writing, earlier destruction. Notify Inc. or AiCuris before destroying any trial records after the required retention period. It is the responsibility of the Sponsor to inform the Investigator/institution as to when these documents no longer need to be retained. x Make available all trial subjects’ records to staff and representatives from Inc., AiCuris GmbH & Co. KG and FDA or other Regulatory Agency personnel. x Return to AiCuris GmbH & Co. KG or their agent, trial materials (which may include unused trial supplies) following completion, discontinuation or suspension of the trial. x Be thoroughly familiar with the properties of the investigational agent as described in the Investigator Brochure. x Ensure that sufficient time is allotted to conduct and complete the trial; ensure adequate staff and facilities are available for the duration of the trial; and ensure that other studies do not divert essential subjects or facilities from the trial at hand. x Provide information to all staff members involved with the trial or with other elements of the subject’s management. x Notify Inc. and AiCuris GmbH & Co. KG in the event the blinding is broken. x Ensure that the confidentiality of all information about subjects and the information supplied by Inc. and AiCuris GmbH & Co. KG is respected by all persons.

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20.2 Swabbing for HSV PCR

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Home Instructions for Women for daily HSV PCR swabbing

Thank you for volunteering for this trial. Please read this sheet over carefully to understand how swabs are collected in this trial.

Supplies You will receive plastic vials for the PCRs (a specific method to analyze the virus content in your collected swabs). You will also receive labels, swabs (similar to Q-tips), and a box and a small cooler with an ice pack. All material can be left at room temperature, except for the ice packs, which should be frozen before using. After using the swabs and labeling the plastic vials, they go into the box. Store the box in your refrigerator or freezer until to your next appointment. Put the box in the cooler with an ice pack and bring it to the clinic for your next scheduled visit.

Sample label: These labels are preprinted with your trial screening number, numbers 1 to 4 coding for the planned times of collection (1=morning, 2=noon, 3=afternoon and 4=evening) and two locations (lesion and genital). They also include blanks for the date the specimen was collected. Please make sure you fill in the date for each sample and circle the appropriate collection time number (1=morning, 2=noon, 3=afternoon and 4=evening) and location (lesion or genital) prior to sticking the labels on the tubes.

Sampling time points: The genital area is to be swabbed 4 times each day during the two treatment periods when you are taking your daily study medication, i.e. two times 28 days. x Morning swab: Do the sampling in the morning before bathing or brushing your teeth. x Noon swab: Do the sampling at noon around 12:00 – 14:00 pm. x Afternoon swab: Do the sampling in the afternoon around 17:00 – 19:00 pm. x Evening swab: Do the sampling in the evening before bathing or brushing your teeth and going to bed.

Be as consistent as you can about the time the swabs are obtained each day.

Please make sure to document the exact time you complete each swab in you daily diary.

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Swabs The genital area is to be swabbed with a Q-tip style swab. One genital swab is to be placed in one plastic vial. Thoroughly wash and dry your hands before beginning. x The genital swab is done by gently inserting the swab into your vaginal opening, just as you would insert a tampon. Gently push the swab until it meets the very back of the vagina (at your cervix). Rotate the swab in a full circle (360 degrees), and wait at least 1 FULL MINUTE before proceeding to allow for any cervical secretions to be fully absorbed onto the swab. Then, rub the same swab from the outer (hairy) edges of your labia to the smooth skin below the vaginal opening, covering the entire area. Proceed by rubbing the swab over the skin between your vagina and anal opening (anus). Lay the swab flat against the skin to cover the greatest area, about 1 ½ inches around the anus. Then, gently insert the swab tip into the rectum, rotating the swab in a full circle (360 degrees).

Withdraw the swab and place it in a capped plastic PCR vial. You will need to break or cut the swab stem in order to fit the swab into the capped vial. You can either snap the stem by bracing the swab against the vial wall or you can use scissors to cut the stem. The stem should be cut at least ¼ inch shorter than the depth of the vial to insure that the cap can be screwed on tightly. Promptly label the plastic vial and check to be sure that the correct location (‘genital’) and sampling time point is marked on the vial label. Place the plastic vials in the box and store them in the refrigerator or freezer until your next appointment at your study doctor. Sometimes, some brown stool gets on the swabs. Stool does not alter the results and is not a problem for the lab. If you think you are having any symptoms typical of herpes or have developed genital herpes lesion(s), collect one additional swab of the lesion(s) parallel to each genital swab day until it is no longer present. x Lesion (genital) swabs should be collected in addition to all genital swabs if visible lesions are present. This is done by rubbing a sterile swab in a circular motion over each lesion. Withdraw the swab and place it in a plastic vial. Promptly label the plastic vial and check to be sure that the correct location (‘lesion’) and sampling time point is marked on the vial label.

Please make sure to properly document all lesion swabs in you daily diary. If you are having genital symptoms and you think they are NOT related to herpes, e.g., a yeast infection, urinary tract infection, rashes, etc., please call and come to the clinic AS SOON AS POSSIBLE to be seen by your study doctor.

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Home Instructions for Men for daily HSV PCR swabbing

Thank you for volunteering for this trial. Please read this sheet over carefully to understand how swabs are collected in this trial.

Supplies You will receive plastic vials for the PCRs (a specific method to analyze the virus content in your collected swabs). You will also receive labels, swabs (similar to Q-tips), and a box and a small cooler with an ice pack. All material can be left at room temperature, except for the ice packs, which should be frozen before using. After using the swabs and labeling the plastic vials, they go into the box. Store the box in your refrigerator or freezer until to your next appointment. Put the box in the cooler with an ice pack and bring it to the clinic for your next scheduled visit.

Sample label: These labels are preprinted with your trial screening number, numbers 1 to 4 coding for the planned times of collection (1=morning, 2=noon, 3=afternoon and 4=evening) and two locations (lesion and genital). They also include blanks for the date the specimen was collected. Please make sure you fill in the date for each sample and circle the appropriate collection time number (1=morning, 2=noon, 3=afternoon and 4=evening) and location (lesion or genital) prior to sticking the labels on the tubes.

Sampling time points: The genital area is to be swabbed 4 times each day during the two treatment periods when you are taking your daily study medication, i.e. two times 28 days. x Morning swab: Do the sampling in the morning before bathing or brushing your teeth. x Noon swab: Do the sampling at noon around 12:00 – 14:00 pm. x Afternoon swab: Do the sampling in the afternoon around 17:00 – 19:00 pm. x Evening swab: Do the sampling in the evening before bathing or brushing your teeth and going to bed.

Be as consistent as you can about the time the swabs are obtained each day.

Please make sure to document the exact time you complete each swab in you daily diary.

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Swabs The genital area is to be swabbed with a Q-tip style swab. One genital swab is to be placed in one plastic vial. Thoroughly wash and dry your hands before beginning. x The genital swab is done by rubbing the swab over the skin of the penis first and then the rectal region which extends 1 and ½ inches outward from the anal opening. Start at the tip of the penis and rub the swab over the length of the penis, covering the entire area. Lay the swab flat against the skin to cover the greatest area. Then, rub the swab in the rectal area in a starburst pattern to cover the entire area, then gently insert the swab tip into the rectum, rotating the swab in a full circle (360 degrees).

Withdraw the swab and place it in a capped plastic PCR vial. You will need to break or cut the swab stem in order to fit the swab into the capped vial. You can either snap the stem by bracing the swab against the vial wall or you can use scissors to cut the stem. The stem should be cut at least ¼ inch shorter than the depth of the vial to insure that the cap can be screwed on tightly. Promptly label the plastic vial and check to be sure that the correct location (‘genital’) and sampling time point is marked on the vial label. Place the plastic vials in the box and store them in the refrigerator or freezer until your next appointment at your study doctor. Sometimes, some brown stool gets on the swabs. Stool does not alter the results and is not a problem for the lab.

If you think you are having any symptoms typical of herpes or have developed genital herpes lesion, collect one additional swab of the lesion(s) parallel to each genital swab day until it is no longer present. x Lesion (genital) swabs should be collected in addition to all genital swabs if visible lesions are present. This is done by rubbing a sterile swab in a circular motion over each lesion. Withdraw the swab and place it in a plastic vial. Promptly label the plastic vial and check to be sure that the correct location (‘lesion’) and sampling time point is marked on the vial label.

Please make sure to properly document all lesion swabs in you daily diary.

If you are not sure what to mark, please call the clinic or page the clinician on-call so that the symptom can be recorded accurately. If you have ANY genital symptoms, please phone the clinic or page the clinician on-call AS SOON AS POSSIBLE to be seen by your study doctor.

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20.3 HSV lesion Score

CONFIDENTIAL

Downloaded From: https://jamanetwork.com/ on 09/25/2021 HSV lesion Score The morphology of lesions will be described according the beneath displayed Score (Table 1). In case there is more than one lesion present the most advanced lesion will be scored.

Table 1: HSV lesion Score

Score Morphology Description

0 Prodrome Presence of prodrome. 1 Erythema Any redness, without evidence of higher score. 2 Papule Any swelling or solid superficial elevation with or without erythema but without any fluid. 3 Vesicle / Presence of a blister containing clear or cloudy fluid, respectively Pustule with or without an erythematous base. 4 Ulcer/soft Collapse or rupture of a blister forming an ulcer crust with or without a moist floor. Big ulcer can appear with irregular shape and size due to confluence of evolving vesicles and pustules. 5 Hard crust Dry ulcer formed a noticeably hard, consolidated, firm mass or scab, an eschar. 6 Hard crust Loss of hard crust. loss 7 Residual Residual abnormalities visual: erythema or flat residual scar tissue abnormalities may be present, swelling / dry flaking. 8 Healed Normal skin / no signs or symptoms: re-epithelialization, no crust, swelling, or ulceration.

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20.4 List of medical concepts for consideration of seriousness stratified by system-organ class

CONFIDENTIAL

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Blood and lymphatic system disorders Agranulocytosis aplastic anemia blast cell proliferation bone marrow depression Coombs negative hemolytic disseminated intravascular anemia coagulation Pancytopenia thrombocytopenia (<30,000 platelets per microliter) Cardiac disorders angina unstable atrial flutter atrioventricular block complete cardiac arrest cardiac failure cardiac fibrillation cardiogenic shock cardiomyopathy acute coronary artery spasm cor pulmonale hemopericardium myocardial infarction myocarditis pulmonary edema Torsade de Pointes ventricular fibrillation ventricular tachycardia Ear and labyrinth disorders deafness vestibular ataxia Endocrine disorders adrenocortical insufficiency acute Eye disorders cataract glaucoma macular degeneration optic atrophy papilledema retinal artery thrombosis sudden visual loss vitreous detachment Gastrointestinal disorders colitis hemorrhagic gastric ulcer hemorrhage hemoperitoneum hematemesis intestinal perforation melena intestinal ischemia mesenteric vein thrombosis pancreatitis mesenteric occlusion gastric ulcer perforation Hepato-biliary disorders hepatic failure hepatitis fulminant hepatic necrosis hepatorenal syndrome portal hypertension Reye's syndrome Immune system disorders amyloidosis anaphylactic reaction anaphylactic shock graft versus host disease meningitis systemic sclerosis Infections and infestations sepsis Injury, poisoning and procedural complications intentional misuse Metabolism and nutrition disorders diabetic coma hypercalcemia (>3.4 mmol/L) hyperkalemia (>7 mmol/L) hypocalcemia (<1.5 mmol/L) hypokalemia (<2.5 mmol/L) lactic acidosis shock hypoglycemic Musculoskeletal, connective tissue and bone disorders aseptic necrosis bone muscle necrosis rhabdomyolysis serotonin syndrome systemic lupus erythematosus

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 Nervous system disorders amnesia cerebral edema chorea coma convulsions convulsions neonatal encephalitis encephalopathy allergic epilepsy grand mal convulsion Guillain Barré syndrome hemiparesis hemiplegia hydrocephalus myelitis opisthotonus paralysis scotoma stroke tunnel vision Pregnancy, puerperium and perinatal conditions abortion missed abortion intra-uterine death Psychiatric disorders complete suicide delirium drug dependence suicidal ideation suicide attempt Renal and urinary disorders anuria Goodpasture's syndrome hemolytic uremic syndrome oliguria renal failure acute renal tubular necrosis Respiratory, thoracic and mediastinal disorders acute respiratory failure adult respiratory distress syndrome allergic alveolitis (ARDS) asphyxia bronchospasm laryngeal edema pulmonary fibrosis pulmonary hemorrhage pulmonary infarction pulmonary vasculitis respiratory arrest status asthmaticus Skin and subcutaneous tissue disorders angioneurotic edema Stevens-Johnson syndrome toxic epidermal necrolysis vascular purpura Vascular disorders acute circulatory failure arterial thrombosis limb brain stem infarction brain stem ischemia carotid artery thrombosis cerebral artery embolism cerebral venous thrombosis intracranial hemorrhage malignant hypertension ischemic necrosis pelvic venous thrombosis pulmonary embolism venous thrombosis deep limb venous thrombosis NOS

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20.5 DAIDS toxicity criteria

CONFIDENTIAL

Downloaded From: https://jamanetwork.com/ on 09/25/2021 DIVISION OF AIDS TABLE FOR GRADING THE SEVERITY OF ADULT AND PEDIATRIC ADVERSE EVENTS VERSION 1.0, DECEMBER, 2004; CLARIFICATION AUGUST 2009

The Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (“DAIDS AE Grading Table”) is a descriptive terminology which can be utilized for Adverse Event (AE) reporting. A grading (severity) scale is provided for each AE term.

This clarification of the DAIDS Table for Grading the Severity of Adult and Pediatric AE’s provides additional explanation of the DAIDS AE Grading Table and clarifies some of the parameters.

I. Instructions and Clarifications Grading Adult and Pediatric AEs The DAIDS AE Grading Table includes parameters for grading both Adult and Pediatric AEs. When a single set of parameters is not appropriate for grading specific types of AEs for both Adult and Pediatric populations, separate sets of parameters for Adult and/or Pediatric populations (with specified respective age ranges) are given in the Table. If there is no distinction in the Table between Adult and Pediatric values for a type of AE, then the single set of parameters listed is to be used for grading the severity of both Adult and Pediatric events of that type. Note: In the classification of adverse events, the term “severe” is not the same as “serious.” Severity is an indication of the intensity of a specific event (as in mild, moderate, or severe chest pain). The term “serious” relates to a participant/event outcome or action criteria, usually associated with events that pose a threat to a participant’s life or functioning.

Addenda 1-3 Grading Tables for Microbicide Studies For protocols involving topical application of products to the female genital tract, male genital area or rectum, strong consideration should be given to using Appendices I-III as the primary grading scales for these areas. The protocol would need to specifically state that one or more of the Appendices would be primary (and thus take precedence over the main Grading Table) for items that are listed in both the Appendix and the main Grading Table. x Addendum 1 - Female Genital Grading Table for Use in Microbicide Studies - PDF x Addendum 2 - Male Genital Grading Table for Use in Microbicide Studies - PDF x Addendum 3 - Rectal Grading Table for Use in Microbicide Studies - PDF

Grade 5 For any AE where the outcome is death, the severity of the AE is classified as Grade 5.

Estimating Severity Grade for Parameters Not Identified in the Table In order to grade a clinical AE that is not identified in the DAIDS AE grading table, use the category “Estimating Severity Grade” located on Page 3.

Determining Severity Grade for Parameters “Between Grades” If the severity of a clinical AE could fall under either one of two grades (e.g., the severity of an AE could be either Grade 2 or Grade 3), select the higher of the two grades for the AE. If a laboratory value that is graded as a multiple of the ULN or LLN falls between two grades, select the higher of the two grades for the AE. For example, Grade 1 is 2.5 x ULN and Grade 2 is 2.6 x ULN for a parameter. If the lab value is 2.53 x ULN (which is between the two grades), the severity of this AE would be Grade 2, the higher of the two grades.

Values Below Grade 1 Any laboratory value that is between either the LLN or ULN and Grade 1 should not be graded.

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Determining Severity Grade when Local Laboratory Normal Values Overlap with Grade 1 Ranges In these situations, the severity grading is based on the ranges in the DAIDS AE Grading Table, even when there is a reference to the local lab LLN.

For example: Phosphate, Serum, Low, Adult and Pediatric > 14 years (Page 20) Grade 1 range is 2.50 mg/dL - < LLN. A particular laboratory’s normal range for Phosphate is 2.1 – 3.8 mg/dL. A participant’s actual lab value is 2.5. In this case, the value of 2.5 exceeds the LLN for the local lab, but will be graded as Grade 1 per DAIDS AE Grading Table. . II. Definitions of terms used in the Table: Basic Self-care Functions Adult Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding.

Young Children Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement).

LLN Lower limit of normal

Medical Intervention Use of pharmacologic or biologic agent(s) for treatment of an AE.

NA Not Applicable

Operative Intervention Surgical OR other invasive mechanical procedures.

ULN Upper limit of normal

Usual Social & Functional Adult Activities Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc.

Young Children Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

ESTIMATING SEVERITY GRADE

Clinical adverse event Symptoms causing no Symptoms causing Symptoms causing Symptoms causing NOT identified or minimal greater than minimal inability to perform usual inability to perform basic elsewhere in this interference with interference with usual social & functional self-care functions OR DAIDS AE Grading usual social & social & functional activities Medical or operative Table functional activities activities intervention indicated to prevent permanent impairment, persistent disability, or death

SYSTEMIC

Acute systemic Localized urticaria Localized urticaria with Generalized urticaria Acute anaphylaxis OR allergic reaction (wheals) with no medical intervention OR Angioedema with Life-threatening medical intervention indicated OR Mild medical intervention bronchospasm OR indicated angioedema with no indicated OR laryngeal edema medical intervention Symptomatic mild indicated bronchospasm Chills Symptoms causing no Symptoms causing Symptoms causing NA or minimal greater than minimal inability to perform usual interference with interference with usual social & functional usual social & social & functional activities functional activities activities Fatigue Symptoms causing no Symptoms causing Symptoms causing Incapacitating fatigue/ Malaise or minimal greater than minimal inability to perform usual malaise symptoms interference with interference with usual social & functional causing inability to usual social & social & functional activities perform basic self-care functional activities activities functions

Fever (nonaxillary) 37.7 – 38.6qC 38.7 – 39.3qC 39.4 – 40.5qC > 40.5qC Pain (indicate body Pain causing no or Pain causing greater Pain causing inability to Disabling pain causing site) minimal interference than minimal perform usual social & inability to perform basic DO NOT use for pain with usual social & interference with usual functional activities self-care functions OR due to injection (See functional activities social & functional Hospitalization (other Injection Site activities than emergency room Reactions: Injection visit) indicated site pain) See also Headache, Arthralgia, and Myalgia

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Unintentional weight NA 5 – 9% loss in body 10 – 19% loss in body t 20% loss in body loss weight from baseline weight from baseline weight from baseline OR Aggressive intervention indicated [e.g., tube feeding or total parenteral nutrition (TPN)]

INFECTION

Infection (any other Localized, no Systemic antimicrobial Systemic antimicrobial Life-threatening than HIV infection) systemic antimicrobial treatment indicated treatment indicated consequences (e.g., treatment indicated OR Symptoms AND Symptoms causing septic shock) AND Symptoms causing greater than inability to perform usual causing no or minimal minimal interference social & functional interference with with usual social & activities OR Operative usual social & functional activities intervention (other than functional activities simple incision and drainage) indicated

INJECTION SITE REACTIONS

Injection site pain Pain/tenderness Pain/tenderness Pain/tenderness Pain/tenderness causing (pain without touching) causing no or minimal limiting use of limb OR causing inability to inability to perform basic Or limitation of use of Pain/tenderness perform usual social & self-care function OR limb causing greater than functional activities Hospitalization (other Tenderness (pain minimal interference than emergency room when area is touched) with usual social & visit) indicated for functional activities management of pain/tenderness

Injection site reaction (localized) Adult > 15 years Erythema OR Erythema OR Ulceration OR Necrosis (involving Induration Induration OR Edema Secondary infection OR dermis and deeper of 5x5 cm – 9x9 cm > 9 cm any diameter Phlebitis OR Sterile tissue) (or 25 cm2 – 81cm2) (or > 81 cm2) abscess OR Drainage

Pediatric d 15 Erythema OR Erythema OR Erythema OR Induration Necrosis (involving years Induration OR Edema Induration OR Edema OR Edema involving dermis and deeper present but d 2.5 cm > 2.5 cm diameter but t 50% surface area of tissue) diameter < 50% surface area of the extremity segment the extremity segment (e.g., upper arm/thigh) (e.g., upper arm/thigh) OR Ulceration OR Secondary infection OR Phlebitis OR Sterile abscess OR Drainage

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Pruritis associated Itching localized to Itching beyond the Generalized itching NA with injection injection site AND injection site but not causing inability to See also Skin: Pruritis Relieved generalized OR Itching perform usual social & (itching - no skin spontaneously or with localized to injection functional activities lesions) < 48 hours treatment site requiring t 48 hours treatment

SKIN – DERMATOLOGICAL

Alopecia Thinning detectable Thinning or patchy hair Complete hair loss NA by study participant loss detectable by (or by caregiver for health care provider young children and disabled adults) Cutaneous reaction – Localized macular Diffuse macular, Diffuse macular, Extensive or generalized rash rash maculopapular, or maculopapular, or bullous lesions OR morbilliform rash OR morbilliform rash with Stevens-Johnson Target lesions vesicles or limited syndrome OR Ulceration number of bullae OR of mucous membrane Superficial ulcerations involving two or more of mucous membrane distinct mucosal sites limited to one site OR Toxic epidermal necrolysis (TEN) Hyperpigmentation Slight or localized Marked or generalized NA NA Hypopigmentation Slight or localized Marked or generalized NA NA Pruritis (itching – no Itching causing no or Itching causing greater Itching causing inability NA skin lesions) minimal interference than minimal to perform usual social (See also Injection with usual social & interference with usual & functional activities Site Reactions: functional activities social & functional Pruritis associated activities with injection)

CARDIOVASCULAR

Cardiac arrhythmia Asymptomatic AND Asymptomatic AND Symptomatic, non-life- Life-threatening (general) No intervention Non-urgent medical threatening AND Non- arrhythmia OR Urgent (By ECG or physical indicated intervention indicated urgent medical intervention indicated exam) intervention indicated Cardiac- NA NA Symptomatic ischemia Unstable angina OR ischemia/infarction (stable angina) OR Acute myocardial Testing consistent with infarction ischemia

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Hemorrhage NA Symptomatic AND No Symptomatic AND Life-threatening (significant acute transfusion indicated Transfusion of d 2 units hypotension OR blood loss) packed RBCs (for Transfusion of > 2 units children d 10 cc/kg) packed RBCs (for indicated children > 10 cc/kg) indicated Hypertension Adult > 17 years 140 – 159 mmHg 160 – 179 mmHg • 180 mmHg systolic Life-threatening (with repeat testing systolic systolic OR consequences (e.g., at same visit) OR OR malignant hypertension) • 110 mmHg diastolic OR Hospitalization 90 – 99 mmHg 100 – 109 mmHg indicated (other than diastolic diastolic emergency room visit) Correction: in Grade 2 to 160 - 179 from > 160-179 (systolic) and to t 100 -109 from > 100-109 (diastolic) and in Grade 3 to t 180 from > 180 (systolic) and to t 110 from > 110 (diastolic). Pediatric d 17 NA 91st – 94th percentile • 95th percentile Life-threatening years adjusted for age, adjusted for age, height, consequences (e.g., (with repeat height, and gender and gender (systolic malignant hypertension) testing at same (systolic and/or and/or diastolic) OR Hospitalization visit) diastolic) indicated (other than emergency room visit)

Hypotension NA Symptomatic, Symptomatic, IV fluids Shock requiring use of corrected with oral indicated vasopressors or fluid replacement mechanical assistance to maintain blood pressure

Pericardial effusion Asymptomatic, small Asymptomatic, Effusion with non-life Life-threatening effusion requiring no moderate or larger threatening physiologic consequences (e.g., intervention effusion requiring no consequences OR tamponade) OR Urgent intervention Effusion with non-urgent intervention indicated intervention indicated

Prolonged PR interval Adult > 16 years PR interval PR interval Type II 2nd degree AV Complete AV block 0.21 – 0.25 sec > 0.25 sec block OR Ventricular pause > 3.0 sec Pediatric ” 16 1st degree AV block Type I 2nd degree AV Type II 2nd degree AV Complete AV block years (PR > normal for age block block and rate)

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Prolonged QTc Adult > 16 years Asymptomatic, QTc Asymptomatic, QTc Asymptomatic, QTc Life-threatening interval 0.45 – 0.47 interval 0.48 – 0.49 interval t 0.50 sec OR consequences, e.g. sec OR Increase sec OR Increase in Increase in interval Torsade de pointes or interval < 0.03 sec interval 0.03 – 0.05 t 0.06 sec above other associated serious above baseline sec above baseline baseline ventricular dysrhythmia Pediatric ” 16 Asymptomatic, QTc Asymptomatic, QTc Asymptomatic, QTc Life-threatening years interval 0.450 – interval 0.465 – interval t 0.480 sec consequences, e.g. 0.464 sec 0.479 sec Torsade de pointes or other associated serious ventricular dysrhythmia Thrombosis/embolism NA Deep vein thrombosis Deep vein thrombosis Embolic event (e.g., AND No intervention AND Intervention pulmonary embolism, indicated (e.g., indicated (e.g., life-threatening anticoagulation, lysis anticoagulation, lysis thrombus) filter, invasive filter, invasive procedure) procedure) Vasovagal episode Present without loss Present with transient NA NA (associated with a of consciousness loss of consciousness procedure of any kind) Ventricular NA Asymptomatic New onset with Life-threatening dysfunction diagnostic finding AND symptoms OR congestive heart failure (congestive heart intervention indicated Worsening symptomatic failure) congestive heart failure

GASTROINTESTINAL

Anorexia Loss of appetite Loss of appetite Loss of appetite Life-threatening without decreased associated with associated with consequences OR oral intake decreased oral intake significant weight loss Aggressive intervention without significant indicated [e.g., tube weight loss feeding or total parenteral nutrition (TPN)] Comment: Please note that, while the grading scale provided for Unintentional Weight Loss may be used as a guideline when grading anorexia, this is not a requirement and should not be used as a substitute for clinical judgment. Ascites Asymptomatic Symptomatic AND Symptomatic despite Life-threatening Intervention indicated intervention consequences (e.g., diuretics or therapeutic paracentesis)

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Cholecystitis NA Symptomatic AND Radiologic, endoscopic, Life-threatening Medical intervention or operative intervention consequences (e.g., indicated indicated sepsis or perforation)

Constipation NA Persistent constipation Obstipation with manual Life-threatening requiring regular use evacuation indicated consequences (e.g., of dietary obstruction) modifications, laxatives, or enemas Diarrhea Adult and Transient or Persistent episodes of Bloody diarrhea OR Life-threatening Pediatric t 1 year intermittent episodes unformed to watery Increase of • 7 stools consequences (e.g., of unformed stools stools OR Increase of per 24-hour period OR hypotensive shock) OR Increase of ” 3 4 – 6 stools over IV fluid replacement stools over baseline baseline per 24-hour indicated per 24-hour period period Pediatric < 1 year Liquid stools (more Liquid stools with Liquid stools with Liquid stools resulting in unformed than usual) increased number of moderate dehydration severe dehydration with but usual number of stools OR Mild aggressive rehydration stools dehydration indicated OR Hypotensive shock Dysphagia- Symptomatic but able Symptoms causing Symptoms causing Life-threatening Odynophagia to eat usual diet altered dietary intake severely altered dietary reduction in oral intake without medical intake with medical intervention indicated intervention indicated Mucositis/stomatitis Erythema of the Patchy Confluent Tissue necrosis OR (clinical exam) mucosa pseudomembranes or pseudomembranes or Diffuse spontaneous Indicate site (e.g., ulcerations ulcerations OR Mucosal mucosal bleeding OR larynx, oral) bleeding with minor Life-threatening trauma consequences (e.g., See Genitourinary for aspiration, choking) Vulvovaginitis See also Dysphagia- Odynophagia and Proctitis Nausea Transient (< 24 hours) Persistent nausea Persistent nausea Life-threatening or intermittent nausea resulting in decreased resulting in minimal oral consequences (e.g., with no or minimal oral intake for 24 – 48 intake for > 48 hours hypotensive shock) interference with oral hours OR Aggressive intake rehydration indicated (e.g., IV fluids)

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Pancreatitis NA Symptomatic AND Symptomatic AND Life-threatening Hospitalization not Hospitalization indicated consequences (e.g., indicated (other than (other than emergency circulatory failure, emergency room visit) room visit) hemorrhage, sepsis) Proctitis (functional- Rectal discomfort Symptoms causing Symptoms causing Life-threatening symptomatic) AND No intervention greater than minimal inability to perform usual consequences (e.g., Also see indicated interference with usual social & functional perforation) Mucositis/stomatitis social & functional activities OR Operative for clinical exam activities OR Medical intervention indicated intervention indicated

Vomiting Transient or Frequent episodes of Persistent vomiting Life-threatening intermittent vomiting vomiting with no or resulting in orthostatic consequences (e.g., with no or minimal mild dehydration hypotension OR hypotensive shock) interference with oral Aggressive rehydration intake indicated (e.g., IV fluids)

NEUROLOGIC

Alteration in Alteration causing no Alteration causing Alteration causing Behavior potentially personality-behavior or minimal greater than minimal inability to perform usual harmful to self or others or in mood (e.g., interference with interference with usual social & functional (e.g., suicidal and agitation, anxiety, usual social & social & functional activities homicidal ideation or depression, mania, functional activities activities attempt, acute psychosis) psychosis) OR Causing inability to perform basic self-care functions Altered Mental Status Changes causing no Mild lethargy or Confusion, memory Delirium OR For Dementia, see or minimal somnolence causing impairment, lethargy, or obtundation, OR coma Cognitive and interference with greater than minimal somnolence causing behavioral/attentional usual social & interference with usual inability to perform usual disturbance (including functional activities social & functional social & functional dementia and activities activities attention deficit disorder) Ataxia Asymptomatic ataxia Symptomatic ataxia Symptomatic ataxia Disabling ataxia causing detectable on exam causing greater than causing inability to inability to perform basic OR Minimal ataxia minimal interference perform usual social & self-care functions causing no or minimal with usual social & functional activities interference with functional activities usual social & functional activities

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Cognitive and Disability causing no Disability causing Disability causing Disability causing behavioral/attentional or minimal greater than minimal inability to perform usual inability to perform basic disturbance (including interference with interference with usual social & functional self-care functions OR dementia and usual social & social & functional activities OR Institutionalization attention deficit functional activities activities OR Specialized resources indicated disorder) OR Specialized Specialized resources on a full-time basis resources not on part-time basis indicated indicated indicated CNS ischemia NA NA Transient ischemic Cerebral vascular (acute) attack accident (CVA, stroke) with neurological deficit Developmental delay Mild developmental Moderate Severe developmental Developmental – Pediatric d 16 delay, either motor or developmental delay, delay, either motor or regression, either motor years cognitive, as either motor or cognitive, as determined or cognitive, as determined by cognitive, as by comparison with a determined by comparison with a determined by developmental comparison with a developmental comparison with a screening tool developmental screening tool developmental appropriate for the screening tool appropriate for the screening tool setting appropriate for the setting appropriate for the setting setting Headache Symptoms causing no Symptoms causing Symptoms causing Symptoms causing or minimal greater than minimal inability to perform usual inability to perform basic interference with interference with usual social & functional self-care functions OR usual social & social & functional activities Hospitalization indicated functional activities activities (other than emergency room visit) OR Headache with significant impairment of alertness or other neurologic function Insomnia NA Difficulty sleeping Difficulty sleeping Disabling insomnia causing greater than causing inability to causing inability to minimal interference perform usual social & perform basic self-care with usual social & functional activities functions functional activities Neuromuscular Asymptomatic with Muscle weakness Muscle weakness Disabling muscle weakness decreased strength causing greater than causing inability to weakness causing (including myopathy & on exam OR Minimal minimal interference perform usual social & inability to perform basic neuropathy) muscle weakness with usual social & functional activities self-care functions OR causing no or minimal functional activities Respiratory muscle interference with weakness impairing usual social & ventilation functional activities

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Neurosensory Asymptomatic with Sensory alteration or Sensory alteration or Disabling sensory alteration (including sensory alteration on paresthesia causing paresthesia causing alteration or paresthesia paresthesia and exam or minimal greater than minimal inability to perform usual causing inability to painful neuropathy) paresthesia causing interference with usual social & functional perform basic self-care no or minimal social & functional activities functions interference with activities usual social & functional activities Seizure: (new onset) NA 1 seizure 2 – 4 seizures Seizures of any kind – Adult • 18 years which are prolonged, See also Seizure: repetitive (e.g., status (known pre-existing epilepticus), or difficult seizure disorder) to control (e.g., refractory epilepsy) Seizure: (known pre- NA Increased frequency of Change in seizure Seizures of any kind existing seizure pre-existing seizures character from baseline which are prolonged, disorder) (non-repetitive) without either in duration or repetitive (e.g., status – Adult • 18 years change in seizure quality (e.g., severity or epilepticus), or difficult For worsening of character OR focality) to control (e.g., existing epilepsy the Infrequent break- refractory epilepsy) grades should be through seizures while based on an increase on stable medication from previous level of in a previously control to any of these controlled seizure levels. disorder Seizure Seizure, generalized Seizure, generalized Seizure, generalized Seizure, generalized – Pediatric < 18 onset with or without onset with or without onset with or without onset with or without years secondary secondary secondary secondary generalization, lasting generalization, lasting generalization, lasting generalization, requiring < 5 minutes with < 24 5 – 20 minutes with > 20 minutes intubation and sedation hours post ictal state < 24 hours post ictal state Syncope (not NA Present NA NA associated with a procedure) Vertigo Vertigo causing no or Vertigo causing Vertigo causing inability Disabling vertigo minimal interference greater than minimal to perform usual social causing inability to with usual social & interference with usual & functional activities perform basic self-care functional activities social & functional functions activities

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

RESPIRATORY

Bronchospasm (acute) FEV1 or peak flow FEV1 or peak flow FEV1 or peak flow Cyanosis OR FEV1 or reduced to 50 – 69% 25 – 49% peak flow < 25% OR 70 – 80% Intubation Dyspnea or respiratory distress Adult • 14 years Dyspnea on exertion Dyspnea on exertion Dyspnea at rest causing Respiratory failure with with no or minimal causing greater than inability to perform usual ventilatory support interference with minimal interference social & functional indicated usual social & with usual social & activities functional activities functional activities Pediatric < 14 Wheezing OR Nasal flaring OR Dyspnea at rest causing Respiratory failure with years minimal increase in Intercostal retractions inability to perform usual ventilatory support respiratory rate for OR Pulse oximetry 90 social & functional indicated age – 95% activities OR Pulse oximetry < 90%

MUSCULOSKELETAL

Arthralgia Joint pain causing no Joint pain causing Joint pain causing Disabling joint pain See also Arthritis or minimal greater than minimal inability to perform usual causing inability to interference with interference with usual social & functional perform basic self-care usual social & social & functional activities functions functional activities activities Arthritis Stiffness or joint Stiffness or joint Stiffness or joint Disabling joint stiffness See also Arthralgia swelling causing no or swelling causing swelling causing or swelling causing minimal interference greater than minimal inability to perform usual inability to perform basic with usual social & interference with usual social & functional self-care functions functional activities social & functional activities activities Bone Mineral Loss Adult • 21 years BMD t-score BMD t-score < -2.5 Pathological fracture Pathologic fracture -2.5 to -1.0 (including loss of causing life-threatening vertebral height) consequences Pediatric < 21 BMD z-score BMD z-score < -2.5 Pathological fracture Pathologic fracture years -2.5 to -1.0 (including loss of causing life-threatening vertebral height) consequences Myalgia Muscle pain causing Muscle pain causing Muscle pain causing Disabling muscle pain (non-injection site) no or minimal greater than minimal inability to perform usual causing inability to interference with interference with usual social & functional perform basic self-care usual social & social & functional activities functions functional activities activities

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Osteonecrosis NA Asymptomatic with Symptomatic bone pain Disabling bone pain with radiographic findings with radiographic radiographic findings AND No operative findings OR Operative causing inability to intervention indicated intervention indicated perform basic self-care functions

GENITOURINARY

Cervicitis Symptoms causing no Symptoms causing Symptoms causing Symptoms causing (symptoms) or minimal greater than minimal inability to perform usual inability to perform basic (For use in studies interference with interference with usual social & functional self-care functions evaluating topical usual social & social & functional activities study agents) functional activities activities For other cervicitis see Infection: Infection (any other than HIV infection) Cervicitis Minimal cervical Moderate cervical Severe cervical Epithelial disruption (clinical exam) abnormalities on abnormalities on abnormalities on > 75% total surface (For use in studies examination examination examination (erythema, evaluating topical (erythema, (erythema, mucopurulent study agents) mucopurulent mucopurulent discharge, or friability) discharge, or friability) discharge, or friability) OR Epithelial disruption For other cervicitis see OR Epithelial OR Epithelial 50 – 75% total surface Infection: Infection disruption disruption of 25 – 49% (any other than HIV < 25% of total surface total surface infection) Inter-menstrual Spotting observed by Inter-menstrual Inter-menstrual bleeding Hemorrhage with life- bleeding (IMB) participant OR bleeding not greater in greater in duration or threatening hypotension Minimal blood duration or amount amount than usual OR Operative observed during than usual menstrual menstrual cycle intervention indicated clinical or colposcopic cycle examination Urinary tract NA Signs or symptoms of Signs or symptoms of Obstruction causing life- obstruction (e.g., urinary tract urinary tract obstruction threatening stone) obstruction without with hydronephrosis or consequences hydronephrosis or renal dysfunction renal dysfunction

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Vulvovaginitis Symptoms causing no Symptoms causing Symptoms causing Symptoms causing (symptoms) or minimal greater than minimal inability to perform usual inability to perform basic (Use in studies interference with interference with usual social & functional self-care functions evaluating topical usual social & social & functional activities study agents) functional activities activities For other vulvovaginitis see Infection: Infection (any other than HIV infection) Vulvovaginitis Minimal vaginal Moderate vaginal Severe vaginal Vaginal perforation OR (clinical exam) abnormalities on abnormalities on abnormalities on Epithelial disruption (Use in studies examination OR examination OR examination OR > 75% total surface evaluating topical Epithelial disruption Epithelial disruption of Epithelial disruption study agents) < 25% of total surface 25 - 49% total surface 50 - 75% total surface For other vulvovaginitis see Infection: Infection (any other than HIV infection)

OCULAR/VISUAL

Uveitis Asymptomatic but Symptomatic anterior Posterior or pan-uveitis Disabling visual loss in detectable on exam uveitis OR Medical OR Operative affected eye(s) intervention indicated intervention indicated Visual changes (from Visual changes Visual changes Visual changes causing Disabling visual loss in baseline) causing no or minimal causing greater than inability to perform usual affected eye(s) interference with minimal interference social & functional usual social & with usual social & activities functional activities functional activities

ENDOCRINE/METABOLIC

Abnormal fat Detectable by study Detectable on physical Disfiguring OR Obvious NA accumulation participant (or by exam by health care changes on casual (e.g., back of neck, caregiver for young provider visual inspection breasts, abdomen) children and disabled adults) Diabetes mellitus NA New onset without New onset with initiation Life-threatening need to initiate of medication indicated consequences (e.g., medication OR OR Diabetes ketoacidosis, Modification of current uncontrolled despite hyperosmolar non- medications to regain treatment modification ketotic coma) glucose control

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Gynecomastia Detectable by study Detectable on physical Disfiguring OR Obvious NA participant or exam by health care on casual visual caregiver (for young provider inspection children and disabled adults) Hyperthyroidism Asymptomatic Symptomatic causing Symptoms causing Life-threatening greater than minimal inability to perform usual consequences (e.g., interference with usual social & functional thyroid storm) social & functional activities OR activities OR Thyroid Uncontrolled despite suppression therapy treatment modification indicated Hypothyroidism Asymptomatic Symptomatic causing Symptoms causing Life-threatening greater than minimal inability to perform usual consequences (e.g., interference with usual social & functional myxedema coma) social & functional activities OR activities OR Thyroid Uncontrolled despite replacement therapy treatment modification indicated Lipoatrophy Detectable by study Detectable on physical Disfiguring OR Obvious NA (e.g., fat loss from the participant (or by exam by health care on casual visual face, extremities, caregiver for young provider inspection buttocks) children and disabled adults)

Basic Self-care Functions – Adult: Activities such as bathing, dressing, toileting, transfer/movement, continence, and feeding. Basic Self-care Functions – Young Children: Activities that are age and culturally appropriate (e.g., feeding self with culturally appropriate eating implement). Usual Social & Functional Activities – Adult: Adaptive tasks and desirable activities, such as going to work, shopping, cooking, use of transportation, pursuing a hobby, etc. Usual Social & Functional Activities – Young Children: Activities that are age and culturally appropriate (e.g., social interactions, play activities, learning tasks, etc.).

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LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

HEMATOLOGY Standard International Units are listed in italics

Absolute CD4+ count 300 – 400/mm3 200 – 299/mm3 100 – 199/mm3 < 100/mm3 – Adult and Pediatric 300 – 400/μL 200 – 299/μL 100 – 199/μL < 100/μL > 13 years (HIV NEGATIVE ONLY) Absolute lymphocyte 600 – 650/mm3 500 – 599/mm3 350 – 499/mm3 < 350/mm3 count 0.600 x 109 – 0.500 x 109 – 0.350 x 109 – < 0.350 x 109/L – Adult and Pediatric 0.650 x 109/L 0.599 x 109/L 0.499 x 109/L > 13 years (HIV NEGATIVE ONLY) Comment: Values in children ” 13 years are not given for the two parameters above because the absolute counts are variable. Absolute neutrophil count (ANC) Adult and Pediatric, 1,000 – 1,300/mm3 750 – 999/mm3 500 – 749/mm3 < 500/mm3 > 7 days 1.000 x 109 – 0.750 x 109 – 0.500 x 109 – < 0.500 x 109/L 1.300 x 109/L 0.999 x 109/L 0.749 x 109/L Infant † , 2 – d 7 days 1,250 – 1,500/mm3 1,000 – 1,249/mm3 750 – 999/mm3 < 750/mm3 1.250 x 109 – 1.000 x 109 – 0.750 x 109 – < 0.750 x 109/L 1.500 x 109/L 1.249 x 109/L 0.999 x 109/L Infant † , ”1 day 4,000 – 5,000/mm3 3,000 – 3,999/mm3 1,500 – 2,999/mm3 < 1,500/mm3 4.000 x 109 – 3.000 x 109 – 1.500 x 109 – < 1.500 x 109/L 5.000 x 109/L 3.999 x109/L 2.999 x 109/L Comment: Parameter changed from “Infant, < 1 day” to “Infant, ”1 day” Fibrinogen, decreased 100 – 200 mg/dL 75 – 99 mg/dL 50 – 74 mg/dL < 50 mg/dL 1.00 – 2.00 g/L 0.75 – 0.99 g/L 0.50 – 0.74 g/L < 0.50 g/L OR OR OR OR 0.75 – 0.99 x LLN 0.50 – 0.74 x LLN 0.25 – 0.49 x LLN < 0.25 x LLN OR Associated with gross bleeding

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Hemoglobin (Hgb) Comment: The Hgb values in mmol/L have changed because the conversion factor used to convert g/dL to mmol/L has been changed from 0.155 to 0.6206 (the most commonly used conversion factor). For grading Hgb results obtained by an analytic method with a conversion factor other than 0.6206, the result must be converted to g/dL using the appropriate conversion factor for that lab. Adult and Pediatric 8.5 – 10.0 g/dL 7.5 – 8.4 g/dL 6.50 – 7.4 g/dL < 6.5 g/dL t 57 days 5.24 – 6.23 mmol/L 4.62–5.23 mmol/L 4.03–4.61 mmol/L < 4.03 mmol/L (HIV POSITIVE ONLY) Adult and Pediatric 10.0 – 10.9 g/dL 9.0 – 9.9 g/dL 7.0 – 8.9 g/dL < 7.0 g/dL t 57 days 6.18 – 6.79 mmol/L 5.55 - 6.17 mmol/L 4.34 - 5.54 mmol/L < 4.34 mmol/L (HIV NEGATIVE OR OR OR ONLY) Any decrease Any decrease Any decrease 2.5 – 3.4 g/dL 3.5 – 4.4 g/dL t 4.5 g/dL 1.58 – 2.13 mmol/L 2.14 – 2.78 mmol/L > 2.79 mmol/L Comment: The decrease is a decrease from baseline Infant †, 36 – 56 days 8.5 – 9.4 g/dL 7.0 – 8.4 g/dL 6.0 – 6.9 g/dL < 6.00 g/dL (HIV POSITIVE OR 5.24 – 5.86 mmol/L 4.31 – 5.23 mmol/L 3.72 – 4.30 mmol/L < 3.72 mmol/L NEGATIVE) Infant †, 22 – 35 days 9.5 – 10.5 g/dL 8.0 – 9.4 g/dL 7.0 – 7.9 g/dL < 7.00 g/dL (HIV POSITIVE OR 5.87 - 6.54 mmol/L 4.93 – 5.86 mmol/L 4.34 – 4.92 mmol/L < 4.34 mmol/L NEGATIVE) Infant † , ” 21 days 12.0 – 13.0 g/dL 10.0 – 11.9 g/dL 9.0 – 9.9 g/dL < 9.0 g/dL (HIV POSITIVE OR 7.42 – 8.09 mmol/L 6.18 – 7.41 mmol/L 5.59- 6.17 mmol/L < 5.59 mmol/L NEGATIVE) Correction: Parameter changed from “Infant < 21 days” to “Infant ” 21 days” International Normalized 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 3.0 x ULN > 3.0 x ULN Ratio of prothrombin time (INR) Methemoglobin 5.0 – 10.0% 10.1 – 15.0% 15.1 – 20.0% > 20.0% Prothrombin Time (PT) 1.1 – 1.25 x ULN 1.26 – 1.50 x ULN 1.51 – 3.00 x ULN > 3.00 x ULN Partial Thromboplastin 1.1 – 1.66 x ULN 1.67 – 2.33 x ULN 2.34 – 3.00 x ULN > 3.00 x ULN Time (PTT) Platelets, decreased 100,000 – 50,000 – 25,000 – < 25,000/mm3 124,999/mm3 99,999/mm3 49,999/mm3 < 25.000 x 109/L 100.000 x 109 – 50.000 x 109 – 25.000 x 109 – 124.999 x 109/L 99.999 x 109/L 49.999 x 109/L WBC, decreased 2,000 – 2,500/mm3 1,500 – 1,999/mm3 1,000 – 1,499/mm3 < 1,000/mm3 2.000 x 109 – 1.500 x 109 – 1.000 x 109 – < 1.000 x 109/L 2.500 x 109/L 1.999 x 109/L 1.499 x 109/L

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

CHEMISTRIES Standard International Units are listed in italics

Acidosis NA pH < normal, but t 7.3 pH < 7.3 without life- pH < 7.3 with life- threatening threatening consequences consequences Albumin, serum, low 3.0 g/dL – < LLN 2.0 – 2.9 g/dL < 2.0 g/dL NA 30 g/L – < LLN 20 – 29 g/L < 20 g/L Alkaline Phosphatase 1.25 – 2.5 x ULN† 2.6 – 5.0 x ULN† 5.1 – 10.0 x ULN† > 10.0 x ULN†

Alkalosis NA pH > normal, but d 7.5 pH > 7.5 without life- pH > 7.5 with life- threatening threatening consequences consequences ALT (SGPT) 1.25 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10.0 x ULN > 10.0 x ULN AST (SGOT) 1.25 – 2.5 x ULN 2.6 – 5.0 x ULN 5.1 – 10.0 x ULN > 10.0 x ULN Bicarbonate, serum, low 16.0 mEq/L – < LLN 11.0 – 15.9 mEq/L 8.0 – 10.9 mEq/L < 8.0 mEq/L 16.0 mmol/L – < LLN 11.0 – 15.9 mmol/L 8.0 – 10.9 mmol/L < 8.0 mmol/L

Comment: Some laboratories will report this value as Bicarbonate (HCO3) and others as Total Carbon Dioxide (CO2). These are the same tests; values should be graded according to the ranges for Bicarbonate as listed above. Bilirubin (Total) Adult and Pediatric > 1.1 – 1.5 x ULN 1.6 – 2.5 x ULN 2.6 – 5.0 x ULN > 5.0 x ULN 14 days

Infant † , ” 14 days NA 20.0 – 25.0 mg/dL 25.1 – 30.0 mg/dL > 30.0 mg/dL (non-hemolytic) 342 – 428 μmol/L 429 – 513 μmol/L > 513.0 μmol/L Infant † , ” 14 days NA NA 20.0 – 25.0 mg/dL > 25.0 mg/dL (hemolytic) 342 – 428 μmol/L > 428 μmol/L Calcium, serum, high Adult and Pediatric 10.6 – 11.5 mg/dL 11.6 – 12.5 mg/dL 12.6 – 13.5 mg/dL > 13.5 mg/dL • 7 days 2.65 – 2.88 mmol/L 2.89 – 3.13 mmol/L 3.14 – 3.38 mmol/L > 3.38 mmol/L Infant †, < 7 days 11.5 – 12.4 mg/dL 12.5 – 12.9 mg/dL 13.0 – 13.5 mg/dL > 13.5 mg/dL 2.88 – 3.10 mmol/L 3.11 – 3.23 mmol/L 3.245 – 3.38 mmol/L > 3.38 mmol/L Calcium, serum, low Adult and Pediatric 7.8 – 8.4 mg/dL 7.0 – 7.7 mg/dL 6.1 – 6.9 mg/dL < 6.1 mg/dL • 7 days 1.95 – 2.10 mmol/L 1.75 – 1.94 mmol/L 1.53 – 1.74 mmol/L < 1.53 mmol/L Infant †, < 7 days 6.5 – 7.5 mg/dL 6.0 – 6.4 mg/dL 5.50 – 5.90 mg/dL < 5.50 mg/dL 1.63 – 1.88 mmol/L 1.50 – 1.62 mmol/L 1.38 – 1.51 mmol/L < 1.38 mmol/L Comment: Do not adjust Calcium, serum, low or Calcium, serum, high for albumin

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Cardiac troponin I (cTnI) NA NA NA Levels consistent with myocardial infarction or unstable angina as defined by the manufacturer

Cardiac troponin T (cTnT) NA NA NA t 0.20 ng/mL OR Levels consistent with myocardial infarction or unstable angina as defined by the manufacturer Cholesterol (fasting) Adult • 18 years 200 – 239 mg/dL 240 – 300 mg/dL > 300 mg/dL NA 5.18 – 6.19 mmol/L 6.20 – 7.77 mmol/L > 7.77 mmol/L Pediatric < 18 years 170 – 199 mg/dL 200 – 300 mg/dL > 300 mg/dL NA 4.40 – 5.15 mmol/L 5.16 – 7.77 mmol/L > 7.77 mmol/L Creatine Kinase 3.0 – 5.9 x ULN† 6.0 – 9.9 x ULN† 10.0 – 19.9 x ULN† t 20.0 x ULN† Creatinine 1.1 – 1.3 x ULN† 1.4 – 1.8 x ULN† 1.9 – 3.4 x ULN† t 3.5 x ULN†

LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Glucose, serum, high Nonfasting 116 – 160 mg/dL 161 – 250 mg/dL 251 – 500 mg/dL > 500 mg/dL 6.44 – 8.88 mmol/L 8.89 – 13.88 mmol/L 13.89 – 27.75 mmol/L > 27.75 mmol/L Fasting 110 – 125 mg/dL 126 – 250 mg/dL 251 – 500 mg/dL > 500 mg/dL 6.11 – 6.94 mmol/L 6.95 – 13.88 mmol/L 13.89 – 27.75 mmol/L > 27.75 mmol/L Glucose, serum, low Adult and Pediatric 55 – 64 mg/dL 40 – 54 mg/dL 30 – 39 mg/dL < 30 mg/dL • 1 month 3.05 – 3.55 mmol/L 2.22 – 3.06 mmol/L 1.67 – 2.23 mmol/L < 1.67 mmol/L Infant †, < 1 month 50 – 54 mg/dL 40 – 49 mg/dL 30 – 39 mg/dL < 30 mg/dL 2.78 – 3.00 mmol/L 2.22 – 2.77 mmol/L 1.67 – 2.21 mmol/L < 1.67 mmol/L

Lactate ULN - < 2.0 x ULN t 2.0 x ULN without Increased lactate with Increased lactate with without acidosis acidosis pH < 7.3 without life- pH < 7.3 with life- threatening threatening consequences consequences

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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Comment: Added ULN to Grade 1 parameter LDL cholesterol (fasting)

Adult • 18 years 130 – 159 mg/dL 160 – 190 mg/dL t 190 mg/dL NA 3.37 – 4.12 mmol/L 4.13 – 4.90 mmol/L t 4.91 mmol/L Pediatric > 2 - < 18 110 – 129 mg/dL 130 – 189 mg/dL • 190 mg/dL NA years 2.85 – 3.34 mmol/L 3.35 – 4.90 mmol/L • 4.91 mmol/L Lipase 1.1 – 1.5 x ULN 1.6 – 3.0 x ULN 3.1 – 5.0 x ULN > 5.0 x ULN Magnesium, serum, low 1.2 – 1.4 mEq/L 0.9 – 1.1 mEq/L 0.6 – 0.8 mEq/L < 0.60 mEq/L 0.60 – 0.70 mmol/L 0.45 – 0.59 mmol/L 0.30 – 0.44 mmol/L < 0.30 mmol/L Pancreatic amylase 1.1 – 1.5 x ULN 1.6 – 2.0 x ULN 2.1 – 5.0 x ULN > 5.0 x ULN Phosphate, serum, low Adult and Pediatric 2.5 mg/dL – < LLN 2.0 – 2.4 mg/dL 1.0 – 1.9 mg/dL < 1.00 mg/dL > 14 years 0.81 mmol/L – < LLN 0.65 – 0.80 mmol/L 0.32 – 0.64 mmol/L < 0.32 mmol/L Pediatric 1 year – 14 3.0 – 3.5 mg/dL 2.5 – 2.9 mg/dL 1.5 – 2.4 mg/dL < 1.50 mg/dL years 0.97 – 1.13 mmol/L 0.81 – 0.96 mmol/L 0.48 – 0.80 mmol/L < 0.48 mmol/L Pediatric < 1 year 3.5 – 4.5 mg/dL 2.5 – 3.4 mg/dL 1.5 – 2.4 mg/dL < 1.50 mg/dL 1.13 – 1.45 mmol/L 0.81 – 1.12 mmol/L 0.48 – 0.80 mmol/L < 0.48 mmol/L Potassium, serum, high 5.6 – 6.0 mEq/L 6.1 – 6.5 mEq/L 6.6 – 7.0 mEq/L > 7.0 mEq/L 5.6 – 6.0 mmol/L 6.1 – 6.5 mmol/L 6.6 – 7.0 mmol/L > 7.0 mmol/L Potassium, serum, low 3.0 – 3.4 mEq/L 2.5 – 2.9 mEq/L 2.0 – 2.4 mEq/L < 2.0 mEq/L 3.0 – 3.4 mmol/L 2.5 – 2.9 mmol/L 2.0 – 2.4 mmol/L < 2.0 mmol/L

Sodium, serum, high 146 – 150 mEq/L 151 – 154 mEq/L 155 – 159 mEq/L t 160 mEq/L 146 – 150 mmol/L 151 – 154 mmol/L 155 – 159 mmol/L t 160 mmol/L Sodium, serum, low 130 – 135 mEq/L 125 – 129 mEq/L 121 – 124 mEq/L d 120 mEq/L 130 – 135 mmol/L 125 – 129 mmol/L 121 – 124 mmol/L d 120 mmol/L Triglycerides (fasting) NA 500 – 750 mg/dL 751 – 1,200 mg/dL > 1,200 mg/dL 5.65 – 8.48 mmol/L 8.49 – 13.56 mmol/L > 13.56 mmol/L

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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LABORATORY

PARAMETER GRADE 1 GRADE 2 GRADE 3 GRADE 4 MILD MODERATE SEVERE POTENTIALLY LIFE-THREATENING

Uric acid 7.5 – 10.0 mg/dL 10.1 – 12.0 mg/dL 12.1 – 15.0 mg/dL > 15.0 mg/dL 0.45 – 0.59 mmol/L 0.60 – 0.71 mmol/L 0.72 – 0.89 mmol/L > 0.89 mmol/L

URINALYSIS Standard International Units are listed in italics

Hematuria (microscopic) 6 – 10 RBC/HPF > 10 RBC/HPF Gross, with or without Transfusion indicated clots OR with RBC casts Proteinuria, random 1 + 2 – 3 + 4 + NA collection Proteinuria, 24 hour collection Adult and Pediatric 200 – 999 mg/24 h 1,000 – 1,999 mg/24 h 2,000 – 3,500 mg/24 h > 3,500 mg/24 h t 10 years 0.200 – 0.999 g/d 1.000 – 1.999 g/d 2.000 – 3.500 g/d > 3.500 g/d Pediatric > 3 mo - 201 – 499 mg/m2/24 h 500 – 799 mg/m2/24 h 800 – 1,000 > 1,000 mg/ m2/24 h < 10 years 0.201 – 0.499 g/d 0.500 – 0.799 g/d mg/m2/24 h > 1.000 g/d 0.800 – 1.000 g/d

Values are for term infants. Preterm infants should be assessed using local normal ranges.

† Use age and sex appropriate values (e.g., bilirubin).

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20.6 Valtrex® Summary of Product Characteristics

CONFIDENTIAL

Downloaded From: https://jamanetwork.com/ on 09/25/2021 Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) can be prepared from HIGHLIGHTS OF PRESCRIBING INFORMATION the 500 mg VALTREX Caplets. (2.3) These highlights do not include all the information needed to use VALTREX safely and effectively. See full prescribing information for ------DOSAGE FORMS AND STRENGTHS ------VALTREX. Caplets: 500 mg (unscored), 1 gram (partially scored) (3) ------CONTRAINDICATIONS ------VALTREX (valacyclovir hydrochloride) Caplets Hypersensitivity to valacyclovir (e.g., anaphylaxis), acyclovir, or any Initial U.S. Approval: 1995 component of the formulation. (4) ------RECENT MAJOR CHANGES ------WARNINGS AND PRECAUTIONS ------Warnings and Precautions, Central Nervous System x Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome Effects (5.3) 3/2010 (TTP/HUS): Has occurred in patients with advanced HIV disease and in ------INDICATIONS AND USAGE ------allogenic bone marrow transplant and renal transplant patients receiving VALTREX is a nucleoside analogue DNA polymerase inhibitor indicated for: 8 grams per day of VALTREX in clinical trials. Discontinue treatment if Adult Patients (1.1) clinical symptoms and laboratory findings consistent with TTP/HUS x Cold Sores (Herpes Labialis) occur. (5.1) x Genital Herpes x Acute renal failure: May occur in elderly patients (with or without x Treatment in immunocompetent patients (initial or recurrent reduced renal function), patients with underlying renal disease who episode) receive higher than recommended doses of VALTREX for their level of x Suppression in immunocompetent or HIV-infected patients renal function, patients who receive concomitant nephrotoxic drugs, or x Reduction of transmission inadequately hydrated patients. Use with caution in elderly patients and x Herpes Zoster reduce dosage in patients with renal impairment. (2.4, 5.2) Pediatric Patients (1.2) x Central nervous system adverse reactions (e.g., agitation, hallucinations, x Cold Sores (Herpes Labialis) confusion, and encephalopathy): May occur in both adult and pediatric patients (with or without reduced renal function) and in patients with x Chickenpox underlying renal disease who receive higher than recommended doses of Limitations of Use (1.3) VALTREX for their level of renal function. Elderly patients are more x The efficacy and safety of VALTREX have not been established in likely to have central nervous system adverse reactions. Use with immunocompromised patients other than for the suppression of genital caution in elderly patients and reduce dosage in patients with renal herpes in HIV-infected patients. impairment. (2.4, 5.3) ------DOSAGE AND ADMINISTRATION ------ADVERSE REACTIONS ------Adult Dosage (2.1) x The most common adverse reactions reported in at least one indication Cold Sores 2 grams every 12 hours for 1 day by >10% of adult patients treated with VALTREX and more commonly Genital Herpes than in patients treated with placebo are headache, nausea, and Initial episode 1 gram twice daily for 10 days abdominal pain. (6.1) Recurrent episodes 500 mg twice daily for 3 days x The only adverse reaction occurring in >10% of pediatric patients Suppressive therapy <18 years of age was headache. (6.2) Immunocompetent patients 1 gram once daily To report SUSPECTED ADVERSE REACTIONS, contact Alternate dose in patients 500 mg once daily GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or with d9 recurrences/yr www.fda.gov/medwatch. HIV-infected patients 500 mg twice daily

Reduction of transmission 500 mg once daily See 17 for PATIENT COUNSELING INFORMATION and FDA- Herpes Zoster 1 gram 3 times daily for 7 days approved patient labeling. Pediatric Dosage (2.2) Revised: March 2010 Cold Sores (t12 years of age) 2 grams every 12 hours for 1 day Chickenpox (2 to <18 years of 20 mg/kg 3 times daily for 5 days; not age) to exceed 1 gram 3 times daily

8.4 Pediatric Use FULL PRESCRIBING INFORMATION: CONTENTS* 8.5 Geriatric Use 1 INDICATIONS AND USAGE 8.6 Renal Impairment 1.1 Adult Patients 10 OVERDOSAGE 1.2 Pediatric Patients 11 DESCRIPTION 1.3 Limitations of Use 12 CLINICAL PHARMACOLOGY 2 DOSAGE AND ADMINISTRATION 12.1 Mechanism of Action 2.1 Adult Dosing Recommendations 12.3 Pharmacokinetics 2.2 Pediatric Dosing Recommendations 12.4 Microbiology 2.3 Extemporaneous Preparation of Oral 13 NONCLINICAL TOXICOLOGY Suspension 13.1 Carcinogenesis, Mutagenesis, Impairment of 2.4 Patients With Renal Impairment Fertility 3 DOSAGE FORMS AND STRENGTHS 14 CLINICAL STUDIES 4 CONTRAINDICATIONS 14.1 Cold Sores (Herpes Labialis) 5 WARNINGS AND PRECAUTIONS 14.2 Genital Herpes Infections 5.1 Thrombotic Thrombocytopenic 14.3 Herpes Zoster Purpura/Hemolytic Uremic Syndrome 14.4 Chickenpox (TTP/HUS) 16 HOW SUPPLIED/STORAGE AND HANDLING 5.2 Acute Renal Failure 17 PATIENT COUNSELING INFORMATION 5.3 Central Nervous System Effects 17.1 Importance of Adequate Hydration 6 ADVERSE REACTIONS 17.2 Cold Sores (Herpes Labialis) 6.1 Clinical Trials Experience in Adult Patients 17.3 Genital Herpes 6.2 Clinical Trials Experience in Pediatric Patients 17.4 Herpes Zoster 6.3 Postmarketing Experience 17.5 Chickenpox 7 DRUG INTERACTIONS *Sections or subsections omitted from the full prescribing information are not 8 USE IN SPECIFIC POPULATIONS listed. 8.1 Pregnancy 8.3 Nursing Mothers 1

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FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE 1.1 Adult Patients Cold Sores (Herpes Labialis): VALTREX® (valacyclovir hydrochloride) Caplets are indicated for treatment of cold sores (herpes labialis). The efficacy of VALTREX initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Genital Herpes: Initial Episode: VALTREX is indicated for treatment of the initial episode of genital herpes in immunocompetent adults. The efficacy of treatment with VALTREX when initiated more than 72 hours after the onset of signs and symptoms has not been established. Recurrent Episodes: VALTREX is indicated for treatment of recurrent episodes of genital herpes in immunocompetent adults. The efficacy of treatment with VALTREX when initiated more than 24 hours after the onset of signs and symptoms has not been established. Suppressive Therapy: VALTREX is indicated for chronic suppressive therapy of recurrent episodes of genital herpes in immunocompetent and in HIV-infected adults. The efficacy and safety of VALTREX for the suppression of genital herpes beyond 1 year in immunocompetent patients and beyond 6 months in HIV-infected patients have not been established. Reduction of Transmission: VALTREX is indicated for the reduction of transmission of genital herpes in immunocompetent adults. The efficacy of VALTREX for the reduction of transmission of genital herpes beyond 8 months in discordant couples has not been established. The efficacy of VALTREX for the reduction of transmission of genital herpes in individuals with multiple partners and non-heterosexual couples has not been established. Safer sex practices should be used with suppressive therapy (see current Centers for Disease Control and Prevention [CDC] Sexually Transmitted Diseases Treatment Guidelines). Herpes Zoster: VALTREX is indicated for the treatment of herpes zoster (shingles) in immunocompetent adults. The efficacy of VALTREX when initiated more than 72 hours after the onset of rash and the efficacy and safety of VALTREX for treatment of disseminated herpes zoster have not been established. 1.2 Pediatric Patients Cold Sores (Herpes Labialis): VALTREX is indicated for the treatment of cold sores (herpes labialis) in pediatric patients •12 years of age. The efficacy of VALTREX initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer) has not been established. Chickenpox: VALTREX is indicated for the treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age. Based on efficacy data from clinical

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 studies with oral acyclovir, treatment with VALTREX should be initiated within 24 hours after the onset of rash [see Clinical Studies (14.4)]. 1.3 Limitations of Use The efficacy and safety of VALTREX have not been established in: x Immunocompromised patients other than for the suppression of genital herpes in HIV-infected patients with a CD4+ cell count •100 cells/mm3. x Patients <12 years of age with cold sores (herpes labialis). x Patients <2 years of age or t18 years of age with chickenpox. x Patients <18 years of age with genital herpes. x Patients <18 years of age with herpes zoster. x Neonates and infants as suppressive therapy following neonatal herpes simplex virus (HSV) infection.

2 DOSAGE AND ADMINISTRATION x VALTREX may be given without regard to meals. x Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) may be prepared extemporaneously from 500 mg VALTREX Caplets for use in pediatric patients for whom a solid dosage form is not appropriate [see Dosage and Administration (2.3)]. 2.1 Adult Dosing Recommendations Cold Sores (Herpes Labialis): The recommended dosage of VALTREX for treatment of cold sores is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). Genital Herpes: Initial Episode: The recommended dosage of VALTREX for treatment of initial genital herpes is 1 gram twice daily for 10 days. Therapy was most effective when administered within 48 hours of the onset of signs and symptoms. Recurrent Episodes: The recommended dosage of VALTREX for treatment of recurrent genital herpes is 500 mg twice daily for 3 days. Initiate treatment at the first sign or symptom of an episode. Suppressive Therapy: The recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 1 gram once daily in patients with normal immune function. In patients with a history of 9 or fewer recurrences per year, an alternative dose is 500 mg once daily. In HIV-infected patients with a CD4+ cell count t100 cells/mm3, the recommended dosage of VALTREX for chronic suppressive therapy of recurrent genital herpes is 500 mg twice daily. Reduction of Transmission: The recommended dosage of VALTREX for reduction of transmission of genital herpes in patients with a history of 9 or fewer recurrences per year is 500 mg once daily for the source partner. Herpes Zoster: The recommended dosage of VALTREX for treatment of herpes zoster is 1 gram 3 times daily for 7 days. Therapy should be initiated at the earliest sign or symptom of

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 herpes zoster and is most effective when started within 48 hours of the onset of rash. 2.2 Pediatric Dosing Recommendations Cold Sores (Herpes Labialis): The recommended dosage of VALTREX for the treatment of cold sores in pediatric patients •12 years of age is 2 grams twice daily for 1 day taken 12 hours apart. Therapy should be initiated at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). Chickenpox: The recommended dosage of VALTREX for treatment of chickenpox in immunocompetent pediatric patients 2 to <18 years of age is 20 mg/kg administered 3 times daily for 5 days. The total dose should not exceed 1 gram 3 times daily. Therapy should be initiated at the earliest sign or symptom [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. 2.3 Extemporaneous Preparation of Oral Suspension Ingredients and Preparation per USP-NF: VALTREX Caplets 500 mg, cherry flavor, and Suspension Structured Vehicle USP-NF (SSV). Valacyclovir oral suspension (25 mg/mL or 50 mg/mL) should be prepared in lots of 100 mL. Prepare Suspension at Time of Dispensing as Follows: x Prepare SSV according to the USP-NF. x Using a pestle and mortar, grind the required number of VALTREX 500 mg Caplets until a fine powder is produced (5 VALTREX Caplets for 25 mg/mL suspension; 10 VALTREX Caplets for 50 mg/mL suspension). x Gradually add approximately 5 mL aliquots of SSV to the mortar and triturate the powder until a paste has been produced. Ensure that the powder has been adequately wetted. x Continue to add approximately 5 mL aliquots of SSV to the mortar, mixing thoroughly between additions, until a concentrated suspension is produced, to a minimum total quantity of 20 mL SSV and a maximum total quantity of 40 mL SSV for both the 25 mg/mL and 50 mg/mL suspensions. x Transfer the mixture to a suitable 100 mL measuring flask. x Transfer the cherry flavor* to the mortar and dissolve in approximately 5 mL of SSV. Once dissolved, add to the measuring flask. x Rinse the mortar at least 3 times with approximately 5 mL aliquots of SSV, transferring the rinsing to the measuring flask between additions. x Make the suspension to volume (100 mL) with SSV and shake thoroughly to mix. x Transfer the suspension to an amber glass medicine bottle with a child-resistant closure. x The prepared suspension should be labeled with the following information “Shake well before using. Store suspension between 2q to 8qC (36q to 46qF) in a refrigerator. Discard after 28 days.” *The amount of cherry flavor added is as instructed by the suppliers of the cherry flavor. 2.4 Patients With Renal Impairment Dosage recommendations for adult patients with reduced renal function are provided in Table 1 [see Use in Specific Populations (8.5, 8.6), Clinical Pharmacology (12.3)]. Data are not

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Table 1. VALTREX Dosage Recommendations for Adults With Renal Impairment Normal Dosage Creatinine Clearance (mL/min) Regimen (Creatinine Clearance Indications t50 mL/min) 30-49 10-29 <10 Cold sores (Herpes Two 2 gram Two 1 gram Two 500 mg 500 mg single labialis) doses taken doses taken doses taken dose 12 hours apart 12 hours apart 12 hours apart Do not exceed 1 day of treatment. Genital herpes: 1 gram every no reduction 1 gram every 500 mg every Initial episode 12 hours 24 hours 24 hours Genital herpes: 500 mg every no reduction 500 mg every 500 mg every Recurrent episode 12 hours 24 hours 24 hours Genital herpes: Suppressive therapy Immunocompetent 1 gram every no reduction 500 mg every 500 mg every patients 24 hours 24 hours 24 hours

Alternate dose for 500 mg every no reduction 500 mg every 500 mg every immunocompetent 24 hours 48 hours 48 hours patients with d9 recurrences/year

HIV-infected patients 500 mg every no reduction 500 mg every 500 mg every 12 hours 24 hours 24 hours Herpes zoster 1 gram every 1 gram every 1 gram every 500 mg every 8 hours 12 hours 24 hours 24 hours

Hemodialysis: Patients requiring hemodialysis should receive the recommended dose of VALTREX after hemodialysis. During hemodialysis, the half-life of acyclovir after administration of VALTREX is approximately 4 hours. About one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Peritoneal Dialysis: There is no information specific to administration of VALTREX in patients receiving peritoneal dialysis. The effect of chronic ambulatory peritoneal dialysis (CAPD) and continuous arteriovenous hemofiltration/dialysis (CAVHD) on acyclovir

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 pharmacokinetics has been studied. The removal of acyclovir after CAPD and CAVHD is less pronounced than with hemodialysis, and the pharmacokinetic parameters closely resemble those observed in patients with end-stage renal disease (ESRD) not receiving hemodialysis. Therefore, supplemental doses of VALTREX should not be required following CAPD or CAVHD.

3 DOSAGE FORMS AND STRENGTHS Caplets: x 500 mg: blue, film-coated, capsule-shaped tablets printed with “VALTREX 500 mg.” x 1 gram: blue, film-coated, capsule-shaped tablets, with a partial scorebar on both sides, printed with “VALTREX 1 gram.”

4 CONTRAINDICATIONS VALTREX is contraindicated in patients who have had a demonstrated clinically significant hypersensitivity reaction (e.g., anaphylaxis) to valacyclovir, acyclovir, or any component of the formulation [see Adverse Reactions (6.3)].

5 WARNINGS AND PRECAUTIONS 5.1 Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome (TTP/HUS) TTP/HUS, in some cases resulting in death, has occurred in patients with advanced HIV disease and also in allogeneic bone marrow transplant and renal transplant recipients participating in clinical trials of VALTREX at doses of 8 grams per day. Treatment with VALTREX should be stopped immediately if clinical signs, symptoms, and laboratory abnormalities consistent with TTP/HUS occur. 5.2 Acute Renal Failure Cases of acute renal failure have been reported in: x Elderly patients with or without reduced renal function. Caution should be exercised when administering VALTREX to geriatric patients, and dosage reduction is recommended for those with impaired renal function [see Dosage and Administration (2.4), Use in Specific Populations (8.5)]. x Patients with underlying renal disease who received higher than recommended doses of VALTREX for their level of renal function. Dosage reduction is recommended when administering VALTREX to patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.6)]. x Patients receiving other nephrotoxic drugs. Caution should be exercised when administering VALTREX to patients receiving potentially nephrotoxic drugs. x Patients without adequate hydration. Precipitation of acyclovir in renal tubules may occur when the solubility (2.5 mg/mL) is exceeded in the intratubular fluid. Adequate hydration should be maintained for all patients. In the event of acute renal failure and anuria, the patient may benefit from hemodialysis until renal function is restored [see Dosage and Administration (2.4), Adverse Reactions (6.3)].

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 5.3 Central Nervous System Effects Central nervous system adverse reactions, including agitation, hallucinations, confusion, delirium, seizures, and encephalopathy, have been reported in both adult and pediatric patients with or without reduced renal function and in patients with underlying renal disease who received higher than recommended doses of VALTREX for their level of renal function. Elderly patients are more likely to have central nervous system adverse reactions. VALTREX should be discontinued if central nervous system adverse reactions occur [see Adverse Reactions (6.3), Use in Specific Populations (8.5, 8.6)].

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: x Thrombotic Thrombocytopenic Purpura/Hemolytic Uremic Syndrome [see Warnings and Precautions (5.1)]. x Acute Renal Failure [see Warnings and Precautions (5.2)]. x Central Nervous System Effects [see Warnings and Precautions (5.3)]. The most common adverse reactions reported in at least 1 indication by >10% of adult patients treated with VALTREX and observed more frequently with VALTREX compared to placebo are headache, nausea, and abdominal pain. The only adverse reaction reported in >10% of pediatric patients <18 years of age was headache. 6.1 Clinical Trials Experience in Adult Patients Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. Cold Sores (Herpes Labialis): In clinical studies for the treatment of cold sores, the adverse reactions reported by patients receiving VALTREX 2 grams twice daily (n = 609) or placebo (n = 609) for 1 day, respectively, included headache (14%, 10%) and dizziness (2%, 1%). The frequencies of abnormal ALT (>2 x ULN) were 1.8% for patients receiving VALTREX compared with 0.8% for placebo. Other laboratory abnormalities (hemoglobin, white blood cells, alkaline phosphatase, and serum creatinine) occurred with similar frequencies in the 2 groups. Genital Herpes: Initial Episode: In a clinical study for the treatment of initial episodes of genital herpes, the adverse reactions reported by t5% of patients receiving VALTREX 1 gram twice daily for 10 days (n = 318) or oral acyclovir 200 mg 5 times daily for 10 days (n = 318), respectively, included headache (13%, 10%) and nausea (6%, 6%). For the incidence of laboratory abnormalities see Table 2. Recurrent Episodes: In 3 clinical studies for the episodic treatment of recurrent genital herpes, the adverse reactions reported by t5% of patients receiving VALTREX 500 mg twice daily for 3 days (n = 402), VALTREX 500 mg twice daily for 5 days (n = 1,136) or placebo (n = 259), respectively, included headache (16%, 11%, 14%) and nausea (5%, 4%, 5%).

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 For the incidence of laboratory abnormalities see Table 2. Suppressive Therapy: Suppression of Recurrent Genital Herpes in Immunocompetent Adults: In a clinical study for the suppression of recurrent genital herpes infections, the adverse reactions reported by patients receiving VALTREX 1 gram once daily (n = 269), VALTREX 500 mg once daily (n = 266), or placebo (n = 134), respectively, included headache (35%, 38%, 34%), nausea (11%, 11%, 8%), abdominal pain (11%, 9%, 6%), dysmenorrhea (8%, 5%, 4%), depression (7%, 5%, 5%), arthralgia (6%, 5%, 4%), vomiting (3%, 3%, 2%), and dizziness (4%, 2%, 1%). For the incidence of laboratory abnormalities see Table 2. Suppression of Recurrent Genital Herpes in HIV-Infected Patients: In HIV-infected patients, frequently reported adverse reactions for VALTREX (500 mg twice daily; n = 194, median days on therapy = 172) and placebo (n = 99, median days on therapy = 59), respectively, included headache (13%, 8%), fatigue (8%, 5%), and rash (8%, 1%). Post-randomization laboratory abnormalities that were reported more frequently in valacyclovir subjects versus placebo included elevated alkaline phosphatase (4%, 2%), elevated ALT (14%, 10%), elevated AST (16%, 11%), decreased neutrophil counts (18%, 10%), and decreased platelet counts (3%, 0%), respectively. Reduction of Transmission: In a clinical study for the reduction of transmission of genital herpes, the adverse reactions reported by patients receiving VALTREX 500 mg once daily (n = 743) or placebo once daily (n = 741), respectively, included headache (29%, 26%), nasopharyngitis (16%, 15%), and upper respiratory tract infection (9%, 10%). Herpes Zoster: In 2 clinical studies for the treatment of herpes zoster, the adverse reactions reported by patients receiving VALTREX 1 gram 3 times daily for 7 to 14 days (n = 967) or placebo (n = 195), respectively, included nausea (15%, 8%), headache (14%, 12%), vomiting (6%, 3%), dizziness (3%, 2%), and abdominal pain (3%, 2%). For the incidence of laboratory abnormalities see Table 2.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 2. Incidence (%) of Laboratory Abnormalities in Herpes Zoster and Genital Herpes Study Populations Herpes Zoster Genital Herpes Treatment Genital Herpes Suppression VALTREX VALTREX VALTREX VALTREX VALTREX 1 gram Place- 1 gram 500 mg Place- 1 gram 500 mg Place- Laboratory 3 times daily bo twice daily twice daily bo once daily once daily bo Abnormality (n = 967) (n = 195) (n = 1,194) (n = 1,159) (n = 439) (n = 269) (n = 266) (n = 134) Hemoglobin 0.8% 0% 0.3% 0.2% 0% 0% 0.8% 0.8% (<0.8 x LLN) White blood cells 1.3% 0.6% 0.7% 0.6% 0.2% 0.7% 0.8% 1.5% (<0.75 x LLN) Platelet count 1.0% 1.2% 0.3% 0.1% 0.7% 0.4% 1.1% 1.5% (<100,000/mm3) AST (SGOT) 1.0% 0% 1.0% a 0.5% 4.1% 3.8% 3.0% (>2 x ULN) Serum creatinine 0.2% 0% 0.7% 0% 0% 0% 0% 0% (>1.5 x ULN) a Data were not collected prospectively. LLN = Lower limit of normal. ULN = Upper limit of normal.

6.2 Clinical Trials Experience in Pediatric Patients The safety profile of VALTREX has been studied in 177 pediatric patients 1 month to <18 years of age. Sixty-five of these pediatric patients, 12 to <18 years of age, received oral caplets for 1 to 2 days for treatment of cold sores. The remaining 112 pediatric patients, 1 month to <12 years of age, participated in 3 pharmacokinetic and safety studies and received valacyclovir oral suspension. Fifty-one of these 112 pediatric patients received oral suspension for 3 to 6 days. The frequency, intensity, and nature of clinical adverse reactions and laboratory abnormalities were similar to those seen in adults. Pediatric Patients 12 to <18 Years of Age (Cold Sores): In clinical studies for the treatment of cold sores, the adverse reactions reported by adolescent patients receiving VALTREX 2 grams twice daily for 1 day, or VALTREX 2 grams twice daily for 1 day followed by 1 gram twice daily for 1 day (n = 65, across both dosing groups), or placebo (n = 30), respectively, included headache (17%, 3%) and nausea (8%, 0%). Pediatric Patients 1 Month to <12 Years of Age: Adverse events reported in more than 1 subject across the 3 pharmacokinetic and safety studies in children 1 month to <12 years of age were diarrhea (5%), pyrexia (4%), dehydration (2%), herpes simplex (2%), and rhinorrhea (2%). No clinically meaningful changes in laboratory values were observed. 6.3 Postmarketing Experience

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 In addition to adverse events reported from clinical trials, the following events have been identified during postmarketing use of VALTREX. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. These events have been chosen for inclusion due to a combination of their seriousness, frequency of reporting, or potential causal connection to VALTREX. General: Facial edema, hypertension, tachycardia. Allergic: Acute hypersensitivity reactions including anaphylaxis, angioedema, dyspnea, pruritus, rash, and urticaria [see Contraindications (4)]. CNS Symptoms: Aggressive behavior; agitation; ataxia; coma; confusion; decreased consciousness; dysarthria; encephalopathy; mania; and psychosis, including auditory and visual hallucinations, seizures, tremors [see Warnings and Precautions (5.3), Use in Specific Populations (8.5), (8.6)]. Eye: Visual abnormalities. Gastrointestinal: Diarrhea. Hepatobiliary Tract and Pancreas: Liver enzyme abnormalities, hepatitis. Renal: Renal failure, renal pain (may be associated with renal failure) [see Warnings and Precautions (5.2), Use in Specific Populations (8.5), (8.6)]. Hematologic: Thrombocytopenia, aplastic anemia, leukocytoclastic vasculitis, TTP/HUS [see Warnings and Precautions (5.1)]. Skin: Erythema multiforme, rashes including photosensitivity, alopecia.

7 DRUG INTERACTIONS No clinically significant drug-drug or drug-food interactions with VALTREX are known [see Clinical Pharmacology (12.3)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category B. There are no adequate and well-controlled studies of VALTREX or acyclovir in pregnant women. Based on prospective pregnancy registry data on 749 pregnancies, the overall rate of birth defects in infants exposed to acyclovir in-utero appears similar to the rate for infants in the general population. VALTREX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. A prospective epidemiologic registry of acyclovir use during pregnancy was established in 1984 and completed in April 1999. There were 749 pregnancies followed in women exposed to systemic acyclovir during the first trimester of pregnancy resulting in 756 outcomes. The occurrence rate of birth defects approximates that found in the general population. However, the small size of the registry is insufficient to evaluate the risk for less common defects or to permit reliable or definitive conclusions regarding the safety of acyclovir in pregnant women and their developing fetuses. Animal reproduction studies performed at oral doses that provided up to 10 and 7 times the human plasma levels during the period of major organogenesis in rats and rabbits,

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 respectively, revealed no evidence of teratogenicity. 8.3 Nursing Mothers Following oral administration of a 500 mg dose of VALTREX to 5 nursing mothers, peak

acyclovir concentrations (Cmax) in breast milk ranged from 0.5 to 2.3 times (median 1.4) the corresponding maternal acyclovir serum concentrations. The acyclovir breast milk AUC ranged from 1.4 to 2.6 times (median 2.2) maternal serum AUC. A 500 mg maternal dosage of VALTREX twice daily would provide a nursing infant with an oral acyclovir dosage of approximately 0.6 mg/kg/day. This would result in less than 2% of the exposure obtained after administration of a standard neonatal dose of 30 mg/kg/day of intravenous acyclovir to the nursing infant. Unchanged valacyclovir was not detected in maternal serum, breast milk, or infant urine. Caution should be exercised when VALTREX is administered to a nursing woman. 8.4 Pediatric Use VALTREX is indicated for treatment of cold sores in pediatric patients t12 years of age and for treatment of chickenpox in pediatric patients 2 to <18 years of age [see Indications and Usage (1.2), Dosage and Administration (2.2)]. The use of VALTREX for treatment of cold sores is based on 2 double-blind, placebo-controlled clinical trials in healthy adults and adolescents (t12 years of age) with a history of recurrent cold sores [see Clinical Studies (14.1)]. The use of VALTREX for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label trial with valacyclovir and supported by efficacy and safety data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients with chickenpox [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. The efficacy and safety of valacyclovir have not been established in pediatric patients: x <12 years of age with cold sores x <18 years of age with genital herpes x <18 years of age with herpes zoster x <2 years of age with chickenpox x for suppressive therapy following neonatal HSV infection. The pharmacokinetic profile and safety of valacyclovir oral suspension in children <12 years of age were studied in 3 open-label studies. No efficacy evaluations were conducted in any of the 3 studies. Study 1 was a single-dose pharmacokinetic, multiple-dose safety study in 27 pediatric patients 1 to <12 years of age with clinically suspected varicella-zoster virus (VZV) infection [see Dosage and Administration (2.2), Adverse Reactions (6.2), Clinical Pharmacology (12.3), Clinical Studies (14.4)]. Study 2 was a single-dose pharmacokinetic and safety study in pediatric patients 1 month to <6 years of age who had an active herpes virus infection or who were at risk for herpes virus infection. Fifty-seven subjects were enrolled and received a single dose of 25 mg/kg valacyclovir

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 oral suspension. In infants and children 3 months to 6 years of age, this dose provided comparable systemic acyclovir exposures to that from a 1 gram dose of valacyclovir in adults (historical data). In infants 1 month to <3 months of age, mean acyclovir exposures resulting

from a 25 mg/kg dose were higher (Cmax: n30%, AUC: n60%) than acyclovir exposures following a 1 gram dose of valacyclovir in adults. Acyclovir is not approved for suppressive therapy in infants and children following neonatal HSV infections; therefore valacyclovir is not recommended for this indication because efficacy cannot be extrapolated from acyclovir. Study 3 was a single-dose pharmacokinetic, multiple-dose safety study in 28 pediatric patients 1 to <12 years of age with clinically suspected HSV infection. None of the children enrolled in this study had genital herpes. Each subject was dosed with valacyclovir oral suspension, 10 mg/kg twice daily for 3 to 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of recurrent genital herpes. The mean projected daily acyclovir systemic exposures in pediatric patients across all age-groups (1 to <12 years of age) were lower

(Cmax: p20%, AUC: p33%) compared with the acyclovir systemic exposures in adults receiving valacyclovir 500 mg twice daily, but were higher (daily AUC: n16%) than systemic exposures in adults receiving acyclovir 200 mg 5 times daily. Insufficient data are available to support valacyclovir for the treatment of recurrent genital herpes in this age-group because clinical information on recurrent genital herpes in young children is limited; therefore, extrapolating efficacy data from adults to this population is not possible. Moreover, valacyclovir has not been studied in children 1 to 12 years of age with recurrent genital herpes. 8.5 Geriatric Use Of the total number of subjects in clinical studies of VALTREX, 906 were 65 and over, and 352 were 75 and over. In a clinical study of herpes zoster, the duration of pain after healing (post-herpetic neuralgia) was longer in patients 65 and older compared with younger adults. Elderly patients are more likely to have reduced renal function and require dose reduction. Elderly patients are also more likely to have renal or CNS adverse events [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3), Clinical Pharmacology (12.3)]. 8.6 Renal Impairment Dosage reduction is recommended when administering VALTREX to patients with renal impairment [see Dosage and Administration (2.4), Warnings and Precautions (5.2, 5.3)].

10 OVERDOSAGE Caution should be exercised to prevent inadvertent overdose [see Use in Specific Populations (8.5), (8.6)]. 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 [see Dosage and Administration (2.4)].

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 11 DESCRIPTION VALTREX (valacyclovir hydrochloride) is the hydrochloride salt of the L-valyl ester of the antiviral drug acyclovir. VALTREX Caplets are for oral administration. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir and the inactive ingredients carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide. The blue, film-coated caplets are printed with edible white ink. The chemical name of valacyclovir hydrochloride is L-valine, 2-[(2-amino-1,6-dihydro-6- oxo-9H-purin-9-yl)methoxy]ethyl ester, monohydrochloride. It has the following structural formula:

Valacyclovir hydrochloride is a white to off-white powder with the molecular formula

C13H20N6O4•HCl and a molecular weight of 360.80. The maximum solubility in water at 25°C is

174 mg/mL. The pkas for valacyclovir hydrochloride are 1.90, 7.47, and 9.43.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Valacyclovir is an antiviral drug [see Clinical Pharmacology (12.4)]. 12.3 Pharmacokinetics The pharmacokinetics of valacyclovir and acyclovir after oral administration of VALTREX have been investigated in 14 volunteer studies involving 283 adults and in 3 studies involving 112 pediatric subjects from 1 month to <12 years of age. Pharmacokinetics in Adults: Absorption and Bioavailability: After oral administration, valacyclovir hydrochloride is rapidly absorbed from the gastrointestinal tract and nearly completely converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. The absolute bioavailability of acyclovir after administration of VALTREX is 54.5% r 9.1% as determined following a 1 gram oral dose of VALTREX and a 350 mg intravenous acyclovir dose to 12 healthy volunteers. Acyclovir bioavailability from the administration of VALTREX is not altered by administration with food (30 minutes after an 873 Kcal breakfast, which included 51 grams of fat). Acyclovir pharmacokinetic parameter estimates following administration of VALTREX

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 to healthy adult volunteers are presented in Table 3. There was a less than dose-proportional

increase in acyclovir maximum concentration (Cmax) and area under the acyclovir concentration-time curve (AUC) after single-dose and multiple-dose administration (4 times daily) of VALTREX from doses between 250 mg to 1 gram. There is no accumulation of acyclovir after the administration of valacyclovir at the recommended dosage regimens in adults with normal renal function.

Table 3. Mean (rSD) Plasma Acyclovir Pharmacokinetic Parameters Following Administration of VALTREX to Healthy Adult Volunteers Single-Dose Administration Multiple-Dose Administrationa (N = 8) (N = 24, 8 per treatment arm) Cmax (rSD) AUC (rSD) Cmax (rSD) AUC (rSD) Dose (mcg/mL) (hrƔmcg/mL) (mcg/mL) (hrƔmcg/mL) 100 mg 0.83 (r0.14) 2.28 (r0.40) ND ND 250 mg 2.15 (r0.50) 5.76 (r0.60) 2.11 (r0.33) 5.66 (r1.09) 500 mg 3.28 (r0.83) 11.59 (r1.79) 3.69 (r0.87) 9.88 (r2.01) 750 mg 4.17 (r1.14) 14.11 (r3.54) ND ND 1,000 mg 5.65 (r2.37) 19.52 (r6.04) 4.96 (r0.64) 15.70 (r2.27) a Administered 4 times daily for 11 days. ND = not done.

Distribution: The binding of valacyclovir to human plasma proteins ranges from 13.5% to 17.9%. The binding of acyclovir to human plasma proteins ranges from 9% to 33%. Metabolism: Valacyclovir is converted to acyclovir and L-valine by first-pass intestinal and/or hepatic metabolism. Acyclovir is converted to a small extent to inactive metabolites by aldehyde oxidase and by alcohol and aldehyde dehydrogenase. Neither valacyclovir nor acyclovir is metabolized by cytochrome P450 enzymes. Plasma concentrations of unconverted valacyclovir are low and transient, generally becoming non-quantifiable by 3 hours after administration. Peak plasma valacyclovir concentrations are generally less than 0.5 mcg/mL at all doses. After single-dose administration of 1 gram of VALTREX, average plasma valacyclovir concentrations observed were 0.5, 0.4, and 0.8 mcg/mL in patients with hepatic dysfunction, renal insufficiency, and in healthy volunteers who received concomitant cimetidine and probenecid, respectively. Elimination: The pharmacokinetic disposition of acyclovir delivered by valacyclovir is consistent with previous experience from intravenous and oral acyclovir. Following the oral administration of a single 1 gram dose of radiolabeled valacyclovir to 4 healthy subjects, 46% and 47% of administered radioactivity was recovered in urine and feces, respectively, over 96 hours. Acyclovir accounted for 89% of the radioactivity excreted in the urine. Renal clearance of acyclovir following the administration of a single 1 gram dose of VALTREX to 12 healthy volunteers was approximately 255 ± 86 mL/min which represents 42% of total acyclovir

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 apparent plasma clearance. The plasma elimination half-life of acyclovir typically averaged 2.5 to 3.3 hours in all studies of VALTREX in volunteers with normal renal function. Specific Populations: Renal Impairment: Reduction in dosage is recommended in patients with renal impairment [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)]. Following administration of VALTREX to volunteers with ESRD, the average acyclovir half-life is approximately 14 hours. During hemodialysis, the acyclovir half-life is approximately 4 hours. Approximately one third of acyclovir in the body is removed by dialysis during a 4-hour hemodialysis session. Apparent plasma clearance of acyclovir in dialysis patients was 86.3 r 21.3 mL/min/1.73 m2 compared with 679.16 r 162.76 mL/min/1.73 m2 in healthy volunteers. Hepatic Impairment: Administration of VALTREX to patients with moderate (biopsy-proven cirrhosis) or severe (with and without ascites and biopsy-proven cirrhosis) liver disease indicated that the rate but not the extent of conversion of valacyclovir to acyclovir is reduced, and the acyclovir half-life is not affected. Dosage modification is not recommended for patients with cirrhosis. HIV Disease: In 9 patients with HIV disease and CD4+ cell counts <150 cells/mm3 who received VALTREX at a dosage of 1 gram 4 times daily for 30 days, the pharmacokinetics of valacyclovir and acyclovir were not different from that observed in healthy volunteers. Geriatrics: After single-dose administration of 1 gram of VALTREX in healthy geriatric volunteers, the half-life of acyclovir was 3.11 r 0.51 hours, compared with 2.91 r 0.63 hours in healthy younger adult volunteers. The pharmacokinetics of acyclovir following single- and multiple-dose oral administration of VALTREX in geriatric volunteers varied with renal function. Dose reduction may be required in geriatric patients, depending on the underlying renal status of the patient [see Dosage and Administration (2.4), Use in Specific Populations (8.5), (8.6)]. Pediatrics: Acyclovir pharmacokinetics have been evaluated in a total of 98 pediatric patients (1 month to <12 years of age) following administration of the first dose of an extemporaneous oral suspension of valacyclovir [see Adverse Reactions (6.2), Use in Specific Populations (8.4)]. Acyclovir pharmacokinetic parameter estimates following a 20 mg/kg dose are provided in Table 4.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 Table 4. Mean (rSD) Plasma Acyclovir Pharmacokinetic Parameter Estimates Following First-Dose Administration of 20 mg/kg Valacyclovir Oral Suspension to Pediatric Patients vs. 1 Gram Single Dose of VALTREX to Adults Pediatric Patients Adults (20 mg/kg Oral Suspension) 1 gram Solid Dose of a 1 - <2 yr 2 - <6 yr 6 - <12 yr VALTREX Parameter (N = 6) (N = 12) (N = 8) (N = 15) AUC (mcg•hr/mL) 14.4 (±6.26) 10.1 (±3.35) 13.1 (±3.43) 17.2 (±3.10) Cmax (mcg/mL) 4.03 (±1.37) 3.75 (±1.14) 4.71 (±1.20) 4.72 (±1.37) a Historical estimates using pediatric pharmacokinetic sampling schedule.

Drug Interactions: When VALTREX is coadministered with antacids, cimetidine and/or probenicid, digoxin, or thiazide diuretics in patients with normal renal function, the effects are not considered to be of clinical significance (see below). Therefore, when VALTREX is coadministered with these drugs in patients with normal renal function, no dosage adjustment is recommended. Antacids: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of a single dose of antacids (Al3+ or Mg++).

Cimetidine: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 8% and 32%, respectively, after a single dose of cimetidine (800 mg).

Cimetidine Plus Probenecid: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 30% and 78%, respectively, after a combination of cimetidine and probenecid, primarily due to a reduction in renal clearance of acyclovir. Digoxin: The pharmacokinetics of digoxin were not affected by coadministration of VALTREX 1 gram 3 times daily, and the pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) was unchanged by coadministration of digoxin (2 doses of 0.75 mg).

Probenecid: Acyclovir Cmax and AUC following a single dose of VALTREX (1 gram) increased by 22% and 49%, respectively, after probenecid (1 gram). Thiazide Diuretics: The pharmacokinetics of acyclovir after a single dose of VALTREX (1 gram) were unchanged by coadministration of multiple doses of thiazide diuretics. 12.4 Microbiology Mechanism of Action: Valacyclovir is a nucleoside analogue DNA polymerase inhibitor. Valacyclovir hydrochloride is rapidly converted to acyclovir which has demonstrated antiviral activity against HSV types 1 (HSV-1) and 2 (HSV-2) and VZV both in cell culture and in vivo. The inhibitory activity of acyclovir is highly selective due to its affinity for the enzyme thymidine kinase (TK) encoded by HSV and VZV. This viral enzyme converts acyclovir into acyclovir monophosphate, a nucleotide analogue. The monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. In biochemical assays, acyclovir triphosphate inhibits replication of herpes viral DNA. This is accomplished in 3 ways: 1) competitive inhibition of viral DNA polymerase, 2) incorporation

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 and termination of the growing viral DNA chain, and 3) inactivation of the viral DNA polymerase. The greater antiviral activity of acyclovir against HSV compared with VZV is due to its more efficient phosphorylation by the viral TK. Antiviral Activities: The quantitative relationship between the cell culture susceptibility of herpesviruses to antivirals and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. Sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell

culture (EC50), vary greatly depending upon a number of factors. Using plaque-reduction assays, the EC50 values against herpes simplex virus isolates range from 0.09 to 60 PM (0.02 to

13.5 mcg/mL) for HSV-1 and from 0.04 to 44 PM (0.01 to 9.9 mcg/mL) for HSV-2. The EC50 values for acyclovir against most laboratory strains and clinical isolates of VZV range from 0.53 to 48 PM (0.12 to 10.8 mcg/mL). Acyclovir also demonstrates activity against the Oka vaccine

strain of VZV with a mean EC50 of 6 PM (1.35 mcg/mL). Resistance: Resistance of HSV and VZV to acyclovir can result from qualitative and quantitative changes in the viral TK and/or DNA polymerase. Clinical isolates of VZV with reduced susceptibility to acyclovir have been recovered from patients with AIDS. In these cases, TK-deficient mutants of VZV have been recovered. Resistance of HSV and VZV to acyclovir occurs by the same mechanisms. While most of the acyclovir-resistant mutants isolated thus far from immunocompromised patients have been found to be TK-deficient mutants, other mutants involving the viral TK gene (TK partial and TK altered) and DNA polymerase have also been isolated. TK-negative mutants may cause severe disease in immunocompromised patients. The possibility of viral resistance to valacyclovir (and therefore, to acyclovir) should be considered in patients who show poor clinical response during therapy.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility The data presented below include references to the steady-state acyclovir AUC observed in humans treated with 1 gram VALTREX given orally 3 times a day to treat herpes zoster. Plasma drug concentrations in animal studies are expressed as multiples of human exposure to acyclovir [see Clinical Pharmacology (12.3)]. Valacyclovir was noncarcinogenic in lifetime carcinogenicity bioassays at single daily doses (gavage) of valacyclovir giving plasma acyclovir concentrations equivalent to human levels in the mouse bioassay and 1.4 to 2.3 times human levels in the rat bioassay. There was no significant difference in the incidence of tumors between treated and control animals, nor did valacyclovir shorten the latency of tumors. Valacyclovir was tested in 5 genetic toxicity assays. An Ames assay was negative in the absence or presence of metabolic activation. Also negative were an in vitro cytogenetic study with human lymphocytes and a rat cytogenetic study. In the mouse lymphoma assay, valacyclovir was not mutagenic in the absence of

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 metabolic activation. In the presence of metabolic activation (76% to 88% conversion to acyclovir), valacyclovir was mutagenic. Valacyclovir was mutagenic in a mouse micronucleus assay. Valacyclovir did not impair fertility or reproduction in rats at 6 times human plasma levels.

14 CLINICAL STUDIES 14.1 Cold Sores (Herpes Labialis) Two double-blind, placebo-controlled clinical trials were conducted in 1,856 healthy adults and adolescents (t12 years old) with a history of recurrent cold sores. Patients self-initiated therapy at the earliest symptoms and prior to any signs of a cold sore. The majority of patients initiated treatment within 2 hours of onset of symptoms. Patients were randomized to VALTREX 2 grams twice daily on Day 1 followed by placebo on Day 2, VALTREX 2 grams twice daily on Day 1 followed by 1 gram twice daily on Day 2, or placebo on Days 1 and 2. The mean duration of cold sore episodes was about 1 day shorter in treated subjects as compared with placebo. The 2 day regimen did not offer additional benefit over the 1-day regimen. No significant difference was observed between subjects receiving VALTREX or placebo in the prevention of progression of cold sore lesions beyond the papular stage. 14.2 Genital Herpes Infections Initial Episode: Six hundred forty-three immunocompetent adults with first-episode genital herpes who presented within 72 hours of symptom onset were randomized in a double-blind trial to receive 10 days of VALTREX 1 gram twice daily (n = 323) or oral acyclovir 200 mg 5 times a day (n = 320). For both treatment groups: the median time to lesion healing was 9 days, the median time to cessation of pain was 5 days, the median time to cessation of viral shedding was 3 days. Recurrent Episodes: Three double-blind trials (2 of them placebo-controlled) in immunocompetent adults with recurrent genital herpes were conducted. Patients self-initiated therapy within 24 hours of the first sign or symptom of a recurrent genital herpes episode. In 1 study, patients were randomized to receive 5 days of treatment with either VALTREX 500 mg twice daily (n = 360) or placebo (n = 259). The median time to lesion healing was 4 days in the group receiving VALTREX 500 mg versus 6 days in the placebo group, and the median time to cessation of viral shedding in patients with at least 1 positive culture (42% of the overall study population) was 2 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. The median time to cessation of pain was 3 days in the group receiving VALTREX 500 mg versus 4 days in the placebo group. Results supporting efficacy were replicated in a second trial. In a third study, patients were randomized to receive VALTREX 500 mg twice daily for 5 days (n = 398) or VALTREX 500 mg twice daily for 3 days (and matching placebo twice daily for 2 additional days) (n = 402). The median time to lesion healing was about 4½ days in both

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 treatment groups. The median time to cessation of pain was about 3 days in both treatment groups. Suppressive Therapy: Two clinical studies were conducted, one in immunocompetent adults and one in HIV-infected adults. A double-blind, 12-month, placebo- and active-controlled study enrolled immunocompetent adults with a history of 6 or more recurrences per year. Outcomes for the overall study population are shown in Table 5.

Table 5. Recurrence Rates in Immunocompetent Adults at 6 and 12 Months 6 Months 12 Months VALTREX Oral acyclovir VALTREX Oral acyclovir 1 gram 400 mg 1 gram once 400 mg once daily twice daily Placebo daily twice daily Placebo Outcome (n = 269) (n = 267) (n = 134) (n = 269) (n = 267) (n = 134) Recurrence free 55% 54% 7% 34% 34% 4% Recurrences 35% 36% 83% 46% 46% 85% Unknowna 10% 10% 10% 19% 19% 10% a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

Subjects with 9 or fewer recurrences per year showed comparable results with VALTREX 500 mg once daily. In a second study, 293 HIV-infected adults on stable antiretroviral therapy with a history of 4 or more recurrences of ano-genital herpes per year were randomized to receive either VALTREX 500 mg twice daily (n = 194) or matching placebo (n = 99) for 6 months. The median duration of recurrent genital herpes in enrolled subjects was 8 years, and the median number of recurrences in the year prior to enrollment was 5. Overall, the median prestudy HIV-1

RNA was 2.6 log10 copies/mL. Among patients who received VALTREX, the prestudy median CD4+ cell count was 336 cells/mm3; 11% had <100 cells/mm3, 16% had 100 to 199 cells/mm3, 42% had 200 to 499 cells/mm3, and 31% had t500 cells/mm3. Outcomes for the overall study population are shown in Table 6.

Table 6. Recurrence Rates in HIV-Infected Adults at 6 Months VALTREX 500 mg twice daily Placebo Outcome (n = 194) (n = 99) Recurrence free 65% 26% Recurrences 17% 57% Unknowna 18% 17% a Includes lost to follow-up, discontinuations due to adverse events, and consent withdrawn.

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Reduction of Transmission of Genital Herpes: A double-blind, placebo-controlled study to assess transmission of genital herpes was conducted in 1,484 monogamous, heterosexual, immunocompetent adult couples. The couples were discordant for HSV-2 infection. The source partner had a history of 9 or fewer genital herpes episodes per year. Both partners were counseled on safer sex practices and were advised to use condoms throughout the study period. Source partners were randomized to treatment with either VALTREX 500 mg once daily or placebo once daily for 8 months. The primary efficacy endpoint was symptomatic acquisition of HSV-2 in susceptible partners. Overall HSV-2 acquisition was defined as symptomatic HSV-2 acquisition and/or HSV-2 seroconversion in susceptible partners. The efficacy results are summarized in Table 7.

Table 7. Percentage of Susceptible Partners Who Acquired HSV-2 Defined by the Primary and Selected Secondary Endpoints VALTREXa Placebo Endpoint (n = 743) (n = 741) Symptomatic HSV-2 acquisition 4 (0.5%) 16 (2.2%) HSV-2 seroconversion 12 (1.6%) 24 (3.2%) Overall HSV-2 acquisition 14 (1.9%) 27 (3.6%) a Results show reductions in risk of 75% (symptomatic HSV-2 acquisition), 50% (HSV-2 seroconversion), and 48% (overall HSV-2 acquisition) with VALTREX versus placebo. Individual results may vary based on consistency of safer sex practices.

14.3 Herpes Zoster Two randomized double-blind clinical trials in immunocompetent adults with localized herpes zoster were conducted. VALTREX was compared with placebo in patients less than 50 years of age, and with oral acyclovir in patients greater than 50 years of age. All patients were treated within 72 hours of appearance of zoster rash. In patients less than 50 years of age, the median time to cessation of new lesion formation was 2 days for those treated with VALTREX compared with 3 days for those treated with placebo. In patients greater than 50 years of age, the median time to cessation of new lesions was 3 days in patients treated with either VALTREX or oral acyclovir. In patients less than 50 years of age, no difference was found with respect to the duration of pain after healing (post-herpetic neuralgia) between the recipients of VALTREX and placebo. In patients greater than 50 years of age, among the 83% who reported pain after healing (post-herpetic neuralgia), the median duration of pain after healing [95% confidence interval] in days was: 40 [31, 51], 43 [36, 55], and 59 [41, 77] for 7-day VALTREX, 14-day VALTREX, and 7-day oral acyclovir, respectively. 14.4 Chickenpox The use of VALTREX for treatment of chickenpox in pediatric patients 2 to <18 years of age is based on single-dose pharmacokinetic and multiple-dose safety data from an open-label

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 trial with valacyclovir and supported by safety and extrapolated efficacy data from 3 randomized, double-blind, placebo-controlled trials evaluating oral acyclovir in pediatric patients. The single-dose pharmacokinetic and multiple-dose safety study enrolled 27 pediatric patients 1 to <12 years of age with clinically suspected VZV infection. Each subject was dosed with valacyclovir oral suspension, 20 mg/kg 3 times daily for 5 days. Acyclovir systemic exposures in pediatric patients following valacyclovir oral suspension were compared with historical acyclovir systemic exposures in immunocompetent adults receiving the solid oral dosage form of valacyclovir or acyclovir for the treatment of herpes zoster. The mean projected daily acyclovir exposures in pediatric patients across all age-groups (1 to <12 years of age) were

lower (Cmax: p13%, AUC: p30%) than the mean daily historical exposures in adults receiving valacyclovir 1 gram 3 times daily, but were higher (daily AUC: n50%) than the mean daily historical exposures in adults receiving acyclovir 800 mg 5 times daily. The projected daily exposures in pediatric patients were greater (daily AUC approximately 100% greater) than the exposures seen in immunocompetent pediatric patients receiving acyclovir 20 mg/kg 4 times daily for the treatment of chickenpox. Based on the pharmacokinetic and safety data from this study and the safety and extrapolated efficacy data from the acyclovir studies, oral valacyclovir 20 mg/kg 3 times a day for 5 days (not to exceed 1 gram 3 times daily) is recommended for the treatment of chickenpox in pediatric patients 2 to 18 years of age. Because the efficacy and safety of acyclovir for the treatment of chickenpox in children 2 years of age have not been established, efficacy data cannot be extrapolated to support valacyclovir treatment in children 2 years of age with chickenpox. Valacyclovir is also not recommended for the treatment of herpes zoster in children because safety data up to 7 days’ duration are not available [see Use in Specific Populations (8.4)].

16 HOW SUPPLIED/STORAGE AND HANDLING VALTREX Caplets (blue, film-coated, capsule-shaped tablets) containing valacyclovir hydrochloride equivalent to 500 mg valacyclovir and printed with “VALTREX 500 mg.” Bottle of 30 (NDC 0173-0933-08). Bottle of 90 (NDC 0173-0933-10). Unit dose pack of 100 (NDC 0173-0933-56). VALTREX Caplets (blue, film-coated, capsule-shaped tablets, with a partial scorebar on both sides) containing valacyclovir hydrochloride equivalent to 1 gram valacyclovir and printed with “VALTREX 1 gram.” Bottle of 30 (NDC 0173-0565-04). Bottle of 90 (NDC 0173-0565-10). Storage: Store at 15° to 25°C (59° to 77°F). Dispense in a well-closed container as defined in the USP.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. 17.1 Importance of Adequate Hydration Patients should be advised to maintain adequate hydration. 17.2 Cold Sores (Herpes Labialis) Patients should be advised to initiate treatment at the earliest symptom of a cold sore (e.g., tingling, itching, or burning). There are no data on the effectiveness of treatment initiated after the development of clinical signs of a cold sore (e.g., papule, vesicle, or ulcer). Patients should be instructed that treatment for cold sores should not exceed 1 day (2 doses) and that their doses should be taken about 12 hours apart. Patients should be informed that VALTREX is not a cure for cold sores. 17.3 Genital Herpes Patients should be informed that VALTREX is not a cure for genital herpes. Because genital herpes is a sexually transmitted disease, patients should avoid contact with lesions or intercourse when lesions and/or symptoms are present to avoid infecting partners. Genital herpes is frequently transmitted in the absence of symptoms through asymptomatic viral shedding. Therefore, patients should be counseled to use safer sex practices in combination with suppressive therapy with VALTREX. Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes can determine whether risk for HSV-2 acquisition exists. VALTREX has not been shown to reduce transmission of sexually transmitted infections other than HSV-2. If medical management of a genital herpes recurrence is indicated, patients should be advised to initiate therapy at the first sign or symptom of an episode. There are no data on the effectiveness of treatment initiated more than 72 hours after the onset of signs and symptoms of a first episode of genital herpes or more than 24 hours after the onset of signs and symptoms of a recurrent episode. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 1 year’s duration in otherwise healthy patients. There are no data on the safety or effectiveness of chronic suppressive therapy of more than 6 months’ duration in HIV-infected patients. 17.4 Herpes Zoster There are no data on treatment initiated more than 72 hours after onset of the zoster rash. Patients should be advised to initiate treatment as soon as possible after a diagnosis of herpes zoster. 17.5 Chickenpox Patients should be advised to initiate treatment at the earliest sign or symptom of chickenpox.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 This product’s prescribing information may have been updated. Please refer to www.gsk.com for the most current version.

Distributed by: GlaxoSmithKline Research Triangle Park, NC 27709

Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709 or DSM Pharmaceuticals, Inc. Greenville, NC 27834

©2010, GlaxoSmithKline. All rights reserved.

March 2010 VTX:3PI

PHARMACIST-DETACH HERE AND GIVE INSTRUCTIONS TO PATIENT ______

PATIENT INFORMATION VALTREX® (VAL-trex) (valacyclovir hydrochloride) Caplets

Read the Patient Information that comes with VALTREX before you start using it and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment. Ask your healthcare provider or pharmacist if you have questions.

What is VALTREX? VALTREX is a prescription antiviral medicine. VALTREX lowers the ability of herpes viruses to multiply in your body.

VALTREX is used in adults: x to treat cold sores (also called fever blisters or herpes labialis)

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VALTREX used daily with the following safer sex practices can lower the chances of passing genital herpes to your partner. x Do not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. x Use a condom made of latex or polyurethane whenever you have sexual contact.

VALTREX is used in children: x to treat cold sores (for children t12 years of age) x to treat chickenpox (for children 2 to <18 years of age).

VALTREX does not cure herpes infections (cold sores, chickenpox, shingles, or genital herpes).

The efficacy of VALTREX has not been studied in children who have not reached puberty.

What are cold sores, chickenpox, shingles, and genital herpes? Cold sores are caused by a herpes virus that may be spread by kissing or other physical contact with the infected area of the skin. They are small, painful ulcers that you get in or around your mouth. It is not known if VALTREX can stop the spread of cold sores to others.

Chickenpox is caused by a herpes virus. It causes an itchy rash of multiple small, red bumps that look like pimples or insect bites usually appearing first on the abdomen or back and face. It can spread to almost everywhere else on the body and may be accompanied by flu-like symptoms.

Shingles is caused by the same herpes virus that causes chickenpox. It causes small, painful blisters that happen on your skin. Shingles occurs in people who have already had chickenpox. Shingles can be spread to people who have not had chickenpox or the chickenpox vaccine by contact with the infected areas of the skin. It is not known if VALTREX can stop the spread of shingles to others.

Genital herpes is a sexually transmitted disease. It causes small, painful blisters on your genital area. You can spread genital herpes to others, even when you have no symptoms. If you are sexually active, you can still pass herpes to your partner, even if you are taking VALTREX.

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 VALTREX, taken every day as prescribed and used with the following safer sex practices, can lower the chances of passing genital herpes to your partner.

x Do not have sexual contact with your partner when you have any symptom or outbreak of genital herpes. x Use a condom made of latex or polyurethane whenever you have sexual contact.

Ask your healthcare provider for more information about safer sex practices.

Who should not take VALTREX? Do not take VALTREX if you are allergic to any of its ingredients or to acyclovir. The active ingredient is valacyclovir. See the end of this leaflet for a complete list of ingredients in VALTREX.

Before taking VALTREX, tell your healthcare provider: About all your medical conditions, including: x if you have had a bone marrow transplant or kidney transplant, or if you have advanced HIV disease or "AIDS". Patients with these conditions may have a higher chance for getting a blood disorder called thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). TTP/HUS can result in death. x if you have kidney problems. Patients with kidney problems may have a higher chance for getting side effects or more kidney problems with VALTREX. Your healthcare provider may give you a lower dose of VALTREX. x if you are 65 years of age or older. Elderly patients have a higher chance of certain side effects. Also, elderly patients are more likely to have kidney problems. Your healthcare provider may give you a lower dose of VALTREX. x if you are pregnant or planning to become pregnant. Talk with your healthcare provider about the risks and benefits of taking prescription drugs (including VALTREX) during pregnancy. x if you are breastfeeding. VALTREX may pass into your milk and it may harm your baby. Talk with your healthcare provider about the best way to feed your baby if you are taking VALTREX. x about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. VALTREX may affect other medicines, and other medicines may affect VALTREX. It is a good idea to keep a complete list of all the medicines you take. Show this list to your healthcare provider and pharmacist any time you get a new medicine.

How should I take VALTREX? Take VALTREX exactly as prescribed by your healthcare provider. Your dose of VALTREX

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 and length of treatment will depend on the type of herpes infection that you have and any other medical problems that you have. x Do not stop VALTREX or change your treatment without talking to your healthcare provider. x VALTREX can be taken with or without food. x If you are taking VALTREX to treat cold sores, chickenpox, shingles, or genital herpes, you should start treatment as soon as possible after your symptoms start. VALTREX may not help you if you start treatment too late. x If you miss a dose of VALTREX, take it as soon as you remember and then take your next dose at its regular time. However, if it is almost time for your next dose, do not take the missed dose. Wait and take the next dose at the regular time. x Do not take more than the prescribed number of VALTREX Caplets each day. Call your healthcare provider right away if you take too much VALTREX.

What are the possible side effects of VALTREX? Kidney failure and nervous system problems are not common, but can be serious in some patients taking VALTREX. Nervous system problems include aggressive behavior, unsteady movement, shaky movements, confusion, speech problems, hallucinations (seeing or hearing things that are really not there), seizures, and coma. Kidney failure and nervous system problems have happened in patients who already have kidney disease and in elderly patients whose kidneys do not work well due to age. Always tell your healthcare provider if you have kidney problems before taking VALTREX. Call your doctor right away if you get a nervous system problem while you are taking VALTREX.

Common side effects of VALTREX in adults include headache, nausea, stomach pain, vomiting, and dizziness. Side effects in HIV-infected adults include headache, tiredness, and rash. These side effects usually are mild and do not cause patients to stop taking VALTREX.

Other less common side effects in adults include painful periods in women, joint pain, depression, low blood cell counts, and changes in tests that measure how well the liver and kidneys work.

The most common side effect seen in children <18 years of age was headache.

Talk to your healthcare provider if you develop any side effects that concern you.

These are not all the side effects of VALTREX. For more information ask your healthcare provider or pharmacist.

How should I store VALTREX?

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Downloaded From: https://jamanetwork.com/ on 09/25/2021 x Store VALTREX Caplets at room temperature, 59q to 77qF (15° to 25°C). x Store VALTREX suspension between 2q to 8qC (36q to 46qF) in a refrigerator. Discard after 28 days. x Keep VALTREX in a tightly closed container. x Do not keep medicine that is out of date or that you no longer need. x Keep VALTREX and all medicines out of the reach of children.

General information about VALTREX Medicines are sometimes prescribed for conditions that are not mentioned in patient information leaflets. Do not use VALTREX for a condition for which it was not prescribed. Do not give VALTREX to other people, even if they have the same symptoms you have. It may harm them.

This leaflet summarizes the most important information about VALTREX. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about VALTREX that is written for health professionals. More information is available at www.VALTREX.com.

What are the ingredients in VALTREX? Active Ingredient: valacyclovir hydrochloride Inactive Ingredients: carnauba wax, colloidal silicon dioxide, crospovidone, FD&C Blue No. 2 Lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.

Distributed by: GlaxoSmithKline Research Triangle Park, NC 27709

Manufactured by: GlaxoSmithKline Research Triangle Park, NC 27709 or DSM Pharmaceuticals, Inc. Greenville, NC 27834

©2008, GlaxoSmithKline. All rights reserved.

September 2008

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20.7 Protocol amendment #1

This protocol amendment dated 24 September 2012 was issued due to the feedback and comments given by the Quorum IRB on the final protocol AIC316-01-II-02 dated 05 July 2012. x Excluded concomitant drugs listed on page ten of the protocol have been specifically added to the exclusion criteria.

In addition, the following changes were made: x Update of AiCuris pharamacokineticist x Update or UW lab addresses x Addition of a reference to the AIC316 INN x Correction of minor formal issues like e.g. typos and missing spaces, etc.

The Protocol Amendment #1 (dated 24 September 2012) changes the following text in the protocol with inserted text changes indicated by underlining and deleted text indicated by strikethrough.

Minor formal issues like typos and missing spaces were corrected as seen, but are not listed.

1. Signatures 1.1 Protocol Approval (page 2)

Pharmacokineticist Consultant date

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1. Signatures 1.3 Involved parties (page 5ff) 6. Sponsor’s Pharmacokineticist Pharmacokinetics Consultant

10. HSV Western Blot, HSV University of Washington DNA PCR, Sequencing Virology Division Fred Hutchinson Cancer Research Center 1100 Fairview Avenue N, D3-100 Seattle, WA 98109, USA 10.HSV Western Blot, Anne Cent University of Washington, Virology Laboratory Children’s Hospital & Medical Center Room W8814 4800 Sand Point Way N. E. Seattle, WA 98105, USA Office phone: Email: 11.HSV DNA PCR, Meei-Li Huang Sequencing University of Washington Molecular Diagnostic Laboratory 1616 Eastlake Ave E, Suite 320 Seattle, WA 98102, USA Office Phone: E-Mail:

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12. 11. Preparation and supply of Trial medication kits

2. Protocol Synopsis Exclusion Criteria (page 13) ... 17. Evidence of active abuse of alcohol or drugs 18. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 18. 19.Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial

8. Introduction 8.1. Background information (page 33) … One such potential drug is AIC316 which is currently being developed by AiCuris GmbH & Co. KG. The free base AIC316 (INN Pritelivir, synonym: AIC090093, BAY 57-1293) is a thiazolylamide belonging to a novel active class of non-nucleoside compounds against HSV-1 and 2.

11. Trial Population 11.1.4 Exclusion Criteria (page 48f) ... 17. Evidence of active abuse of alcohol or drugs 18. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 18. 19.Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial

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20.8 Protocol amendment #2

This protocol amendment dated 17 October 2012 was issued due to the feedback and comments given by the FDA on the final protocol AIC316-01-II-02 dated 05 July 2012. x “Medical history of acute or chronic pancreatitis” has been specifically added to the exclusion criteria. x Exclusion of subjects with known medical history of macular or maculopapular skin reactions (exanthema or eruption) has been added to the exclusion criteria. x Instructions to investigators were added in the protocol in regards to activities required in case of any skin disorder. x Withdrawal criteria were amended to withdraw any case of pancreatitis, grade 3 or 4 rash judged to be related to study treatment and any grade 2 rash accompanied by constitutional symptoms.

The Protocol Amendment #2 (dated 17 October 2012) changes the following text in the protocol with inserted text changes indicated by underlining and deleted text indicated by strikethrough.

Minor formal issues like typos and missing spaces were corrected as seen, but are not listed.

2. Protocol Synopsis Exclusion Criteria (page 13) ... 12. Known to have other genital tract disorders or sexually transmitted diseases that may interfere with assessment of the trial medication efficacy 13. Medical history of acute or chronic pancreatitis 14. Medical history of macular or maculopapular skin reactions (exanthema or eruption) 13. 15. Clinically relevant abnormalities in clinical chemical, hematological or any other laboratory variables 14. 16. Electrocardiogram (ECG) abnormalities of clinical relevance (e.g.: QTc >450 ms) 15. 17. Positive results in any of the serology tests for HCV-Ab or HBsAg 16. 18. Pregnancy or breastfeeding 17. 19. Evidence of active abuse of alcohol or drugs 18. 20. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or

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troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 19. 21. Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial

11. Trial Population 11.1.4 Exclusion Criteria (page 49f) ... 12. Known to have other genital tract disorders or sexually transmitted diseases that may interfere with assessment of the trial medication efficacy 13. Medical history of acute or chronic pancreatitis 14. Medical history of macular or maculopapular skin reactions (exanthema or eruption) 13. 15. Clinically relevant abnormalities in clinical chemical, hematological or any other laboratory variables 14. 16. Electrocardiogram (ECG) abnormalities of clinical relevance (e.g.: QTc >450 ms) 15. 17. Positive results in any of the serology tests for HCV-Ab or HBsAg 16. 18. Pregnancy or breastfeeding 17. 19. Evidence of active abuse of alcohol or drugs 18. 20. Treatment with carbamazepine, dexamethasone, efavirenz, nevirapine, modafinil, oxcarbazepine, pioglitazone, phenobarbital, phenytoin, rifabutin, rifampin, St. John's wort, or troglitazone. Use of topical application of remedies and drugs (including over-the counter drugs) in the genital area of recurrence from screening until final examination. 19. 21. Any other conditions that in the judgment of the investigator would preclude successful completion of the clinical trial

11. Trial Population 11.2 Removal of subjects from the trial, trial assessments or investigational medicinal product(s) (page 50f) A subject may terminate participation in the trial at any time without providing a reason and without any personal disadvantage. ... Removal of a subject from trial treatment: No further investigation and treatment will be performed; nevertheless an Early Termination Visit will be done and ideally a Final Examination Visit 28 days after last trial medication intake.

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The Investigator has to remove a subject from the study treatment in the following situations: x occurrence of an adverse event or any other condition which in the opinion of the Investigator does not justify a safe continuation of the trial treatment in this subject x any case of pancreatitis, regardless of causality x any case of grade 3 or 4 rash judged to be related to study treatment x any grade 2 rash accompanied by constitutional symptoms x any serious adverse event considered to be possibly, probably or definitely related to trial medication and clinically relevant …

15. Adverse Events 15.9.4 Adverse Event Reporting (page 80)

The investigator must report all AEs that occur during the clinical trial, regardless of their relationship to the trial medication by documentation in the eCRF. Recurrence of HSV episode that occur during the screening period (Day -21 to -1) will be documented as AE. HSV recurrences that occur during the treatment period will not be documented as AEs since they are captured in a separate section of the electronic data capture system in this trial. In case of any skin disorder; patients should be referred to a dermatologist for further diagnosis and qualified treatment. The diagnosis and the description of the skin disorder as well as the treatment, if any, shall be documented in the eCRF. This includes any concurrent viral and/or bacterial infection.

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20.9 Protocol amendment #3

This protocol amendment dated 18 December 2012 was issued due to: x Inclusion of a sample for pharmacogenetic analysis x Correction of minor formal issues like e.g. typos and missing spaces, etc.

The Protocol Amendment #3 (dated 18 December 2012) changes the following text in the protocol with inserted text changes indicated by underlining and deleted text indicated by strikethrough. Minor formal issues like typos and missing spaces were corrected as seen, but are not listed.

1. Signatures 1.3 Involved parties (page 5ff) …

12. Preparation and supply of Trial medication kits

13. Pharmacogenetic analysis

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2. Protocol Synopsis Trial Objective (page 9f) Secondary Objectives ... x Predose blood concentrations for AIC316 and valacyclovir at steady-state x Pharmacogenetic evaluation

2. Protocol Synopsis Criteria for evaluation (page 13ff) Secondary endpoints x … x Standard 12-lead electrocardiogram (ECG) PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state

PHAMACOGENETICS x Pharmacogenetic data to evaluate possible influences on drug metabolism.

2. Protocol Synopsis Schedule and course of the trial (page 15ff) Day 1: Randomization and Treatment Period 1 Prior to randomization and first treatment the following examinations/ evaluations will be done: concomitant medications, adverse events (AEs), physical examination, weight measurements, vital signs, 12-lead ECG, laboratory measurements, inclusion/exclusion criteria, blood sampling for safety analyses, and predose PK and pharmacogenetics, urinalysis, urine pregnancy test (women of child- bearing potential only) and swabbing of the anogenital region. After randomization the subject starts treatment by taking the first (loading) dose. Swabbing kits, subject diary and trial medication will be provided. …

Day 29 through Day 56: Wash-out Period (28 +14 days) … Same examinations and evaluations as described for the weekly visits will be done, including a 12- lead ECG and a urine pregnancy test for women of child-bearing potential. Pharmacogenetics sample may be taken at this visit if not already done on Day 1.

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Should subjects require HSV treatment during washout this must have been discontinued at least 7 days prior to start of the second treatment period. …

Day 57: Start of Treatment Period 2 Same examinations and evaluations will be done as listed for Day 1. Pharmacogenetics sample may be taken at this visit if not already done at previous visits. …

Day 112(r1): Final Examination During the final examination visit, the following examinations and evaluations will be done: concomitant medications, AEs, physical examination, weight, vital signs, 12-lead ECG, swabbing of the anogenital region, blood & urine sampling for safety analyses and, PK and pharmacogenetics (only if not already done), urine pregnancy test, collection of remaining trial medication.

2. Protocol Synopsis Statistics (page 17f) Trial analysis populations … Safety population All randomized subjects who received the trial medication at least once. Pharmacogenetic population All randomised subjects who consented to pharmacogenetic sampling. … Safety analyses (Safety population) The results of safety measurements (clinical laboratory parameters, urinalysis, vital signs, ECGs) and adverse events will be listed by subject and treatment group and analyzed descriptively. Pharmacogenetic analysis (Pharmacogenetic population) The results of pharmacogenetic testing will be analyzed descriptively, listed by subject and treatment group and will be reported in a separate report.

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9. Trial objectives and endpoint criteria 9.1.2 Secondary objectives (page 45f) ... x Predose blood concentrations for AIC316 and valacyclovir at steady state x Pharmacogenetic evaluation

9. Trial objectives and endpoint criteria 9.2.2 Secondary endpoints (page 46ff) ... PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state, determined at each pre-scheduled visit starting from Day 1. PHARMACOGENETIC x Pharmacogenetic data to evaluate possible influences on drug metabolism.

13. Trial procedures 13.1.1 Information of subjects and informed consent (page 60f) … The consent administration process must be described in the subject’s source documents. A separate patient information and informed consent form will be available for pharmacokinetic sampling and tests. A subject’s refusal to participate the pharmacogenetic tests is NOT a reason for exclusion from the study.

13. Trial procedures 13.1.2.1 Screening visit (within 21 days before Day 1) (page 61) … x Written informed consents …

13. Trial procedures 13.1.3.1 Randomization visit (page 62f)

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Evaluations before randomization and treatment … x Blood draw for trial medication plasma level (blank value) x Preparation of sample for pharmacogenetic tests (if consented to by subject).

13. Trial procedures 13.1.4.1 Day 29 ± 1 visit (page 65) … x Blood draw for trial medication plasma level (through value). x Only if not done at Day 1: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. …

13. Trial procedures 13.1.5.1 Start of second treatment period (Visit Day 57r1) (page 65f) … x Blood draw for trial medication plasma level (through value). x Only if not done at Day 1 or Day 29: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. …

13. Trial procedures 13.1.6.1 Visit Day 85r1 day (page 67) … x Blood draw for trial medication plasma level (through value). x Only if not done at Day 1, Day 29, or Day 57: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. …

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13. Trial procedures 13.1.7 Final Examination Visit - Day 112r1 (page 68) … x Blood draw for trial medication plasma level (through value). x Only if not done at Day 1, Day 29, Day 57 or Day 85: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. …

13. Trial procedures 13.1.9 Early Termination Visit (page 69) … x Blood draw for trial medication plasma level (through value). x Only if not done at Day 1, Day 29, Day 57 or Day 85: Preparation of sample for pharmacogenetic tests (if consented to by subject). x Swabbing of the anogenital region and lesion(s) if any, by Investigator for HSV DNA PCR measurement. …

13. Trial procedures 13.2 Flow Charts (page 71f)

… Day 1 … Day …Early 29±1 terminationh)

… Blood sampling for PK (pre-dose) X k) X k) X k) … …

Day …Day … Final Examination …Early 57±1 85±1 Day 112±1 terminati onh) … Blood sampling for PK (pre-dose) X k) X k) X k) X k) …

… i) Required only if visit occurs during treatment phases. k) Pharmacogenetic sample to be prepared at one of these visits. Blood to be taken from pk sample.

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14 Trial Variables 14.5 Laboratory Monitoring (page 76f) … Pharmacogenetics One sample will be prepared for pharmacogenetics tests (will be reported separately). Preferably on Day 1 500μL of the blood volume collected for the PK sample preparation will be transferred into a separate tube. Further details will be included in the Laboratory Manual. This sample will only be prepared after subject has given his written consent. A separate subject information and informed consent form will be available. Denying consent to collect this sample does not exclude the subject from participating in the study.

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20.10 Protocol amendment #4

This protocol amendment dated 02 May 2013 was issued due to: x Inclusion of interim results of a 39 week toxicology study in monkeys x Inclusion of an additional blood and urine sample at the ends of each treatment period for evaluation of potential AIC316 drug metabolites. x Correction of minor formal issues like e.g. typos and missing spaces, etc.

The Protocol Amendment #4.0 (dated 02 May 2013) changes the following text in the protocol with inserted text changes indicated by underlining and deleted text indicated by strikethrough. Minor formal issues like typos and missing spaces were corrected as seen, but are not listed.

1. Signatures 1.1 Protocol Approval (page 2)

Pharmacokineticist date Dirk Kropeit, MD AiCuris GmbH & Co. KG

1. Signatures 1.3 Involved parties (page 5ff)

…

6. Sponsor’s Pharmacokineticist Dirk Kropeit, MD AiCuris GmbH & Co. KG Friedrich-Ebert-Straße 475 42117 Wuppertal, Germany Office phone: 49 202 31763 Office fax: 49 202 31763 Email:

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7. Bioanalysis of pharmacokinetic samples and samples for evaluation of potential drug metabolites

…

2. Protocol Synopsis Trial Objective (page 9f) Secondary Objectives ... x Predose blood concentrations for AIC316 and valacyclovir at steady-state x Pharmacogenetic evaluation x Evaluation of potential AIC316 drug metabolites

2. Protocol Synopsis Criteria for evaluation (page 13ff) Secondary endpoints ... PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state x Evaluation of potential AIC316 drug metabolites PHAMACOGENETICS x Pharmacogenetic data to evaluate possible influences on drug metabolism.

2. Protocol Synopsis Schedule and course of the trial (page 15ff) Day 29 through Day 56: Wash-out Period (28 +14 days) …

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On day 29 subjects will visit the clinical trial site for a pre-scheduled visit. Same examinations and evaluations as described for the weekly visits will be done, including a 12-lead ECG, a blood and urine sample for evaluation of potential drug metabolites, and a urine pregnancy test for women of child- bearing potential. …

8. Introduction 8.1. Background Information (page 34ff) … Crystalloid spaces were only observed at exposures >30-fold with respect to exposure with 100 mg once daily (qd) dosing at steady state in humans. Interim analysis of an ongoing 39 week toxicological study in monkeys showed severe anemia and decrease in urinary pH. The relevance of these observations is currently unclear. Genotoxicity and developmental reproductive toxicity studies did not identify adverse findings. …

8. Introduction 8.4.2. Potential risk profile of AIC316 (page 42) … x Crystalloid spaces and foreign body reactions (granulomatous reaction, inflammatory signs) in the digestive tract (tongue, small intestine) and adjacent tissues/organs including lymph nodes and the lung were observed at high dose AIC316 in mice and monkeys (25-fold greater exposure vs. steady state exposure at 100 mg qd in humans). In monkeys, the following clinically relevant changes have been observed: a decrease in hemoglobin, RBC numbers and hematocrit and an increase in percent reticulocytes. It should be noted that adverse changes were not accompanied by impairment of the general health status of mice and monkeys in these studies. x In an ongoing 39 week toxicology study in monkeys, preliminary data show severe anemia in 7 of 40 animals which was accompanied by increase in percent reticulocytes in most of the animals. Reduction in body weight was observed in some of the animals. …

9. Trial objectives and endpoint criteria 9.1.2 Secondary objectives (page 43) ... x Predose blood concentrations for AIC316 and valacyclovir at steady state

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x Pharmacogenetic evaluation x Evaluation of potential AIC316 drug metabolites

9. Trial objectives and endpoint criteria 9.2.2 Secondary endpoints (page 44ff) ... PHARMACOKINETIC x Predose (trough level) blood concentrations of AIC316 and valacyclovir at steady state, determined at each pre-scheduled visit starting from Day 1. x Evaluation of potential AIC316 drug metabolites in blood and urine samples taken at the end of each treatment period. PHARMACOGENETIC x Pharmacogenetic data to evaluate possible influences on drug metabolism.

13. Trial procedures 13.1.4.1 Day 29 ± 1 visit (page 62f) … x Blood draw for trial medication plasma level (through value). x Blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only if not done at Day 1: Preparation of sample for pharmacogenetic tests (if consented to by subject). …

13. Trial procedures 13.1.6.1 Visit Day 85r1 day (page 65) … x Blood draw for trial medication plasma level (through value). x Blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only if not done at Day 1, Day 29, or Day 57: Preparation of sample for pharmacogenetic tests (if consented to by subject). …

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13. Trial procedures 13.1.9 Early Termination Visit (page 66f) … x Blood draw for trial medication plasma level (through value). x In case of early termination of a treatment period: blood and urine sampling for evaluation of potential AIC316 drug metabolites. x Only if not done at Day 1, Day 29, Day 57 or Day 85: Preparation of sample for pharmacogenetic tests (if consented to by subject). …

13. Trial procedures 13.2 Flow Charts (page 68f)

…Day …Early 29±1 terminationh)

… Blood sampling for PK (pre-dose) and drug metabolites l) X k) l) X k) l) … …

…Day …Early 85±1 terminationh)

… Blood sampling for PK (pre-dose) and drug metabolites l) X k) l) X k) l) …

… c) Hematology, Coagulation, Serum chemistry, Urinalysis – Urine sample for evaluation of potential AIC316 drug metabolites to be collected … i) Required only if visit occurs during treatment phases. k) Pharmacogenetic sample to be prepared at one of these visits. Blood to be taken from pk sample. l) Blood sampling for evaluation of potential AIC316 drug metabolites on Day 29 and Day 85, and/or at Early Termination Visit, respectively.

14. Trial variables 14.5 Laboratory monitoring (page 73ff) … Pharmacokinetics … At all pre-scheduled visits and in case of premature termination 4.0 mL blood samples will be taken in a K3-EDTA collection tube prior to trial medication intake. Further details will be included in the Laboratory Manual.

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At the end of each treatment period (Day 29 and Day 85) an additional 4.0 mL blood sample will be taken in a K3-EDTA tube and a 5.0 mL urine sample will be separated from the urine sample collected for routine dipstick analysis for evaluation of potential AIC316 drug metabolites. Further details will be included in the Laboratory Manual.

17. Statistical methods 17.3.6 Further analysis 17.3.6.1 Pharmacokinetic analysis (page 92) AIC316 and valacyclovir trough levels over time will be graphed by treatment group. Details regarding data analyses will be provided in the SAP. The results of the evaluation of potential AIC316 drug metabolites will be reported separately.

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