Product: MK-5172 1 Protocol/Amendment No.: 048-01 · MK-5172, MK-8742, and R should be taken...

Product: MK-5172 1Protocol/Amendment No.: 048-01

MK-5172-048-01 Final Protocol 17-Mar-2014Confidential

THIS PROTOCOL AMENDMENT AND ALL OF THE INFORMATION RELATING TO IT ARE CONFIDENTIAL AND PROPRIETARY PROPERTY OF MERCK SHARP & DOHME CORP., A SUBSIDIARY OF MERCK & CO., INC., WHITEHOUSE STATION, NJ, U.S.A.

SPONSOR:Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (hereafter referred to as the Sponsor or Merck)One Merck DriveP.O. Box 100Whitehouse Station, NJ 08889-0100, U.S.A.

Protocol-specific Sponsor Contact information can be found in the Investigator Trial FileBinder (or equivalent).

TITLE:

A Phase II Clinical Trial to Study the Efficacy and Safety of the combination regimen of MK-5172 + MK-8742 + Ribavirin (R) in Subjects with Chronic Hepatitis C Virus Infection who failed prior Direct Acting Antiviral Therapy

IND NUMBER: 110,261EudraCT NUMBER: 2013-004213-41

03VY5N



TABLE OF CONTENTS

SUMMARY OF CHANGES................................................................................................ 10

1.0 TRIAL SUMMARY.................................................................................................. 11

2.0 TRIAL DESIGN........................................................................................................ 11

Trial Design ........................................................................................................... 112.1

Trial Diagram........................................................................................................ 122.2

3.0 OBJECTIVE(S) & HYPOTHESIS(ES).................................................................. 12

Primary Objective(s) & Hypothesis(es) .............................................................. 123.1

Secondary Objective(s) & Hypothesis(es)........................................................... 123.2

Exploratory Objectives......................................................................................... 133.3

4.0 BACKGROUND & RATIONALE.......................................................................... 14

Background ........................................................................................................... 144.1

Pharmaceutical and Therapeutic Background .................................................... 144.1.1

Pre-clinical and Clinical Trials ........................................................................... 164.1.2

Ongoing Clinical Trials....................................................................................... 164.1.3

Rationale ................................................................................................................ 164.2

Rationale for the Trial and Selected Subject Population .................................... 164.2.1

Rationale for Dose Selection/Regimen/Modification ......................................... 234.2.2

Rationale for Endpoints ...................................................................................... 274.2.3

4.2.3.1 Efficacy Endpoints....................................................................................... 27

4.2.3.1.1 Measurements of HCV RNA ................................................................ 27

Definition of Efficacy Endpoints ................................................... 284.2.3.1.1.1

Definition of Virologic Failure: Non-Response, Rebound, 4.2.3.1.1.2Virologic Breakthrough, and Relapse ..................................................... 28

4.2.3.1.2 Viral Resistance Measurements ............................................................ 29

4.2.3.1.3 Genomic Exploratory Measurements ................................................... 29

4.2.3.2 Safety Endpoints .......................................................................................... 30

4.2.3.3 Pharmacokinetic Endpoints ......................................................................... 30

4.2.3.4 Planned Exploratory Biomarker Research................................................... 30

4.2.3.5 Future Biomedical Research ........................................................................ 30

03VY5N



5.0 METHODOLOGY ................................................................................................... 31

Entry Criteria........................................................................................................ 315.1

Diagnosis/Condition for Entry into the Trial ...................................................... 315.1.1

Subject Inclusion Criteria.................................................................................... 315.1.2

Subject Exclusion Criteria .................................................................................. 345.1.3

Trial Treatment(s) ................................................................................................ 365.2

Dose Selection/Modification .............................................................................. 375.2.1

5.2.1.1 Dose Selection ............................................................................................. 37

5.2.1.2 Dose Modification ....................................................................................... 37

Timing of Dose Administration .......................................................................... 385.2.2

Trial Blinding/Masking....................................................................................... 385.2.3

Randomization or Treatment Allocation............................................................ 395.3

Stratification.......................................................................................................... 395.4

Concomitant Medications/Vaccinations (Prohibited & Allowed) .................... 395.5

Rescue Medications & Supportive Care ............................................................. 415.6

Diet/Activity/Other Considerations..................................................................... 415.7

Subject Withdrawal/Discontinuation Criteria ................................................... 415.8

Subject Replacement Strategy ............................................................................. 435.9

Beginning and End of the Trial ........................................................................... 435.10

Clinical Criteria for Early Trial Termination ................................................... 435.11

6.0 TRIAL FLOW CHART ........................................................................................... 44

7.0 TRIAL PROCEDURES ........................................................................................... 47

Trial Procedures ................................................................................................... 477.1

Administrative Procedures .................................................................................. 477.1.1

7.1.1.1 Informed Consent......................................................................................... 47

7.1.1.1.1 General Informed Consent.................................................................... 47

7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research................................................................................................ 48

7.1.1.2 Inclusion/Exclusion Criteria ........................................................................ 48

7.1.1.3 Subject Identification Card .......................................................................... 48

7.1.1.4 Medical History ........................................................................................... 48

7.1.1.5 Prior and Concomitant Medications Review ............................................... 48

03VY5N



7.1.1.5.1 Prior Medications.................................................................................. 48

7.1.1.5.2 Concomitant Medications ..................................................................... 48

7.1.1.6 Assignment of Screening Number ............................................................... 48

7.1.1.7 Assignment of Randomization Number....................................................... 49

7.1.1.8 Trial Compliance (Medication).................................................................... 49

Clinical Procedures/Assessments........................................................................ 497.1.2

7.1.2.1 Physical Examination................................................................................... 49

7.1.2.2 Weight and Height Assessment ................................................................... 50

7.1.2.3 12-Lead ECG ............................................................................................... 50

7.1.2.4 Vital Signs.................................................................................................... 50

7.1.2.5 Birth Control Confirmation.......................................................................... 50

7.1.2.6 Adverse Events ............................................................................................ 50

7.1.2.7 Noninvasive Methods of Cirrhosis Evaluation ............................................ 51

Laboratory Procedures/Assessments .................................................................. 517.1.3

7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry, and Other) ......... 52

7.1.3.2 Pharmacokinetic/Pharmacodynamic Evaluations ........................................ 53

7.1.3.2.1 Blood Collection for Plasma MK-5172, MK-8742, &R ...................... 53

7.1.3.3 Future Biomedical Research ........................................................................ 54

7.1.3.4 HCV Evaluation........................................................................................... 54

Other Procedures................................................................................................. 547.1.4

7.1.4.1 Withdrawal/Discontinuation ........................................................................ 54

7.1.4.1.1 Withdrawal From Future Biomedical Research ................................... 55

7.1.4.2 Blinding/Unblinding .................................................................................... 55

7.1.4.3 Calibration of Critical Equipment................................................................ 55

7.1.4.4 Rescreening.................................................................................................. 55

7.1.4.5 PK Sampling Time Points............................................................................ 56

Visit Requirements.............................................................................................. 567.1.5

7.1.5.1 Screening...................................................................................................... 56

7.1.5.2 Treatment Period.......................................................................................... 57

7.1.5.3 Drug Administration .................................................................................... 57

7.1.5.4 Follow-up Visits........................................................................................... 58

7.1.5.5 Evaluations of Laboratory Safety Signals.................................................... 58

03VY5N



Assessing and Recording Adverse Events .......................................................... 597.2

Definition of an Overdose for This Protocol and Reporting of Overdose to 7.2.1the Sponsor.......................................................................................................... 59

Reporting of Pregnancy and Lactation to the Sponsor ....................................... 607.2.2

Immediate Reporting of Adverse Events to the Sponsor .................................... 607.2.3

7.2.3.1 Serious Adverse Events ............................................................................... 60

7.2.3.2 Events of Clinical Interest............................................................................ 61

Evaluating Adverse Events ................................................................................. 617.2.4

Sponsor Responsibility for Reporting Adverse Events ...................................... 647.2.5

TRIAL GOVERNANCE AND OVERSIGHT ................................................... 647.3

Scientific Advisory Committee........................................................................... 647.3.1

8.0 STATISTICAL ANALYSIS PLAN ........................................................................ 64

Statistical Analysis Plan Summary ..................................................................... 648.1

Efficacy Analyses ............................................................................................... 648.1.1

Safety Analyses................................................................................................... 658.1.2

8.1.3 Power and Sample Size....................................................................................... 65

Statistical Analysis Plan ....................................................................................... 658.2

Responsibility for Analyses ................................................................................ 668.2.1

Hypotheses/Estimation ....................................................................................... 668.2.2

Analysis Endpoints ............................................................................................. 668.2.3

8.2.3.1 Efficacy/Pharmacokinetic Endpoints ........................................................... 66

8.2.3.1.1 Efficacy Endpoints................................................................................ 66

8.2.3.1.2 Pharmacokinetic Endpoints .................................................................. 67

8.2.3.1.3 Exploratory Endpoints .......................................................................... 67

8.2.3.2 Safety Endpoints .......................................................................................... 67

Analysis Populations........................................................................................... 678.2.4

8.2.4.1 Efficacy Analysis Populations ..................................................................... 67

8.2.4.2 Safety Analysis Populations ........................................................................ 68

Statistical Methods.............................................................................................. 698.2.5

8.2.5.1 Statistical Methods for Efficacy Analyses ................................................... 69

8.2.5.2 Statistical Methods for Safety Analyses ...................................................... 72

03VY5N



8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses....................................................................................................... 72

Multiplicity ......................................................................................................... 738.2.6

Sample Size and Power Calculations.................................................................. 738.2.7

8.2.7.1 Efficacy Analysis ......................................................................................... 73

8.2.7.2 Safety Analysis ............................................................................................ 74

Subgroup Analyses and Effects of Baseline Factors .......................................... 758.2.8

9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ................................................................................................................. 75

Investigational Product ........................................................................................ 759.1

Packaging and Labeling Information ................................................................. 759.2

Clinical Supplies Disclosure ................................................................................. 769.3

Storage and Handling Requirements .................................................................. 769.4

Returns and Reconciliation.................................................................................. 769.5

Standard Policies................................................................................................... 769.6

10.0 ADMINISTRATIVE AND REGULATORY DETAILS....................................... 76

Confidentiality....................................................................................................... 7610.1

Confidentiality of Data ....................................................................................... 7610.1.1

Confidentiality of Subject Records ..................................................................... 7710.1.2

Confidentiality of Investigator Information ........................................................ 7710.1.3

Confidentiality of IRB/IEC Information............................................................. 7710.1.4

Compliance with Financial Disclosure Requirements....................................... 7810.2

Compliance with Law, Audit and Debarment ................................................... 7810.3

Compliance with Trial Registration and Results Posting Requirements ........ 8010.4

Quality Management System............................................................................... 8010.5

Data Management................................................................................................. 8010.6

Publications ........................................................................................................... 8110.7

11.0 LIST OF REFERENCES ......................................................................................... 82

12.0 APPENDICES ........................................................................................................... 84

Merck Code of Conduct for Clinical Trials........................................................ 8412.1

Collection and Management of Specimens for Future Biomedical 12.2Research................................................................................................................. 86

03VY5N



Understanding the Intent, Scope and Public Health Benefits of 12.3Exploratory Biomarker Research: A Guide for IRBs/IECs and Investigational Site Staff ...................................................................................... 92

List of Abbreviations and Definitions of Terms............................................... 10312.4

Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and 12.5by Sample Types ................................................................................................. 105

13.0 SIGNATURES......................................................................................................... 106

Sponsor's Representative ................................................................................... 10613.1

Investigator.......................................................................................................... 10613.2

03VY5N



LIST OF TABLES

Table 1 In Vitro Potency of MK-5172 and Other HCV PIs Against Replicons

Containing HCV G1 NS3 RAVs .................................................................... 19Table 2 Impact of Baseline Q80 Mutations in G1a on the Efficacy of MK-5172-

based Regimens .............................................................................................. 21Table 3 In Vitro Potency of MK-8742 Against Replicons Containing HCV G1

NS3 RAVs ...................................................................................................... 21Table 4 In Vitro Potency of MK-8742 and MK-5172 Against Replicons

Containing an HCV G1 NI RAV.................................................................... 22Table 5 Potency of MK-8742 in HCV replicons that contain common NS5A

resistance associated variants.......................................................................... 26Table 6 Nomenclature for Describing HCV RNA Levels ........................................... 28Table 7 Trial Treatments.............................................................................................. 36Table 8 Recommended Guidelines for Dose Modification of Ribavirin ..................... 37Table 9 Recommended R Dose Reduction for Selected Hematologic and

Biochemical Parameters.................................................................................. 38Table 10 Laboratory Tests ............................................................................................. 52Table 11 Pharmacokinetic Sampling Time Points......................................................... 53Table 12 Evaluating Adverse Events ............................................................................. 62Table 13 Summary of Analysis Strategy for Key Efficacy Endpoints .......................... 65Table 14 Analysis Strategy for Efficacy Variables........................................................ 71Table 15 Analysis Strategy for Safety Parameters......................................................... 72Table 16 Two-Sided 95% Confidence Interval† Assuming Various Number of

Successes for SVR12 (Per Protocol Population=72) ....................................... 74Table 17 Upper Bound of the Two-Sided 95% Confidence Interval for the True

Proportion of Subjects With an AE (n=80)..................................................... 74Table 18 Probability of Observing Late Transaminase Elevations (n=80).................... 74Table 19 Product Descriptions....................................................................................... 75

03VY5N



LIST OF FIGURES

Figure 1 Trial Design .................................................................................................... 12Figure 2 Common RAVs in Patients who Experienced Lack of Efficacy on

Treatment with boceprevir, telaprevir or simeprevir in Combination with pegylated interferon and ribavirin................................................................... 22

Figure 3 Inhibition Kinetics of MK-8742 and MK-5172 Against PI and NS5A RAVs, Respectively, in Genotype 1a Replicons ............................................ 23

Figure 4 Coverage of NS5A RAVs at Different Doses of MK-8742 ........................... 25

03VY5N



SUMMARY OF CHANGES

PRIMARY REASON(S) FOR THIS AMENDMENT:

Section Number (s)

Section Title(s) Description of Change (s)

7.1.1.2 Inclusion/Exclusion Criteria

Exclusionary lab criteria were updated to include creatinine clearance, and several other exclusionary criteria were updated for the safety of subjects on a ribavirin containing regimen.

ADDITIONAL CHANGE(S) FOR THIS AMENDMENT:

Section Number (s) Section Title(s) Description of Change (s)

4.2.3.1.1.2 Definition of Virologic Failure: Non-Response, Rebound, Virologic Breakthrough, and Relapse

Definition of a Non-Response was added

7.1.1.2 Inclusion/Exclusion Criteria Inclusion Criterion #6 was updated with additional language on abstinence and contraception

5.5 Concomitant Medications/Vaccinations (Prohibited & Allowed)

This section was updated with concomitant medications that are allowed.

5.8 Subject Withdrawal/Discontinuation Criteria

Deleted pregnancy as a reason to discontinue a subject from the trial, and added a reason of pregnancy to discontinue a subject from treatment

7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry, and Other)

Added coagulation as a laboratory test

03VY5N



1.0 TRIAL SUMMARY

Abbreviated Title MK-5172 + MK-8742 + R in prior DAA failures

Trial Phase II

Clinical Indication Treatment of hepatitis C virus infection

Trial Type Interventional

Type of control No treatment control

Route of administration Oral

Trial Blinding Unblinded Open-label

Treatment Groups MK-5172 (100 mg QD) + MK-8742 (50 mg QD) + R (weight based BID) for 12 weeks duration

Number of trial subjects Approximately 80 subjects will be enrolled.

Estimated duration of trial The sponsor estimates that the trial will require approximately 51 weeksfrom the time the first subject signs the informed consent until the last subject’s last visit.

Duration of Participation Each subject will participate in the trial for approximately 42.5 weeks from the time the subject signs the Informed Consent Form (ICF) through the final contact. After a screening phase of 45 days (or 6.5 weeks), each subject will receive assigned treatment for approximately 12 weeks. After the end of treatment, each subject will be followed for 24 weeks for a total duration of participation of up to 42.5 weeks in the study.

Randomization Ratio none

A list of abbreviations used in this document can be found in Section 12.4.

2.0 TRIAL DESIGN

Trial Design2.1

This is a multi-site, open-label trial of MK-5172 in combination with MK-8742 + ribavirin (R) in subjects with chronic hepatitis C virus infection who failed a prior approved direct acting antiviral (DAA) therapy regimen of boceprevir, telaprevir, simeprevir, or sofosbuvir taken concomitantly with peginterferon and ribavirin (PR); to be conducted in conformance with Good Clinical Practices.

A total of eighty (80) genotype 1 (GT1) subjects who failed prior direct acting antiviral (DAA) therapy + PR will be assigned to receive open label MK-5172 at 100 mg once daily (QD) administered concomitantly with MK-8742 at 50 mg QD with weight-based twice daily (BID) R. All patients must have received at least 4 weeks of treatment with a DAA on the prior regimen, and approximately 80% of the subjects must have met criteria for virologic failure (with or without resistance associated variants [RAVs]) on the prior regimen. The balance of the subjects may have failed a prior regimen for other reasons such as adverse events or administrative reasons. The study will permit both subjects with and without

03VY5N



cirrhosis, but the proportion of cirrhotic patients in the study will be limited to a maximum of 40%.

Subjects in this study will be treated for 12 weeks. At the end of 12 weeks of treatment,subjects will be in follow-up (FU) for 24 weeks.

Specific procedures to be performed during the trial, as well as their prescribed times and associated visit windows, are outlined in the Trial Flow Chart - Section 6.0. Details of each procedure are provided in Section 7.0 – Trial Procedures.

Trial Diagram2.2

The trial design is depicted in Figure 1.

Figure 1 Trial Design

3.0 OBJECTIVE(S) & HYPOTHESIS(ES)

Primary Objective(s) & Hypothesis(es)3.1

As this is a hypothesis-generating study, there are no formal hypotheses for this study.

In subjects with chronic HCV GT 1 infection who have failed prior DAA + PR treatment,with pre-treatment HCV RNA of at least 10,000 IU/mL:

(1) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the proportion of subjects achieving SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy), defined as HCV RNA <LLoQ (either TD[u] or TND) 12 weeks after the end of all study therapy.

(2) Objective: To evaluate the safety and tolerability of MK-5172 in combination with MK-8742 + R.

Secondary Objective(s) & Hypothesis(es)3.2

In subjects with chronic HCV GT1 infection who have failed prior DAA + PR treatment,with pre-treatment HCV RNA of at least 10,000 IU/mL:

(1) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the proportion of subjects achieving SVR12 (Sustained Virologic Response

Arm 1:MK-5172 100 mg +MK-8742 50 mg + R

24 weeks follow-up

W12

SVR 4 SVR 12 SVR 24

W4 W8D1 W16 W24 W36

03VY5N



12 weeks after the end of all study therapy) by prior DAA and prior DAA class, defined as HCV RNA <LLoQ (either TD[u] or TND) 12 weeks after the end of all study therapy.

(2) Objective: To evaluate the emergence of RAVs to MK-5172 and MK-8742 when administered as part of a combination regimen + R by population sequencing and deep sequencing as applicable.

(3) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the proportion of subjects achieving SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy), defined as HCV RNA <LLoQ (either TD[u] or TND) 24 weeks after the end of all study therapy.

(4) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the time to first achievement of undetectable (TND) HCV RNA.

(5) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R as assessed by the proportion of subjects achieving undetectable (TND) HCV RNA and HCV RNA <LLoQ at Week 2, 4, 12, and Follow-up Week 4 (SVR 4).

Exploratory Objectives3.3

(1) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R in patients who had met a criterion for virologic failure in prior DAA + PR therapy

(2) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R in patients who had met a criterion for virologic failure (see inclusion criterion #5 in Section 5.1.2) in prior DAA + PR therapy and had RAVs at baseline in this study (by population sequencing or deep sequencing as applicable)

(3) Objective: To evaluate the efficacy of MK-5172 in combination with MK-8742 + R by prior mode of virologic failure in prior DAA + PR therapy (i.e., nonresponse, breakthrough, or relapse)

(4) Objective: To evaluate the pharmacokinetics (PK) of MK-5172, MK-8742, and R.

(5) Objective: To evaluate the pharmacokinetic/pharmacodynamic (PK/PD) relationship which may include MK-5172, MK-8742, and/or R.

(6) Objective: To explore the relationship between genetic variation and subject response to the treatment(s) administered.

(7) Objective: To evaluate biomarkers (e.g., proteins and metabolite production), that may be predictive of tolerability of study drugs and virologic response to MK -5172 in combination with MK-8742 + R by comparing biomarker levels over time in subjects who respond to or fail study therapy.

03VY5N



4.0 BACKGROUND & RATIONALE

Background4.1

Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on MK-5172, MK-8742, and Ribavirin. Details regarding specific benefits and risks for subjects participating in this clinical trial may be found in the accompanying Investigators Brochure (IB) and Informed Consent documents.

Pharmaceutical and Therapeutic Background4.1.1

The details of the rationale for this trial are presented in Section 4.2.1.

MK-5172 is a rapidly reversible non-covalent competitive inhibitor of the HCV NS3/4Aprotease and is a candidate antiviral drug for the treatment of chronic HCV infection. In the replicon assay MK-5172 potently inhibits GT1a or GT1b viral replication (EC90 = 0.7 and 1.1 nM respectively). In vitro, MK-5172 inhibits the NS3/4A enzyme from GT 1-6 with IC50

values 1 nM.

MK-8742 is a small molecule inhibitor of Hepatitis C Virus (HCV) non-structural protein 5A (NS5A) that is being developed for the treatment of chronic HCV infection. NS5A is a pleiotropic protein with important roles in both HCV RNA replication and modulation of cell physiology of the host cell. Using a panel of sub-genomic replicon cell lines, MK-8742 has been shown to be highly potent against most HCV GTs and clinical resistance mutations, and as a result, it efficiently suppressed the emergence of resistance in replicon assays.

MK-8742 in combination with NS3/4A protease inhibitor MK-5172 in replicon cells demonstrated additive effects over most dose ranges tested and no evidence for antagonism[1]. In vivo, MK-5172 (100mg QD) combined with MK-8742 (20-50mg QD) with or without R for 12 weeks was tested in a Phase 2b trial which enrolled 65 GT1 treatment naïve patients (Protocol Number [PN]035A). The regimen was well tolerated, generally safe, and led to sustained virologic response (SVR) rates exceeding 90% [2]. To date, no patient in PN035A has discontinued due to an adverse event (AE) (see Section 4.1.3, Ongoing Studies).

In the past, the standard of care for the treatment of HCV infection GT1 had been peg-interferon with ribavirin (PR) which led to SVR rates of 40-50%. In 2011, 2 direct-acting antiviral agents (DAAs), telaprevir and boceprevir, were approved for use in combination with PR, as triple therapy, increasing overall SVR rates by 20-30% when compared to PR alone [3,4]. The triple therapy reduced treatment duration to 24-28 weeks, in the majority of treatment-naïve patients. These DAAs were designed to target GT1 NS3/4A protease a protein essential to virus replication.

The HCV replication strategy promotes rapid emergence of drug resistance. The virus replicates at a fast rate with an estimated production and clearance of virions in the range of 1010- 1012 per day [5,6]. The RNA polymerase lacks a proof-reading mechanism which makes the virus replication error-prone with an error rate in an order of 10-3 to 10-5 mutations per nucleotide per genomic replication. Consequently, HCV in patients is not a single

03VY5N



homogeneous population, but rather a population of diverse variants termed quasispecies which contain defective but replication competent viral genomes. These are drug-resistant viruses carrying 1-2 mutations likely to be present before antiviral therapy is started. These mutations typically impair virus replication fitness. A treatment-naive patient who carries a predominant wild-type (WT) virus population carries along a low concentration of mutated variants that can rapidly be selected in the setting of drug therapy. Under selective drug pressure, WT variants are rapidly eliminated from the replication space giving way to resistance-associated variants (RAVs) that continue to replicate, eventually becoming the dominant viral strain. Emergence of RAVs correlates to viral breakthrough or relapse due to re-emergence of resistant virus that had not been fully eradicated [7].

The understanding of HCV viral dynamics and RAVs led to the conclusion that a regimen combining drugs designed to target different mechanisms of viral replication are necessary to prevent the emergence of drug-resistant HCV strains. Currently, many promising DAA candidates have been identified and are under development. They can be divided into fourcategories: protease inhibitors (PIs) that can be administered once a day with resistance profile overlapping with those of boceprevir and telaprevir, newer PIs with activity against various GTs, NS5A inhibitors (NS5AIs) and polymerase inhibitors (includes two classes nucleos(t)ide [NIs] and non-nucleoside polymerase inhibitors[NNIs]).

Virologic failure due to RAVs during DAA-based triple therapy (telaprevir or boceprevir with PR) led to the question of whether these variants may impair future treatment options in these patients. There is preliminary evidence that SVR can be achieved in patients who present emergent RAVs associated with PIs and were re-treated with the same drug. Some patients treated with boceprevir and simeprevir in phase 1 studies who presented RAVs during the initial treatment were subsequently re-treated with the same drug and these RAVs were not reselected during the second course of DAA exposure. Furthermore, 9 patients who received short-term telaprevir therapy in Phase 1 studies were retreated with a full course of telaprevir-based triple therapy after an interval of approximately 6 years and no RAVs were detected even in deep-sequencing methods before initiating re-treatment. However, one viral breakthrough was reported prior to treatment Week 8 [7].

There is also preliminary evidence that prior failure to a DAA agent can be suppressed with treatment using two different classes of DAAs. This was reported recently, in a Phase 2 study of 40 patients who had not achieved SVR after prior treatment with a PI (telaprevir or boceprevir). The patients were randomized to receive 12 weeks of sofosbuvir (NI) combined with ledipasvir (NS5AI) + R and achieved 95% SVR4 [8]. Another group of 41 subjects who reported virologic failure to telaprevir or boceprevir were randomized to receive 12 weeks of sofosbuvir combined with daclastavir (NS5AI) + R and achieved 95-100% SVR12 [9].

These study results suggest that sustained drug selective pressure to inhibit WT virus and RAVs can occur in patients who harbor RAVs that have emerged during a prior DAA-based treatment. We hypothesize that MK-5172 100mg QD with MK-8742 50mg QD and R, having in vitro activity to suppress signature RAVs associated to PIs, NS5AI, and polymerase inhibitors, will be able to successfully treat patients who have reported virologic failure during prior DAA-containing treatment regimens.

03VY5N



Therefore, it is proposed that combining 2 DAAs, such as MK-5172 and MK-8742, will inhibit 2 essential enzymes for viral replication and increase the barrier to r esistance compared to each inhibitor alone, as well as increase the antiviral potency of the treatment regimen synergistically. This study will investigate the safety, tolerability, pharmacokinetics, and antiviral activity of the combination treatment of MK-5172 and MK-8742 with R for 12 weeks in subjects with GT1 chronic hepatitis C infection who were not able to complete a prior course of a DAA-based treatment.

Pre-clinical and Clinical Trials4.1.2

Refer to the Investigator’s Brochure (IB)/ approved labeling for detailed pre-clinical information on MK-5172, MK-8742, and ribavirin.

Ongoing Clinical Trials4.1.3

Protocol Number 035 Part A (PN035A) is an ongoing, randomized trial comparing 100 mg of MK-5172 in combination with two doses of MK-8742 ± R in treatment-naïve, non-cirrhotic subjects with chronic HCV infection. Part A of the trial randomized 65 subjects in a 1:1:1 ratio to 3 treatment arms in which open label MK-5172 at 100 mg once daily (QD) was administered concomitantly with blinded MK-8742 doses of either 20 or 50 mg QD +/- R.

Regardless of the treatment regimen or the HCV sub-genotype, all but one of the subjects that have reached the follow-up (FU) 12 visit have achieved SVR12.

In the intent to treat population, the combination of MK-5172 and MK-8742 with and without R was generally safe and well tolerated, and, to date no patient has discontinued due to an AE.

These clinical data demonstrate the robust efficacy of each of the regimens studied in Part A of PN035 and support advancing the two-drug combination of MK-5172 and MK-8742 ± R into a larger number of subjects, including more difficult to cure populations.

In Part B of PN035, which is ongoing, the harder to cure patient population such as the cirrhotics and the prior PR null responders are being studied; preliminary (unpublished) efficacy and safety data in these patient populations reveal that the proposed therapy regimen in this study is appropriate.

Rationale4.2

Rationale for the Trial and Selected Subject Population4.2.1

There are approximately 20 DAAs currently in development. They are being investigated in combination with PR or as all oral DAA-combination regimens, with or without R. Overall, SVR rates range between 60% to 80% in the older PIs + PR regimens, approximating 90% in the sofosbuvir + PR regimen and exceeding 90% in all oral DAA regimens. In spite of the high SVR rates, a proportion of patients (approximately 10% to 40% depending on the type of regimen) experience virologic failure.

03VY5N



In this study, the selected DAAs from prior failed regimens include protease PIs with an approved label or a near-future approved label, boceprevir, telaprevir, and simeprevir, and the nucleotide analog inhibitor (NI) with a near-future approved label, sofosbuvir, all given in combination with PR.

Despite the improvement in SVR rates with triple therapy, since the approval of boceprevir and telaprevir in 2011, there are patients that failed to achieve SVR despite being treated withan approved regimen of boceprevir or telaprevir in combination with PR, because they did not complete a full course of therapy, because of virologic failure, tolerability/safety, or other reasons. In a longitudinal, observational study of ~ 1500 North American patients with chronic HCV infection treated with boceprevir or telaprevir + PR, 335 patients (~23%) discontinued therapy early [10]: approximately 8% due to lack of efficacy, 9% due to AEs, 5% due to other reasons. The patients who prematurely discontinued therapy due to lack of efficacy in these studies and the community at large are expected to have high response rates to therapy with MK-5172 + MK-8742 + R.

The RAV profile observed in failures to several PIs have been characterized. Figure 2displays the amino acid substitutions observed in at least 10% of patients who failed to achieve SVR following therapy with boceprevir, telaprevir, and simeprevir.

Table 1 lists the most common RAVs associated with failure among patients who receive boceprevir + PR or telaprevir + PR. RAVs present in >30% of these failures include V36M/A/L, R155K/T, and V36M+R155K in G1a patients, and T54A/S and V170A in G1b patients.

Among G1a patients without baseline Q80K who failed to achieve SVR following administration of simeprevir + PR, the most frequently emerging mutations were R155K alone or in combination with other mutations at position 80, 122 and/or 168; among virologic failure patients with Q80K at baseline, single R155K mutations emerged most frequently. In G1b patients, mutations at D168, in particular D168V, were commonly observed among patients who failed simeprevir + PR treatment.

Table 1 also illustrates that RAVs commonly selected by boceprevir (at amino acid [AA] positions 36, 54, 55, 155, 156 and 170), telaprevir (at AA positions 36, 54, 155 and 156) and simeprevir (at AA positions 155, and 168) remain susceptible to MK-5172. R155T, D168A/E/T/V/H and the double mutants R155K+168N and R155K+V36M display a low-moderate level of resistance to MK-5172. At 100 mg, the steady state Ctrough for MK-5172 is approximately 33 nM which is 1- to 20-fold higher than the EC50s of these variants with the exception of A156V which is unfit and uncommonly seen in vivo. Q80K, a RAV that led to significant reduced SVR rate in simeprevir studies, is susceptible to MK-5172 inhibition. Clinical data confirm this finding (Table 2).

In long-term follow-up studies, RAVs that were selected by boceprevir and telaprevir were found to return to wild-type (WT) over time. The median time for boceprevir and telaprevir RAVs to return to WT are approximately 1.1 and 0.9 years, respectively [11,12]. Dependingon the time when the patient is retreated with the MK-5172 + MK-8742 ± R, the level of

03VY5N



previously elicited RAVs should decrease from that observed at failure. These data suggest that patients who failed a PI-based regimen much earlier may have few or no RAVs prior to enrollment in C-SALVAGE; thus, they are also expected to have high response rates to MK-5172 + MK-8742 ± R.

MK-8742 targets NS5a, a viral factor distinct from the NS3/4a protease which is the target of the protease inhibitors. Hence RAVs selected by HCV PIs should show little if any change in susceptibility to MK-8742 as exemplified by data in Table 3. Note specifically the WT potency of MK-8742 against the NS3 mutation R155K or the double mutation V36M+R155K associated with PI failures (Table 3). In the presence of MK-8742, the rates of inhibiting HCV RNA replication are similar between a WT replicon and a replicon containing a PI RAV (R155K). Similarly, the rates of viral inhibition are similar among a WT replicon and replicons containing a Y93H or Q30D RAV in the presence of MK-5172 (Figure 3). In an in vitro combination resistance study, the barrier to resistance in the combination of MK-5172 + MK-8742 is higher than each agent alone. The number of resistant colonies is significantly reduced when treated with the dual agent combinations.

These data support the hypothesis that MK5172 + MK-8742 ± R is likely to be effective in the treatment of patients who experienced virologic failure on prior boceprevir, telaprevir or simeprevir therapy with or without RAVs.

Failure to achieve SVR with sofosbuvir + PR is generally associated with relapse; RAVs are not often detected, and among those detected other than S282T, the clinical relevance remains to be defined. It is expected that MK-5172 + MK-8742 ± R will be highly effective in the re-treatment of these patients. Both agents target viral factors other than the NS5b polymerase, the target of sofosbuvir, and hence the patients who have experienced virologic failure on sofosbuvir + PR are essentially treatment naïve with respect to either MK-5172 or MK-8742. In addition, S282T is known to be very unfit and remains susceptible to both MK-5172 and MK-8742, with EC50s of 1.1 nM and 0.002 nM in a G1a background for MK-5172 and MK-8742, respectively (Table 4).

From a safety perspective, the regimen of MK-5172 + MK-8742 + R is expected provide a safer and more tolerable regimen to patients who prematurely discontinued boceprevir or telaprevir therapy due to tolerability or AEs. This assessment is based on lack of significant anemia, rash, or any other safety findings in the MK-5172 + MK-8742 +/- R Phase II studies. Phototoxicity and hyperbilirubinemia were reported in the simeprevir Phase III clinical trials [13]. Thus the rationale presented also applies to re-treatment of patients who prematurely discontinued a regimen of simeprevir + PR.

03VY5N



Table 1 In Vitro Potency of MK-5172 and Other HCV PIs Against Replicons Containing HCV G1 NS3 RAVs

RAVs with ~>5-fold potency shift are shaded.

n/a = not available

GT RAV

% Patients with RAVs

in Boceprevir

Phase 3 Studiesa


in Telaprevir

Ph2/3 Studiesb


in Simeprevir

Ph2/3 Studiesc

EC50 (nM)

MK-5172 Boceprevir Telaprevir Simeprevir

1a (H77)

WT - - - 0.3 254 329 3.8

V36A 3%10%

0.5 873 6,310 15

V36L n/a n/a 0.5 753 2,059 6.4

V36M 56% 49% 0.3 919 3,754 11

T54A 6%9%

0.3 767 1,939 2.4

T54S 18% n/a 0.3 652 552 5.3

V55A 3% n/a n/a 0.5 1,013 1014 5.7

Q80K n/a n/a n/a 0.5 183 184 19

R155K 66%56%

23% 1.3 1,444 3,877 495

R155T 8% n/a 3.4 2,601 8,928 115

R155K_Q80K n/a n/a

57%d,e

n/a n/a n/a n/a

R155K_S122X n/a n/a n/a n/a n/a

R155K_D168N n/a n/a 2.7 3,022 8,204 >2,500

A156S 5% 8% 0.9 3,996 12,191 1.9

A156T 4% n/a n/af n/af n/af n/af

V36M + R155K <10% 40% n/a 4.9 4,785 >20,000 745

A156V 0% <2% n/a n/af n/af n/af n/af

V158I 7% n/a n/a 0.1 568 370 6.3

D168E n/a n/a 5%d 5.0 239 280 133

D168E_Q80K n/a n/a n/a n/a n/a n/a

D168N 7% <2% n/a 0.9 229 409 32

1b (con1)

WT - - - 0.5 257 338 1.4

V36A 3%17%

n/a 1.0 686 2,048 2.7

V36L n/a 0.5 308 687 2.6

V36M 3% 3% n/a 0.9 802 2,293 n/a

T54A 41%22%

n/a 0.6 1,255 2,434 0.9

T54S 35% n/a 0.6 974 1,354 1.7

V55A 22% n/a n/a 0.7 843 1,173 1.1

Q80R n/a n/a n/a 0.9 156 141 19

R155K 3%0.3%

n/a 1.1 1,023 3,177 22

R155T 0% 6.7 6,000 >10,000 15

A156S 24%12%

n/a 1.1 3,677 8,990 0.3

A156T 3% 103 >20,000 >20,000 40

03VY5N



GT RAV


in Boceprevir

Phase 3 Studiesa


in Telaprevir

Ph2/3 Studiesb


in Simeprevir

Ph2/3 Studiesc

EC50 (nM)

MK-5172 Boceprevir Telaprevir Simeprevir

A156V 5% <2% n/a 172 19,800 >20,000 316

V158I 5% n/a n/a n/a 1,200 500 n/a

D168A n/a n/a

17%

6.8 88 43 723

D168E n/a n/a 1.6 87 107 27

D168H n/a n/a 26 813 418 847

D168T n/a n/a 13 676 728 807

D168V n/a n/a 60% 7.2 107 123 >2,000

D168N 0% <2% n/a 0.4 204 400 49

V170A 30% n/a n/a 0.7 2,340 389 1.8

a: based on combined Phase 2/3 studies except V36A/L, T54A, V55%, R155T, A156T/V/S, D168N in GT1a and V36A/L/M, R155K/T, A156T/V and D168N in GT1b were derived from 2 phase 3 studies

b: based on telaprevir product label 2013

c: estimated from the October 24, 2013 Meeting of the Antiviral Drugs Advisory Committee for simeprevir. Variants indicated as “others” were reported in 15% and 23% GT1a and GT1b patients who experienced virologic failure.

d: Assuming baseline Q80K persisted in all non-SVR patients who had post-baseline R155K or D168E detected during virologic failure.

e: R155K and D168 mutations were reported.

f: A156T/V replicon cell line did not survive G418 selection and could not be established.

03VY5N



Table 2 Impact of Baseline Q80 Mutations in G1a on the Efficacy of MK-5172-based Regimens

Patients with Baseline RAV Results

MK-5172 100 mg/PR(PN003/PN038; N = 64)

MK-5172/MK-8742/R(PN035; N = 37)

Q80K/L/H/R NOT detected N = 37 N = 22

SVR/TND at last recorded visit 32/37 (86%) 21 (95%)

Virologic failure 5/37† (14%) 1 (5%)§

Q80K, L, H, or R detected N = 27 N = 15

SVR/TND at last recorded visit 25/27 (93%) 14/15 (93%)

Virologic failure 2/27‡ (7%) 1/15¥ (7%)

† 2 MK-5172 relapses; 3 breakthroughs after >2 wks of trace/no MK-5172 levels‡ 1 relapse; 1 breakthrough but with >2 wks of no detectable MK-5172§ 1 pt discontinued at Day 3 due to pre-D1 lab exclusion criterion¥ 1 relapse

Table 3 In Vitro Potency of MK-8742 Against Replicons Containing HCV G1 NS3 RAVs

GT RAV% Patients with RAVs in

Boceprevir Phase III StudiesMK-8742EC50 (nM)

1a (H77)

WT - 0.003

V36M 56% Not Done

T54S 18% 0.002

V55A <10% Not Done

Q80K n/a Not Done

R155K 66% 0.013

A156S <10% Not Done

V36M + R155K <10% 0.0026

1b (con1)

WT - 0.002

T54A 41% Not Done

T54S 35% 0.0013

V55A 22% Not Done

Q80R n/a Not Done

A156S 24% Not Done

D168V n/a Not Done

V170A 30% Not Done

03VY5N



Table 4 In Vitro Potency of MK-8742 and MK-5172 Against Replicons Containing an HCV G1 NI RAV

NS5A Inhibitor

NS3/4A Protease Inhibitors

MK-8742 MK-5172Bocep-revir

Simep-revir

Telap-revir

GT RAV EC50 (nM)

NI 1a S282T 0.002 1.1 Not Done Not Done Not Done

Figure 2 Common RAVs in Patients who Experienced Lack of Efficacy on Treatment with boceprevir, telaprevir or simeprevir in Combination with pegylated interferon and ribavirin

03VY5N



Figure 3 Inhibition Kinetics of MK-8742 and MK-5172 Against PI and NS5A RAVs, Respectively, in Genotype 1a Replicons

Rationale for Dose Selection/Regimen/Modification4.2.2

Please refer to the MK-5172 and MK-8742 Investigators’ Brochures (IB) for further details of preclinical data and study results in humans.

This study will investigate the effect of MK-5172 100 mg QD with MK-8742 50 mg QD combined with R in chronic HCV GT1 infected subjects who have failed a prior approvedDAA therapy regimen of boceprevir, telaprevir, simeprevir, or sofosbuvir taken concomitantly with PR. Duration of therapy will be 12 weeks.

Dose selection for MK-5172

This trial will study MK-5172 at a dose of 100 mg.

MK-5172 has demonstrated evidence of robust antiviral activity in GT1 HCV-infected subjects when administered orally once daily (QD) as monotherapy for 7 days in a Phase Ib trial (PN004) in HCV infected subjects. Monotherapy with MK-5172 at doses of 30, 50, 100, 200, 400 or 800 mg for 7 days in GT1 HCV-infected subjects each led to a mean decline in HCV RNA of approximately 5-log10 at all of the doses studied, with no clear dose-

03VY5N



response relationship, and resulted in a prolonged suppression of the viral load lasting several weeks post-dosing.

In a Phase 2 dose-ranging study of MK-5172 in combination with PR (PN003), the dose of 100 mg was equally efficacious as the higher doses of 200 mg, 400 mg and 800 mg. However, elevations in ALT/AST occurred in a subset of patients at the higher doses of 400 mg and 800 mg. A detailed PK-AE analysis determined that there is a 4-fold safety margin between exposures at 100 mg and the higher doses of 400 mg and 800 mg. Consequently the MK-5172 100 mg dose has been selected. For additional information, please refer to the IB.

In addition, the doses of MK-5172 100 mg to 800 mg have been evaluated in over 400 treatment naive, non-cirrhotic, GT1, HCV patients in various combination regimens with and without PR and with and without MK-8742 (see Section 4.1.3, Ongoing Clinical Trials).

In summary, based on in vitro data (see Section 4.2.1) and data from the Phase Ib and Phase II studies in HCV-infected subjects, MK-5172 at a dose of 100 mg has been selected for this study.

Dose selection for MK-8742

A dose of 50 mg QD of MK-8742 will be used in this study.

In an HCV monotherapy study, doses from 5-50 mg QD for 5 days were administered in GT1-infected male individuals. Following a single dose of 5 mg MK-8742 QD x 5 days, the mean (SE) maximum reduction in HCV viral load in GT1 patients (5 GT1a and 1 GT1b) was -4.17 (0.23 log10 IU/ml. Viral load (VL) decline was rapid over Day 1, achieving a >3 log VL decline during the first day. The mean viral load reduction was ~-3.56 at 24 hours post-dose on Day 5. Following cessation of 5 mg dosing on Day 5, the viral load rebounded to a mean -1.3 log10 IU/ml of VL decline by Day 13, -0.6 log10 IU/ml of VL decline by 3 weeks post-dose, and returned to approximately baseline by Month 1 after dosing. Following administration of 50 mg QD, steady-state is achieved within 5 days of once-daily dosing in HCV-infected patients and within 7 days of dosing in healthy subjects.

HCV-infected patients and healthy subjects receiving 50-100 mg have comparable plasma exposures at steady-state. A dose of 20 mg or 50 mg of MK-8742 was evaluated in PN035Ain combination with MK-5172 with and without R. Both doses of MK-8742 demonstrated an excellent efficacy and tolerability profile (see Section 4.1.3, Ongoing Clinical Trials). However, as illustrated in Figure 4, MK-8742 at 50 mg provides sufficient coverage for most RAVs, whereas doses higher or lower than 50 mg provide either no tangible benefit or insufficient coverage for suppressing RAVs, respectively. The in vitro activities of MK-8742 against these RAVs are shown also in Table 5. In summary, based on in vitro data and data from the Phase Ib and Phase II studies in HCV-infected subjects, MK-8742 at a dose of 50 mg has been selected for this study.

03VY5N



MK-8742

MK

-8742 E

C50 o

n R

AV

s(1

00%

NH

S a

dju

ste

d,

nM

)

GT1a GT1b GT2 GT3 GT4 GT5 GT60.01

0.1

1

10

100

1000

C24h 5 and 10 mg

C24h 50 mgC24h 100 mg

M28VY93H/N

GT2(31M)

Plasma drug concentration measured on D5 in HCV patients

Figure 4 Coverage of NS5A RAVs at Different Doses of MK-8742

03VY5N



Table 5 Potency of MK-8742 in HCV replicons that contain common NS5A resistance associated variants

Replicon EC50 + SD (nM)a EC90 + SD (nM)

1a_H77 (WT) 0.004 + 0.002 0.006 + 0.002

1a_H77 (40% NHS)b 0.008 + 0.002 0.013 + 0.007

1a M28V 12 18

1a Q30E 0.2 0.4

1a Q30H 0.03 + 0.002 0.2 + 0.09

1a Q30K 0.3 0.4

1a Q30R 0.5 + 0.5 2.5 + 1.6

1a L31F 0.08 + 0.04 0.6 + 0.4

1a L31M <0.005 0.06

1a L31V 0.5 + 0.3 1.0 + 0.6

1a Y93C 0.2 + 0.07 1.1 + 0.3

1a Y93H 2.4 + 1.3 28 + 26

1a Y93N 8 18

1b_con1 (WT) 0.003 + 0.001 0.006 + 0.004

1b L28M 0.006 + 0.003 0.02 + 0.006

1b L28V 0.004 + 0.001 0.01 + 0.004

1b R30Q 0.009 + 0.003 0.02 + 0.007

1b L31F 0.05 + 0.02 0.2

1b L31V 0.01 + 0.01 0.07 + 0.03

1b Q62E 0.007 0.012

1b Y93C 0.005 + 0.001 0.01 + 0.002

1b Y93H 0.05 + 0.03 0.4 + 0.2

2a_JFH (31L) 0.003 + 0.001 0.02 + 0.01

2a_J6CH (31M) 20 38

2b_0907 (31M) 3.4 11 + 4.8

3a_NC009824/con1c 0.03 + 0.01 0.1 + 0.06

4a_DQ418782/con1c 0.003 + 0.001 0.016 + 0.009

5a_AF064490/JFHd 0.001 + 0.001 0.002 + 0.002

6_DQ278892/JFHd 0.009 + 0.006 0.017 + 0.009

6d_D84263/JFHd 0.003 + 0.002 0.008 + 0.005

a: SD is calculated from N > 3 independent experiments.

b: NHS = normal human serum

c: Chimeric replicons that contains an NS5A in the background of genotype 1b_con1

d: Chimeric replicons that contains an NS5A in the background of genotype 2a JFH1

03VY5N



Ribavirin (R)

Ribavirin (Rebetol™) will be administered BID orally at a total daily dose of 800- to 1400-mg based on subject weight on Day 1 as per the product label. See Section 5.2 for details o n R dosing.

Duration

Data from the Phase II study of MK-5172 and MK-8742 +/- R, PN035A (see Section 4.1.3) support the efficacy of a 12-week treatment duration.

Study Treatment Regimens

See Section 4.2.1, Rationale for the Trial.

Rationale for Endpoints4.2.3

4.2.3.1 Efficacy Endpoints

Overview of Efficacy Endpoints

The primary measurement for efficacy in this study is the plasma HCV RNA level. Long term suppression of HCV RNA, typically reported as Sustained Virologic Response (SVR), has been associated with improved outcomes in patients with chronic hepatitis C infection as measured by biochemical and histological remission of liver disease. Most available data suggest that SVR following antiviral therapy reduces the risk of progression to cirrhosis and may prevent the development of severe liver complications and improve survival [14].

The primary evaluation of efficacy in this trial is based on SVR 12 (Sustained Virologic Response 12 weeks after the end of all study therapy). The primary endpoint used in the Phase III trials for all currently approved anti-HCV therapy has been based on SVR24

(Sustained Virologic Response 24 weeks after the end of all study therapy). However, a high degree of concordance has been observed between SVR12 and SVR24 [15], and SVR12 is being used as the primary endpoint in more recent Phase III trials. Therefore, it is appropriate to use SVR12 as the primary efficacy endpoint in this trial; SVR24 will be a key secondary efficacy endpoint.

Other secondary evaluations of efficacy are based on SVR4 (Sustained Virologic Response 4 weeks after the end of all study therapy), HCV RNA measurements at Week 2, Week 4, and Week 12.

Detailed definitions for evaluating for SVR are provided later in this section.

4.2.3.1.1 Measurements of HCV RNA

HCV-RNA levels in plasma will be measured using the Roche COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® on blood samples drawn from each

03VY5N



subject at various time points prior to, during, and after dosing, as indicated in the Study Flow Chart (Section 6.0). Samples are collected and processed as per instructions provided.

Results from the sample collected at the screening visit are used to determine eligi bility. Samples collected at other time points are used for efficacy analyses. They are also used to identify subjects who meet virologic failure criteria.

The nomenclature detailed in Table 6 will be used when describing HCV RNA levels:

Table 6 Nomenclature for Describing HCV RNA Levels

Abbreviation Definition HCV RNA Level

TND Target not detected HCV RNA not detected

TD(u) Target detected but unquantifiable HCV RNA <LLoQ

TD(q) Target Detected, quantifiable HCV RNA ≥LLoQ

Definition of Efficacy Endpoints4.2.3.1.1.1

Efficacy will be defined at different timepoints during the trial. Specific endpoints are:

SVR4 (Sustained Virologic Response 4 weeks after the end of all study therapy). The subject has HCV RNA <LLoQ (either TD[u] or TND) 4 weeks after the end of all study therapy.



Definition of Virologic Failure: Non-Response, Rebound, Virologic 4.2.3.1.1.2Breakthrough, and Relapse

Lack of efficacy at different timepoints in the trial will be categorized as:

Non-Response:

– Subject has HCV RNA detected at end of treatment without HCV RNA < LLoQ on treatment (note that breakthrough is captured elsewhere).

03VY5N



Rebound:

– Subject has a rebound defined as >1 log10 IU/mL increase in HCV RNA from nadir while on treatment and confirmed from a separate blood draw within 2 weeks.

Virologic breakthrough:

– Subject has a confirmed HCV RNA ≥ LLoQ (TD[q]) after being < LLoQpreviously while on treatment. Confirmation is defined as an HCV RNA ≥ LLoQfrom a separate blood draw repeated within 2 weeks.

Relapse:

– Subject has a confirmed HCV RNA ≥ LLoQ (TD[q]) following end of all study therapy after becoming undetectable (TND) at end of treatment. Confirmation is defined as an HCV RNA ≥ LLoQ from a separate blood draw repeated within 2 weeks.

4.2.3.1.2 Viral Resistance Measurements

Measurements for viral resistance (RAVs) are included in the protocol in order to characterize patients who received prior DAA therapies (some of whom may have failed with presence of RAVs), to assess whether the presence of RAVs at baseline affects the response to MK-5172/MK-8742, and to determine the appearance of RAVs to MK-5172/MK-8742 in patients who fail on this regimen.

Samples will be collected at baseline and assessed for the presence of RAVs to prior therapies or to MK-5172/MK-8742, using population sequencing. Enrollment in the trial does NOT depend on the presence or absence of RAVs at baseline.

Samples will also be collected from patients who meet criteria for virologic failure at the time of the virologic failure confirmation and follow-up visits. In these patients, baseline and virologic failure samples will be assayed using also deep sequencing if RAVs are not detected by population sequencing at the time of failure. Patients will undergo follow-up testing in this study and the long-term follow-up study (PN017) to assess the return of RAVs to WT virus.

4.2.3.1.3 Genomic Exploratory Measurements

Understanding genetic determinants of drug response is an important endeavor during medical research. This research will evaluate whether genetic variation within a clinical trial population correlates with response to the treatment(s) under evaluation. If genetic variation is found to predict efficacy or adverse events, the data might inform optimal use of therapies in the patient population. A biosample will be collected and may be used for exploring the relationship between genetic variation and subject response to the treatment(s) administered. Variation across the human genome may be analyzed for association with clinical data collected in this study (For example: to assess the genetic variation in the human IL28B gene as a predictor of virologic response in each treatment arm, for ADME and HLA genes associated with liver injury). This research contributes to understanding genetic

03VY5N



determinants of efficacy and toxicity associated with the treatments in this study. Pharmacogenomic data from this study may be combined with data from other studies using these treatments.

4.2.3.2 Safety Endpoints

The safety and tolerability of MK-5172 in combination with MK-8742 + R are assessed by a clinical evaluation of adverse events and inspection of other study parameters including vital signs, physical examinations, 12-lead ECGs, and standard laboratory safety tests at appropriate time points as specified in the Trial Flow Chart. Adverse events are graded and recorded according to Section 7.2. Subjects may be asked to return for unscheduled visits in order to perform additional safety monitoring.

4.2.3.3 Pharmacokinetic Endpoints

The PK endpoints for MK-5172 and MK-8742 are C2hr, C4hr, and Ctrough; and Ctrough for R. PK samples will be collected from all subjects on each visit as described in the Trial Flow Chart (Section 6.0) and Table 11 (sparse, population PK sampling scheme). These samples will be used to evaluate not only PK concentrations, but also PK/PD and PK/AE relationships of MK-5172, MK-8742, and R, as appropriate. The predose time points outlined were chosen in order to capture Ctrough for all three compounds. The frequency of Ctrough collections will allow a thorough assessment of both patient drug concentrations and drug compliance, should a breakthrough occur. In addition, the postdose time points reflect the Cmax for MK-5172 and MK-8742 and will be used, in conjunction with the other samples, for PK-AE and PK-efficacy modeling.

4.2.3.4 Planned Exploratory Biomarker Research

Protein and metabolites may be measured from blood samples to compare biomarkers measured prior to treatment to biomarkers measured at various time points during treatment that correlate with subject response to treatment (sustained viral response). Plasma samples will be digested into peptides by proteases. These peptides will then be measured to determine the sequence and/or abundance to tens of thousands of peptides. The pattern of peptides will be compared between subjects who respond to drug treatment and subjects who do not respond to treatment. In addition, standard immunoassays for protein characterization may be used to characterize levels of specific proteins identified. Metabolites will be measured by mass spectrometry or other standard assays to identify and/or quantify thousands of metabolites in plasma. For all of the plasma biomarkers measured, associations between response to drug treatment and biomarker levels will be assessed. Some biomarkers of interest could include potential markers of inflammation (e.g., TNF-, IL-6, IL-8) or biomarkers of cell necrosis/apoptosis (e.g., HMGB1 and K18).

4.2.3.5 Future Biomedical Research

The Sponsor will conduct Future Biomedical Research on specimens routinely and specifically collected during this clinical trial. This research may include genetic analyses

03VY5N



(DNA), gene expression profiling (RNA), proteomics, metabolomics (serum, plasma) and/or the measurement of other analytes.

Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. For instance, exploratory pharmacogenetic (PGt) studies may be performed if significant Pharmacokinetic/Pharmacodynamic (PK/PD) relationships are observed or adv erse events are identified. Genomic markers of disease may also be investigated. Such retrospective pharmacogenetic studies will be conducted with appropriate biostatistical design and analysis and compared to PK/PD results or clinical outcomes. Any significant PGt relationships to outcome would require validation in future clinical trials. The overarching goal is to use such information to develop safer, more effective drugs/vaccines, and/or to ensure that subjects receive the correct dose of the correct drug/vaccine at the correct time. The details of this Future Biomedical Research sub-trial are presented in Section 12.2 - Collection and Management of Specimens for Future Biomedical Research. Additional informational material for institutional review boards/ethics committees (IRBs/ERCs) and investigational site staff is provided in Section 12.3.

5.0 METHODOLOGY

Entry Criteria5.1

Diagnosis/Condition for Entry into the Trial5.1.1

Male/Female subjects with CHC genotype 1 virus infection of at least 18 years of age who have failed prior DAA-based therapy will be enrolled in this trial.

Subject Inclusion Criteria5.1.2

In order to be eligible for participation in this trial, the subject must:

1. be ≥18 years of age on day of signing informed consent.

2. HCV RNA (≥ 10,000 IU/mL in peripheral blood) at the time of screening

3. have documented chronic HCV GT1 (with no evidence of non-typable or mixed genotype) infection:

Positive for anti-HCV antibody, HCV RNA, or an HCV genotype at least 6 months before screening or

Positive for anti-HCV antibody or HCV RNA at the time of screening with a liver biopsy consistent with chronic HCV infection (or a liver biopsy performed before enrollment with evidence of CHC disease, such as presence of fibrosis)

03VY5N



4. have liver disease staging assessment as follows:

Cirrhosis is defined as any one of the following [16,17]:

A liver biopsy performed prior to Day 1 of this study showing cirrhosis (F4) Fibroscan performed within 12 calendar months of Day 1 of this study showing

cirrhosis with result >12.5 kPa [17]* A FibroSure® (Fibrotest®) performed during Screening with a score of >0.75 and

an aspartate aminotransferase (AST):platelet ratio index (APRI) of >2. APRI formula: AST÷lab upper limit of normal (ULN) for AST x 100 ÷ {platelet count ÷100} (APRI calculation to be provided by the central laboratory.)

Absence of cirrhosis is defined as any one of the following:

Liver biopsy performed within 24 months of Day 1 of this study showing absence of cirrhosis

Fibroscan performed within 12 months of Day 1 of this study with a result of ≤12.5 kPa[17]*

*Fibroscan cut-off of 12.5 kPa has a positive predictive value of 90% and a sensitivity of 95% for ≥F3. Based on box and whisker plot of interquartile distribution >12.5 kPa will exclude the majority of subjects with metavir F3 fibrosis

A FibroSure® (Fibrotest®) score of ≤0.48 and Aspartate Aminotransferase to Platelet Ratio Index (APRI) of ≤1 during Screening

In the absence of a definitive diagnosis of presence or absence of cirrhosis by the above criteria, a liver biopsy is required. Liver biopsy results supersede the results obtained by Fibroscan or FibroSure®.

5. have received a prior regimen containing an approved DAA (boceprevir, telaprevir, simeprevir, or sofosbuvir) co-administered for at least 4 weeks with PR (note: due to the 4 week PR lead-in for boceprevir, a subject would meet this criterion after 8 weeks on this regimen). If prior to the approved DAA + PR containing regimen, the subject received a regimen only containing ribavirin and/or interferon (i.e., PR or interferon alone; unaccompanied by a DAA), this is also permitted.

Subject’s HCV treatment history (i.e., type of therapy and duration of therapy) and reason for discontinuation of prior treatment (i.e., virologic failure, safety/tolerability, or administrative reasons) should be available.

Subjects that discontinued prior therapy due to virologic failure must have met one of the following definitions:

PR+DAA Nonresponder: HCV RNA detected at end of treatment with a regimen that included one HCV DAA dosed in combination with PR. Subject must not have had undetectable HCV RNA during treatment. Can include subjects who

03VY5N



met protocol-defined virologic futility rule (except for breakthrough, which is captured elsewhere).

PR+DAA Breakthrough: Confirmed increase in HCV RNA ≥LLoQ after HCV RNA previously declined to < LLOQ. Occurred during the DAA dosing period with a regimen that included one DAA dosed in combination with PR.

PR+DAA Tail Breakthrough: Confirmed increase in HCV RNA ≥LLoQ after HCV RNA previously declined to <LLoQ. Occurred during the PR ‘tail’ dosing period that followed a PR + DAA dosing period.

PR+DAA Relapser: HCV RNA undetectable (TND) at end of treatment with a regimen that included one DAA dosed in combination with PR, but HCV RNA quantifiable (≥LLoQ) during follow-up

6. agree (if a subject is of reproductive potential) to remain truly abstinent or use (or have their partner use) 2 acceptable methods of birth control from at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations.

If acceptable by local regulatory agencies, methods of birth control allowed in the study are: intrauterine device (IUD), diaphragm with spermicide, hormonal contraceptives (e.g., birth control pills, transdermal patch, or injectables), contraceptive sponge, female condom, male condom with spermicide, or vasectomy.

NOTE: Abstinence (relative to heterosexual activity) can be used as the sole method of contraception if it is consistently employed as the subject’s preferred and usual lifestyle and if considered acceptable by local regulatory agencies and ERCs/IRBs. Periodic abstinence (e.g., calendar, ovulation, sympto-thermal, post-ovulation methods, etc.) and withdrawal are not acceptable methods of contraception.

NOTE: If a contraceptive method listed above is restricted by local regulations/guidelines, then it does not qualify as an acceptable method of contraception for subjects participating at sites in this country/region.

A female subject who is not of reproductive potential is eligible without requiring the use of contraception. A female subject who is not of reproductive potential is defined as one who has either 1) reached natural menopause (defined as 12 months with no menses without an alternative medical cause), 2) 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy, or 3) bilateral tubal ligation.

A male subject who is not of reproductive potential is eligible without requiring the use of contraception. A male subject who is not of reproductive potential is defined as: one who has undergone a successful vasectomy. A successful vasectomy is

03VY5N



defined as: (1) microscopic documentation of azoospermia, or (2) a vasectomy more than 2 years ago with no resultant pregnancy despite sexual activity post vasectomy.

7. understand the study procedures, alternative treatments available, risks involved with the study, and voluntarily agrees to participate by giving written informed consent.

8. provide written informed consent for the trial. The subject may also provide consent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research

Subject Exclusion Criteria5.1.3

The subject must be excluded from participating in the trial if the subject:

1. is under the age of legal consent, is mentally or legally incapacitated, has significant emotional problems at the time of pre-study screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures.

2. has received any HCV regimen containing a DAA with the exception of boceprevir, telaprevir, simeprevir, or sofosbuvir in combination with PR. Subjects who have been treated with one of these regimens more than once are excluded. Patients who have taken any DAAs in an interferon-free regimen are excluded.

3. Has evidence of decompensated liver disease manifested by the presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver disease. For cirrhotics, subjects that are Child-Pugh Class B or C or who have a Child-Pugh-Turcotte (CPT) score >6, must be excluded.

NOTE: To calculate the Child-Pugh score, refer to the following website: http://www.mdcalc.com/child-pugh-score-for-cirrhosis-mortality.

4. is coinfected with hepatitis B virus (e.g., HBsAg positive) or HIV.

5. has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in situ; or is under evaluation for other active or suspected malignancy.

6. Cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC.

NOTE: If liver imaging within 6 months of Day 1 is not available, imaging is required during screening

7. is taking or plans to take any of the prohibited medications listed in Section 5 of this protocol or is taking herbal supplements, including but not limited to St . John’s Wort

03VY5N



(Hypericum perforatum) within 2 weeks of Day 1. Only silymarin (Milk Thistle, Silybum marianum) is permitted during the trial.

8. is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent and is not willing to refrain from participating in another such study during the course of this study.

9. has clinically-relevant drug or alcohol abuse within 12 months of screening

10. is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggsfrom at least 2 weeks prior to Day 1 and continue throughout treatment and follow up, or longer if dictated by local regulations; or is a male subject who is expecting to donate sperm from at least 2 weeks prior to Day 1 and continue throughout treatment and follow up, or longer if dictated by local regulations.

11. is a male whose female partner is/are pregnant (this is a contraindication for R use).

12. has any of the following conditions:

Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair.

Poor venous access that precludes routine peripheral blood sampling required for this trial.

Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease).

Hemoglobinopathy, including, but not limited to, thalassemia major

Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial.

13. has any condition or prestudy laboratory abnormality, or history of any illness, which, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering the study drugs to the subject.

14. had a life-threatening SAE during the screening period.

15. has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis.

NOTE: Subjects with history of acute non-HCV-related hepatitis, which resolved > 6 months before study entry, can be enrolled.

03VY5N



16. has exclusionary laboratory values as listed below:

NOTE: If any of the laboratory exclusion criteria below are met, the site may have the abnormal value retested one time.

Laboratory AssessmentPatient Population

Noncirrhotic/Cirrhotic Subjectscreatinine clearance <50 mL/min

hemoglobin < 12 g/dL for male, <11 g/dL for female subjectsplatelets <50 x 103/μL

Serum Albumin < 3.0 g/dL (lower limit of normal) of laboratory reference range

INR >1.7

HbA1c >10%

ALT >10xULN

AST >10xULN

17. is or has an immediate family member (spouse or children) who is investigational site or sponsor staff directly involved with this trial.

Trial Treatment(s)5.2

The treatments to be used in this trial are outlined below in Table 7

Table 7 Trial Treatments

Drug Weight Dose/PotencyDose

Frequency

Route of Administra

tionRegimen/Treat

ment Period UseMK-5172 N/A 100 mg QD Oral 12 Weeks ExperimentalMK-8742 N/A 50 mg QD Oral 12 Weeks Experimental

Ribavirin(Rebetol™),

200 mg capsules

<66 kg(<145 lbs.)

800 mg(2 in AM, 2 in PM)

BID Oral 12 Weeks Experimental

66-80 kg(145-177 lbs.)


81-105 kg(178-231 lbs.)


>105 kg(>231 lbs.)


The first dose of trial treatment will be administered at the trial site at Visit 2 (Day 1). Subsequent dosing will be performed by the subject (i.e., unsupervised at his/her home) at approximately the same time each day as shown in the study medication diary.

03VY5N



MK-5172 and MK-8742

Subjects will be allocated to receive MK-5172 100 mg QD orally administered concomitantly with MK-8742 50 mg QD orally with R for 12 weeks. Drug will be supplied once monthly in a bottle(s). Subjects will be instructed to take their daily medication as instructed on the bottle label(s).

Ribavirin

Ribavirin (Rebetol™) will be administered BID orally at a total daily dose of 800 mg to 1400 mg based on subject weight on Day 1 (Refer to Table 7 in Section 5.2).

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of trial treatments in accordance with the protocol and any applicable laws and regulations.

Dose Selection/Modification5.2.1

5.2.1.1 Dose Selection

The rationale for selection of doses to be used in this trial is provided in Section 4.0 -Background and Rationale.

5.2.1.2 Dose Modification

Dose modification of MK-5172 and MK-8742 is not permitted.

If severe adverse events or laboratory abnormalities develop during the study, R can be modified based on the recommended guidelines provided in Table 8.

Table 8 Recommended Guidelines for Dose Modification of Ribavirin

Body Weight on Day 1

Full Daily Dose

(mg/day)

1st R Dose Reduction 2nd R Dose Reduction 3rd R Dose Reduction

Dose(mg/day)

Number of 200-mg R Capsules

Dose(mg/day)


Dose(mg/day)


<66 kg (<145 lb) 800 600

1 in AM/2 in PM 400

1 in AM/1 in PM 200 1 in PM

66 to 80 kg (145 to 177 lb) 1000 800

2 in AM/2 in PM 600

1 in AM/2 in PM 400

1 in AM/1 in PM

81 to 105 kg (178 to 231 lb) 1200 1000

2 in AM/3 in PM 800

2 in AM/2 in PM 600

1 in AM/2 in PM

>105 kg (>231 lb) 1400 1000

2 in AM/3 in PM 800

2 in AM/2 in PM 600

1 in AM/2 in PM

Table 9 provides recommended dose reduction of R for selected hematologic and biochemical parameters per product labeling.

03VY5N



Table 9 Recommended R Dose Reduction for Selected Hematologic and Biochemical Parameters

Parameter Dose Reduction of R Discontinuation or Interruption1 of RHemoglobin < 10 g/dL < 8.5 g/dLALT/AST See Section 5.8 on

Withdrawal/Discontinuation 1 Individual study drug regimen interruptions are permissible based on the results of abnormal laboratory

parameters. Treatment interruptions should not exceed 2 consecutive weeks in duration.ALT = Alanine aminotransferase; AST = Aspartate aminotransferase;ULN – Upper limit of normal.

Protocol Regimens and Treatment Modification:

The subject should return for assessment at a recommended interval of every week until the AE resolves or the subject is stable. If further dose reduction is required, the second (or third for R) level of dose reduction may be used. If the AE persists but does not fall into the range for discontinuation/treatment interruption, the reduced dose may be continued. At the discretion of the physician, doses may be increased to the full dose or directly in steps when the AE subsides.

If for any reason either MK-5172 or MK-8742 needs to be interrupted, it can be interrupted for up to 3 days. If either MK-5172 and/or MK-8742 is interrupted for more than 3 days, all study drug dosing should be discontinued.

If for any reason R needs to be interrupted (e.g., for safety reasons), if possible, it should be restarted within 14 days.

Timing of Dose Administration5.2.2

Subjects will be instructed to take MK-5172, MK-8742, and R orally, in the morning. Ribavirin should be taken with food. A second daily dose of R should be taken by itself, with food, in the evening.

If a subject misses a dose of MK-5172 and/or MK-8742, the next dose should be taken as soon as possible unless it is less than 8 hours before the next dose. Then the missed dose should be skipped and the normal dosing schedule resumed. Subject should not double the next dose in order to compensate for what has been missed.

If a subject misses a dose of R, then they should take the missed dose as soon as possible with food during the same day. If an entire day has gone by, then these missed doses should be skipped, and the normal dosing schedule should be resumed. Subjects should not double the next dose in order to "make up" what has been missed.

Trial Blinding/Masking5.2.3

This is an open-label trial; therefore, the Sponsor, investigator and subject will know the treatment administered.

03VY5N



Randomization or Treatment Allocation5.3

Subjects participating in this trial will be allocated by non-random assignment.

Stratification5.4

No stratification based on age, sex or other characteristics will be used in this trial.

Concomitant Medications/Vaccinations (Prohibited & Allowed)5.5

Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed during the dosing period. If there is a clinical indication for any medication or vaccinationspecifically prohibited during dosing period, discontinuation from trial therapy or vaccinationmay be required. The investigator should discuss any questions regarding this with the Sponsor Clinical Director. The final decision on any supportive therapy or vaccination rests with the investigator and/or the subject's primary physician. However, the decision to continue the subject on trial therapy or vaccination schedule requires the mutual agreement of the investigator, the Sponsor and the subject.

Prohibited Medications

The following medications/therapies are contraindicated during the dosing period:

Strong and moderate CYP3A/P-gp inducers, including but not limited to:

Anti-infectives: nafcillin, rifampin Anticonvulsants: carbamazepine, phenytoin, phenobarbital bosentan modafinil St. John's Wort

OATP inhibitors, including but not limited to: Immunosuppressants: cyclosporine Anti-infectives: rifampin Diabetes agents: glibenclamide, glyburide Lipid lowering agents: gemfibrozil eltrombopag lapatinib

HMG-CoA reductase inhibitors (statins), including but not limited to: simvastatin fluvastatin rosuvastatin greater than 10 mg (see Allowed Medications, below) atorvastatin greater than 10 mg (see Allowed Medications, below)

03VY5N



The following classes of drugs: Proton pump inhibitors H2 antagonists Other anti-ulcer agents and gastric acid suppressants

In general, CYP3A4 substrates with narrow therapeutic ranges (e.g. alfentanil, astemizole, cisapride, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, terfenadine) are not prohibited, but their levels have the potential to be increased by approximately 30%. Therefore, subjects taking these medications should be monitored closely or dose adjusted appropriately.

Investigational agents are not permitted.

Systemic corticosteroids (dose equivalent to ≥ 10 mg prednisone per day, except in the case of rapid steroid tapers <1 week in duration) are not permitted.

Medications contraindicated during therapy with R are not permitted in this trial.

Concomitant medications and therapies discontinued during the dosing period may be restarted 2 weeks after the last dose of study drug is administered and may continue during the follow-up period.

Note: For other medications not listed here, please consult the Sponsor.

Allowed Medications

The following concomitant medications are allowed in this study:

Antihypertensives:

ACE inhibitors/ARB: enalapril, captopril, lisinopril, ramipril, valsartan, losartan,

telmisartan

Beta blockers: atenolol, metoprolol, propranolol

Note: for other beta blockers, please consult with the Sponsor

Calcium-channel blockers: verapamil, diltiazem, amlodipine

Note: for other calcium-channel blockers, please consult with the Sponsor

hydralazine, clonidine, minoxidil, isosorbide nitrates

Anemia: erythropoetin

Diuretics: HCTZ, furosemide, spironolactone, triamterene

Hypoglycemic agents: insulin, sitagliptin, glipizide

Contraceptives: oral contraceptive pills, progesterone injects, intrauterine devices

03VY5N



Antidepressants/anxiolytics: citalopram, paroxetine, duloxetine, escitalopram, fluoxetine,

bupropion, trazodone, diazepam, clonazepam, temazepam, lorazepam

HMG-CoA reductase inhibitors (statins):

Pravastatin and pitavastatin: may be coadministered without dose adjustment

Rosuvastatin: use the lowest possible effective dose of rosuvastatin, but do not exceed

a daily dose of 10 mg

Atorvastatin: use the lowest possible effective dose of atorvastatin, but do not exceed

a daily dose of 10 mg

Rescue Medications & Supportive Care5.6

No rescue or supportive medications are specified to be used in this trial.

Diet/Activity/Other Considerations5.7

Diet Considerations

MK-5172, MK-8742, and R should be taken together once daily. MK-5172 and MK-8742 do not need to be taken with food, however, R must be taken with food. A second daily dose of R should be taken alone, with food. Intake of grapefruit or grapefruit juice is prohibited during the treatment period of the trial.

Considerations for Study Visits

Visits and associated procedures should be scheduled as close to the indicated study days and study weeks as possible. See the Study Flow Chart in Section 6 for a complete listing of study procedures required at each visit. Collection of PK samples (predose and/or postdose) must be taken as indicated in Table 11 in Section 7.1.3.2.1.

Subject Withdrawal/Discontinuation Criteria5.8

Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of the investigator should any untoward effect occur. In addition, a subject may be withdrawn by the investigator or the Sponsor if enrollment into the trial is inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. Specific details regarding discontinuation or withdrawal procedures; including specific details regarding withdrawal from Future Biomedical Research, are provided in Section 7.1.4 – Other Procedures.

In this trial, a subject may discontinue from treatment but continue to participate in the regularly scheduled activities, as long as the subject does not withdraw consent. Discontinuation from treatment is permanent. Once a subject has discontinued treatment, even though he/she continues to be monitored in the trial, he/she shall not be allowed to begin treatment again.

03VY5N



A subject must be discontinued from the trial for any of the following reasons:

● The subject or legal representative (such as a parent or legal guardian) withdraws consent.

The subject has a medical condition or personal circumstance which, in the opinion of the investigator and/or Sponsor, places the subject at unnecessary risk through continued participation in the trial or does not allow the subject to adhere to the requirements of the protocol.

A subject must be discontinued from treatment (but may continue to be monitored in the trial) for any of the following reasons:

Subject meets any virologic failure criteria (see Section 4.2.3.1.1.2)

Subject becomes pregnant during the trial.

Male subject whose partner becomes pregnant during the trial

A physician investigator feels it is in best interest of the subject to discontinue.

The subject’s ALT or AST increases to >500 IU/L

The subject’s ALT or AST increases to >3x baseline, is >100 IU/L, and there is a simultaneous increase in total bilirubin >2x ULN and/or INR >1.5.

The subject’s ALT or AST increases to >3x the nadir value, is >100 IU/L, and there is a simultaneous increase in total bilirubin > 2x ULN and/or INR >1.5.

The subject’s ALT or AST increases to >3x baseline, is >100 IU/L, and is temporally associated with the new onset or worsening of any of the following adverse events that are of moderate or severe intensity and deemed by the investigator to be at least possibly related to MK-5172 and or MK-8742: nausea, vomiting, right upper quadrant pain or tenderness, and/or eosinophilia (>5%).

The subject’s ALT or AST increases to >3x the nadir value, is >100 IU/L, and is temporally associated with the new onset or worsening of any of the following adverse events that are of moderate or severe intensity and deemed by the investigator to be at least possibly related to MK-5172 and or MK-8742: nausea, vomiting, right upper quadrant pain or tenderness, and/or eosinophilia (>5%).

The subject’s alkaline phosphatase increases to >3x ULN, there is a simultaneous increase in total bilirubin > 2x ULN and other causes of elevated alkaline phosphatase are excluded.

03VY5N



The subject’s alkaline phosphatase increases to >5x ULN and other causes of elevated alkaline phosphatase are excluded.

A subject may be discontinued from treatment for any of the following reasons:

1. SAE assessed by the physician investigator as possibly or probably related to study medication. Investigator may continue the subject in the trial, if it is deemed to be in the best interest of the subject to stay on the study treatment.

2. Failure to comply with the dosing, evaluations, or other requirements of the trial

Subject Replacement Strategy5.9

A subject that discontinues from the trial will not be replaced.

Beginning and End of the Trial5.10

The overall trial begins when the first subject signs the informed consent form. The overall trial ends when the last subject completes the last trial visit, discontinues from the trial or is lost to follow-up (i.e. the subject is unable to be contacted by the investigator).

Clinical Criteria for Early Trial Termination5.11

Early trial termination will be the result of the criteria specified below:

Early Trial Termination Due to Failure Criteria (non-response, rebound,breakthrough, and relapse) and Treatment Duration Modification for Relapse

If > 4 of the first 12 subjects who were previously treated with a particular DAA meet a virologic failure criterion other than relapse, then enrollment for subjects previously treated with that DAA will halt. If the above criterion for halting enrollment is not met but >2 of the first 12 subjects previously treated with a particular DAA relapse, then the duration of therapy will be extended to 18 weeks for those who were treated with that particular DAA and have not completed study therapy.

In addition, enrollment for the trial will halt if >20 subjects (treated with any prior DAA) meet a virologic failure criterion other than relapse. If the criterion for halting enrollment for the entire trial is not met but > 10 subjects (treated with any prior DAA) relapse, then the duration of therapy will be extended to 18 weeks for all those who have not completed therapy study therapy; prior to making this decision, data will be reviewed to determine whether relapse is occurring primarily in patients with specific prior DAA therapy or in patients with specific patient baseline characteristics Based upon this review of data in patients who relapsed, treatment duration will be extended in all patients or in a relevant subset of patients.

03VY5N



6.0 TRIAL FLOW CHART

Study Period

Scr

Treatment Weeks Follow-Up Weeks Unscheduled Visits

Day

18

Day

7 2 4 6 8 10 12 NA NA FU 4 FU 8 FU 12 FU 24Unsched/HCV Viral Fail Conf

Visit

Early Discon

Visit

Treatment Modification13

NA


NA NA NA NA NA NA NA 12 16 18 FU 4 FU 8 FU 12 FU 24Unsched/HCV Viral Fail Conf

Visit

Early Discon

VisitVisit No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Visit Window -45 days

NA -6/+7 days

-6/+14 days

±2 weeks -2/+4 weeks

-4/+2 weeks

-2/+4 weeks


-12/+4 weeks

NA NA

ADMINISTRATIVE PROCEDURESInformed Consent xInformed Consent for Future Biomedical Research xInclusion/Exclusion Criteria x xSubject Identification Card xMedical History xPrior and Con-med Review x x x x x x x x x x x x xTreatment Allocation xReview Study Medication Diary x x x x x x x x x x x xCLINICAL SAFETY EVALUATIONSPhysical Examination1 x x x x xWeight x x xHeight x12-Lead ECG x x x x xVital Signs x x x x x x x x x x x xSubject confirmation of birth control x x x x x x x x x x x x x x x x xReview (Serious) Adverse Events2 x x x x x x x x x x x x x x x x xLABORATORY SAFETY EVALUATIONSCoagulation x x x x x x x x x x x x x x xChemistry & Hematology x x x x x x x x x x x x x x xHBA1C xHBsAg xHIV RNA xLiver Ultrasound6 xUrine Pregnancy Test (females of child bearing potential only)3 x x x x x x x x x x x x xPHARMACOKINETICSMK-5172 PK x x x x x x x xMK-8742 PK x x x x x x x xR PK x x x x x x x xHCV EVALUATIONS

03VY5N



Study Period

Scr


Day

18

Day


Visit

Early Discon

Visit


NA



Visit

Early Discon

VisitVisit No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17


NA -6/+7 days

-6/+14 days


-4/+2 weeks

-2/+4 weeks


-12/+4 weeks

NA NA

HCV Genotype Determination xHCV RNA Level7 x x x x x x x x x x x x x x x x x10

Plasma for HCV Viral Resistance and Biomarker4, 7 x x x x x x x10

Blood (DNA) for genetic analysis5 xDRUG ADMINISTRATIONMK-5172 (open-label) 9 x x x x x x x x11 x12

MK-8742 (open-label)9 x x x x x x x x11 x12

R (open-label)9 x x x x x x x x11 x12

1 A comprehensive PE will be done at screening. For all other visits a focused PE will be conducted when clinically indicated.2 Review of Adverse Events should include collecting serious adverse events throughout the study and collecting all adverse events Day 1 (post-dose) through 14 days following the last dose of

study drug. Adverse events occurring prior to study drug administration or after study drug discontinuation, as a result of a protocol-specified procedure or intervention, should also be reported.

3 When study visits are spaced more than one month apart in the follow-up period, urine pregnancy test kits will be dispensed to female subjects of childbearing potential so that monthlypregnancy testing can continue for 6 months post dosing. The test results must be provided to the investigator and/or site personnel. Subjects should be instructed to contact the investigator and/or site personnel immediately if the result of the self-pregnancy test is positive.

4 Blood samples will be collected for HCV viral resistance testing at baseline, viral failure confirmation visit, and FU visits. At the same time points, samples will be collected for proteomics, and metabolomics and other exploratory analysis. Population sequencing will be performed on all samples at baseline and virologic failure. Deep sequencing at baseline and virologic failure will be performed if subject does not have RAVs by population sequencing at the time of failure.

5 Blood sample will be collected for IL28B and genetic analysis. Any leftover DNA extracted from blood will be stored for future biomedical research if consent is obtained. Testing will be limited to IL28B if there is a documented law or regulation prohibiting genetic analysis.

6 For cirrhotic patients only, an ultrasound of the liver should be performed within 4 weeks prior to allocation to rule out hepatocellular carcinoma. If a patient already had a CT scan or an MRI scan within 6 months of allocation to study therapy, readings from these imaging techniques are also acceptable.

7 Any leftover plasma from HCV RNA and leftover plasma for HCV viral resistance and biomarker will be stored for future research if the subject consents to participate in the FBR sub-study. 8 Procedures on Day 1 should be performed prior to the first morning dose unless specified otherwise.9 MK-5172, MK-8742, and Ribavirin will be provided on a monthly basis. The site will call the Interactive Voice Response System (IVRS) to obtain component ID assignment. Duration will be 12

weeks or 18 weeks if treatment modification (refer to Section 5.11) is implemented.10 If a subject is a confirmed viral failure during therapy (i.e., rebound, breakthrough), then the sample collection for HCV RNA and Viral Resistance/Biomarker is not needed for the early

discontinuation visit.11 There will be no dispensing of study medication on this day unless the Treatment Modification is applied. Subjects on the 12 week regimen will take their last doses of study drug on this day.12 Study drug will only be dispensed on this day if the Treatment Arm Modification has been applied.

03VY5N



Study Period

Scr


Day

18

Day


Visit

Early Discon

Visit


NA



Visit

Early Discon

VisitVisit No. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17


NA -6/+7 days

-6/+14 days


-4/+2 weeks

-2/+4 weeks


-12/+4 weeks

NA NA

13 Treatment Modification may occur based on the guidance in Section 5.11 (Early Trial Termination Due to Failure Criteria (rebound and breakthrough) and Treatment Duration Modification for relapse)

03VY5N



7.0 TRIAL PROCEDURES

Trial Procedures7.1

The Trial Flow Chart - Section 6.0 summarizes the trial procedures to be performed at each visit. Individual trial procedures are described in detail below. It may be necessary to perform these procedures at unscheduled time points if deemed clinically necessary by the investigator.

Furthermore, additional evaluations/testing may be deemed necessary by the investigator and or the Sponsor for reasons related to subject safety. In some cases, such evaluation/testing may be potentially sensitive in nature (e.g., HIV, Hepatitis C, etc.), and thus local regulations may require that additional informed consent be obtained from the subject. In these cases, such evaluations/testing will be performed in accordance with those regulations.

Administrative Procedures7.1.1

7.1.1.1 Informed Consent

The investigator or qualified designee must obtain documented consent from each potential subject or each subject’s legally acceptable representative prior to participating in a clinical trial or Future Biomedical Research.

7.1.1.1.1 General Informed Consent

Consent must be documented by the subject’s dated signature or by the subject’s legally acceptable representative’s dated signature on a consent form along with the dated signature of the person conducting the consent discussion.

A copy of the signed and dated consent form should be given to the subject before participation in the trial.

The initial informed consent form, any subsequent revised written informed consent form and any written information provided to the subject must receive the IRB/ERC’s approval/favorable opinion in advance of use. The subject or his/her legally acceptable representative should be informed in a timely manner 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 will be provided and documented via a revised consent form or addendum to the original consent form that captures the subject’s dated signature or by the subject’s legally acceptable representative’s dated signature.

Specifics about a trial and the trial population will be added to the consent form template at the protocol level.

The informed consent will adhere to IRB/ERC requirements, applicable laws and regulations and Sponsor requirements.

03VY5N



7.1.1.1.2 Consent and Collection of Specimens for Future Biomedical Research

The investigator or qualified designee will explain the Future Biomedical Research consent to the subject, answer all of his/her questions, and obtain written informed consent before performing any procedure related to the Future Biomedical Research sub-trial. A copy of the informed consent will be given to the subject.

7.1.1.2 Inclusion/Exclusion Criteria

All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to ensure that the subject qualifies for the trial.

7.1.1.3 Subject Identification Card

All subjects will be given a Subject Identification Card identifying them as participants in a research trial. The card will contain trial site contact information (including direct telephone numbers) to be utilized in the event of an emergency. The investigator or qualified designee will provide the subject with a Subject Identification Card after the subject provides written informed consent.

7.1.1.4 Medical History

A medical history will be obtained by the investigator or qualified designee.

7.1.1.5 Prior and Concomitant Medications Review

7.1.1.5.1 Prior Medications

The investigator or qualified designee will review prior medication use, including any protocol-specified washout requirement, and record prior medication taken by the subject within 30 days before starting the trial. In addition, all HCV therapy regimens received at any time in the past must also be recorded; in this protocol, subjects must have previously received one of the protocol-specified DAAs in combination with PR.

7.1.1.5.2 Concomitant Medications

The investigator or qualified designee will record medication, if any, taken by the subject during the trial.

7.1.1.6 Assignment of Screening Number

All consented subjects will be given a unique screening number that will be used to identify the subject for all procedures that occur prior to randomization or allocation. Each subject will be assigned only one screening number. Screening numbers must not be re-used for different subjects.

03VY5N



Specific details on the screening visit requirements (screening/rescreening) are provided in Section 7.1.5.1.

7.1.1.7 Assignment of Randomization Number

All eligible subjects will be allocated, by non-random assignment, and will receive a randomization number. The randomization number identifies the subject for all procedures occurring after treatment allocation. Once a randomization number is assigned to a subject, it can never be re-assigned to another subject.

A single subject cannot be assigned more than 1 randomization number.

7.1.1.8 Trial Compliance (Medication)

The investigator/study coordinator will give the subject a Study Medication Diary to be completed during the study period. The investigator/study coordinator will be responsible for entering the subject’s identification (allocation number), visit number, and dates before giving the diary card to the subject. The subject will be instructed to record dates/times and the number of tablets or capsules of study drug doses on the diary card for the entire time period. Only the subject should enter information on the diary card. The subject is to return the completed diary card at each scheduled visit. At visits when used/unused study medications are returned, site personnel must verify the accuracy of the dosing diary by comparing entries with amounts of returned study medication. If a discrepancy is noted, investigator/study coordinator must discuss the discrepancy with the subject, and the explanation must be documented. Only the subject shall make any changes to the entries on the diary card. The subject will initial the diary card to confirm that the information is accurate. The investigator/study coordinator will be responsible for transferring the appropriate information from the diary card onto the appropriate case report form.

Interruptions from the protocol specified treatment for >= 3 days for MK-5172/MK8742 or more than 14 days for RBV require consultation between the investigator and the Sponsor and written documentation of the collaborative decision on subject management.

Clinical Procedures/Assessments7.1.2

7.1.2.1 Physical Examination

All physical examinations must be performed by the principal investigator or sub -investigator (physician, physician assistant or nurse practitioner).

A complete physical examination, performed at the Screening visit includes the following assessments: general appearance, head, eyes, ears/nose/ throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and neurologic evaluations. Breast, re ctal, and genitourinary/pelvic exams should be performed when clinically indicated. For all other visits, a focused exam will be performed when clinically indicated. Any significant changes between the screening visit and subsequent visits should be noted in the Medical History eCRF. Any significant changes after receiving study therapy at Day 1 must be reported as

03VY5N



adverse events and entered on the adverse event eCRF. If the subject is discontinued for any reason during the treatment phase, every attempt should be made to perform a final physical examination.

7.1.2.2 Weight and Height Assessment

The subject's weight should be assessed as mentioned in the flow chart. Clinically significant changes from Day 1 should also be captured as AEs in the CRF.

7.1.2.3 12-Lead ECG

Special care must be taken for proper lead placement. Subjects should be shaved as necessary for proper lead placement. Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to having ECG readings obtained. However, clinically significant findings from the screening ECG must be captured in the medical history eCRF. For ECGs performed during treatment or during the follow-up period, any clinically significant changes compared with the screening ECG must be captured as AEs.

7.1.2.4 Vital Signs

Vital signs will include heart rate (sitting), blood pressure (sitting), and oral temperature. Subjects should be resting in a semi-recumbent position for at least 10 minutes prior to having vital sign measurements obtained.

Note: Oral temperatures should be taken, but if oral is not possible, tympanic, rectal, and axillary temps may be taken,

After the screening visit, the site should indicate whether or not the result is clinically significant and if any subsequent changes constitute an adverse event.

7.1.2.5 Birth Control Confirmation

Extreme care must be taken to avoid pregnancy in female subjects of childbearing potential and female partners of childbearing potential of male subjects.

Confirmation must be obtained by site personnel that subjects and their partner(s) are using acceptable methods of contraception. This assessment must be documented in the subject's study chart at each specified visit.

7.1.2.6 Adverse Events

During the screening period only SAEs and adverse events occurring as a result of a protocol-specified procedure or intervention should be reported.

The principal investigator or sub-investigator (physician, physician assistant or nurse practitioner) must determine the severity and relationship to study medication(s) of all adverse events. A physician investigator must review, initial and date the severity of all

03VY5N



adverse events and their relationship to study medications when initial assessment of an adverse event is made by a physician assistant or nurse practitioner. Designated medical practitioners must be licensed and the responsibilities transferred to them must be documented in the site file. For details please refer to Section 7.2.

7.1.2.7 Noninvasive Methods of Cirrhosis Evaluation

FibroScan - This method for assessing liver cirrhosis has gained increasing acceptance. In the US, this methodology is FDA approved and in other countries it is often the preferred method of assessment. Fibroscan results are influenced by a number of confounders including ALT, ascites, and underlying disease. Hepatitis C is one of the best studied and is the disease state with the most reproducible/reliable results. Fibroscan has been evaluated in many liver diseases for the staging of liver fibrosis, and has been demonstrated to be very effective or differentiating cirrhosis (F4) from no cirrhosis (<F4), but it is less capable of differentiating gradations of fibrosis. In a large study by Castera, et al [18], a population of patients with chronic hepatitis C, a cut-off of 12.5 kPa was selected for cirrhotics. At this cut-off, the sensitivity and specificity of the test for cirrhosis were 87% and 91%, respectively and the negative predictive value was 95%. Since this analysis was assessed specifically in patients with chronic hepatitis C, the cut-off value ≤ 12.5 kPa used by Castera was selected to exclude cirrhotics in the current study.

FibroTest + APRI – Various methodologies have been developed in order to improve the sensitivity and specificity of blood tests used to diagnose cirrhosis in patients with chro nic hepatitis C infections. One such algorithm, the Sequential Algorithm for Fibrosis Evaluation (SAFE), which uses a combination of Fibrotest and the aspartate aminotransferase -to platelet ratio index (APRI) is very accurate for diagnosing cirrhosis [19]. For cirrhosis, the SAFE for F4 algorithm provides a diagnostic accuracy of 89.5% with a negative predictive value of 94.6%. Using this algorithm, it is estimated that only 6.2% of the patients would need a liver biopsy to confirm the diagnosis of cirrhosis. The cut-off values for excluding cirrhotics using the two tests, without the use of liver biopsy, are ≤1 and ≤0.48 for FibroTest and APRI when the SAFE for F4 is used. This study uses this method with one variation and that is the more stringent requirement that both the APRI and FibroTest need to be consistent with no cirrhosis, i.e. APRI is ≤1 AND Fibrotest ≤0.48. Accordingly, the Sponsor is confident these cut-off values that will differentiate cirrhotic from non-cirrhotic patients with reasonable accuracy in this study.

Laboratory Procedures/Assessments7.1.3

Details regarding specific laboratory procedures/assessments to be performed in this trial are provided in the following sections. The total amount of blood/tissue to be drawn/collected over the course of the trial (from pre-trial to post-trial visits), including approximate blood/tissue volumes drawn/collected by visit and by sample type per subject can be found in Section 12.5.

03VY5N



7.1.3.1 Laboratory Safety Evaluations (Hematology, Chemistry, and Other)

Laboratory tests for hematology and chemistry are specified in Table 10.

Table 10 Laboratory Tests

Hematology Chemistry Other

Hematocrit Albumin Hemoglobin A1c (HbA1c)

Hemoglobin Alkaline phosphatase Hepatitis C Virus Genotype

Platelet count Alanine aminotransferase (ALT)

HBsAg (screening only)

WBC (total and differential) Aspartate aminotransferase (AST)

HIV-1 serology (screening only)

Erythrocytes (RBC count) Creatinine Prothrombin time (PT)

Creatinine Clearance (screening only)

International Normalized Ratio (INR)

Creatine Kinase Choriogonadotropin Beta (Urine pregnancy test kits to sites)

Gamma-glutamyltransferase Plasma HCV RNA

Glucose (serum glucose) Fibrosure® (Fibrotest) as requested by site for entry criteria (may be performed locally)

Amylase APRI calculation

Lipase Coagulation

Potassium

Sodium

Total Bilirubin

Direct Bilirubin

Indirect Bilirubin

Total protein

Blood Urea Nitrogen

03VY5N



7.1.3.2 Pharmacokinetic/Pharmacodynamic Evaluations

The decision as to which plasma samples collected will be assayed for evaluation of pharmacokinetics/pharmacodynamics will be collaboratively determined by the Departments of Quantitative Pharmacology and Pharmacometrics (QPP) and the appropriate department within Clinical Research (e.g., samples at lower doses may not be assayed if samples at higher doses reveal undetectable drug concentrations). If indicated, these samples may also be assayed and/or pooled for assay in an exploratory manner for metabolites and/or additional pharmacodynamic markers.

7.1.3.2.1 Blood Collection for Plasma MK-5172, MK-8742, &R

Sample collection, storage and shipment instructions for plasma samples will be provided in the operations/laboratory manual.

Population PK samples will be collected from all subjects in this study (i.e., sparse PK sampling scheme) as outlined in Table 11. Specific time points may be analyzed for individual subjects to verify compliance with study medications in the event of virologic failure or to evaluate the relationship between an adverse event and PK parameters, as needed. On all PK visits where predose sample will be collected, subject must withhold their dose on the day of the PK visit; the dose will be administered at the site after collection of the predose PK sample.

Table 11 Pharmacokinetic Sampling Time Points

Visit Number

Study Day/WeekTime Relative to Dose of MK-5172,

MK-8742, and R4MK-5172 PK

Sample1MK-8742 PK

Sample1R PK

Sample2

2 Day 1 Predose x x x

3 Day 7 Predose x x x

4 Week 2 Anytime Postdose5 x x x

5 Week 4 Predose x x x

6 Week 8 Predose x x x

7 Week 12

Predose x x x

~2 hrs Postdose x x

~4 hrs Postdose x x

17Unsched/Viral

Failure Conf VisitNA3 x x x

18 Early Discon Visit NA3 x x x1 ~4 mL of blood will be collected at each specified time point for plasma PK assessments of MK-5172 and MK-8742.2 ~3 mL of blood will be collected at each specified time point for plasma PK assessment of R.3 Time Relative to last Dose of MK-5172, MK-8742, and R must be recorded in INFORM4 The date and time of the last MK-5172, MK-8742, and R dose prior to all PK sample collection must be recorded in INFORM5 Samples may be collected anytime after the morning dose of study medication

Note: At the time of PK sample collection, subjects will be asked to provide information regarding, the time/date of the last MK-5172, MK-8742, and R dose prior to the PK sample collection (This can also be obtained by referencing the subject's study medication diary).

03VY5N



7.1.3.3 Future Biomedical Research

The following specimens are to be obtained as part of Future Biomedical Research:

Leftover DNA for future use

Leftover plasma from HCV RNA

Leftover plasma from viral resistance and biomarkers

Note: Samples may also be used for future assay development and validation

7.1.3.4 HCV Evaluation

The following specimens are to be obtained as part of Efficacy/Pharmacogenetic Measurements:

Samples for HCV Genotype evaluation must be obtained as part of the main consent for inclusion in the study.

Blood must be drawn from each subject as part of the main consent to assess HCV RNA plasma levels at various time points as shown in the flow chart. HCV-RNA in plasma will be measured using a COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®. Any leftover plasma may be used for future biomedical research only if the subject signed for future biomedical consent.

Blood must be drawn from each subject as part of the main consent to assess viral resistance mutation and processed as instructed by the central laboratory manual. Any leftover plasma may be used for future biomedical research only if the subject signed for future biomedical consent.

Protein and metabolites may be measured from blood samples to compare biomarkers measured prior to treatment, to biomarkers measured at several time points during treatment that correlate with subject response to treatment (sustained viral response).

Samples collected for genetic analysis are obtained at Day 1 as part of the main consent. Any remaining specimen will be stored for future biomedical research if the subject signs the future biomedical research consent.

Other Procedures7.1.4

7.1.4.1 Withdrawal/Discontinuation

Subjects who discontinue/withdraw from treatment prior to completion of the treatment regimen should be encouraged to continue to be followed for all remaining study visits.

03VY5N



7.1.4.1.1 Withdrawal From Future Biomedical Research

Subjects may withdraw their consent for Future Biomedical Research and have their specimens and all derivatives destroyed. Subjects may withdraw consent at any time by contacting the principal investigator for the main trial. If medical records for the main trial are still available, the investigator will contact the Sponsor using the designated mailbox ([email protected]), and a form will be provided by the Sponsor to obtain appropriate information to complete specimen withdrawal. Subsequently, the subject's specimens will be removed from the biorepository and be destroyed. A letter will be sent from the Sponsor to the investigator confirming the destruction. It is the responsibility of the investigator to inform the subject of completion of destruction. Any analyses in progress at the time of request for destruction or already performed prior to the request being received by the Sponsor will continue to be used as part of the overall research trial data and results. No new analyses would be generated after the request is received.

In the event that the medical records for the main trial are no longer available (e.g., if the investigator is no longer required by regulatory authorities to retain the main trial records) or the specimens have been completely anonymized, there will no longer be a link between the subject’s personal information and their specimens. In this situation, the request for specimen destruction cannot be processed.

7.1.4.2 Blinding/Unblinding

This is an open label trial; there is no blinding for this trial.

7.1.4.3 Calibration of Critical Equipment

The investigator or qualified designee has the responsibility to ensure that any critical device or instrument used for a clinical evaluation/test during a clinical trial that provides important information about inclusion/exclusion criteria and/or safety or efficacy parameters shall be suitably calibrated and maintained to ensure that the data obtained is reliable and/or reproducible. Documentation of equipment calibration must be retained with the study documentation as source documentation at the trial site.

Critical Equipment for this trial includes:

None

7.1.4.4 Rescreening

Subjects who have previously completed the screening visit (Visit 1) and were deemed eligible for enrollment into this study but failed to be allocated to study therapy within the 45 day window, may be rescreened to re-evaluate study eligibility. To reconfirm the subject’s

03VY5N



eligibility, all pre-study evaluations should be repeated, after approval from the SPONSOR, except for the following:

Hepatitis C Virus Genotype

HBsAg

HIV-1 serology

Liver Biopsy/Fibroscan/ FibroSure® (Fibrotest®)

Liver Ultrasound

12-Lead ECG

7.1.4.5 PK Sampling Time Points

Subjects must follow the protocol defined specific time points for predose or postdose in respect to study medication administration for PK sample collection. If predose PK sample is required by the protocol, the subject should withhold their dose the day of PK sample. For detailed time points of PK sample collection, please refer to Table 11 in Section 7.1.3.2.1.

Visit Requirements7.1.5

Visit requirements are outlined in Section 6.0 - Trial Flow Chart. Specific procedure-related details are provided above in Section 7.1 - Trial Procedures.

7.1.5.1 Screening

Within 45 days prior to administration of the initial study dose, potential subjects will be evaluated to determine if they fulfill the Inclusion/Exclusion entry requirements as describedin Section 5.1. Verification should be obtained to confirm the subject’s cirrhosis status and the subject’s fibrosis score must be captured to support secondary data analysis. The investigator will discuss with each potential subject the nature of the study, its requirements, and its restrictions. Screening procedures may be repeated after consultation with the Sponsor.

Subjects will be instructed that they are required to use two acceptable methods of birth control from at least 2 weeks prior to Day 1, throughout treatment, and for at least 6 months (or longer if dictated by local regulations) after the last dose of study medication.

Subjects will be instructed about the restrictions for concomitant medications, as noted i n Section 5.5.

All screening procedures listed for Visit 1 in the Trial Flow Chart must be completed and subject eligibility confirmed by the investigator prior to the subject’s allocation and drug administration.

03VY5N



All subjects will be given a card, at the time of screening, identifying them as participants in a research study. The card will contain contact information (including direct telephone numbers) to be utilized in the event of an emergency.

7.1.5.2 Treatment Period

Treatment Day 1 (Visit 2)

Pretreatment Procedures

Day 1 procedures listed on the Trial Flow Chart should be performed prior to dosing unless specified otherwise. For female subjects, a urine pregnancy test will be performed at the site prior to study drug initiation. If the urine pregnancy test result is negative, the subject will be eligible for allocation to study therapy and the remainder of the pretreatment (Day 1) testing/procedures will be performed. If the urine pregnancy test result is positive, the subject must not be allocated to study therapy.

Blood will be collected for assay of safety evaluations, plasma HCV RNA, and PK measurements. These samples will be sent to the appropriate central laboratory(ies) following the procedure(s) set forth in the manual(s).

Additional samples will be collected for genetic evaluation of host parameters related to the response of HCV subjects to MK-5172, MK-8742, and R therapies.

7.1.5.3 Drug Administration

Following completion of the Day 1 procedures and confirmation of eligibility, the site pharmacist or study coordinator will contact the IVRS for assignment of the drug to be administered. Sites should not call IVRS for drug administration until the subject has met all criteria for the study and are ready to receive the first dose of study medication on Day 1.

The first dose of prescribed study medications should be administered at the Day 1 visit.

For subjects who undergo treatment modification, additional study medication will be dispensed via IVRS.

Subjects who discontinue therapy in the trial prior to the last scheduled treatment visit should have an Early Discontinuation visit and then continue into follow-up visits.

At a minimum, collect the following information when a subject discontinues:

1. The reason the subject discontinued.

2. The date of the last dose of study medications from the trial.

3. The date of the last assessment and/or contact. A follow-up contact (telephone or visit) will be arranged as appropriate.

4. (Serious) Adverse events.

03VY5N



5. Final Assessments: Every effort should be made to ensure that all procedures and evaluations scheduled for the Early Discon Visit are performed.

6. Retrieve all study medications from the subject.

7.1.5.4 Follow-up Visits

At the completion of study therapy (see Section 5.6) subjects will return to the study site for follow-up visits at 4, 8, 12, and 24 weeks after the last dose of study drug.

Subjects who discontinue because they have met criteria for virologic failure while on study therapy should complete an Early Discontinuation Visit as outlined in the Trial Flow Chart (Section 6), and return to the study site for follow-up visits at 4, 8, 12, and 24 weeks following the confirmation of virologic failure. Subjects who meet the virologic failure criterion of relapse (having HCV RNA ≥ LLoQ following end of all study therapy, after becoming undetectable [TND] at end of treatment) will return to the study site for the remainder of their follow-up visits (e.g., 4, 8, 12, and 24 weeks) as outlined in the Trial Flow Chart (Section 6.0).

Subjects who discontinue for reasons other than virologic failure should complete an Early Discontinuation Visit as outlined in the Trial Flow Chart and return to the study site for follow-up visits at 4, 8, 12, and 24 weeks following the discontinuation of treatment.

Follow-up after Trial Completion

All subjects who have taken at least one dose of MK-5172 or MK-8742 will be asked to consent to a follow-up protocol (MK-5172 Protocol 017, a 3 year follow-up program to study efficacy and/or resistance associated variants to any compound used in a MK-5172 treatment regimen). Subjects included in this follow-up protocol may include subjects who have initiated other HCV treatments (i.e., rescue or other clinical trials, subjects who failed therapy in this trial who do not want to initiate a new HCV treatment, and subjects who achieved viral remission during this trial). The purpose of this follow-up protocol is to follow resistance associated variants (RAVs) over time and in the case of treatment responders, to follow durability of response.

7.1.5.5 Evaluations of Laboratory Safety Signals

Laboratory safety measurements will be evaluated throughout the study to assess potential liver safety signals.

If a subject has one or more of the laboratory ECI criteria (see Section 7.2.3.2) at the last dosing visit (Week 12 or Week 18 for treatment modification), then the subject should return to the site weekly for additional monitoring until the values normalize.

03VY5N



Assessing and Recording Adverse Events7.2

An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol -specified procedure, whether or not considered related to the medicinal product or protocol -specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an adverse event.

Changes resulting from normal growth and development that do not vary significantly in frequency or severity from expected levels are not to be considered adverse events. Examples of this may include, but are not limited to, teething, typical crying in infants and children and onset of menses or menopause occurring at a physiologically appropriate time.

Sponsor's product includes any pharmaceutical product, biological product, device, diagnostic agent or protocol-specified procedure, whether investigational (including placebo or active comparator medication) or marketed, manufactured by, licensed by, provided by or distributed by the Sponsor for human use.

Adverse events may occur during the course of the use of the Sponsor's product in clinical trials or within the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose (whether accidental or intentional), from abuse and from withdrawal.

Adverse events may also occur in screened subjects during any pre-allocation baseline period as a result of a protocol-specified intervention, including washout or discontinuation of usual therapy, diet, placebo treatment or a procedure.

All adverse events will be recorded from the time the consent form is signed through 14 days following cessation of treatment and at each examination on the Adverse Event case report forms/worksheets. The reporting timeframe for adverse events meeting any serious criteria is described in section 7.2.3.1

Definition of an Overdose for This Protocol and Reporting of Overdose to the 7.2.1Sponsor

In this trial, an overdose is any dose higher than: any intake in excess of the prescribed dose per calendar day for MK-5172 and MK-8742, and a dose that exceeds 1600 mg in a calendar day for REBETOL™.

If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product or vaccine, the adverse event(s) is reported as a serious adverse event, even if no other seriousness criteria are met.

03VY5N



If a dose of Sponsor's product or vaccine meeting the protocol definition of overdose is taken without any associated clinical symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest (ECI), using the terminology “accidental or intentional overdose without adverse effect.”

All reports of overdose with and without an adverse event must be reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent).

Reporting of Pregnancy and Lactation to the Sponsor7.2.2

Although pregnancy and lactation are not considered adverse events, it is the responsibility of investigators or their designees to report any pregnancy or lactation in a subject (spontaneously reported to them), including the pregnancy of a male subject's female partner that occurs during the trial or within 14 days of completing the trial. All subjects and female partners of male subjects who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, intrauterine death, miscarriage and stillbirth must be reported as serious events (Important Medical Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported.

Such events must be reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent).

Immediate Reporting of Adverse Events to the Sponsor7.2.3

7.2.3.1 Serious Adverse Events

A serious adverse event is any adverse event occurring at any dose or during any use of Sponsor's product that:

● Results in death;● Is life threatening;● Results in persistent or significant disability/incapacity;● Results in or prolongs an existing inpatient hospitalization;● Is a congenital anomaly/birth defect;● Is a cancer;● Is associated with an overdose;● Is an other important medical event

Refer to Table 12 for additional details regarding each of the above criteria.

Any serious adverse event, or follow up to a serious adverse event, including death due to any cause that occurs to any subject from the time the consent is signed through 14 days following cessation of treatment or within the established off therapy follow-up period for safety described in the protocol, whether or not related to the Sponsor's product, must be

03VY5N



reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent).

Additionally, any serious adverse event, considered by an investigator who is a qualified physician to be related to the Sponsor's product that is brought to the attention of the investigator at any time outside of the time period specified in the previous paragraph also must be reported immediately to the Sponsor.

All subjects with serious adverse events must be followed up for outcome.

7.2.3.2 Events of Clinical Interest

Selected non-serious and serious adverse events are also known as Events of Clinical Interest (ECI) and must be recorded as such on the Adverse Event case report forms/worksheets and reported within 24 hours to the Sponsor either by electronic media or paper. Sponsor Contact information can be found in the Investigator Trial File Binder (or equivalent).

Events of clinical interest for this trial include:

1. an overdose of Sponsor's product, as defined in Section 7.2.1 - Definition of an Overdose for This Protocol and Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory results.

2. first instance of ALT or AST >500 IU/L from the initiation of study therapy through 14 days following treatment and not associated with virologic failure*

3. first instance of ALT or AST >3x baseline AND >100 IU/L from the initiation of study therapy through 14 days following treatment and not associated with virologic failure*

4. first instance of alkaline phosphatase >3x ULN from the initiation of study therapy through 14 days following treatment and not associated with virologic failure.*

*Note: The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying etiology. The trial site guidance for assessment and follow up of these criteria can be found in the Investigator Trial File Binder (or equivalent).

Evaluating Adverse Events7.2.4

An investigator who is a qualified physician will evaluate all adverse events with respect to the elements outlined in Table 12. The investigator’s assessment of causality is required for each adverse event. Refer to Table 12 for instructions in evaluating adverse events.

03VY5N



Table 12 Evaluating Adverse Events

Maximum Mild awareness of sign or symptom, but easily tolerated (for pediatric trials, awareness of symptom, but easily tolerated)Intensity Moderate discomfort enough to cause interference with usual activity (for pediatric trials, definitely acting like something is wrong)

Severe incapacitating with inability to work or do usual activity (for pediatric trials, extremely distressed or unable to do usual activities)Seriousness A serious adverse event (AE) is any adverse event occurring at any dose or during any use of Sponsor's product that:

†Results in death; or†Is life threatening; or places the subject, in the view of the investigator, at immediate risk of death from the event as it occurred [Note: This does not include an adverse event that, had it occurred in a more severe form, might have caused death.]; or†Results in a persistent or significant disability/incapacity (substantial disruption of one’s ability to conduct normal life functions); or†Results in or prolongs an existing inpatient hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay, even if the hospitalization is a precautionary measure for continued observation. (Note: Hospitalization [including hospitalization for an elective procedure] for a preexisting condition which has not worsened does not constitute a serious adverse event.); or†Is a congenital anomaly/birth defect (in offspring of subject taking the product regardless of time to diagnosis); orIs a cancer; orIs associated with an overdose (whether accidental or intentional). Any adverse event associated with an overdose is considered a serious adverse event. Anoverdose that is not associated with an adverse event is considered a non-serious event of clinical interest and must be reported within 24 hours.Other important medical events that may not result in death, not be life threatening, or not require hospitalization may be considered a serious adverse event when, based upon appropriate medical judgment, the event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed previously (designated above by a †).

Duration Record the start and stop dates of the adverse event. If less than 1 day, indicate the appropriate length of time and unitsAction taken Did the adverse event cause the Sponsor's product to be discontinued?Relationship to Sponsor's Product

Did the Sponsor's product cause the adverse event? The determination of the likelihood that the Sponsor's product caused the adverse event will be provided by an investigator who is a qualified physician. The investigator’s signed/dated initials on the source document or worksheet that supports the causality noted on the AE form, ensures that a medically qualified assessment of causality was done. This initialed document must be retained for the required regulatory time frame. The criteria below are intended as reference guidelines to assist the investigator in assessing the likelihood of a relationship between the test drug and the adverse event based upon the available information.The following components are to be used to assess the relationship between the Sponsor's product and the AE; the greater the correlation with the components and their respective elements (in number and/or intensity), the more likely the Sponsor's product caused the adverse event:Exposure Is there evidence that the subject was actually exposed to the Sponsor's product such as: reliable history, acceptable compliance assessment (pill

count, diary, etc.), expected pharmacologic effect, or measurement of drug/metabolite in bodily specimen?Time Course Did the AE follow in a reasonable temporal sequence from administration of the Sponsor's product?

Is the time of onset of the AE compatible with a drug-induced effect (applies to trials with investigational medicinal product)?Likely Cause Is the AE not reasonably explained by another etiology such as underlying disease, other drug(s)/vaccine(s), or other host or environmental

factors

03VY5N



Relationship The following components are to be used to assess the relationship between the Sponsor's product and the AE: (continued)to Sponsor's Product(continued)

Dechallenge Was the Sponsor's product discontinued or dose/exposure/frequency reduced? If yes, did the AE resolve or improve? If yes, this is a positive dechallenge. If no, this is a negative dechallenge.(Note: This criterion is not applicable if: (1) the AE resulted in death or permanent disability; (2) the AE resolved/improved despite continuation of the Sponsor's product; (3) the trial is a single-dose drug trial); or (4) Sponsor's product(s) is/are only used one time.)

Rechallenge Was the subject re-exposed to the Sponsor's product in this trial? If yes, did the AE recur or worsen? If yes, this is a positive rechallenge. If no, this is a negative rechallenge.(Note: This criterion is not applicable if: (1) the initial AE resulted in death or permanent disability, or (2) the trial is a single-dose drug trial); or (3) Sponsor's product(s) is/are used only one time.)NOTE: IF A RECHALLENGE IS PLANNED FOR AN ADVERSE EVENT WHICH WAS SERIOUS AND WHICH MAY HAVE BEEN CAUSED BY THE SPONSOR'S PRODUCT, OR IF RE-EXPOSURE TO THE SPONSOR'S PRODUCT POSES ADDITIONAL POTENTIAL SIGNIFICANT RISK TO THE SUBJECT THEN THE RECHALLENGE MUST BE APPROVED IN ADVANCE BY THE SPONSORCLINICAL DIRECTOR AND THE INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE.

Consistency with Trial Treatment Profile

Is the clinical/pathological presentation of the AE consistent with previous knowledge regarding the Sponsor's product or drug class pharmacology or toxicology?

The assessment of relationship will be reported on the case report forms /worksheets by an investigator who is a qualified physician according to his/her best clinical judgment, including consideration of the above elements.Record one of the following: Use the following scale of criteria as guidance (not all criteria must be present to be indicative of a Sponsor's product relationship).

Yes, there is a reasonable possibility of Sponsor's product relationship.

There is evidence of exposure to the Sponsor's product. The temporal sequence of the AE onset relative to the administration of the Sponsor's product is reasonable. The AE is more likely explained by the Sponsor's product than by another cause.

No, there is not a reasonable possibility of Sponsor's product relationship

Subject did not receive the Sponsor's product OR temporal sequence of the AE onset relative to administration of the Sponsor's product is not reasonable OR there is another obvious cause of the AE. (Also entered for a subject with overdose without an associated AE.)

03VY5N



Sponsor Responsibility for Reporting Adverse Events7.2.5

All Adverse Events will be reported to regulatory authorities, IRB/IECs and investigators in accordance with all applicable global laws and regulations.

TRIAL GOVERNANCE AND OVERSIGHT7.3

Scientific Advisory Committee7.3.1

This trial was developed in collaboration with a Scientific Advisory Committee (SAC). The SAC comprises both Sponsor and non-Sponsor scientific experts who provide input with respect to trial design, interpretation of trial results and subsequent peer-reviewed scientific publications.

8.0 STATISTICAL ANALYSIS PLAN

Statistical Analysis Plan Summary8.1

This section contains a brief summary of the statistical analyses for this trial. Full detail is in the Statistical Analysis Plan (SAP) (Section 8.2).

Efficacy Analyses8.1.1

The primary and key secondary endpoints, primary analysis population, and statistical methods that will be employed for the efficacy analyses are presented in Table 13.

The primary efficacy objective of this study is to estimate the SVR12 rates in subjects that have previously failed DAA + PR therapy. A two-sided 95% confidence interval will be constructed for SVR12. There will be no formal efficacy hypothesis testing conducted in this study.

Estimating the SVR12 rate in subjects by prior DAA class and by prior DAA (i.e. boceprevir, telaprevir, simeprevir, sofosbuvir) are key secondary efficacy objectives and will be assessed in a similar fashion as the primary efficacy objective.

03VY5N



Table 13 Summary of Analysis Strategy for Key Efficacy Endpoints

Endpoint/Variable(Description, Time point)

Primary vs

Secondary Approach† Statistical Method

Analysis Population

Missing Data Approach ‡

Primary:

Proportion of subjects achieving SVR12

P 95% Confidence Interval (Clopper-Pearson)

PP OF

Secondary:

Proportion of subjects achieving SVR12 by prior DAA and DAA class


PP OF

† P=Primary approach‡ Imputation for specific missing values described in Section 8.2.5.1OF = Observed FailurePP=Per Protocol

Safety Analyses8.1.2

The All-Subjects-as-Treated population will be employed for safety analyses. For this protocol, the proportion of subjects who experience the following adverse events during the study treatment period will be estimated: adverse experiences of elevated transaminases thatare reported as ECIs during the study therapy period.

8.1.3 Power and Sample Size

This estimation study will enroll approximately 80 subjects. Assuming a protocol violation rate of 10%, the PP population will include 72 subjects. If the observed SVR12 rate is approximately 83% (60 successes out of 72), the exact 95% CI is (72.7%, 91.1%). Detailed information is in 8.2.7.1.

Statistical Analysis Plan8.2

This section outlines the statistical analysis strategy and procedures for the study. If, after the study has begun, changes are made to primary and/or key secondary objectives, or the statistical methods related to those objectives, then the protocol will be amended (consistent with ICH Guideline E-9). Changes to exploratory or other non-confirmatory analyses made after the protocol has been finalized, along with an explanation as to when and why they occurred, will be listed in the Clinical Study Report (CSR) for the study. Post hoc exploratory analyses will be clearly identified in the CSR. No separate Statistical Analysis Plan (SAP) will be issued for this study.

03VY5N



Responsibility for Analyses8.2.1

The statistical analysis of the data obtained from this study will be the responsibility of the Clinical Biostatistics department of the SPONSOR. Certain specific analyses such as PK, pharmacogenetics and resistance will be the responsibility of the appropriate departments of the SPONSOR.

This is an open-label study. All subjects will receive 100 mg MK-5172 plus 50 mg MK-8742 with Ribavirin (R, weight-based dose).

Hypotheses/Estimation8.2.2

There are no formal hypotheses for this study. Objectives of the study are stated in Section 3.0.

Analysis Endpoints8.2.3

Efficacy and safety endpoints that will be evaluated are listed in the following sections.

8.2.3.1 Efficacy/Pharmacokinetic Endpoints

8.2.3.1.1 Efficacy Endpoints

An initial description of efficacy measures is provided in Section 4.2.3.1.

The primary efficacy endpoint is the proportion of subjects achieving SVR12.

The secondary efficacy endpoints are:

1) the proportion of subjects achieving SVR12 by prior DAA (i.e. boceprevir, telaprevir, simeprevir, sofosbuvir) and by prior DAA class

2) the emergence of antiviral resistance to MK-5172 and MK-8742 when administered as a combination regimen with R

3) the proportion of subjects achieving SVR24 and SVR4

4) the time to first achievement of undetectable (TND) HCV RNA

5) the proportion of subjects achieving undetectable (TND) HCV RNA and HCV RNA < LLoQ at Week 2, Week 4, and Week 12

The exploratory efficacy endpoints are:

1) the proportion of subjects achieving SVR12 who met criteria for virologic failure in prior therapy

2) the proportion of subjects achieving SVR12 who met criteria for virologic failure in prior therapy and have baseline RAVs in this study

03VY5N



3) the proportion of subjects achieving SVR12 by mode of virologic failure in prior regimen

During the course of the trial, there will be periodic analyses conducted to evaluate safety and efficacy. The purpose of these analyses is for planning the nex t phase of program development.

These assessments are in addition to the regular medical monitoring that is performed throughout the study.

8.2.3.1.2 Pharmacokinetic Endpoints

Additional details are in 4.2.3.3.

The PK endpoints will be C2hr, C4hr, and Ctrough for MK-5172 and MK-8742, and Ctrough for R.

8.2.3.1.3 Exploratory Endpoints

1. The effect of various baseline factors including genetic variation in the human IL28Bgene as a predictor of virologic response.

2. The effect of biomarkers (proteins, RNA expression, and metabolite production), that may be predictive of the tolerability of study drugs and virologic response to MK -5172 and MK-8742 + R by comparing biomarker levels over time in subjects who respond or fail study therapy.

3. The PK/PD relationship which may include MK-5172, MK-8742, and R.

8.2.3.2 Safety Endpoints

An initial description of safety measures is provided in Section 4.2.3.2.

For this protocol, the proportion of subjects who experience the following adv erse events during the study therapy period will be estimated: adverse experiences of elevated transaminases that are reported as ECIs during the study therapy period.

The following events will also be investigated: proportion of subjects with adverse experiences of the following types at any time during the study therapy period: (1) at least one adverse experience; (2) a drug-related adverse experience; (3) a serious adverse experience; (4) a serious and drug-related adverse experience and (5) an adverse experience leading to discontinuation.

Serious adverse experiences will continue to be collected throughout the study.

Analysis Populations8.2.4

8.2.4.1 Efficacy Analysis Populations

The Per-Protocol (PP) population will serve as the primary population for the anal ysis of efficacy data in this study. The PP population excludes subjects due to important deviations

03VY5N



from the protocol that may substantially affect the results of the primary and key secondary efficacy endpoints. Potential violations that may result in the exclusion of a subject from the PP population include, but are not limited to:

The subject did not meet specific inclusion/exclusion criteria:

– For example, the subject has not received a prior approved regimen containing aDAA (boceprevir, telaprevir, simeprevir, or sofosbuvir) coadministered for at least 4 weeks with PR.

The subject met criteria for virologic failure but had undetectable MK-5172 levelsand/or MK-8742 levels at one or more pharmacokinetic sampling timepoints temporally associated with the failure timepoint

The subject received concomitant medications that are prohibited due to their potential to result in a clinically significant lowering of the MK-5172 or MK8742 concentrations (See Section 5.5). Further, any co-administered medication, currently unidentified, but for which subsequent clinical DDI data indicate that co-administration with MK leads to a clinically significant lowering of MK concentrations.

Other violations may be identified during the course of data collection that will affect the composition of the PP population. These will be specified prior to the final analyses, and they will be listed specifically in the CSR

A subject with important deviations from the protocol as described above at the start of treatment will be excluded from the PP population. For subjects with important deviations from the protocol as described above during course of the treatment, data obtained subsequent to the violation will be excluded from analysis.

A supportive analysis using the Full Analysis Set (FAS) population will be performed for the primary and key secondary efficacy endpoints. The FAS population consists of all subjects who have received at least one dose of study treatment. The PP population is a subset of the FAS population.

Details on the approach to handling missing data are provided in Section 8.2.5.1 Statistical Methods.

8.2.4.2 Safety Analysis Populations

The All Subjects as Treated (ASaT) population will be used for the analysis of safety data in this study. The ASaT population consists of all subjects who received at least one dose of study treatment.

At least one laboratory or vital sign measurement obtained subsequent to at least one dose of study treatment is required for inclusion in the analysis of each specific parameter. To assess change from baseline, a baseline measurement is also required.

Details on the approach to handling missing data for safety analyses are provided in Section 8.2.5.1 Statistical Methods.

03VY5N



Statistical Methods8.2.5

The approach to handling missing data is described in Section 8.2.5.1. A summary of the analysis strategy for efficacy variables is shown in Table 14. Nominal p-values may be computed for some efficacy analyses as a measure of strength but no formal tests of hypotheses are planned in this study.

Statistical inference for safety analyses are described in 8.2.5.2.

8.2.5.1 Statistical Methods for Efficacy Analyses

Missing Values

There are 3 types of approaches to handle missing values for subjects who prematurely discontinue assigned treatment. Missing values refer to missing observations (rather than subjects):

Observed Failure (OF) approach: Subjects who 1) discontinued assigned treatment early due to lack of efficacy or 2) discontinued from the study following a confirmed HCV RNA TD(q) during follow-up are considered as failures thereafter. Otherwise, any subject missing an HCV RNA evaluation at any particular visit will be excluded from the analysis at that time point.

Data As Observed (DAO) approach: During the treatment period, any subject missing an HCV RNA evaluation at any particular visit will be excluded from the analysis at that time point.

Missing=Failure (M=F) approach: Any subject missing an HCV RNA evaluation at any particular visit will be considered a non-responder for that visit. An exception will be made in the case where a missing on-treatment visit is immediately preceded and followed by a TND HCV RNA, where the missing value would be imputed to be TND as well. The same rule will be applied when the endpoint is defined using HCV RNA <LLoQ. When a missing value is flanked by TND RNA and HCV RNA<LLoQ, then HCV RNA <LLoQ will be imputed.

If a subject does not have an HCV RNA evaluation on the last scheduled follow-up visit (i.e., no SVR24) but has a value assigned to the 12-week follow-up visit, then SVR12 will be used in place of SVR24. If an earlier SVR assessment is missing but a later SVR assessment is available (e.g., a subject missed his 4-week follow-up visit, but returned for his 12-week follow-up visit), then the later result can be used to impute the missing earlier result.

For the endpoint of time to first achievement of undetectable HCV RNA, discontinued subjects who do not achieve undetectable HCV RNA will be considered censored at the discontinuation time point. Summary statistics will be provided to show the number of subjects discontinued due to virologic failures and AEs.

03VY5N



Proportions of Subjects With Virologic Responses

For the primary efficacy analysis to estimate the proportion of subjects achieving SVR12, a 95% confidence interval for this rate will be calculated using the Clopper-Pearson method[20]. The missing data approach of OF described above will be utilized for the primary analysis. The same method will be used to analyze all binary endpoints.

Sensitivity analyses will be performed for the primary endpoint using the FAS populationand the M=F missing data approach.

Exploratory analyses will be performed to better understand the prognostic value of early endpoints (e.g., HCV viral response at Weeks 2 and 4) to predict later endpoints (SVR12 and SVR24).

Table 14 includes a summary of the key efficacy analyses.

03VY5N



Table 14 Analysis Strategy for Efficacy Variables

Endpoint/Variable(Description, Time point)

Primary vs

Secondary Approach† Statistical Method

Analysis Population

Missing Data Approach ‡

Primary:



PP OF


S 95% Confidence Interval (Clopper-Pearson)

FAS M=F

Secondary:

Proportion of subjects achieving SVR12 by prior DAA and DAA class


PP OF

Proportion of subjects achieving SVR24 and SVR4


PP OF

Time to first achievement of undetectable (TND) HCV RNA

P Kaplan-Meier plot and summary statistics

PP DAO

Proportion of subjects achieving undetectable (TND) HCV RNA and HCV RNA < LLoQ at Week 2, Week 4, and Week 12


PP OF

Exploratory:

Proportion of subjects achieving SVR12 who were previous virologic failures


PP OF

Proportion of subjects achieving SVR12 who were previous virologic failures and have baseline RAVs in this study


PP OF

Proportion of subjects achieving SVR12 by mode of failure on prior regimen


PP OF

† P=Primary approach; S=Secondary approach.‡ Imputation for specific missing values described in Section 8.2.5.1OF = Observed FailureM=F = Missing = FailureDAO = Data as observedPP = Per ProtocolFAS = Full Analysis Set

03VY5N



Subject Virologic Failure: Non-Response, Rebound, Breakthrough, or Relapse

Summary statistics will be provided to describe the rates of occurrence of subject virologic non-response, rebound, breakthrough, or relapse. Definitions for subject virologic non-response, rebound, breakthrough, or relapse are in Section 4.2.3.1.1.2.

8.2.5.2 Statistical Methods for Safety Analyses

Safety and tolerability will be assessed by clinical review of all relevant parameters including adverse experiences and laboratory parameters.

The proportion of subjects with adverse experiences of elevated transaminases that are reported as ECIs during the study therapy period will be provided along with corresponding 95% confidence intervals.

In addition, the broad clinical and laboratory AE categories consisting of the percentage of subjects with any AE, a drug related AE, a serious AE, an AE which is both drug-related and serious, and who discontinued due to an AE will be summarized in the same manner (Table 15).

Missing values will be handled using the Data-As-Observed (DAO) approach.

Table 15 Analysis Strategy for Safety Parameters

Safety Endpoint† 95% CI Descriptive Statistics

AEs of elevated transaminases that are reported as ECIs X X

Any AE X X

Any Serious AE X X

Any Drug-Related AE X X

Any Serious and Drug-Related AE X X

Discontinuation due to AE X X

Specific AEs or SOCs X

Change from Baseline Results (laboratory) X†Adverse experiences refer to both clinical and laboratory AEs.

95% confidence intervals will be calculated using the Clopper-Pearson method.

Note: SOC = System Organ Class; X = results will be posted

8.2.5.3 Summaries of Baseline Characteristics, Demographics, and Other Analyses

Demographic and Baseline Characteristics

No statistical hypothesis tests will be performed on these characteristics. The number and percentage of subjects screened, enrolled, the primary reasons for screen failure, and the primary reason for discontinuation will be displayed. Demographic variables (e.g., age, gender, and genotype subtype), primary and secondary diagnoses, and prior and concomitant therapies will be summarized using descriptive statistics for continuous or categorical

03VY5N



variables, as appropriate. Summary statistics for the baseline efficacy measure (HCV RNA) will also be provided.

Pharmacokinetic Analyses

Summary statistics for the concentrations of MK-5172, MK-8742, and R will be provided. PK/PD analysis will also be performed, as needed, which may include MK-5172, MK-8742, and/or R.

Viral Resistance Measurements

Viral resistance testing will focus on the entire NS3/4A and NS5A regions for all subjects and for those who meet the subject virologic failure criteria (see Section 4.2.3.1.1.2). For subjects who failed previously from sofosbuvir treatment, resistance testing on NS5B will also be conducted.

IL28B Analyses and Other Genetic Analysis

Exploratory descriptive analyses will include demographics and selected baseline characteristics by IL28B genotype overall, as well as SVR12 by IL28B genotype. Additional genetic analysis may be conducted to identify variations in genes related to liver in jury or other safety findings.

Multiplicity8.2.6

During the course of the study, periodic efficacy and safety analyses will be performed for programmatic decisions that will not change the conduct of the current study. There will be no multiplicity adjustments made to account for the periodic assessments in the final analysis of this estimation study.

Sample Size and Power Calculations8.2.7

8.2.7.1 Efficacy Analysis

This estimation study will enroll approximately 80 subjects. Assuming a 10% protocol violation rate in this sample size, the PP population will include 72 subjects. Table 16 shows the estimates of the 95% confidence interval for SVR12 under varying assumptions of number of successes. Note that these intervals are not symmetric around the point estimate.

03VY5N



Table 16 Two-Sided 95% Confidence Interval† Assuming Various Number of Successes for SVR12 (Per Protocol Population=72)

Observed Number of Successes (%‡) Two-Sided 95% Confidence Interval50 (69.4%) (57.5, 79.8)55 (76.4%) (64.9, 85.6)60 (83.3%) (72.7, 91.1)65 (90.3%) (81.0, 96.0)

†Based on the Clopper-Pearson method‡Assuming 72 of 80 subjects were included in the per-protocol (PP) population

8.2.7.2 Safety Analysis

The primary safety objective of this study will be assessed by a review of the accumulated safety data. Certain safety endpoints of special interest have been identified in Section 8.2.3.2 of this document. The proportion of subjects with these events will be provided along with corresponding 95% confidence intervals based on the exact binomial method proposed by Clopper and Pearson. Table 17 gives the upper bound of the two-sided 95% Clopper-Pearson exact confidence interval for the true proportion of subjects with a particular adverse experience corresponding to various observed numbers of subjects with such adverse experience in a sample of 80 subjects.

Table 17 Upper Bound of the Two-Sided 95% Confidence Interval for the True Proportion of Subjects With an AE (n=80)

Observed Number of SubjectsWith AE (%)

95% Upper Bound for the True Proportion (%)

0 (0.0) 4.5

1 (1.25) 6.8

4 (5.0) 12.3

8 (10.0) 18.8

ALT and AST elevations were observed in Protocol 003 (Section 4.2.2). Table 18 shows the probability of observing at least one case of any specific type of elevation, given a range of true rates:

Table 18 Probability of Observing Late Transaminase Elevations (n=80)

True rate of late transaminase elevations

Probability of observing at least one case

1% 0.55

2% 0.80

03VY5N



Subgroup Analyses and Effects of Baseline Factors8.2.8

To assess the consistency of the treatment effect across various subgroups, SVR12 (with a nominal 95% CI) will be tabulated for each category of the following classification variables, as appropriate:

Sex (female, male)

GT (1a vs 1b)

IL28B CC genotype vs. non-CC genotype

HCV RNA at Screening , low (≤ 800,000 IU/mL) versus high (> 800,000 IU/mL)

Stage of fibrosis (Cirrhotic vs. non-cirrhotic)

Prior virologic failures vs. prior failures for other reasons (safety/tolerability, other)

Presence of signature RAVs at baseline vs. absence of signature RAVs at baseline in this study

9.0 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES

Investigational Product9.1

The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the protocol and any applicable laws and regulations.

Clinical Supplies will be provided by the Sponsor as summarized in Table 19.

Table 19 Product Descriptions

Product Name & Potency Dosage Form

MK-5172 100mg TabletMK-8742 10mg CapsuleRibavirin (R) 200mg Capsule

Packaging and Labeling Information9.2

Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements.

Subjects will receive open label monthly bottles. No kitting is required.

03VY5N



Clinical Supplies Disclosure9.3

This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or designee are not blinded. Treatment (name, strength or potency) is included in the label text; random code/disclosure envelopes or lists are not provided.

Storage and Handling Requirements9.4

Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on the label.

Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site.

Clinical supplies may not be used for any purpose other than that stated in the protocol.

Returns and Reconciliation9.5

The investigator is responsible for keeping accurate records of the clinical supplies received from the Sponsor or designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion of the trial.

For all trial sites, the local country Sponsor personnel or designee will provide appropriate documentation that must be completed for drug accountability and return.

Standard Policies9.6

Trial site personnel will have access to a central electronic randomization system (IVRS/IWRS system) to allocate subjects, to assign treatment to subjects and to manage the distribution of clinical supplies. Each person accessing the IVRS system must be assigned an individual unique PIN. They must use only their assigned PIN to access the system, and they must not share their assigned PIN with anyone.

10.0 ADMINISTRATIVE AND REGULATORY DETAILS

Confidentiality10.1

Confidentiality of Data10.1.1

By signing this protocol, the investigator affirms to the Sponsor that information furnished to the investigator by the Sponsor will be maintained in confidence, and such information will be divulged to the institutional review board, ethics review committee (IRB/ERC) or similar or expert committee; affiliated institution and employees, only under an appropriate understanding of confidentiality with such board or committee, affiliated institution and employees. Data generated by this trial will be considered confidential by the investigator, except to the extent that it is included in a publication as provided in the Publications section of this protocol.

03VY5N



Confidentiality of Subject Records10.1.2

By signing this protocol, the investigator agrees that the Sponsor (or Sponsor representative), IRB/ERC, or regulatory authority representatives may consult and/or copy trial documents in order to verify worksheet/case report form data. By signing the consent form, the subject agrees to this process. If trial documents will be photocopied during the process of verifying worksheet/case report form information, the subject will be identified by unique code only; full names/initials will be masked prior to transmission to the Sponsor.

By signing this protocol, the investigator agrees to treat all subject data used and disclosed in connection with this trial in accordance with all applicable privacy laws, rules and regulations.

Confidentiality of Investigator Information10.1.3

By signing this protocol, the investigator recognizes that certain personal identifying information with respect to the investigator, and all subinvestigators and trial site personnel, may be used and disclosed for trial management purposes, as part of a regulatory submissions, and as required by law. This information may include:

1. name, address, telephone number and e-mail address;

2. hospital or clinic address and telephone number;

3. curriculum vitae or other summary of qualifications and credentials; and

4. other professional documentation.

Consistent with the purposes described above, this information may be transmitted to the Sponsor, and subsidiaries, affiliates and agents of the Sponsor, in your country and other countries, including countries that do not have laws protecting such information. Additionally, the investigator’s name and business contact information may be included when reporting certain serious adverse events to regulatory authorities or to other investigators. By signing this protocol, the investigator expressly consents to these uses and disclosures.

If this is a multicenter trial, in order to facilitate contact between investigators, the Sponsor may share an investigator’s name and contact information with other participating investigators upon request.

Confidentiality of IRB/IEC Information10.1.4

The Sponsor is required to record the name and address of each IRB/IEC member that reviews and approves this trial. The Sponsor is also required to document that each IRB/IEC meets regulatory and ICH GCP requirements by requesting and maintaining records of the names and qualifications of the IRB/IEC members and to make these records available for regulatory agency review upon request by those agencies.

03VY5N



Compliance with Financial Disclosure Requirements10.2

Financial Disclosure requirements are outlined in the US Food and Drug Administration Regulations, Financial Disclosure by Clinical Investigators (21 CFR Part 54). It is the Sponsor's responsibility to determine, based on these regulations, whether a request for Financial Disclosure information is required. It is the investigator's/subinvestigator's responsibility to comply with any such request.

The investigator/subinvestigator(s) agree, if requested by the Sponsor in accordance with 21 CFR Part 54, to provide his/her financial interests in and/or arrangements with the Sponsor to allow for the submission of complete and accurate certification and disclosure statements. The investigator/subinvestigator(s) further agree to provide this information on a Certification/Disclosure Form, commonly known as a financial disclosure form, provided by the Sponsor or through a secure password-protected electronic portal provided by the Sponsor. The investigator/subinvestigator(s) also consent to the transmission of this information to the Sponsor in the United States for these purposes. This may involve the transmission of information to countries that do not have laws protecting personal data.

Compliance with Law, Audit and Debarment10.3

By signing this protocol, the investigator agrees to conduct the trial in an efficient and diligent manner and in conformance with this protocol; generally accepted standards of Good Clinical Practice (e.g., International Conference on Harmonizat ion of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice: Consolidated Guideline and other generally accepted standards of good clinical practice); and all applicable federal, state and local laws, rules and regulations relating to the conduct of the clinical trial.

The Code of Conduct, a collection of goals and considerations that govern the ethical and scientific conduct of clinical investigations sponsored by Merck, is provided in Section 12.1 -Merck Code of Conduct for Clinical Trials.

The investigator also agrees to allow monitoring, audits, IRB/ERC review and regulatory authority inspection of trial-related documents and procedures and provide for direct access to all trial-related source data and documents.

The investigator agrees not to seek reimbursement from subjects, their insurance providers or from government programs for procedures included as part of the trial reimbursed to the investigator by the Sponsor.

The investigator shall prepare and maintain complete and accurate trial documentation in compliance with Good Clinical Practice standards and applicable federal, state and local laws, rules and regulations; and, for each subject participating in the trial, provide all data, and, upon completion or termination of the clinical trial, submit any other reports to the Sponsor as required by this protocol or as otherwise required pursuant to any agreement with the Sponsor.

03VY5N



Trial documentation will be promptly and fully disclosed to the Sponsor by the investigator upon request and also shall be made available at the trial site upon request for inspection, copying, review and audit at reasonable times by representatives of the Sponsor or any regulatory authorities. The investigator agrees to promptly take any reasonable steps that are requested by the Sponsor as a result of an audit to cure deficiencies in the trial documentation and worksheets/case report forms.

The investigator must maintain copies of all documentation and records relating to the conduct of the trial in compliance with all applicable legal and regulatory requirements. This documentation includes, but is not limited to, the protocol, worksheets/case report forms, advertising for subject participation, adverse event reports, subject source data, correspondence with regulatory authorities and IRBs/ERCs, consent forms, investigator’s curricula vitae, monitor visit logs, laboratory reference ranges, laboratory certification or quality control procedures and laboratory director curriculum vitae. By signing this protocol, the investigator agrees that documentation shall be retained until at least 2 years after the last approval of a marketing application in an ICH region or until there are no pending or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical development of the investigational product. Because the clinical development and marketing application process is variable, it is anticipated that the retention period can be up to 15 years or longer after protocol database lock. The Sponsor will determine the minimum retention period and notify the investigator when documents may be destroyed. The sponsor also recognizes that documents may need to be retained for a longer period if required by local regulatory requirements. All trial documents shall be made available if required by relevant regulatory authorities. The investigator must consult with and obtain written approval by the Sponsor prior to discarding trial and/or subject files.

ICH Good Clinical Practice guidelines recommend that the investigator inform the subject’s primary physician about the subject’s participation in the trial if the subject has a primary physician and if the subject agrees to the primary physician being informed.

The investigator will promptly inform the Sponsor of any regulatory authority inspection conducted for this trial.

Persons debarred from conducting or working on clinical trials by any court or regulatory authority will not be allowed to conduct or work on this Sponsor’s trials. The investigator will immediately disclose in writing to the Sponsor if any person who is involved in conducting the trial is debarred or if any proceeding for debarment is pending or, to the best of the investigator’s knowledge, threatened.

In the event the Sponsor prematurely terminates a particular trial site, the Sponsor will promptly notify that trial site’s IRB/IEC.

According to European legislation, a Sponsor must designate an overall coordinating investigator for a multi-center trial (including multinational). When more than one trial site is open in an EU country, Merck, as the Sponsor, will designate, per country, a national

03VY5N



principal coordinator (Protocol CI), responsible for coordinating the work of the principal investigators at the different trial sites in that Member State, according to national regulations. For a single-center trial, the Protocol CI is the principal investigator. In addition, the Sponsor must designate a principal or coordinating investigator to review the trial report that summarizes the trial results and confirm that, to the best of his/her knowledge, the report accurately describes the conduct and results of the trial [Clinical Study Report (CSR) CI]. The Sponsor may consider one or more factors in the selection of the individual to serve as the Protocol CI and or CSR CI (e.g., availability of the CI during the anticipated review process, thorough understanding of clinical trial methods, appropriate enrollment of subject cohort, timely achievement of trial milestones). The Protocol CI must be a participating trial investigator.

Compliance with Trial Registration and Results Posting Requirements10.4

Under the terms of the Food and Drug Administration Modernization Act (FDAMA) and the Food and Drug Administration Amendments Act (FDAAA), the Sponsor of the trial is solely responsible for determining whether the trial and its results are subject to the r equirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. Merck, as Sponsor of this trial, will review this protocol and submit the information necessary to fulfill these requirements. Merck entries are not limited to FDAMA/FDAAA mandated trials. Information posted will allow subjects to identify potentially appropriate trials for their disease conditions and pursue participation by calling a central contact number for further information on appropriate trial locations and trial site contact information.

By signing this protocol, the investigator acknowledges that the statutory obligations under FDAMA/FDAAA are that of the Sponsor and agrees not to submit any information about this trial or its results to the Clinical Trials Data Bank.

Quality Management System10.5

By signing this protocol, the Sponsor agrees to be responsible for implementing and maintaining a quality management system with written development procedures and functional area standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented, and reported in compliance with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, state, and local laws, rules and regulations relating to the conduct of the clinical trial.

Data Management10.6

The investigator or qualified designee is responsible for recording and verifying the accuracy of subject data. By signing this protocol, the investigator acknowledges that his/her electronic signature is the legally binding equivalent of a written signature. By entering his/her electronic signature, the investigator confirms that all recorded data have been verified as accurate.

03VY5N



Detailed information regarding Data Management procedures for this protocol wi ll be provided by the Sponsor.

Publications10.7

This trial is intended for publication, even if terminated prematurely. Publication may include any or all of the following: posting of a synopsis online, abstract and/or presentation at a scientific conference, or publication of a full manuscript. The Sponsor will work with the authors to submit a manuscript describing trial results within 12 months after the last data become available, which may take up to several months after the last subject visit in some cases such as vaccine trials. However, manuscript submission timelines may be extended on OTC trials. For trials intended for pediatric-related regulatory filings, the investigator agrees to delay publication of the trial results until the Sponsor notifies the investigator that all relevant regulatory authority decisions on the trial drug have been made with regard to pediatric-related regulatory filings. Merck will post a synopsis of trial results for approved products on www.clinicaltrials.gov by 12 months after the last subject's last visit for the primary outcome, 12 months after the decision to discontinue development, or product marketing (dispensed, administered, delivered or promoted), whichever is later.

These timelines may be extended for products that are not yet marketed, if additional time is needed for analysis, to protect intellectual property, or to comply with confidentiality agreements with other parties. Authors of the primary results manuscript will be provided the complete results from the Clinical Study Report, subject to the confidentiality agreement. When a manuscript is submitted to a biomedical journal, the Sponsor's policy is to also include the protocol and statistical analysis plan to facilitate the peer and editorial review of the manuscript. If the manuscript is subsequently accepted for publication, the Sponsor will allow the journal, if it so desires, to post on its website the key sections of the protocol that are relevant to evaluating the trial, specifically those sections describing the trial objectives and hypotheses, the subject inclusion and exclusion criteria, the trial design and procedures, the efficacy and safety measures, the statistical analysis plan, and any amendments relating to those sections. The Sponsor reserves the right to redact proprietary information.

For multicenter trials, subsequent to the multicenter publication (or after public disclosure of the results online at www.clinicaltrials.gov if a multicenter manuscript is not planned), an investigator and his/her colleagues may publish their data independently. In most cases, publication of individual trial site data does not add value to complete multicenter results, due to statistical concerns. In rare cases, publication of single trial site data prior to the main paper may be of value. Limitations of single trial site observations in a multicenter trial should always be described in such a manuscript.

Authorship credit should be based on 1) substantial contributions to conception and design, or acquisition of data, or analysis and interpretation of data; 2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the version to be published. Authors must meet conditions 1, 2 and 3. Significant contribu tions to trial execution may also be taken into account to determine authorship, provided that contributions have also been made to all three of the preceding authorship criteria. Although

03VY5N



publication planning may begin before conducting the trial, final decisions on authorship and the order of authors’ names will be made based on participation and actual contributions to the trial and writing, as discussed above. The first author is responsible for defending the integrity of the data, method(s) of data analysis and the scientific content of the manuscript.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.

11.0 LIST OF REFERENCES

1. Lahser F, Liu R, Bystol K, Xia E, Raubertas R, Asante-Appiah E, Howe A YM. A Combination Containing MK-5172 (HCV NS3 protease inhibitor) and MK-8742 (HCV NS5A inhibitor) Demonstrates High Barrier to Resistance in HCV Replicon. AASLD, 2012

2. Lawitz E, Vierling J, Murillo A, Kugelmas M, Gerstoft J, Winkle P, Balart L, Christensen P, Ghalib R, Nahass R, Shaughnessy M, Sun X, Hwang P, Wahl J, Robertson M, Haber B. High Efficacy and Safety of the All-Oral Combination Regimen, MK-5172 / MK-8742 ± RBV for 12 Weeks in HCV Genotype 1 Infected Patients: The C-WORTHY Study. AASLD, 2013.

3. Poordad F, McCone J Jr, Bacon BR, Bruno S, Manns MP, Sulkowski MS, Jacobson IM, Reddy KR, Goodman ZD, Boparai N, DiNubile MJ, Sniukiene V, Brass CA, Albrecht JK, Bronowicki JP; SPRINT-2 Investigators. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011; 364:1195-206.

4. McHutchison JG, Everson GT., Gordon SC, Jacobson IM: Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ., PROV. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N. Engl. J Med. 2009; 360 (18): 1827- 1838.

5. Neumann AU, Lam NP, Dahari H, Gretch DR, Wiley TE, Layden TJ, Perelson AS. Hepatitis C Viral Dynamics in Vivo and the Antiviral Efficacy of Interferon-α Therapy. Science 1998; 282: 103-107

6. Thompson AJ, Locarnini SA, Beard MR. Resistance to anti-HCV protease inhibitors. Current Opinion in Virology 2011, 1:599–606

7. Vermehren J, Sarrazin C. The role of resistance in HCV treatment. Best Practice & Research Clinical Gastroenterology 26 (2012) 487–503

8. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. Lancet 2014; 383: 515–23

03VY5N



9. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T, Jacobson I, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H, Nelson DR, Everson GT, Eley T, Wind-Rotolo M, Huang S, Gao M, Hernandez D, McPhee F, Sherman D, Hindes R, Symonds W, Pasquinelli C, Grasela DM. Daclatasvir plus Sofosbuvir for Previously Treated or Untreated Chronic HCV Infection. N Engl J Med 2014; 370:211-22

10. Fried MW, Reddy KR, Di Bisceglie AM, Jensen DM, Jacobson IM, Sulkowski M, Terrault N, Afdhal NA, Gordon S, Pockros P, Kwo P, Everson G, Sherman KE, Muir AJ, Pearlman B, Stewart TG, Vainorius M, Peter JA, and Nelson DR. HCV-TARGET: A Longitudinal, Observational Study of North American Patients with Chronic Hepatitis C Treated with Boceprevir or Telaprevir. EASL, 2013

11. Howe A, Long J, Thompson S, Barnard R, Alves K, Howe JA, Wahl J. Interim Analysis of the Durability of Response and Persistence of Resistance Associated Variants During Long Term Follow After Boceprevir + Pegylated Interferon/Ribavirin. AASLD 2013

12. Sullivan JC, De Meyer S, Bartels DJ, Dierynck I, Zhang EZ, Spanks J, Tigges AM, Ghys A, Dorrian J, Adda N, Martin EC, Beumont M, Jacobson IM, Sherman KE, Zeuzem S, Picchio G, Kieffer TL. Evolution of Treatment-Emergent Resistant Variants in Telaprevir Phase 3 Clinical Trials. Clinical Infectious Diseases 2013:57: 221-229

13. Olysio™ [package insert]. Titusville, NJ: Janssen Products; 2013.

14. Alberti A. Impact of a sustained virological response on the long-term outcome of hepatitis C. Liver Int. 2011 Jan;31 Suppl 1:18-22.

15. Chen, J; Florian, J; Carter, W; Fleischer, RD; Hammerstrom, TS; Jadhav, PR; Zeng, W; Murray, J; Birnkrant, D. Earlier Sustained Virologic Response End Points for Regulatory Approval and Dose Selection of Hepatitis C Therapies. Gastroenterology 2013;144:1450–1455

16. Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomized, phase 2 trial. Lancet 2014; 383: 515–23

17. Foucher J, Chanteloup E, Vergniol J, Caste´ra L, Le Bail B, Adhoute X, Bertet J,Couzigou P, de Le´dinghen V. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006;55:403–408.

18. Castera L, Forns X, Alberti A. Non-Invasive evaluation of liver fibrosis using transient elastography. Journal of Hepatology 2008; 48: 835-847.

19. Boursier J, de Ledinghen V, Zarski JP, Fouchard-Hubert I, Gallois Y, Overti F, Cales P and multicentric groups from SNIFF 32, VINDIAG 7, and ANRS/HC/EP23 FIRBOSTAR studies. Hepatology 2012; 55(1): 58-67.

20. Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of binomial. Biometrika 1934; 26: 404-13.

03VY5N



12.0 APPENDICES

Merck Code of Conduct for Clinical Trials12.1

Merck*Code of Conduct for Clinical Trials

I. Introduction

A. Purpose

Merck, through its subsidiaries, conducts clinical trials worldwide to evaluate the safety and effectiveness of our products. As such, we are committed to designing, implementing, conducting, analyzing and reporting these trials in compliance with the highest ethical and scientific standards. Protection of subject safety is the overriding concern in the design of clinical trials. In all cases, Merck clinical trials will be conducted in compliance with local and/or national regulations and in accordance with the ethical principles that have their origin in the Declaration of Helsinki.

B. Scope

Such standards shall be endorsed for all clinical interventional investigations sponsored by Merck irrespective of the party (parties) employed for their execution (e.g., contract research organizations, collaborative research efforts). This Code is not intended to apply to trials which are observational in nature, or which are retrospective. Further, this Code does not apply to investigator-initiated trials which are not under the control of Merck.

II. Scientific Issues

A. Trial Conduct

1. Trial Design

Except for pilot or estimation trials, clinical trial protocols will be hypothesis-driven to assess safety, efficacy and/or pharmacokinetic or pharmacodynamic indices of Merck or comparator products. Alternatively, Merck may conduct outcomes research trials, trials to assess or validate various endpoint measures, or trials to determine subject preferences, etc.

The design (i.e., subject population, duration, statistical power) must be adequate to address the specific purpose of the trial. Research subjects must meet protocol entry criteria to be enrolled in the trial.

2. Site Selection

Merck selects investigative sites based on medical expertise, access to appropriate subjects, adequacy of facilities and staff, previous performance in Merck trials, as well as budgetary considerations. Prior to trial initiation, sites are evaluated by Merck personnel to assess the ability to successfully conduct the trial.

3. Site Monitoring/Scientific Integrity

Trial sites are monitored to assess compliance with the trial protocol and general principles of Good Clinical Practice. Merck reviews clinical data for accuracy, completeness and consistency. Data are verified versus source documentation according to standard operating procedures. Per Merck policies and procedures, if fraud, misconduct or serious GCP-non-Compliance are suspected, the issues are promptly investigated. When necessary, the clinical site will be closed, the responsible regulatory authorities and ethics review committees notified anddata disclosed accordingly.

B. Publication and Authorship

To the extent scientifically appropriate, Merck seeks to publish the results of trials it conducts. Some early phase or pilot trials are intended to be hypothesis-generating rather than hypothesis testing. In such cases, publication of results may not be appropriate since the trial may be underpowered and the analyses complicated by statistical issues of multiplicity.

Merck’s policy on authorship is consistent with the requirements outlined in the ICH-Good Clinical Practice guidelines. In summary, authorship should reflect significant contribution to the design and conduct of the trial, performance or interpretation of the analysis, and/or writing of the manuscript. All named authors must be able to defend the trial results and conclusions. Merck funding of a trial will be acknowledged in publications.

03VY5N



III. Subject Protection

A. IRB/ERC review

All clinical trials will be reviewed and approved by an independent IRB/ERC before being initiated at each site. Significant changes or revisions to the protocol will be approved by the IRB/ERC prior to implementation, except that changes required urgently to protect subject safety and well-being may be enacted in anticipation of IRB/ERC approval. For each site, the IRB/ERC and Merck will approve the subject informed consent form.

B. Safety

The guiding principle in decision-making in clinical trials is that subject welfare is of primary importance. Potential subjects will be informed of the risks and benefits of, as well as alternatives to, trial participation. At a minimum, trialdesigns will take into account the local standard of care. Subjects are never denied access to appropriate medical care based on participation in a Merck clinical trial.

All participation in Merck clinical trials is voluntary. Subjects are enrolled only after providing informed consent for participation. Subjects may withdraw from a Merck trial at any time, without any influence on their access to, or receipt of, medical care that may otherwise be available to them.

C. Confidentiality

Merck is committed to safeguarding subject confidentiality, to the greatest extent possible. Unless required by law, only the investigator, sponsor (or representative) and/or regulatory authorities will have access to confidential medical records that might identify the research subject by name.

D. Genomic Research

Genomic Research will only be conducted in accordance with informed consent and/or as specifically authorized by an Ethics Committee.

IV. Financial Considerations

A. Payments to Investigators

Clinical trials are time- and labor-intensive. It is Merck’s policy to compensate investigators (or the sponsoring institution) in a fair manner for the work performed in support of Merck trials. Merck does not pay incentives to enroll subjects in its trials. However, when enrollment is particularly challenging, additional payments may be made to compensate for the time spent in extra recruiting efforts.

Merck does not pay for subject referrals. However, Merck may compensate referring physicians for time spent on chart review to identify potentially eligible subjects.

B. Clinical Research Funding

Informed consent forms will disclose that the trial is sponsored by Merck, and that the investigator or sponsoring institution is being paid or provided a grant for performing the trial. However, the local IRB/ERC may wish to alter the wording of the disclosure statement to be consistent with financial practices at that institution. As noted above, publications resulting from Merck trials will indicate Merck as a source of funding.

C. Funding for Travel and Other Requests

Funding of travel by investigators and support staff (e.g., to scientific meetings, investigator meetings, etc.) will be consistent with local guidelines and practices including, in the U.S., those established by the American Medical Association (AMA).

V. Investigator Commitment

Investigators will be expected to review Merck’s Code of Conduct as an appendix to the trial protocol, and in signing the protocol, agree to support these ethical and scientific standards.

* In this document, "Merck" refers to Merck Sharp & Dohme Corp. and Schering Corporation, each of which is a subsidiary of Merck & Co., Inc. Merck is known as MSD outside of the United States and Canada. As warranted by context, Merck also includes affiliates and subsidiaries of Merck & Co., Inc."

03VY5N



Collection and Management of Specimens for Future Biomedical Research12.2

1. Definitions

a.Biomarker: A biological molecule found in blood, other body fluids, or tissues that is a sign of a normal or abnormal process or of a condition or disease. A biomarker may be used to see how well the body responds to a treatment for a disease or condition.1

b. Pharmacogenomics: The investigation of variations of DNA and RNA characteristics as related to drug/vaccine response.2

c. Pharmacogenetics: A subset of pharmacogenomics, pharmacogenetics is the influence of variations in DNA sequence on drug/vaccine response.2

d. DNA: Deoxyribonucleic acid.

e. RNA: Ribonucleic acid.

2. Scope of Future Biomedical Research

The leftover DNA and plasma specimen(s) collected in the current trial will be used to study various causes for how subjects may respond to a drug/vaccine. The leftover DNA and plasma specimen(s) will be stored to provide a resource for future trials conducted by Merck focused on the study of biomarkers responsible for how a drug/vaccine enters and is removed by the body, how a drug/vaccine works, other pathways a drug/vaccine may interact with, or other aspects of disease. The specimen(s) may be used for future assay development and/or drug/vaccine development.

It is now well recognized that information obtained from studying and testing clinical specimens offers unique opportunities to enhance our understanding of how individuals respond to drugs/vaccines, enhance our understanding of human disease and ultimately improve public health through development of novel treatments targeted to populations with the greatest need. All specimens will be used by Merck or designees and research will be monitored and reviewed by a committee of our scientists and clinicians.

3. Summary of Procedures for Future Biomedical Research

a. Subjects for Enrollment

All subjects enrolled in the clinical trial will be considered for enrollment in the Future Biomedical Research sub-trial.

b. Informed Consent

Informed consent for specimens (i.e., DNA, RNA, protein, etc.) will be obtained during screening for protocol enrollment from all subjects or legal guardians, at a trial visit by the investigator or his or her designate. Informed consent for Future Biomedical Research should be presented to the subjects on Visit 1. If delayed, present consent at next possible Subject Visit. Informed consent must be obtained prior to collection of all Future Biomedical Research specimens. Consent forms signed by the subject will be kept at the clinical trial site under secure storage for regulatory reasons. Information contained on the consent form alone cannot be traced

03VY5N



to any specimens, test results, or medical information once the specimens have been rendered de-identified.

Subjects are not required to participate in the Future Biomedical Research sub-trial in order to participate in the main trial. Subjects who decline to sign the Future Biomedical Research informed consent will not have the specimen collected nor will they be discontinued from the main trial.

A template of each trial site’s approved informed consent will be stored in the Sponsor’s clinical document repository. Each consent will be assessed for appropriate specimen permissions.

Each informed consent approved by an ethics committee is assigned a unique tracking number. The tracking number on this document will be used to assign specimen permissions for each specimen into the Entrusted Keyholder’s Specimen Database.

c. eCRF Documentation for Future Biomedical Research Specimens

Documentation of both consent and acquisition of Future Biomedical Research specimens will be captured in the electronic Case Report Forms (eCRFs). Reconciliation of both forms will be performed to assure that only appropriately-consented specimens are used for this sub-trial's research purposes. Any specimens for which such an informed consent cannot be verified will be destroyed.

d. Future Biomedical Research Specimen Collections

Blood specimens for DNA or RNA isolation will usually be obtained at a time when the subject is having blood drawn for other trial purposes. Specimens like tissue and bone marrow will usually be obtained at a time when the subject is having such a procedure for clinical purposes.

Specimens will be collected and sent to the laboratory designated for the trial where they will be processed (e.g., DNA or RNA extraction, etc) following the Merck approved policies and procedures for specimen handling and preparation.

If specimens are collected for a specific genotype or expression analysis as an objective to the main trial, this analysis is detailed in the main body of this protocol (Section 8.0 –Statistical Analysis Plan). These specimens will be processed, analyzed, and the remainder of the specimen will be destroyed. The results of these analyses will be reported along with the other trial results. A separate specimen will be obtained from properly-consented subjects in this protocol for storage in the biorepository for Future Biomedical Research.

4. Confidential Subject Information for Future Biomedical Research

In order to optimize the research that can be conducted with Future Biomedical Research specimens, it is critical to link subject' clinical information with future test results. In fact little or no research can be conducted without connecting the clinical trial data to the specimen. The clinical data allow specific analyses to be conducted. Knowing subject characteristics like gender, age, medical history and treatment outcomes are critical to understanding clinical context of analytical results.

03VY5N



To maintain privacy of information collected from specimens obtained for Future Biomedical Research, Merck has developed secure policies and procedures. All specimens will be de-identified as described below.

At the clinical trial site, unique codes will be placed on the Future Biomedical Research specimens for transfer to the storage facility. This first code is a random number which does not contain any personally identifying information embedded within it. The link (or key) between subject identifiers and this first unique code will be held at the trial site. No personal identifiers will appear on the specimen tube.

This first code will be replaced with a second code at a Merck designated storage/lab facility. The second code is linked to the first code via a second key. The specimen is now double coded. Specimens with the second code are sometimes referred to as de-identified specimens. The use of the second code provides additional confidentiality and privacy protection for subjects over the use of a single code. Access to both keys would be needed to link any data or specimens back to the subject's identification.

The second code is stored separately from the first code and all associated personal specimen identifiers. A secure link, the second key, will be utilized to match the second code to the first code to allow clinical information collected during the course of the trial to be associated with the specimen. This second key will be transferred under secure procedures by the Merck designated facility to an Entrusted Keyholder at Merck. The second code will be logged into the primary biorepository database at Merck and, in this database, this identifier will not have identifying demographic data or identifying clinical information (i.e., race, sex, age, diagnosis, lab values) associated with it. The specimen will be stored in a designated biorepository site with secure policies and procedures for specimen storage and usage.

The second key can be utilized to reconstruct the link between the results of future biomedical research and the clinical information, at the time of analysis. This linkage would not be possible for the scientist conducting the analysis, but can only be done by the Merck Entrusted Keyholder under strict security policies and procedures. The Merck Entrusted Keyholder will link the information and then issue a de-identified data set for analysis. The only other circumstance by which future biomedical research data would be directly linked to the full clinical data set would be those situations mandated by regulatory authorities (e.g., EMEA, FDA), whereby this information would be directly transferred to the regulatory authority.

5. Biorepository Specimen Usage

Specimens obtained for the Merck Biorepository will be used for analyses using good scientific practices. However, exploratory analyses will not be conducted under the highly validated conditions usually associated with regulatory approval of diagnostics. The scope of research performed on these specimens is limited to the investigation of the variability in biomarkers that may correlate with a clinical phenotype in subjects.

Analyses utilizing the Future Biomedical Research specimens may be performed by Merck, or an additional third party (e.g., a university investigator) designated by Merck. The investigator conducting the analysis will be provided with double coded specimens.

03VY5N



Re-association of analysis results with corresponding clinical data will only be conducted by the Merck Entrusted Keyholder. Any contracted third party analyses will conform to the specific scope of analysis outlined in this sub-trial. Future Biomedical Research specimens remaining with the third party after the specific analysis is performed will be returned to the sponsor or destroyed and documentation of destruction will be reported to Merck.

6. Withdrawal From Future Biomedical Research

Subjects may withdraw their consent for Future Biomedical Research and have their specimens and all derivatives destroyed. Subjects may withdraw consent at any time by writing to the principal investigator for the main trial. If medical records for the main trial are still available, the investigator will contact Merck using the designated mailbox ([email protected]) and a form will be provided by Merck to obtain appropriate information to complete specimen withdrawal. Subsequently, the subject's specimens will be removed from the biorepository and be destroyed. A letter will be sent from Merck to the investigator confirming the destruction. It is the responsibility of the investigator to inform the subject of completion of destruction. Any analyses in progress at the time of request for destruction or already performed prior to the request being received by the Sponsor will continue to be used as part of the overall research trial data and results. No new analyses would be generated after the request is received.

In the event that the medical records for the main trial are no longer available (e.g., if the investigator is no longer required by regulatory authorities to retain the main trial records) or the specimens have been completely anonymized, there will no longer be a link between the subject’s personal information and their specimens. In this situation, the request for specimen destruction can not be processed.

7. Retention of Specimens

Future Biomedical Research specimens will be stored in the biorepository for potential analysis for up to 20 years from acquisition. Specimens may be stored for longer if a regulatory or governmental authority has active questions that are being answered. In this special circumstance, specimens will be stored until these questions have been adequately addressed.

Specimens from the trial site will be shipped to a central laboratory and then shipped to the Merck designated biorepository. The specimens will be stored under strict supervision in a limited access facility which operates to assure the integrity of the specimens. Specimens will be destroyed according to Merck policies and procedures and this destruction will be documented in the biorepository database.

8. Data Security

Separate databases for specimen information and for results from the Future Biomedical Research sub-trial will be maintained by Merck. This is done to separate the future exploratory test results (which include genetic data) from the clinical trial database thereby maintaining a separation of subject number and these results. The separate databases are accessible only to the authorized Sponsor and the designated trial

03VY5N



administrator research personnel and/or collaborators. Database user authentication is highly secure, and is accomplished using network security policies and practices based in international standards (e.g., ISO17799) to protect against unauthorized access. The Merck Entrusted Keyholder maintains control over access to all specimen data. These data are collected for future biomedical research purposes only as specified in this sub-trial will not be used for any other purpose.

9. Reporting of Future Biomedical Research Data to Subjects

There is no definitive requirement in either authoritative ethical guidelines or in relevant laws/regulations globally that research results have to be, in all circumstances, returned to the trial participant. Some guidelines advocate a proactive return of data in certain instances. No information obtained from exploratory laboratory studies will be reported to the subject or family, and this information will not be entered into the clinical database maintained by Merck on subjects. Principle reasons not to inform or return results to the subject include: lack of relevance to subject health, limitations of predictive capability, concerns of misinterpretation and absence of good clinical practice standards in exploratory research typically used for diagnostic testing.

If any exploratory results are definitively associated with clinical significance for subjects while the clinical trial is still ongoing, investigators will be contacted with information as to how to offer clinical diagnostic testing (paid for by Merck) to subjects enrolled and will be advised that counseling should be made available for all who choose to participate in this diagnostic testing.

If any exploratory results are definitively associated with clinical significance after completion of a clinical trial, Merck will publish the results without revealing specific subject information, inform all trial sites who participated in the Merck clinical trial and post anonymized results on our website or other accredited website(s) that allow for public access (e.g., disease societies who have primary interest in the results) in order that physicians and patients may pursue clinical diagnostic testing if they wish to do so.

10. Gender, Ethnicity and Minorities

Although many diagnoses differ in terms of frequency by ethnic population and gender, every effort will be made to recruit all subjects diagnosed and treated on Merck clinical trials for future biomedical research. When trials with specimens are conducted and subjects identified to serve as controls, every effort will be made to group specimens from subjects and controls to represent the ethnic and gender population representative of the disease under current investigation.

11. Risks Versus Benefits of Future Biomedical Research

For future biomedical research, risks to the subject have been minimized. Risks include those associated with venipuncture to obtain the whole blood specimen. This specimen will be obtained at the time of routine blood specimens drawn in the main trial.

Merck has developed strict security, policies and procedures to address subject data privacy concerns. Data privacy risks are largely limited to rare situations involving possible breach of confidentiality. In this highly unlikely situation there is risk that the information, like all medical information, may be misused.

03VY5N



It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug therapy and dosage, age, toxicities, etc.) to be re-associated to double coded specimens at the time of data analysis. These subject data will be kept in a separate, secure Merck database, and all specimens will be stripped of subject identifiers. No information concerning results obtained from future biomedical research will be entered into clinical records, nor will it be released to outside persons or agencies, in any way that could be tied to an individual subject.

12. Self-Reported Ethnicity

Subjects who participate in future biomedical research will be asked to provide self-reported ethnicity. Subjects who do not wish to provide this data may still participate in future biomedical research.

13. Questions

Any questions related to the future biomedical research should be e-mailed directly to [email protected].

14. References

1. National Cancer Institute: http://www.cancer.gov/dictionary/?searchTxt=biomarker

2. International Conference on Harmonization: DEFINITIONS FOR GENOMIC BIOMARKERS, PHARMACOGENOMICS, PHARMACOGENETICS, GENOMIC DATA AND SAMPLE CODING CATEGORIES - E15; http://www.ich.org/LOB/media/MEDIA3383.pdf

03VY5N



Understanding the Intent, Scope and Public Health Benefits of Exploratory Biomarker Research: A Guide for 12.3IRBs/IECs and Investigational Site Staff

03VY5N



03VY5N



List of Abbreviations and Definitions of Terms12.4

Term DefinitionAE Adverse EventAFP Alpha fetoproteinALP Alkaline PhosphataseALT Alanine aminotransferase (SGPT)ANA Anti-nuclear antibodiesAST Aspartate aminotransferase (SGOT)BID Twice a day; twice dailyBOC boceprevir 800 mg three times a day (TID) orally (PO)CBC Complete Blood CountCCDS Company Core Data SheetCD Compact DiskCEC Clinical Endpoints CommitteecEVR Complete Early Viral Response, defined as undetectable (TND) HCV RNA at Week 12CFR Code of Federal RegulationsCKD Chronic Kidney DiseaseCO Country Operations; a local, country-wide, representative of the sponsorCOPD Chronic obstructive pulmonary diseaseCRF Case Report FormCRO Clinical Research OrganizationCSR Clinical Study ReportCTC Clinical Trial CoordinatorCTD Clinical Trial DirectiveDAIDS Division of AIDSDNA Deoxyribonucleic AcidDSMB Data and Safety Monitoring BoardECG ElectrocardiogramECI Events of Clinical InteresteCRF Electronic Case Report FormEDC Electronic Data CaptureEOTR End-of-Treatment Response, defined as undetectable (TND) HCV RNA at the end of therapyEU European UnionFAS Full analysis setFDA Food and Drug Administration, USAFW Follow-up WeekGCP Good Clinical PracticeGCSP Global Clinical Supply PlanningGPV Global Pharmacovigilance, A sub-unit of SPRI that is responsible for worldwide safety

surveillance of all Schering marketed and investigational drugs, biologics and devices.HCV Hepatitis C virushCG Human Chorionic GonadotropinHD HemodialysisIATA International Air Transport AssociationIB Investigator’s BrochureICH International Conference on Harmonization of Technical Requirements for Registration of

Pharmaceuticals for Human UseIEC Independent Ethics CommitteeICMJE International Committee of Medical Journal EditorsIL28B interleukin 28B (interferon, lambda 3)IMP Investigational Medicinal ProductIND Investigational New Drug Application; legal instrument in the USA that allows trial of unapproved,

investigational new drugs in human subjectsInvestigational Product The drug, biologic, and/or device being investigated in the current trialIRB Institutional Review BoardIVRS Interactive Voice Response SystemK-M Kaplan-MeierLDH Lactate DehydrogenaseLLoQ lower limit of quantificationMedDRA Medical Dictionary for Regulatory ActivitiesNA, N/A Not applicableNDD Non-dialysis dependentPDF Portable Document FormatPGt PharmacogeneticsPeg-IFN Peginterferon alfa-2bPGx Pharmacogenomics

03VY5N



Term DefinitionPQC Product Quality ComplaintRBC Red Blood CellRGT Response guided therapyRBV RibavirinRNA Ribonucleic AcidRSI Reference Safety InformationRVR Rapid Viral Response defined as undetectable (TND) HCV RNA at Week 4 of study therapySAE Serious Adverse Event(S)AE All Adverse Events, including Serious Adverse EventsSF-36 Short Form (36) Health SurveySGOT Serum Glutamic Oxaloacetic Transaminase (AST)SGPT Serum Glutamic Pyruvic Transaminase (ALT)SmPC Summary of Product CharacteristicsSOP Standard Operating ProcedureSVR4 Sustained Virologic Response, having plasma HCV RNA < LLoQ at 4 weeks after the end of all

study therapy after becoming undetectable (TND) at end of treatmentSVR12 Sustained Virologic Response, having plasma HCV RNA <LLoQ at 12 weeks after the end of all

study therapy after becoming undetectable (TND) at end of treatmentSVR24 Sustained Virologic Response, having plasma HCV RNA <LLoQ at 24 weeks after the end of all

study therapy after becoming undetectable (TND) at end of treatmentTD Target DetectedTF Treatment FailureTID Three times a day; three times dailyTN Treatment NaïveTND Target NOT Detected (HCV RNA not detected)TD (u) Target detected but unquantifiableTD (q) Target Detected, quantifiableTW Treatment WeekUSA United States of AmericaUser ID User IdentificationvRVR very early Rapid Viral Response defined as undetectable (TND) HCV RNA at Week 2 of study

therapyWBC White Blood Cell

03VY5N



Approximate Blood/Tissue Volumes Drawn/Collected by Trial Visit and by Sample Types12.5

Tes

t

Scr

een

ing

Da

y 1

Da

y 7

Wee

k 2

Wee

k 4

Wee

k 6

Wee

k 8

Wee

k 1

0

Wee

k 1

2

wee

k 1

6

Wee

k 1

8

FU

4

FU

8

FU

12

FU

24

To

tal

Vo

lum

ew

ith

ou

t T

rea

tmen

t M

od

ific

ati

on

To

tal

Vo

lum

ew

ith

Tre

atm

ent

Mo

dif

ica

tio

n

Coagulation 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 4.5 58.5 67.5

Chemistry 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 130 150

Hematology 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 39 45

HbA1C 2 2 2

HBsAg 6 6 6

HIV RNA 6 6 6

MK-5172 PK 4 4 4 4 4 4 24 24

MK-8742 PK 4 4 4 4 4 4 24 24

R PK 3 3 3 3 3 3 18 18

HCV Genotype 4 4 4

HCV RNA Level 6 6 6 6 6 6 6 6 6 6 6 6 6 6 6 78 90

Plasma for HCV Viral Resistance and Biomarker 6 6 6 6 6 30 30

Blood (DNA) for genetic analysis 10 10 10

Total Volume in mL 41.5 59 34.5 34.5 34.5 23.5 34.5 23.5 34.5 23.5 23.5 29.5 29.5 29.5 29.5 429.5 476.5

Shaded visits are only in the case of Treatment Arm Modification.

03VY5N



13.0 SIGNATURES

Sponsor's Representative13.1

TYPED NAME

TITLE

SIGNATURE

DATE SIGNED

Investigator13.2

I agree to conduct this clinical trial in accordance with the design outlined in this protocol and to abide by all provisions of this protocol (including other manuals and documents referenced from this protocol). I agree to conduct the trial in accordance with generally accepted standards of Good Clinical Practice. I also agree to report all information or data in accordance with the protocol and, in particular, I agree to report any serious adverse events as defined in Section 7.0 – Assessing and Recording Adverse Events. I also agree to handle all clinical supplies provided by the Sponsor and collect and handle all clinical specimens in accordance with the protocol. I understand that information that identifies me will be used and disclosed as described in the protocol, and that such information may be transferred to countries that do not have laws protecting such information. Since the information in this protocol and the referenced Investigator’s Brochure is confidential, I understand that its disclosure to any third parties, other than those involved in approval, supervision, or conduct of the trial is prohibited. I will ensure that the necessary precautions are taken to protect such information from loss, inadvertent disclosure or access by third parties.

TYPED NAME

TITLE

SIGNATURE

DATE SIGNED

03VY5N

Product: MK-5172 1 Protocol/Amendment No.: 048-01 · MK-5172, MK-8742, and R should be taken...

Documents

Transcript of Product: MK-5172 1 Protocol/Amendment No.: 048-01 · MK-5172, MK-8742, and R should be taken...