A Phase 3, Global, Multicenter, Open-Label Study to Investigate the Efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected Patients, With Non-severe Fibrosis
Phase: PHASE3
Conditions: Chronic HCV Infection
Sponsor: University Hospital, Clermont-Ferrand

 
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A Phase 3, Global, Multicenter, Open-Label Study to Investigate the Efficacy of 
Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, 
HCV GT1b-Infected Patients, with non-severe fibrosis. 
 
Tittle : STREAGER  
(Short TREAtment course Grazoprevir ElbasviR) 
 
 
 
Code Promoteur
N° EudraCT  ou n° d’enregistrement ANSM
«RBHP 2016 ABERGEL» 
«2016-001363-37» 
 
 
 
 
 

 
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TABLE OF CONTENTS 
 
 
LIST OF TABLE……………………………………………………………………………………………………………..………………. 5 
LIST OF ABBREVIATION………………………………………………………………………………………………………………… 6 
PROTOCOL SYNOPSIS…………………………………………………………………………………………………………………… 7 
 
1. INTRODUCTION ……………………………………………………………………………………………….……………. 12 
1.1 
Study Tittle 
1.2  Promotion Code 
1.3  Promotion 
1.4 
Coordination 
1.5 
Investigators 
1.5.1 Coordinator Investigator 
1.5.2 Co-Investigators and Sites 
1.6 
Data Management 
1.7 
Committee for the protection of persons 
1.8 
Provisional Timelines for the study 
 
2. BACKGROUND ……………………………………………………………………………………………………………… 15 
2.1 
General Background  
2.2 
Pharmaceutical and Therapeutic Background 
2.2.1 In vitro studies EBV/GZR 
2.2.2 Clinical pharmacology EBV/GZR 
2.3 
Clinical trials studies with EBV/GZR combination 
2.4 
Efficacy measurement 
2.5 
Adverse events  
2.6 
Clinical Data 
2.7 
Recent clinical trials with 8 weeks of treatment containing DAAs 
2.8 
Rationale for the Trial  
2.8.1 Overview of Efficacy Endpoints 
2.8.2 Measurements of HCV RNA 
2.8.3 Definition of Efficacy Endpoints 
2.8.4 Definition of Virologic Failure:  Futility, Virologic Breakthrough, Rebound, and 
Relapse 
2.8.5 Safety Endpoints 
 
3 OBJECTIVES …………………………………………………………………………………………………………………… 26 
3.1 
Primary objective  
3.2 
Secondary objective  
 
4 STUDY DESIGN……………………………………………………………………………………………………………….. 26 
 
4.1 
Trial Design 

 
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4.2 
Study category  
 
5 STUDY POPULATION ……………………………………………………………………………………………………… 27 
5.1 
Subject Inclusion Criteria 
5.2 
Subject Exclusion Criteria 
5.3 
Considerations for study visits 
5.4  Subject Withdrawal/Discontinuation Criteria 
5.4.1 Subject Replacement Strategy 
5.4.2 Beginning and End of the Trial 
 
6 STUDY METHODOLOGY …………………………………………………………………………………………………. 33 
6.1 
Entry Criteria 
6.1.1   Primary endpoint 
6.1.2 Secondary Endpoint 
6.2 
Trial Treatment(s) 
6.2.1 
Dose Selection/Modification 
6.2.1.1 Dose Selection 
6.2.1.2Dose Modification 
6.2.2    Timing of Dose Administration 
6.2.3    Trial Blinding/Masking 
6.3 
Rescue Medications & Supportive Care 
 
7 TRIAL FLOW CHART ……………………………………………………………………………………………………….. 36 
 
8 STUDY PROCEDURES ……………………………………………………………………………………………………… 38 
8.1 
Trial Procedures 
8.1.1   Administrative Procedures 
8.1.1.1 Informed Consent 
8.1.1.2 Inclusion/Exclusion Criteria 
8.1.1.3 Subject Identification Card 
8.1.1.4 Medical History 
8.1.1.5 Prior and Concomitant Medications Review 
8.1.1.5.1Prior Medications 
8.1.1.5.2Concomitant Medications 
8.1.1.6 Assignment of Screening Number 
8.1.1.7 Trial Compliance 
8.1.2   Clinical Procedures/Assessments 
8.1.2.1 Physical Examination 
8.1.2.2 Weight and Height Assessment 
8.1.2.3 Fibroscan ® 
8.1.2.4 Vital Signs 
8.1.2.5 Birth Control Confirmation 
8.1.2.6 Adverse Events 

 
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8.1.3   Laboratory Safety Evaluations 
8.1.4 
Other Procedures 
8.1.4.1  Rescreening 
8.1.4.2  Withdrawal/Discontinuation 
8.1.4.3 Blinding/Unblinding  
8.1.5 
Visit Requirements 
8.1.5.1  Screening (Visit 1) 
8.1.5.2  Study/Treatment Visits 
8.1.5.2.1  Baseline/ Day 1 (Visit 2)  
8.1.5.2.2 Week 2 (visit 3 + 3 days) 
8.1.5.2.3Week 4 (visit 4 + 3 days) 
8.1.5.2.4 Week 8 (visit 5 + 3 days) 
8.1.5.2.5 Early termination (ET)/Unscheduled Visit 
8.1.5.3 Post Treatment Assessments 
8.1.5.3.1 Post treatment Week 4 (+ 5 days) 
8.1.5.3.2 Post Treatment Week 12 and 24 (+ 5 days) 
8.1.5.4 Drug Administration 
8.1.6    Evaluations of Laboratory Safety Signals 
8.2 
Assessing and Recording Adverse Events 
8.2.1    Definition of an Overdose for This Protocol and Reporting of Overdose to the 
Sponsor 
8.2.2    Reporting of Pregnancy and Lactation to the Sponsor 
8.2.3   Immediate Reporting of Adverse Events to the Sponsor 
8.2.3.1 Serious Adverse Events 
8.2.3.2 Events of Clinical Interest 
8.2.4    Evaluating Adverse Events 
8.2.5 Sponsor Responsibility for Reporting Adverse Events 
 
9 LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES ……………………….. 54 
9.1    Investigational Product 
9.2    Dosage and Administration  
9.3    Packaging and Labeling Information 
9.4    Clinical Supplies Disclosure 
9.5    Storage and Handling Requirements 
9.6    Returns and Reconciliation 
9.7  Study drug adherence and drug Accountability 
9.8 
Drug Interactions  
 
10 STATISTICAL ANALYSIS PLAN …………………………………………………………………………….…………… 58 
10.1 Sample size estimation 
10.2 Statistical Analysis Plan Summary 
10.3 Analyses for the primary outcome 
10.4 Analyses for the secondary objectives 

 
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11 DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ……………………………………………………………. 60 
11.1 Access to source data 
11.2 Source documents 
11.3 Confidentiality 
11.4 Archiving 
 
12 QUALITY CONTROL AND QUALITY ASSURANCE …………………………………………………………..…. 61 
12.1  Commitment of the investigators and the sponsor 
12.2  Quality assurance 
12.3  Quality control 
12.4 Case Report Form  
 
13 ETHICS ………………………………………………………………………………………………………………………..... 63 
13.1  Independent ethics committee 
13.2  Subject information and consent 
13.3  Amendments to the protocol 
13.4 Reimbursement of travel costs 
 
14 DATA HANDLING AND RECORD KEEPING …………………………………………………….…………….….. 64 
14.1  Electronic Case report forms (e-CRFs): entry and data processing 
14.2  CNIL 
14.3 Archiving 
 
15 FINANCING AND INSURANCE ……………………………………………………………….………………………… 65 
15.1  Budget  
15.2 Insurance  
 
16 PUBLICATION POLICY …………………………………………………………………………………………………….. 66 
 
LIST OF REFERENCES …………………………………………………………………………………………………………………. 67 
 
 
 
 

 
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LIST OF TABLE 
 
 
 
 
Table 1 : Table 1 : Trials Conducted with GZR with EBV...........................................................................18 
 
Table 2 : Adverse Reactions Occuring at ≥5% Frequency in Subjects with Chronic Hepatitis C 
Infection Treated with GZR with EBV for 12 Weeks in Protocol 060/C-EDGE TN or with GZR with 
EBV for 12 weeks in the Pooled Phase 2 and 3 Clinical Trials....................................................................19 
 
Table 3 
Recommended Dosage Regimens and Durations for EBV/GZR for Treatment of Chronic 
Hepatitis C Infection in Patients with or without Cirrhosis......................................................................21 
 
Table 4 
Summary of treatment studies of genotype 1 patients during 8 weeks and without 
cirrhosis...............................................................................................................................................................23 
 
Table 5 
Exclusionary laboratory values………………………………..................................................................... 31 
 
Table 6 
Trial Treatment .............................................................................................................................34 
 
Table 7 
Trial Flow Chart............................................................................................................... …………..…..36 
 
Table 8 
Laboratory Tests during trial...................................................................................................... 43 
 
Table 9 
Evaluating Adverse Events......................................................................................................... 52 
 
Table 10 Summary product information........................................................ ......................................... 54 
 
Table 11 Recommended Dosage Regimens and Durations for EBV/GZR for treatment of HCV 
genotype 1 or 4 in Patients with or without Cirrhosis..............................................................................55 
 
 
 
 
 
 

 
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LIST OF ABBREVIATION 
 
 
 
Term 
Definition 
AE
Adverse Event
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase (SGPT) 
ANSM 
French National Agency for Medicines and Health Products Safety 
AST 
Aspartate aminotransferase (SGOT) 
cEVR 
Complete Early Viral Response, defined as undetectable (TND) HCV RNA at Week 12 
CPP 
Institutional Review Board 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CSR 
Clinical Study Report 
CTC 
Clinical Trial Coordinator 
CTD 
Clinical Trial Directive 
DSMB 
Data and Safety Monitoring Board 
ECI 
Events of Clinical Interest 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EU 
European Union 
FDA 
Food and Drug Administration, USA 
FW 
Follow-up Week 
GCP 
Good Clinical Practice 
HCV 
Hepatitis C visrus 
hCG 
IATA 
Human Chorionic Gonadotropin 
International Air Transport Association 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use 
ICMJE 
International Committee of Medical Journal Editors 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application; legal instrument in the USA that allows trial of
unapproved, investigational new drugs in human subjects 
Investigational Product 
The drug, biologic, and/or device being investigated in the current trial 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
LLoQ 
lower limit of quantification 
 
 
 

 
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PROTOCOL SYNOPSIS 
 
 
Study Title :   
 
 
EudraCT Number :  
 
 
2016-001363-37 
Clinical Trials.gov Identifier :  
160789A-41 
 
Promotor Code  :  
 
 
RBHP 2016 ABERGEL 
 
 
Study Centers  
Planned :  
 
 
 
Objectives :  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14 centers in France
The primary objectives of this study are as follows: 
• 
To evaluate the efficacy of of Elbasvir/Grazoprevir Fixed-Dose Combination 
for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected Patients, with non- 
severe fibrosis as measured by the proportion of subjects with sustained 
viral response 12 weeks after cessation of treatment (SVR 12). 
• 
To evaluate the safety and tolerability of EBV/GZR treatment 
The secondary objectives of this study are as follows:  
• 
To determine the proportion of subjects who attain SVR at 4 and 24 weeks 
after cessation of treatment (SVR4 and SVR24) 
• 
To evaluate the proportion of subjects with virologic failure 
• 
To evaluate the kinetics of circulating HCV RNA during treatment and after 
cessation of treatment. 
• 
To evaluate the emergence of viral resistance to EBV/GZR during treatment 
and after cessation of treatment  
STREAGER : A Phase 3, Global, Multicenter, Open-Label Study to Investigate the 
Efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-
Naïve, HCV GT1b-Infected Patients, with non-severe fibrosis 

 
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Study Design :  
 
 
 
 
 
Target Population :  
 
 
 
Duration of 
treatment :  
 
 
 
Diagnosis and Main 
Eligibility Criteria :  
 
 
 
 
Inclusion Criteria:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approximately one hundred and twenty treatment-naïve subjects with chronic HCV 
GT1b infection without cirrhosis will be enrolled. 
There will be one treatment group with EBV/GZR (50/100 mg) once daily without 
regards to food for 8 weeks. 
Adults with chronic hepatitis C genotype 1b virus (HCV GT1b) infection who have 
not been previously treated. 
Subjects will be treated for 8 weeks.
Treatment-naïve chronic HCV GT1b-infected male and nonpregnant female 
subjects aged 18 years or older. 
Subjects must meet all of the following inclusion criteria to be eligible for 
participation in this study:  
1 - Willing and able to provide written informed consent 
2 - Male or female, age ≥ 18 years 
3 - Body Mass Index (BMI) ≥ 18 kg/m2 
4 - HCV RNA ≥ 104 IU/mL at Screening 
5- Chronic HCV infection (≥ 6 months) documented by prior medical history or liver 
biopsy. Only patients infected by  genotype 1b virus will be included. 
6 - Treatment-naïve with no prior exposure to any IFN, RBV, or approved or 
experimental HCV-specific DAA 
7 – Non severe fibrosis (F < 2) according to combination of theses two tests: 
Fibroscan® lower than 9.5 kPa AND Fibrotest lower than 0.59.  
8 - Females of childbearing potential (as defined in protocol Appendix 4) must have 
a negative serum pregnancy test at screening and a negative urine pregnancy test 
on Day 1 prior to enrollment 

 
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9 - Male subjects and female subjects of childbearing potential who engage in 
heterosexual intercourse must agree to use effective method(s) of contraception 
 
10 - Lactating females must agree to discontinue nursing before starting study drug 
11 - Subject must be of generally good health, with the exception of chronic HCV 
infection, as determined by the Investigator 
 
12 - Subject must be able to comply with the dosing instructions for study drug 
administration and able to complete the study schedule of assessments 
 
 
 
Exclusion Criteria:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study.
1 - Current or prior history of any of the following:  
a) Clinically significant illness (other than HCV) or any other major medical disorder that 
may interfere with subject treatment, assessment or compliance with the protocol; subjects 
currently under evaluation for a potentially clinically significant illness (other than HCV) are 
also excluded 
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug 
c) Difficulty with blood collection and/or poor venous access for the purposes of 
phlebotomy 
d) History of decompensation (e.g., clinical ascites, encephalopathy, and/or variceal 
hemorrhage) 
e) Solid organ transplantation 
f) Significant cardiac disease 
g) Unstable psychiatric condition including hospitalization, suicidal attempt, and/or a 
period of disability as a result of their psychiatric illness within 2 years prior to Screening 
h) Malignancy within the 5 years prior to Screening, with the exception of specific 
cancers that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Subjects 
under evaluation for possible malignancy are not eligible 
I ) Significant drug allergy (e.g., hepatotoxicity) 
 
2 - Subject has the following laboratory parameters at Screening: 
a) ALT > 10 x the upper limit of normal (ULN) 
b) AST > 10 x ULN 
c) Direct bilirubin > 1.5 x ULN 
d) Platelets < 75,000/μL 
e) HbA1c > 8.5% 
f) Creatinine clearance < 50 mL/min as calculated by the Cockcroft-Gault equation 
g) Hemoglobin < 10 g/dL 
h) Albumin < 3 g/dL 
i) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regime affecting INR 
 

 
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Study Procedures/ 
Frequency :  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening assessments will be completed within 28 days of the Day 1 visit. The 
screening window can be extended to 42 days for subjects requiring a liver biopsy, or 
extenuating circumstances. 
All subjects will complete the following study visits: Screening, Day 1, and on-
treatment visits at the end of week 2, week 4 and week 8. 
Posttreatment visits will occur at Weeks 4, 12, and 24 after last dose of study drug. All 
subjects will complete the posttreatment Week 4 and 12 visits. Subjects who achieve 
SVR12 (HCV RNA < LLOQ at posttreatment Week12) will complete the posttreatment 
Week 24 visit. 
Screening assessments will include physical examination, medical history, height, 
weight, vital signs, adverse events related to screening procedures, concomitant 
medications, safety laboratory tests (including hematology, chemistry, and 
coagulation), HCV RNA, serology (HCV, HBV), serology and/or antigen testing for HIV, 
HCV genotyping, hemoglobin A1c (HbA1c), assessment of the absence of cirrhosis or 
severe fibrosis (including Fibrotest® and Fibroscan®), serum β-human chorionic 
gonadotropin (β-hCG) (females of child-bearing potential only), urinalysis. 
On-treatment assessments include adverse events (AEs), concomitant medications, 
study medication dispensation and pill count, physical examination, weight, vital signs, 
safety laboratory tests, HCV RNA, and urine pregnancy tests (females of child bearing 
potential only). 
Posttreatment assessments include Aes, concomitant medications, vital signs, safety 
laboratory tests (including hematology, chemistry, and coagulation), HCV RNA, and 
urine pregnancy tests (females of child-bearing potential only). 
3 - Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, 
alfa-1 antitrypsin deficiency, cholangitis) 
 
4 - Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) 
 
5 - Clinically-relevant alcohol or drug abuse within 12 months of Screening. A positive drug 
screen will exclude subjects unless it can be explained by a prescribed medication; the 
diagnosis and prescription must be approved by the investigator 
6 - Use of any prohibited concomitant medication
7 - Known hypersensitivity to the study drug, the metabolites, or formulation excipient 

 
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Test Product, Dose, 
And Mode of 
Administration :  
 
 
 
 
 
Criteria for Evaluation :  
 
 
Safety : 
 
 
 
 
Efficacy :   
 
 
 
 
 
 
Statistical Methods :  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The sample size estimation was performed according to the precision of 95% 
confidence interval of the primary outcome measured by the proportion of 
subjects with sustained viral response 12 weeks after cessation of treatment. 
Considering an  efficacy at 96%, n=120 patients will be included in this study and 
will be able to obtain an exact 95% confidence interval with a lower bound greater 
than 91.5%, which could be considered as the minimal efficacy obtained in several 
works presented recently in literature. 
The primary efficacy endpoint for the study is the proportion of subjects with 
SVR12 in all enrolled and treated subjects.  
Secondary efficacy endpoints include SVR4 and SVR24, and the proportion of 
subjects with virologic failure. 
Safety endpoints will be analyzed by the number and percent of subjects with 
events or abnormalities for categorical values or 8-number summary (n, mean, 
standart deviation, median, Q1, Q3, minimum, maximum) for continuous data. 
 
EBV/GZR is manufactured as a 50/100 mg tablet for oral administration. Subjects 
will take 1 tablet daily without regards to food. 
AEs and laboratory tests will be collected throughout the study.
Efficacy will be evaluated using scheduled assessments of HCV RNA performed 
using ROCHE COBAS® AmpliPrep / COBAS® TaqMan® HCV Quantitative Test, v2.0 or 
ABBOTT  Amplification Reagent Real Time kit HCV  

 
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1.INTRODUCTION   
 
1.1 Study Tittle 
 
A Phase 3, Global, Multicenter, Randomized, Open-Label Study to Investigate the Efficacy of 
Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in Treatment-Naïve, HCV GT1b-Infected 
Patients, with non-severe fibrosis 
Abbreviated tittle : STREAGER (Short TREAtment course Grazoprevir ElbasviR) 
 
EudraCT Number : 2016-001363-37 
 
ANSM Number : 160789A-41 
 
 
1.2 Promotion Code 
 
RBHP 2016 ABERGEL 
 
1.3 Promotion 
 
CHU de Clermont-Ferrand 
58 Rue Montalembert 
63003 Clermont-Ferrand Cedex 1 
 
Direction Générale Adjointe – Délégation Régionale à la Recherche Clinique 
Tél : 04.73.751.195  / Fax : 04.73.754.730 
 
1.4 Coordination 
 
Pr Armand ABERGEL 
Médecine digestive et Hépato Biliaire 
CHU ESTAING 
Unité Mixte de Recherche Université d'Auvergne-CNRS 6284 
1 PLACE LUCIE AUBRAC 
63100 CLERMONT FERRAND 
Téléphone : 04 73 75 05 23 / Fax : 04 73 75 05 24 
 
 
1.5 Investigators 
 
1.5.1 Coordinator Investigator 
 
Pr Armand ABERGEL 
Médecine digestive et Hépato Biliaire 
CHU ESTAING 
Unité Mixte de Recherche Université d'Auvergne-CNRS 6284 
1 PLACE LUCIE AUBRAC 
63100 CLERMONT FERRAND 
Téléphone : 04 73 75 05 23 / Fax : 04 73 75 05 24 

 
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1.5.2 Co-Investigators and Sites  
 
CHU ESTAING CLERMONT-FERRAND 
1, PLACE LUCIE AUBRAC 
63100 CLERMONT FERRAND 
Investigateur coordinateur : Pr Armand Abergel 
 
CHU ANGERS 
4, rue Larrey  
49 933 Angers Cedex 9 
Investigateur : Dr Isabelle Fouchart-Hubert 
 
CHU BESANCON - Hôpital Jean Minjoz 
3, bd Alexandre Fleming 
25030 Besançon Cedex 
Investigateur : Pr Vincent Di Martino  
 
CHU LIMOGES-Hôpital Dupuytren  
2, avenue Martin Luther King 
87042 Limoges cedex 
Investigateur : Pr Véronique Loustaud Ratti  
 
CHU NANTES-hôtel-Dieu 
1, place Alexis-Ricordeau 
44093 Nantes Cedex 1 
Investigateur : Dr Jérôme Gournay 
 
Hopital BEAUJON 
100, bd du Général Leclerc 
92110 Clichy 
Investigateur : Pr Tarik Asselah  
 
Hopital Paul BROUSSE 
12, avenue Paul Vaillant Couturier 
94804 VILLEJUIF 
Investigateur : Pr Didier Samuel 
 
 
 

 
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CHU MONTPELLIER 
191, Avenue du Doyen Gaston Giraud 
34295 Montpellier cedex 5 
Investigateur : Pr Dominique Larrey 
 
CHU HENRI MONDOR  
51, avenue Maréchal de Lattre Tassigny 
94000 Creteil 
Investigateur : Pr Christophe Hezode 
 
CHU TOULOUSE-Hôpital Purpan  
Place du DocteurBaylac  
31059 Toulouse 
Investigateur : Dr Sophie Metivier 
 
CHU NICE- Hôpital de l’Archet II   
151 route Saint Antoine de Ginestière 
06202 Nice cedex 3  
Investigateur : Pr Albert Tran  
 
HOSPICES CIVILS DE LYON-Hôpital de la Croix-Rousse 
103 Grande rue de la Croix Rousse 
69317Lyon cedex 04  
Investigateur : Dr François Bailly  
 
Hopital COCHIN 
27 rue du Faubourg Saint-Jacques  
75014 Paris 
Investigateur : Pr Stanislas Pol 
 
CHU LILLE   
2, avenue Oscar Lambret  
59037 Lille  
Investigateur : Dr Valérie Canva 
 
 
 
 
 

 
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1.6  Data Management 
 
M. Nicolas ANDANT  
 
Logiciel Clinsight 
Data manager 
Délégation Recherche Clinique & Innovation 
CHU de Clermont-Ferrand - Villa annexe IFSI 
58, Rue Montalembert   
63003 Clermont-Ferrand cedex 
Tél : 04 73 17 84 17 
 
 
1.7 Committee for the protection of persons 
 
Comité de Protection des Personnes Sud Est  
 
 
1.8 Provisional Timelines for the study 
 
CPP Soumission : September 2016 
ANSM Autorisation : November 2016 
Beginning of Study : December 2016 
Inclusions : Starting January 2017 
End of Study : November 2018 
Final Report : December 2018/January2019 
 

 
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2 BACKGROUND 
 
2.1 General Background  
 
 
Hepatitis C (HCV) viral infection is a global health challenge affecting an estimated 170 million 
people (1), but seroprevalence and incidence rates vary significantly by risk group, even within 
world regions or nations.  The majority (55 to 85%) of subjects progress to chronic hepatitis C virus 
(CHC) infection.  Attendant consequences include chronic liver disease (~70%), with annual rates 
of progression to cirrhosis and hepatocellular carcinoma of ~20% and ~1 to 5%, respectively.  HCV 
has become the most common indication for liver transplantation in developed nations.  Given 
the asymptomatic nature of early infection and slow progression to severe chronic liver disease, it 
is expected that the prevalence of subjects diagnosed with HCV will peak over the next 2 decades 
(2). 
 
Six major genotypes (GT) have been identified for HCV. While genotype 1 is by far the most 
common, accounting for about 60% of global infections, the public health burden of other 
genotypes is also significant. In particular, GT2 the next most prevalent genotype worldwide 
accounts for 10-15% of infections in the United States.  In Europe the frequency varies from a 
relatively low prevalence of 0.9% in Turkey to a very significant proportion of HCV infections in 
France and Italy (10.4% and 27%, respectively).  Other genotypes are also responsible  for  a  large  
number  of  CHC  infections,  particularly  in  certain  geographic locations. For example, GT3 is 
endemic in south-east Asia; GT4 is principally found in the Middle East, Egypt, and central Africa; 
and GT 5 and 6 are found almost exclusively in South Africa, and in Asia, respectively (3). 
 
Previously, the standard of care (SOC) treatment for CHC infection with all genotypes was 
pegylated-interferon (peg-IFN) plus RBV (P/R) (4,5) a poorly tolerated drug with moderate efficacy. 
For GT1 infection, a major landmark was the approval of the first two direct-acting antiviral (DAA) 
agents, HCV NS3/4A protease inhibitors (PI), boceprevir or telaprevir. Addition of these DAAs to 
the P/R backbone significantly increased SVR24 rates in GT1 subjects but these regimens are no 
longer recommended (6–9). 
 
Recent drug development has focused on all-oral, interferon (IFN) free regimens that include agents 
that directly and specifically inhibit viral structural proteins (direct-acting antivirals, or DAAs). Four 
DAA classes have been developed: NS3/4A Protease Inhibitors (PIs), NS5A Inhibitors (NS5AIs), 
Nucleoside-Mimetic NS5B Polymerase Inhibitors (NIs), and Non- Nucleoside NS5B Polymerase 
Inhibitors (NNIs). Candidate medicines within each of these categories can vary substantially in 
terms of potency across genotypes and against resistance associated- variants (RAVs) within each 
genotype and subgenotype (10–16). 
 
The most effective regimens are for genotype 1 HCV which accounts for approximately 46% of 
infections worldwide (3). Genotypes 2 and 3 HCV, the next most common genotypes, were 
historically grouped together in treatment guidelines, but recent studies have shown that infection 
with genotype 3, especially in patients with cirrhosis, is more difficult to treat (17,18). Many 
interferon-free combinations are now available for these and the other 3 HCV genotypes (19,20), 

 
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but clinicians must take into account the genotype and even the subtype as well as patterns of 
antiviral resistance in the choice of a regimen. 
 
Shorter durations of therapy using novel combinations of DAAs may offer benefits such as 
increased compliance, lower cost and broader usage and acceptance by treating providers. 
 
 
2.2 
Pharmaceutical and Therapeutic Background 
 
 
Refer to the Investigator’s Brochure (IB)/approved labeling for detailed background information on 
EBV and GZR. 
 
 
2.2.1 In vitro studies EBV/GZR 
 
EBV is a potent inhibitor of the viral protease, NS3/4A, with broad in vitro genotypic activity. It has 
low nanomolar activity (< 1nM) against all 6 (GT 1-6) genotypes as assessed by enzymatic assays.  
In such assays the Ki values were lowest for GT1b virus, highest for GT3 virus, with values in the 
intermediate range for GT2 and GT4-6 HCV. 
Similar trends are seen in replicons studies with EBV. These data suggests that EBV will be a potent 
anchor drug with broad genotypic coverage for the treatment of CHC infection.    
 
GZR is an inhibitor of the HCV non-structural protein, 5A (NS5A), a pleiotropic protein with 
important roles in both HCV RNA replication and viral assembly. Using a panel of sub- genomic 
replicon cell lines, GZR has been shown to be highly potent against most HCV genotypes with EC50 
values in the low picomolar range. 
 
2.2.2 Clinical pharmacology EBV/GZR 
 
Grazoprevir is a substrate of CYP3A/P-gp. Co-administration of moderate or strong inducers of 
CYP3A/P-gp with GZR may decrease grazoprevir plasma concentrations, leading to reduced 
therapeutic effect of GZR. Co-administration of GZR/EBR with moderate or strong CYP3A/P-gp 
inducers is not recommended. Co-administration of GZR with strong CYP3A4/P-gp inhibitors 
increases grazoprevir and elbasvir plasma concentrations, but the increases are not clinically 
relevant. Therefore, CYP3A/P-gp inhibitors may be coadministered with GZR/EBR. 
Grazoprevir is a substrate of organic anion transporting polypeptide 1B (OATP1B) drug 
transporters. Co-administration of GZR with drugs that inhibit OATP1B transporters may result in a 
significant increase in the plasma concentration of grazoprevir. As such, coadministration of 
GZR/EBR with OATP1B inhibitors (such as rifampin and cyclosporine) is not recommended. 
Grazoprevir and elbasvir are inhibitors of the drug transporter breast cancer resistance protein 
(BCRP) at the intestinal level in humans and may increase plasma concentrations of coadministered 
BCRP substrates. Grazoprevir is a weak, but not clinically relevant, CYP3A inhibitor in humans. 
Therefore, no dose adjustment is required for CYP3A substrates when co-administered with 
GZR/EBR. Grazoprevir is not a P-gp or OATP1B inhibitor. Clinically significant drug interactions with 

 
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GZR as an inhibitor of other CYP enzymes, UGT1A1, and esterases (CES1, CES2, and CatA), are not 
expected, and multiple-dose administration of GZR is unlikely to induce the metabolism of drugs 
metabolized by CYP isoforms based on in vitro data. 
 
The GZR/EBR FDC may be coadministered with sofosbuvir and ribavirin (HCV medications). 
Methadone and buprenorphine/naloxone opioid substitution therapies may be coadministered 
with the GZR/EBR FDC without dose adjustment. The following immunosuppressants may be 
coadministered with the GZR/EBR FDC without dose adjustment: mycophenolate mofetil, 
prednisone, and tacrolimus. Coadministration of cyclosporine with the GZR/EBR FDC is not 
recommended. Acid-reducing agents, oral contraceptives, and phosphate binders may be 
coadministered with the GZR/EBR FDC without restriction. 
The GZR/EBR FDC may be coadministered with the following HIV antiretroviral medications: 
lamivudine, emtricitabine, abacavir, tenofovir disoproxil fumarate, raltegravir, dolutegravir, and 
rilpivirine. Coadministration of GZR/EBR FDC with efavirenz, etravirine, atazanavir, and ritonavir-
boosted HIV protease inhibitors is not recommended. 
Pravastatin and pitavastatin HMA-CoA reductase inhibitors may be coadministered with the 
GZR/EBR FDC without dose adjustment. Atorvastatin, rosuvastatin, fluvastatin, lovastatin, or 
simvastatin may be coadministered with GZR/EBR, but may result in increases in exposures of these 
statins. As such, the dose of atorvastatin, fluvastatin, lovastatin, or simvastatin should not exceed a 
daily dose of 20 mg and the dose of rosuvastatin should not exceed a daily dose of 10 mg when 
coadministered with GZR/EBR. 
Relative to fasting conditions, the administration of a single dose of GZR/EBR with a highfat (900 
kcal, 500 kcal from fat) meal to healthy subjects resulted in increases in grazoprevir AUC0-inf and 
Cmax of approximately 1.5-fold and 2.8-fold, respectively. These differences in grazoprevir 
exposure are not clinically relevant; therefore, GZR/EBR may be taken without regard to food. 
 
 
2.3 Clinical trials studies with EBV/GZR combination 
 
 
The core clinical development program includes 4 Phase 2 studies (Protocols 035, 047, 048,074), 
and 4 pivotal Phase 3 registration trials (Protocols 052, 060, 061, 068) in which 2704 HCV-infected 
subjects received GZR without EBR, GZR with EBR (either in the form of two separate tablets, 
termed GZR + EBR, or in the form of a fixed-dose combination tablet, termed GZR/EBR, or MK-
5172A), or placebo for GZR/EBR followed by GZR/EBR. No HCV-infected subject received EBR 
without GZR in Phase 2 or 3. Studies evaluated these regimens alone or in combination with RBV. 
Also, GZR/EBR was evaluated with sofosbuvir in one study. Of the 2704 subjects in these studies, 
1969 received GZR 100 mg with EBR 50 mg and support the key efficacy conclusions summarized 
below and an overview of these trials is provided in Table 1  
 
 
 
 
 

 
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Table 1 : Trials Conducted with GZR with EBV 
Trial
Population
Study Arms and Duration              
(Number of Subjects Treated) 
PN060/C-EDGE TN 
(double-blind) 
GT 1, 4, 6 
TN with or without cirrhosis 
• GZR/EBR for 12 weeks (N=316) 
• Placebo for 12 weeks (N=105)
PN061/C-EDGE 
COINFECTION 
(open-label)
GT 1, 4, 6 
TN with or without cirrhosis 
HCV/HIV-1 co-infection
• GZR/EBR for 12 weeks (N=218) 
PN052/C-SURFER 
(double-blind) 
GT 1 
TN or TE with or without 
cirrhosis 
Chronic Kidney Disease 
• GZR* + EBR* for 12 weeks (N=122) 
• Placebo for 12 weeks (N=113) 
PN035/C-WORTHY 
(open-label) 
GT 1, 3 
TN with or without cirrhosis 
TE Null Responder with or 
without cirrhosis 
TN HCV/HIV-1 co-infection 
without cirrhosis 
• GZR* + EBR* for 8, 12, or 18 weeks 
(N=31, 136, and 63, respectively) 
• GZR* + EBR* + RBV† for 8, 12, or 
18 weeks (N=60, 152, and 65, respectively) 
PN047/C-SCAPE 
(open-label) 
GT 4, 6 
TN without cirrhosis 
• GZR* + EBR* for 12 weeks (N=14) 
• GZR* + EBR* + RBV† for 12 weeks 
(N=14) 
PN068/C-EDGE TE 
(open-label) 
GT 1, 4, 6 
TE with or without cirrhosis 
HCV/HIV-1 co-infection 
• GZR/EBR for 12 or 16 weeks (N=105, and 105, 
respectively) 
• GZR/EBR + RBV† for 12 or 16 weeks 
(N=104 and 106, respectively) 
PN048/ C-SALVAGE 
(open-label) 
GT 1 
TE with HCV protease 
inhibitor regimen‡ with or 
without cirrhosis
• GZR* + EBR* + RBV† for 12 weeks 
(N=79) 
PN074/C-SWIFT 
(open-label) 
GT 1, 3 
TN with or without cirrhosis 
• GZR/EBR + sofosbuvir§ for 8 or 12 weeks 
in GT 3 (N= 15 and N=26, respectively) 
• GZR/EBR + sofosbuvir§ for 4, 6 or 8 weeks 
in GT 1 (N=31, 50, and 21, respectively) 
GT = Genotype 
TN = Treatment-Naïve 
TE = Treatment-Experienced (failed prior treatment with interferon [IFN] or peginterferon alfa [peg-IFN] with or without ribavirin 
(RBV) or were intolerant to prior therapy) 
*GZR = grazoprevir 100 mg; EBR = elbasvir 50 mg; GZR + EBR = co-administered as single agents 
†RBV was administered at a total daily dose of 800 mg to 1400 mg based on weight 
‡ Failed prior treatment with boceprevir, telaprevir, or simeprevir in combination with peg-IFN + RBV 
§ Sofosbuvir dose was 400 mg once a day
 
2.4 Efficacy measurement 
 
 
Sustained virologic response was the primary endpoint in all trials and was defined as HCV RNA less 
than the lower limit of quantification (LLOQ) at 12 weeks after the cessation oftreatment (SVR). 
Serum HCV RNA values were measured during these clinical trials using the COBAS 
AmpliPrep/COBAS Taqman HCV test (version 2.0) with an LLOQ of 15 HCV RNA IU/mL, with the 
exception of Protocol 035/C-WORTHY and Protocol 047/C-SCAPE where the assay had an LLOQ of 
25 HCV RNA IU/mL. 
 
 
2.5 Adverse events  
 
 

 
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GZR/EBR combination was evaluated in safety pharmacology studies (in vitro and in vivo) consistent 
with ICH S7A and S7B guidances to determine the potential cardiovascular, respiratory, and 
neurobehavioral effects. GZR/EBR was devoid of any effects of concern in these studies. 
 
Adverse reactions occurring in a pooled analysis of Phase 2 and 3 clinical trials at ≥5% frequency in 
subjects treated with GZR with EBR for 12 weeks are presented below. The majority of the adverse 
reactions were mild in severity. No subjects treated with GZR with EBR had serious adverse 
reactions. The proportion of subjects who permanently discontinued treatment due to adverse 
reactions was <1%. The type and severity of adverse reactions in subjects with cirrhosis were 
comparable to those seen in subjects without cirrhosis. 
Adverse Reactions Occurring at ≥5% Frequency in Subjects with Chronic Hepatitis C 
Infection Treated with GZR with EBR for 12 Weeks in Protocol 060/C-EDGE TN or with GZR with EBR 
for 12 weeks in the Pooled Phase 2 and 3 Clinical Trials are presented below : 
 
Table 2 : Adverse Reactions Occuring at ≥5% Frequency in Subjects with Chronic Hepatitis 
C Infection Treated with GZR with EBR for 12 Weeks in Protocol 060/C-EDGE TN or with 
GZR with EBR for 12 weeks in the Pooled Phase 2 and 3 Clinical Trials
  
PN060/C-EDGE TN 
Pooled* 
  
GZR with EBR 
   N=316                      
%(n)                          
12 weeks 
Placebo                   
N=105                    
% (n)                      
12 weeks 
GZR with EBR               
N=834                     
% (n)                      
12 weeksh  
Nervous system disorders 
Headache
10% (31) 
9% (9) 
10% (86) 
Gastrointestinal disorders 
Nausea 
4% (14) 
5% (5) 
5% (43) 
General disorders and administration site conditions 
Fatigue 
11% (35) 
10% (10) 
11% (94) 
*Includes C-WORTHY, C-SCAPE, C-SALT, C-EDGE TN, C-EDGE COINFECTION, C-EDGE TE and P058 
The type and severity of adverse reactions were comparable among subjects treated with 8, 12 or 
16 weeks of GZR with EBR. 
 
 
During clinical trials of GZR with EBR with or without ribavirin, regardless of treatment duration, 
<1% of subjects experienced elevations of ALT from normal levels to greater than 5 times the upper 
limit of normal (ULN), generally at or after treatment week 8. ALT elevations were typically 
asymptomatic and most resolved with ongoing or completion of therapy. Hepatic laboratory testing 
should be performed prior to therapy and periodically thereafter. Patients should be instructed to 
consult their healthcare professional without delay if they have onset of fatigue, weakness, lack of 
appetite, nausea and vomiting, jaundice or discolored feces. Consider discontinuing GZR with EBR if 
ALT levels remain persistently greater than 10 times the ULN. Discontinue GZR with EBR if ALT 
elevation is accompanied by signs or symptoms of liver inflammation or increasing conjugated 

 
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bilirubin, alkaline phosphatase, or INR. The frequency of ALT elevations was higher in subjects with 
higher grazoprevir plasma concentration. The incidence of late ALT elevations was not affected by 
treatment duration. 
Cirrhosis was not a risk factor for ALT elevations. 
 
No dose adjustments are recommended for GZR for most intrinsic factors, such as age, gender, 
body weight/BMI, renal impairment, and mild hepatic impairment. No dosage adjustment of 
GZR/EBR is required in patients who are on dialysis. However, the GZR/EBR FDC is not 
recommended for HCV-infected patients with moderate hepatic impairment (Child Pugh B) and is 
contraindicated for HCV-infected patients with severe hepatic impairment (Child Pugh C). 
 
2.6 Clinical Data 
 
 
Based on the efficacy and safety data from the key clinical, Table below (Table 3) provides the 
recommended GZR/EBR treatment regimen and duration based on the patient population and 
genotype in hepatitis C virus (HCV) mono-infected and HCV/HIV-1 co-infected patients with or 
without cirrhosis. 
 
Table 3 : Recommended Dosage Regimens and Durations for EBR/GZR for Treatment of Chronic 
Hepatitis C Infection in Patients with or without Cirrhosis 
 
 
 

 
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In case a dose is missed and it is within 16 hours of the time GZR/EBR is usually taken, the patient 
should be instructed to take GZR/EBR as soon as possible and then take the next dose of GZR/EBR 
at the usual time. If more than 16 hours have passed since GZR/EBR is usually taken, then the 
patient should be instructed that the missed dose should NOT be taken and to take the next dose 
per the usual dosing schedule. Patients should be instructed not to take a double dose. 
If GZR/EBR is co-administered with ribavirin or sofosbuvir, the information for ribavirin or 
sofosbuvir with regard to contraception, pregnancy testing, pregnancy, breastfeeding, and fertility 
also applies to this combination regimen (refer to the prescribing information of the co-
administered medicinal product for additional information). 
 
 
 
2.7 Recent clinical trials with 8 weeks of treatment containing DAAs 
 
 
 
The protease inhibitor ABT-450 with ritonavir (ABT-450/r), the nonnucleoside polymerase 
inhibitor ABT-333, and ribavirin showed efficacy against the hepatitis C virus (HCV) in a pilot study 
involving patients with HCV genotype 1 infection. The addition of another potent agent, the NS5A 
inhibitor ABT-267, may improve efficacy, especially in difficult-to-treat patients. This study was 
designed to evaluate multiple regimens of direct-acting antiviral agents and ribavirin in patients with 
HCV genotype 1 infection without cirrhosis who had not received therapy previously or who had no 
response to prior therapy with pegylated interferon and ribavirin. 
In this phase 2b study of interferon-free antiviral regimens, the treatment regimens were associated 
with rates of sustained virologic response at 24 weeks after treatment that ranged from 83 to 100%. 
Among previously untreated patients, the rate of treatment failure was lower among those 
receiving three direct acting agents plus ribavirin for 12 weeks than among those who received the 
same regimen for only 8 weeks and among those who received fewer agents; extending the 
treatment to 24 weeks offered no further benefit. The rate of sustained virologic response at 24 
weeks after treatment was 88% in the subgroup that received 8 weeks of therapy and 95% in the 
subgroup that received 12 weeks of therapy (difference between 8-week and 12-week subgroups, 
−7 percentage points; 95% conﬁdence interval, −19 to 5; P = 0.24). The higher number of relapses 
among patients in the 8-week treatment group (in 10 of 80 patients, vs. in 1 of 79 patients in the 12-
week treatment group) and the absence of resistance-associated variants in most patients who had 
a relapse in the 8-week treatment group suggest that 8 weeks of treatment might not be sufficient 
to eradicate the susceptible HCV population in these patients. 
Treatment durations longer than 8 weeks were not associated with a less favorable safety profile 
(21). 
 
In a phase 3 trial involving previously untreated patients with HCV genotype 1 infection without 
cirrhosis to explore the feasibility of shortening the treatment duration. It was assessed the single-
tablet regimen of ledipasvir– sofosbuvir administered for 8 weeks, with or without ribavirin 
(Ribasphere, Kadmon Pharmaceuticals), as compared with ledipasvir–sofosbuvir alone administered 
for 12 weeks. 

 
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In conclusion of this phase 3 trial, 8 weeks of treatment with a single-tablet regimen of ledipasvir– 
sofosbuvir resulted in a high rate of sustained virologic response among previously untreated 
patients with HCV genotype 1 infection without cirrhosis. Indeed, the SVR was 94 % (95% confidence 
interval [CI], 90 to 97). This results show that ribavirin worsens the treatment burden without 
enhancing efficacy. A 12 weeks duration of treatment with ledipasvir–sofosbuvir was not more 
effective than 8 weeks of treatment. The uniformly high rates of response in all the patient 
subgroups suggest the efficacy of this regimen across a broad range of previously untreated patients 
with HCV genotype 1 infection without cirrhosis. The 8-week regimen of ledipasvir–sofosbuvir has 
not been evaluated in patients with cirrhosis (12).  
 
In a phase 2 study of treatment-naive noncirrhotic patients treated by Sofosbuvir With Velpatasvir in 
Genotype 1 to 6 Hepatitis C Virus Infection, Rates of SVR were lower with 8 weeks versus 12 weeks 
of treatment in patients with HCV genotype 1 or 2 infection. More particularly for genotype 1, SVR 
was 85% (95% CI). The small sample size and limited number of virologic failures in each treatment 
group precluded analysis of the association between viral load and virologic failure. The high SVR 
rates achieved with 12 weeks of treatment, even in patients with pretreatment RAVs, may indicate 
that the 12-week regimen is more efficacious for patients with negative predictors, such as baseline 
resistance (22).     
 
High efficacy was also demonstrated in treatment-naive, non-cirrhotic (F0-F3) GT1b infected 
patients in 8 weeks of treatment by EBR/GZR. 
 
Indeed, in the Protocol 035/C-WORTHY trial (Cf ANNEXE n°1), treatment-naïve subjects with 
genotype 1b CHC without cirrhosis were treated with GZR + EBR with or without RBV for 8 weeks. In 
subjects treated with GZR + EBR without RBV, the subjects had a median age of 56 years (range: 28 
to 71); 42% of the subjects were male; 81% were White; 19% were Black or African American; 3% 
were Hispanic or Latino; mean body mass index was 28 kg/m2; 87% had baseline HCV RNA levels 
greater than 800,000 IU/mL; and 90% had non-C/C IL28B alleles (CT or TT). By liver biopsy or non-
invasive tests, all were non-cirrhotic and 94% (29/31) had METAVIR scores of F0-F2 and the other 2 
subjects had a METAVIR score of F3. 
Overall SVR was achieved in 94% (29/31) in treatment-naïve subjects with genotype 1b without 
cirrhosis who received GZR + EBR for 8 weeks. Two of the thirty-one subjects did not achieve SVR 
due to relapse. SVR was achieved in 97% (28/29) of subjects with METAVIR scores of F0-F2 and 50% 
(1/2) subjects with METAVIR score of F3. The addition of RBV was not shown to improve the 
treatment outcomes observed with GZR + EBR (23,24).  
 
A summary of this studies are presented in the table 4 :  
 
 
 
 
 
 

 
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Table 4 : Summary of treatment studies of genotype 1 patients during 8 weeks and  
without cirrhosis  
Treatment combination 
SVR Genotype 
1b
SVR Genotype 
1
Comments 
Elbasvir + Grazoprevir
97% (29/31)
NA
F0-F2 patients
3D Abbvie +/- RBV 
NA 
88% (70/80) 
F2- F3 patients 
Sofosbuvir + Ledipasvir  
98% (42/43) 
94% (202/215) 
* 
F0-F3 patients 
* F3 (19%); Genotype 1a : 
80%; Genotype 1b : 20% 
Sofosbuvir + 
Velpatasvir(100mg)
NA 
84% (51/60) 
F0-F3 patients 
Results of these studies suggest that 8 weeks of treatment with EBR/GZR combination might be 
sufficient to eradicate the susceptible HCV population in treatment-naive, non-severe fibrosis (F0-
F2) GT1b infected patients (12,21–25).   
 
 
2.8 Rationale for the Trial  
 
 
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. 
 
2.8.1 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 subjects with chronic hepatitis C infection as measured by 
biochemical and histological remission of liver disease. Though long term outcome data are 
limited, 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  (26). 
 
The primary evaluation of efficacy in this trial is based on SVR12 (Sustained Virologic Response 12 
weeks after the end of all study therapy).  The primary endpoint used in 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 (27) , and SVR12 is increasingly 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 end of 
treatment visit (Week 8). 
 
 
 

 
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2.8.2 Measurements of HCV RNA 
 
HCV-RNA levels in plasma will be measured using the Roche COBAS™ Taqman™ HCV Test, v2.0 for 
use with the High Pure system or ABBOTT Amplification Reagent Real Time kit HCV on blood 
samples drawn from each subject at various time points, prior to, during, and after dosing, as 
indicated in the Study Flow Chart (Section 7).  Samples will be collected and processed as per 
provided instructions. 
 
Results  from  samples  collected  at  the  screening  visit  are  used  to  determine  eligibility. 
Samples collected at other time points are used for efficacy analyses.  They are also used to 
identify subjects who meet virologic failure criteria. 
 
The Roche COBAS™ Taqman™ HCV Test, v2.0 ® for use with the High Pure system assay has a 
lower limit of detection and quantitation (LLoQ) of 15 IU/mL.    
The ABBOTT Amplification Reagent Real Time kit HCV has a lower limit of quantitation and 
detection of 12 IU/mL. 
 
 
 
2.8.3 Definition of Efficacy Endpoints 
 
Efficacy will be defined at different timepoints during the trial. Specific endpoints are: 
a)  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 
 
b) SVR12 (Sustained Virologic Response 12 weeks after the end of all study therapy): The subject 
has HCV RNA <LLoQ [either TD(u) or TND] 12 weeks after the end of all study therapy. 
 
c)  SVR24 (Sustained Virologic Response 24 weeks after the end of all study therapy). The subject 
has HCV RNA <LLoQ [either TD(u) or TND] 24 weeks after the end of all study therapy. 
 
 
2.8.4 Definition of Virologic Failure:  Futility, Virologic Breakthrough, Rebound, and 
Relapse 
 
 
Lack of efficacy at different timepoints in the trial will be categorized as: 
 
• 
Futility: 
 
Subject  has  HCV  RNA  LLoQ  [TD(q)]  at  treatment  Week  4  with confirmation.  The results of 
the next available blood draw will be used as the confirmatory test.  This confirmatory test must 
be obtained within 2 weeks. Futility is defined as HCV RNA ≥25 IU/mL from the confirmatory test. 
 
• 
Rebound 
 
Subject has a rebound defined as >1 log10  increase in HCV RNA from nadir while on treatment 
and confirmed from a separate blood draw within 2 weeks. 

 
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• 
Virologic breakthrough: 
 
Subject has a confirmed HCV RNA ≥ LLOQ [TD(q)] after being < 25 IU/mL previously [TD(u) or TND]. 
Confirmation is defined as an HCV RNA ≥ LLoQ from 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. 
 
 
2.8.5 Safety Endpoints 
 
The safety and tolerability of EBR/GZR combination will be assessed by a clinical evaluation of 
adverse experiences and other study parameters including vital signs, physical examinations, and 
standard laboratory safety tests at appropriate time points as specified in the Study Flow Chart 
(Table 7). Adverse experiences are graded and recorded according to Section 8.2.4/Table 9.   
Subjects may be asked to return for unscheduled visits in order to perform additional safety 
monitoring. 
 
 
3. OBJECTIVES  
 
 
3.1 
Primary objective  
 
 
The primary objectives of this study are as follows:  
• To evaluate the efficacy of of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in 
Treatment-Naïve, HCV GT1b-Infected Patients, with non- severe fibrosis as measured by the 
proportion of subjects with sustained viral response 12 weeks after cessation of treatment 
(SVR 12). 
• To evaluate the safety and tolerability of EBV/GZR treatment 
 
 
3.2 
Secondary objective  
 
 
The secondary objectives of this study are as follows:  

 
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• To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• To evaluate the proportion of subjects with virologic failure 
• To evaluate the kinetics of circulating HCV RNA during treatment and after cessation of 
treatment. 
• To evaluate the emergence of viral resistance to EBR/GZR during treatment and after 
cessation of treatment  
 
4.  STUDY DESIGN 
 
 
4.1 
Trial Design 
 
This is a multi-site, open-label evaluating the efficacy of GRAZOPREVIR (100 mg - second-
generation protease inhibitor) in combination with ELBASVIR (50 mg - NS54A inhibitor), in treating 
non-cirrhotic, treatment-naïve (TN) subjects with chronic hepatitis C (CHC) infection with 
genotypes 1b to be conducted in conformance with Good Clinical Practice. 
 
Approximately 120 subjects will be enrolled in this study. 
There will be one treatment group with EBR/GZR (50/100 mg) once daily without regards to food 
for 8 weeks. 
 
 
Several measures have been included in order to limit risk to the study subject. 
• Subjects will be discontinued from all study therapy (where applicable) if they meet any of 
the criteria for discontinuation (details in Section 5.4). 
 
• Study therapy will also be discontinued for subjects who meet criteria for virologic failure 
(defined in section 2.8.4). 
 
• In the event there is an unacceptable rate of virologic failure (details in section 2.8.4) 
or discontinuation of study medications due to safety concerns, the treatment or the entire 
study may be terminated. 
 
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 - Table 7 Details of each procedure 
are provided in Section 8.1 – Trial Procedures. 
 
 
 
 
 

 
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4.2 
Study category  
 
 
This is a Clinical trial of investigational medicinal products. 
 
 
5. STUDY POPULATION  
 
 
5.1.    Subject Inclusion Criteria 
 
 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this study:  
1 - Willing and able to provide written informed consent 
2 - Male or female, age ≥ 18 years 
3 - Body Mass Index (BMI) ≥ 18 kg/m2 
4 - HCV RNA ≥ 104 IU/mL at Screening 
5- Chronic HCV infection (≥ 6 months) documented by prior medical history or liver biopsy, only 
genotype 1b virus. (Positive for anti HCV antibody, HCV RNA, or an HCV genotype) 
6 - Treatment-naïve with no prior exposure to any IFN, RBV, or approved or experimental HCV-
specific DAA 
7- Non severe fibrosis (F < 2) according to combination of this two tests :    
- Fibroscan® lower than 9.5 kPa AND Fibrotest lower than 0.59 
8 - Females of childbearing potential (as defined in protocol Appendix 4) must have a negative 
serum pregnancy test at screening and a negative urine pregnancy test on Day 1 prior to enrollment 
 
9 - Male subjects and female subjects of childbearing potential who engage in heterosexual 
intercourse must agree to use 2 effective method(s) of contraception from at least two weeks prior 
to Day 1 through 14 days after the last dose of study drugs.   
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: Periodic abstinence (e.g., abstinence only on certain calendar days, abstinence only during 
ovulation period, use of symptothermal methods, use of post-ovulation methods and withdrawal) 
are not acceptable methods of contraception. 
 

 
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10 - A female subject who is not of reproductive potential is eligible without requiring the use of 
contraception. A female subjects who is not of reproductive potentials 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. 
 
11 - 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 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. 
 
12 - Lactating females must agree to discontinue nursing before starting study drug 
13 - Subject must be of generally good health, with the exception of chronic HCV infection, as 
determined by the Investigator 
 
14 - Subject must be able to comply with the dosing instructions for study drug administration and 
able to complete the study schedule of assessments 
 
 
5.2 
Subject Exclusion Criteria 
 
 
Subjects who meet any of the following exclusion criteria are not to be enrolled in this study. 
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 - Current or prior history of any of the following:  
a) Clinically significant illness (other than HCV) or any other major medical disorder that may 
interfere with subject treatment, assessment or compliance with the protocol; subjects currently 
under evaluation for a potentially clinically significant illness (other than HCV) are also excluded 
b) Gastrointestinal disorder or post-operative condition that could interfere with the 
absorption of the study drug 
c) Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy 
d) History of decompensation (e.g., clinical ascites, encephalopathy, and/or variceal 
hemorrhage) 
e) Solid organ transplantation (including hematopoietic stem cell transplants) other than 
cornea and hair. 
f) Significant cardiac disease 
g) Unstable psychiatric condition including hospitalization, suicidal attempt, and/or a period 
of disability as a result of their psychiatric illness within 2 years prior to Screening 

 
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h) Malignancy within the 5 years prior to Screening, with the exception of specific cancers 
that have been cured by surgical resection (e.g., basal cell skin cancer, etc.). Subjects under 
evaluation for possible malignancy are not eligible 
I ) Significant drug allergy (e.g., hepatotoxicity) 
 
3 - Subject has the following laboratory parameters at Screening: 
a) ALT > 10 x the upper limit of normal (ULN) 
b) AST > 10 x ULN 
c) Direct bilirubin > 1.5 x ULN 
d) Platelets < 75,000/μL 
e) HbA1c > 8.5% 
f) Creatinine clearance < 50 mL/min as calculated by the Cockcroft-Gault equation 
g) Hemoglobin < 10 g/dL 
h) Albumin < 3 g/dL 
i) INR > 1.5 x ULN unless subject has known hemophilia or is stable on an anticoagulant 
regime affecting INR 
 
4 - Chronic liver disease of a non-HCV etiology (e.g., hemochromatosis, Wilson’s disease, alfa-1 
antitrypsin deficiency, cholangitis) 
 
5 - Infection with hepatitis B virus (HBV) or human immunodeficiency virus (HIV) 
 
6 - Clinically-relevant alcohol or drug abuse within 12 months of Screening.  
a. 
Alcohol, intravenous drugs, inhalational (not including marijuana), psychotropic, 
narcotics, cocaine use, prescription or over-the-counter drugs: within 1 year of the 
screening visit, or if shorter, is judged by investigator to be capable of complying with study 
procedures  
b. 
receiving opiate agonist substitution therapy within 1 year of screening visit, or if 
shorter, is judged by investigator to be capable of complying with study procedures 
c. 
history of marijuana use if deemed excessive by a physician investigator or  interferes with 
the subject's daily function. If subject's marijuana use is not deemed excessive and does not 
interfere with daily function, subject must agree to discontinue any current use of 
recreational marijuana prior to entry into trial and throughout the trial period 
A positive drug screen will exclude subjects unless it can be explained by a prescribed 
medication; the diagnosis and prescription must be approved by the investigator 
 
7 - Use of any prohibited concomitant medication listed in Section 9.8 of this protocol within 2 
weeks prior to day 1. 
 
8 - Known hypersensitivity to the study drug, the metabolites, or formulation excipient 
9 - 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 study. Collection of additional blood, urine, or tissue samples or additional data, 

 
31 
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beyond that specified in this protocol, is prohibited (other than that related to subject’s 
medical care). 
 
10 - (female) is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing 
potential and unwilling to commit to two methods of birth control throughout treatment and 
after the completion of all treatment (see Inclusion Criteria); or male subject is planning to 
impregnate or provide sperm donation or has a female sexual partner of childbearing 
potential and is unwilling to commit to using a two methods of birth control throughout 
treatment and after the completion of all treatment (see Inclusion Criteria). 
 
11 - Had a life-threatening SAE during the screening period. 
 
12 - Is a member or a family member of the investigational study staff or sponsor staff directly 
involved with this study. 
 
13 - 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, may be enrolled. 
 
14 - For subjects diagnosed with diabetes mellitus, documented HbA1c >8.5% (to exclude 
uncontrolled diabetes).  
 
15 - Has any of the following conditions:. 
• Subject with a history of gastric surgery (e.g., stapling, bypass) or subject with a history of 
malabsorption disorders (e.g., celiac sprue disease). 
• Any medical condition requiring, or likely to require, chronic systemic administration of 
corticosteroids during the course of the trial. 
 
16 - Has exclusionary laboratory values as listed below (see Table 5 for unit conversions of some 
laboratory values specified below): 
 
Note:  If any of the laboratory exclusion criteria below are met, the site may have the 
abnormal value retested one time. 
 
 
Table 5 : Exclusionary laboratory values 
Laboratory Assessment
hemoglobin
< LLN (lower limit of normal) of labora=tory reference range
neutrophils
<1.5 x 103/μL (<1.2 x 103/μL for Blacks) 
platelets
<75 x 103/μL
direct bilirubin
>1.5 x ULN
Total Bilirubin
>1.6 mg/dL unless history of Gilbert's disease. (If Gilbert’s disease is the
proposed etiology, this must be documented in the subject’s chart) 

 
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Serum Albumin
< 3.0 g/dL (lower limit of normal) of laboratory reference range
creatinine clearance
<50 mL/min
INR
>1.5
ALT
>350
AST
>350
 
 
 
5.3 Considerations for study visits 
 
 
Procedures visits should be scheduled as close to the indicated study days and study weeks as 
possible. See the Study Flow Chart in Section 7 for a complete listing of study procedures 
required at each visit.  
 
 
5.4  Subject Withdrawal/Discontinuation Criteria 
 
 
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. 
 
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. 
 
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. 
 
• Request of the subject (subjects have the right to discontinue treatment at any time for any 
reason). 
 
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 2.8.4 for definitions of virologic 
failure) 
 
• Suicidal or homicidal ideation or attempt. 
 
• Severe depression. 

 
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• Subject has a positive test for nonprescription opiates, methamphetamines, or cocaine. 
 
• Subject 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 experiences 
that are of moderate or severe intensity and deemed by the investigator to be at least 
possibly related to EBV/GZR (50/100 mg):  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 experiences that are of moderate or severe intensity and deemed by the 
investigator to be at least possibly related to EBV/GZR (50/100 mg): 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. 
 
• 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: 
 
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. 
 
Failure to comply with the dosing, evaluations, or other requirements of the trial. 
 
 
5.4.1 Subject Replacement Strategy 
 
A subject that discontinues from the trial will not be replaced except if the subject is a screen fail 
or wrongly included. The screen fail rate is estimated at around 20%, so we plan to include about 

 
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145 patients in the study (patient who signed the informed consent form). 
 
5.4.2 Beginning and End of the Trial 
 
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). 
 
 
6. 
STUDY METHODOLOGY 
 
 
6.1    Entry Criteria 
 
 
6.1.1   Primary endpoint 
 
The primary efficacy endpoint is the proportion of subjects with SVR12 (HCV RNA < LLOQ 12 
weeks after cessation of treatment) in the full analysis set 
 
6.1.2 Secondary Endpoint 
 
The secondary objectives of this study are as follows:  
• To determine the proportion of subjects who attain SVR at 4 and 24 weeks after cessation of 
treatment (SVR4 and SVR24) 
• To evaluate the proportion of subjects with virologic failure 
 
 
6.2 Trial Treatment(s) 
The treatments to be used in this trial are outlined below in Table 6 
 
 
 
Table 6 : Trial Treatment  
Drug 
Dose/Potency 
Dose
Frequency
Route of
Administration
Regimen/
Treatment
Period 
Use 
Grazoprevir(GZR)°
100 mg
QD
Oral
8 Weeks
Experimental
Elbasvir (EBV)
50 mg
QD
Oral
8 Weeks
Experimental
 
 
 
Elbasvir/Grazoprevir 

 
35 
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Subjects will receive treatment with EBV/GZR (50/100 mg) fixed dose combination once-daily 
(QD) orally. Study therapy will be supplied once during the treatment period at Day 1. Subjects 
will be instructed to take their daily medications as instructed on the bottle labels. 
 
 
6.2.1 Dose Selection/Modification 
 
6.2.1.1 Dose Selection 
 
The rationale for selection of doses to be used in this trial is provided in Section 2 - 
Background. 
 
6.2.1.2 Dose Modification 
 
Dose modification of EBR/GZR is not permitted. 
 
If for any reason EBR/GZR need to be interrupted, the medication may be interrupted for up to 3 
days. If the drugs are interrupted for more than 3 days, all treatment should be discontinued. 
 
6.2.2    Timing of Dose Administration 
 
EBV/GZR 50/100 mg fixed dose 
 
Subjects will be instructed to take EBR/GZR 50/100 mg fixed dose orally, once daily without regards 
to food for 8 weeks 
 
If a subject misses a dose of EBR/GZR 50/100 mg fixed dose and if less than 8 hours remain 
before the next dose is to be taken, the missed dose should be skipped, and the normal dosing 
schedule should be resumed. Subjects should not double the next dose to compensate for the 
missed dose. 
 
6.2.3    Trial Blinding/Masking 
 
This is an open-label trial; therefore, the Sponsor, investigator and subject will know the 
treatment administered. 
 
 
       6.3 Rescue Medications & Supportive Care 
 
 
No rescue or supportive medications are specified to be used in this trial. 
 
 
 
 
 

 
36 
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7  TRIAL FLOW CHART 
 
Visit No. 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
Study Period 
 
Treatment Weeks 
Follow-Up Wks 
 
Unscheduled 
STUDY PROCEDURES 
 
Scr 
 
Day 14  
 
2 
 
4 
 
8 
 
FU4 
 
FU 
12 
 
FU 
24 
Unsched/ 
Viral Fail 
Conf Visit 
Early 
Discon 
Visit 
ADMINISTRATIVE PROCEDURES 
Informed Consent 
x 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
x 
 
 
 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
 
 
 
Prior and Con-med Review 
x 
x 
x 
x 
x 
x 
X 
X 
x 
x 
DRUG ADMINISTRATION 
EBV/GZR dispensation5 
 
x 
 
 
 
 
 
 
 
 
EBV/GZR compliance5 
 
 
x 
x 
x 
 
 
 
 
 
CLINICAL SAFETY EVALUATIONS 
Physical Examination1 
x 
x 
 
 
x 
 
 
 
 
x 
Weight 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Height 
x 
 
 
 
 
 
 
 
 
 
Fibroscan® 
x 
 
 
 
 
 
 
 
 
 
Vital Signs 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Confirmation of Birth Control 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Review (Serious) Adverse Events2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
LABORATORY SAFETY EVALUATIONS 
Coagulation 
x 
x 
 
 
x 
 
 
 
x 
x 
Fibrotest® 
x 
 
 
 
 
 
 
 
 
 
Chemistry & Hematology 
x 
x 
x 
x 
x 
x 
 
 
x 
x 
HCV, HIV, HBV testing 
x 
 
 
 
 
 
 
 
 
 
HCV Genotyping 
x 
 
 
 
 
 
 
 
 
 
  HCV RNA Level 
x 
x 
x 
x 
x 
x 
x 
x 
x 
X6 
Urine Analysis 
x 
 
 
 
 
 
 
 
 
 
Urine Pregnancy Test (females of child 
bearing potential only)3 
x 
x 
 
x 
x 
x 
x 
x 
x 
x 

 
37 
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1 
A comprehensive PE will be done at screening and baseline (Day 1). For all other visits focused PE will be conducted if necessary 
2  
Review of Adverse Events should include collecting serious adverse events and Events of Clinical Interest 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 monthly pregnancy 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  
Procedures on Day 1 should be performed prior to the first morning dose unless specified otherwise. 
5   
EBV/GZR will be provided at the baseline visit.  
6  
If HCV RNA is collected during viral failure confirmation visit and the subject is confirmed viral failure during therapy (i.e. 
breakthrough/rebound), then the sample collection for HCV RNA is not needed for the early discontinuation visit 
 

 
38 
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8.  STUDY PROCEDURES 
 
 
 
8.1 Trial Procedure  
 
 
The Trial Flow Chart - Section 7 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. 
 
8.1.1 Administrative Procedure 
 
 
8.1.1.1 Informed Consent 
 
The investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
 
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 CPP/ANSM requirements, applicable laws and 

 
39 
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regulations and Sponsor requirements. 
 
8.1.1.2  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. 
 
8.1.1.3 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. 
 
8.1.1.4 Medical History 
 
A medical history will be obtained by the investigator or qualified designee. 
Medical history, including details regarding illnesses and allergies (including sulfa-containing 
drug allergy), date(s) of onset, and whether condition(s) is currently ongoing, and 
medication history will be collected on all subjects during screening. 
 
8.1.1.5 Prior and Concomitant Medications Review 
 
8.1.1.5.1 
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. 
 
8.1.1.5.2 
Concomitant Medications 
 
The investigator or qualified designee will record medication(s), if any, taken by the subject 
during the trial. 
 
8.1.1.6 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 allocation.  Each subject will be assigned 
only one screening number. Screening numbers must not be re-used for different 
subjects. Any subject who is screened multiple times will retain the original screening 
number assigned at the initial screening visit. 
 
All eligible subjects will be allocated and will receive a study number. This number identifies 

 
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the subject for all procedures occurring after treatment allocation. One number is assigned 
to a subject; it can never be re-assigned to another subject. A single subject cannot be 
assigned more than 1 number. 
 
8.1.1.7 Trial Compliance 
 
The investigator/study coordinator will be responsible for entering the subject’s 
identification, visit number. The subject will be instructed to record dates/times and the 
number of tablets of study drug doses (EBR/GZR 50/100mg) on the diary card for the 
entire time period. 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. 
 
 
8.1.2 Clinical Procedures/Assessments 
 
8.1.2.1 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 screening, Day 1 and Week 8 (end of 
treatment), includes the following assessments: general appearance, head, eyes 
ears/nose/ throat, neck, lymph nodes, skin, lungs, heart, abdomen, musculoskeletal, and 
neurologic 
evaluations. Breast, rectal, 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 Day 1 
should be noted in the Medical History eCRF. Any significant changes after receiving study 
therapy at Day 1 must be reported as adverse events and entered on the adverse event 
eCRF.  
If the subject is discontinued for any reason (Early Discontinuation Visit) during the 
treatment phase, every attempt should be made to perform a final physical examination. 
 
8.1.2.2 Weight and Height Assessment 
 
The subject's weight should be assessed as noted in the flow chart (screening, day 1, Week 8 
and post treatment week 4, 12 and 24). The subject height should be measured at screening 
only. Clinically significant changes from Day 1 should also be captured as AEs in the CRF. 
 

 
41 
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8.1.2.3 Fibroscan ® 
The subject eslastography was realized as noted in the flow chart, at the screening Day only. It 
is a non-invasive method to determine presence or absence of cirrhosis. Fibroscan® uses 
elastography, which is a technique similar to ultrasound that measures the stiffness of your 
liver. The absence of cirrhosis is a result of FibroScan < 12.5 kPa. For this study, subject must 
have Fibroscan® lower than 9.5 kPa to be randomized.  
During the procedure the Fibroscan® uses an ultrasound probe which emits a mechanical pulse 
at the surface of the skin, measuring the condition of the liver through sound waves. The data 
is analyzed by a computer which displays a two-dimensional picture of the liver. The level of 
the fibrosis can be measured in relation to the stiffness of the liver – so the harder the liver is, 
the more serious the fibrosis is likely to be. 
 
8.1.2.4 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 results are clinically 
significant. Any subsequent changes constitute an adverse experience. 
 
8.1.2.5 Birth Control Confirmation 
 
Extreme care must be taken to avoid pregnancy in female subjects of childbearing 
potential and female partners of male subjects of childbearing potential. 
Site personnel should confirm 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. 
 
8.1.2.6 Adverse Events 
 
During the screening period only SAEs should be recorded. 
 
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 
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 Table 9. 
 

 
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8.1.3 Laboratory Safety Evaluations 
 
Details regarding specific laboratory procedures/assessments to be performed in this trial are 
provided below. The total amount of blood to be collected by visits is between 45 to 75 
mL over the course of the trial (from pre-trial to  post-trial visits).  
 
Coagulation: INR, Prothrombin time (PT) Activated partial thromboplastin time (APTT) 
 
Hematology : Hematocrit, Hemoglobin (Hb), Platelet Count, Red blood celle count (RBC), 
White blood cell count (WBC) with differential (absolute and percentage) including 
Lymphocytes, Monocytes, Neutrophils, Eosinophils, Basophils, Reticulocytes count and MCV.  
 
Chemistry : Alanine aminotransferase (ALT/SGPT), Aspartate aminotransferase (AST/SGOT), 
Albumin, Alkaline Phosphatase, Creatine Kinase, Creatinine, Total Bilirubin (reflex to Direct 
Bilirubin), Glucose, Lipase, Potassium, Sodium, Direct Bilirubin at screening only, Hemoglobin 
A1c (HbA1c), Fibrotest®, Urea, Hyaluronic Acid. 
 
Virological Tests : Serologies for HCV, HBV and HIV. HCV RNA will measured using the Cobas® 
Taqman® HCV Test, v2.0 for use with Ampliprep. HCV genotype and subtype will be 
determined using classic local process. Samples for HCV genotype evaluation must be 
obtained as part of the main consent for inclusion in the study in each local laboratory 
 
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™ Taqman™ HCV Test, v2.0 ® assay for use with the High Pure 
System with a lower limit of detection and quantification of 15 IU/mL or using ABBOTT 
Amplification Reagent Real Time HCV with limit of detection and quantification of 12 IU/mL. 
 
Urinalysis : Appearance, Blood, Color, Glucose, Leukocyte esterase, pH, Protein, Urobilinogen, 
Reflex to microscopic urinalysis if dipstick result is abnormal.  
 
Urine Pregnancy Test : Serum beta-hCG ou urine beta-hCG (if positive, requires immediate 
confirmation with Serum β-hCG). All females of childbearing potential will have a serum 
pregnancy test at Screening. Urine pregnancy testing will occur at Day 1 and every 4 weeks 
during the dosing period and for 30 days following the last dose of study drug. If required by 
local regulations, additional pregnancy tests beyond 4 weeks may be added. In the event of 
a positive urine pregnancy result, subjects will be instructed to stop study drug immediately 
(if applicable) and return to the clinic as soon as possible for a serum pregnancy test. 
 
Laboratory tests for hematology, chemistry and additional testing are specified in Table 8. 
 
 
 
 
 
 

 
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Table 8 :  Laboratory Tests during trial 
 
Hematology 
Chemistry
Other 
Hematocrit
Albumin
Hemoglobin
Alkaline phosphatase
HBsAg
Platelet count
Alanine aminotransferase (ALT) Hepatitis C Virus 
Genotype 
WBC (total and differential)
Aspartate aminotransferase 
(AST) 
Prothrombin time (PT)
Erythrocytes (RBC count)
Glucose
 APTT 
Urea
Hyaluronic Acid 
 Reticulocytes 
Creatinine
International normalized
Ratio (INR) 
 
Creatinine  clearance  
(screening only) 
Choriogonadotropin Beta
(Urine pregnancy test  
kits to sites) 
 
Creatine Kinase
HCV RNA assay
 
Potassium
Fibrosure®
(Fibrotest)
as requested by site for 
entry critiera (may be 
performed locally) 
 
Sodium
Plasma HIV RNA
 
Total Bilirubin
 HbA1c 
 
Direct Bilirubin
 
Glycemia
 
Lipase
 
 
 
 
8.1.4 Other Procedures 
 
8.1.4.1 Rescreening 
 
Subjects who have previously completed the screening visit (Visit 1) and were deemed 
eligible for randomization into this study, but failed to be randomized within the 28 -days 
window, may be rescreened to re -evaluate study eligibility. To reconfirm the subject 
eligibility, all pre-study evaluations should be repeated, after approval from the SPONSOR. 
The screening window can be extended to 42 days for subjects requiring a liver biopsy, or for 
extenuating circumstances, with sponsor approval. 
 
Note:  Subjects may be retested once within the 28-days screening window if their 
laboratory results are outside the specified criteria. If any of the laboratory exclusion 
criteria are met, the site may have the abnormal value retested one time only.  
 
 
 
 

 
44 
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8.1.4.2 Withdrawal/Discontinuation 
 
When a subject discontinues/withdraws from participation in the trial, all applicable 
activities scheduled for the early discontinuation visit should be performed at the time of 
discontinuation. 
Any 
adverse 
events 
which 
are 
present 
at 
the 
time 
of 
discontinuation/withdrawal should be 
followed in 
accordance with 
the 
safety 
requirements outlined in Section 8.2 - Assessing and Recording Adverse Events. 
 
8.1.4.3 Blinding/Unblinding  
 
This is an open label trial; there is no blinding for this trial. 
 
8.1.5 Visit Requirements 
 
Visit requirements are outlined in Section 7 - Trial Flow Chart.  Specific procedure-related 
details are provided above in Section 8.1 - Trial Procedures. 
 
8.1.5.1  Screening (Visit 1) 
 
During a 28 days period prior to administration of the initial dose of study drug, 
potential subjects will be evaluated to determine if they fulfill the Inclusion/Exclusion 
entry requirements as described in Section 5.1 and 5.2 
 
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. 
 
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. 
 
The following procedures will be performed and documented 
- 
Obtain informed consent 
- 
Determine inclusion/exclusion criteria 
- 
Obtain medical history  
- 
Obtain details of Prior and Concomitant medications 
- 
Perform complete physical examination 
- 
Obtain body height and weight 
- 
Fibroscan®  
- 
Obtain vital signs ( resting blood pressure, pulse, respiratory rate and temperature) 
- 
Confirmation of Birth Control 
- 
Obtain details of adverse events related to screening procedures 
- 
Obtain blood sample for test 
Coagulation tests 

 
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Fibrotest®  
Hematology and chemistry 
HCV antibody, HIV antibody, and HBs antigen 
Determination of genotype and subtype of HCV  
HVC RNA 
Serum beta-hCG pregnancy test for females of childbearing potential only 
- 
Obtain urine sample for urinalysis  
- 
Urine pregnancy test for females of childbearing potential only 
 
Subject meeting all the inclusion criteria and none of the exclusion criteria will return to the 
clinic fort the Baseline/Day 1 visit assessments and randomization. 
 
8.1.5.2  Study/Treatment Visits 
 
8.1.5.2.1  Baseline/ Day 1 (Visit 2)  
 
Day 1 procedures listed on the Study Flow Chart should be performed prior to dosing unless 
specified otherwise.  
 
The following baseline tests and procedures must be completed prior to the first dose of 
study drugs :  
- 
Perform complete physical examination 
- 
Obtain body weight 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood samples for : 
Hematology and chemistry 
Coagulation 
HCV RNA 
- 
Confirmation of birth control 
- 
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 randomization 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 randomized. 
- 
Confirm eligibility 
- 
Drug administration (refer section 8.1.5.4): 
- 
Dispense study drugs as directed by the Promotor Pharmacist 
Instruct the subject on the packaging, storage and administration of study drugs 
Observe the subject taking the first dose of study drugs and record the time of first dose 
 
 
 
 

 
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8.1.5.2.2 Week 2 (visit 3 + 3 days) 
 
The following procedures must be completed at the end of Week 2 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood samples for : 
Hematology and chemistry 
HCV RNA 
- 
Review study drug compliance and drug administration instruction with subject 
 
8.1.5.2.3Week 4 (visit 4 + 3 days) 
 
The following procedures must be completed at the end of Week 4 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood samples for : 
Hematology and chemistry 
HCV RNA 
- 
Obtain urine sample for : 
Beta-HCG pregnancy test for females of childbearing potential only 
- 
Review study drug compliance and drug administration instruction with subject 
- 
Drug administration (refer section 8.1.5.4): 
 
8.1.5.2.4 Week 8 (visit 5 + 3 days) 
 
The following procedures must be completed at the end of Week 8:  
- 
Perform complete physical examination 
- 
Obtain body weight 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood for : 
Hematology and chemistry 
Coagulation 
HCV RNA 
- 
Confirmation of birth control 
- 
Obtain urine sample for : 
Beta-HCG pregnancy test for females of childbearing potential only 
- 
Review study drug compliance and drug administration instruction with subject 
- 
Complete medication pill count 
 
8.1.5.2.5Early termination (ET)/Unscheduled Visit (UV) 
 
A subject should attend an unscheduled visit if requested by the sponsor or the investigator. 
The assessments are at the investigator’s discretion. At all unscheduled visits initiated for the 
purpose of confirming virologic failure.  

 
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The Sponsor and Promotor must be informed as soon as possible, when a subject comes off 
treatment due to an AE.  
 
If a subject discontinues treatment early for any reason then the following assessments for 
the Early Termination (ET) Visit must be performed: 
 
- 
Perform complete physical examination 
- 
Obtain body weight 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood samples  for : 
Hematology and chemistry 
Coagulation 
HCV RNA 
- 
Confirmation of birth control 
- 
Obtain urine sample for : 
Beta-HCG pregnancy test for females of childbearing potential only 
- 
Complete medication pill count 
 
 
8.1.5.3 Post Treatment Assessments 
 
The post treatment Week 4, 12 and 24 visits should be timed from the date of last 
administration of study drugs. All subjects must be complete the post treatment Week 4 and 
12 visits. Subject with HCV RNA < LLOQ at the post treatment week 12 will complete the post 
treatment Week 24 visit, unless viral relapse is determined.  
 
Female subjects of childbearing potential should be provided with Urine Pregnancy Test Kits, 
instructed on their use and requested to continue to self-monitor for pregnancy between 
scheduled study visits, every 4 weeks, for 6 months after their last dose of study drugs. If 
required by regulations, additional pregnancy test beyond 6 months may be added. The 
subject will be contracted every 4 weeks and asked to report results of the urine pregnancy 
tests.  
 
8.1.5.3.1 Post treatment Week 4 (+ 5 days) 
 
The following procedures are to be completed for all subjects, 4 weeks after taking the last 
dose of study drugs :  
- 
Obtain body weight 
- 
Obtain vital signs 
- 
Assessment of AEs and concomitant medications 
- 
Obtain blood samples for : 
Hematology and chemistry 

 
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HCV RNA 
- 
Confirmation of birth control 
- 
Obtain urine sample for : 
Beta-HCG pregnancy test for females of childbearing potential only 
 
8.1.5.3.2Post Treatment Week 12 and 24 (+ 5 days) 
 
The following procedures are to be completed 12 and 24 weeks after taking the last dose 
of study drugs :  
- 
Obtain body weight 
- 
Obtain vital signs 
- 
Assessment of AEs only related to study procedure 
- 
Concomitant medications  
- 
Obtain blood samples for : 
HCV RNA 
- 
Confirmation of birth control 
- 
Obtain urine sample for : 
Beta-HCG pregnancy test for females of childbearing potential only 
 
Subjects with HCV RNA < LLOQ at the post treatment Week 12 Visit will return for the Post 
treatment Week 24 Visit 
 
8.1.5.4 Drug Administration 
 
Following completion of the Day 1 procedures and confirmation of eligibility, the site 
pharmacist or study coordinator will contact the Promotor for assignment of the drug to be 
administered. 
Sites should not call the Promotor for drug administration until the subject has met all 
criteria for the study and is 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. 
Subjects who discontinue therapy in the trial prior to the last scheduled treatment visit 
should have an Early Discontinuation visit and then continue with the follow-up visits. 
 
At a minimum, collect the following information when a subject discontinues from the trial: 
 
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. 
 

 
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4.  (Serious) Adverse events. 
 
5.  Final Assessments: Every effort should be made to ensure that all procedures 
and evaluations scheduled for the Early Discontinuation Visit are performed. 
 
6.  Retrieve all study medications from the subject. 
 
8.1.6    Evaluations of Laboratory Safety Signals 
 
Laboratory safety measurements will be evaluated weekly during the first 2 weeks, followed 
by monthly for the entire treatment period, and during the follow up period to assess 
potential liver safety signals as outlined in the flow chart. 
 
If a subject has one or more of the laboratory ECI criteria (Refer section 8.1.3) at the last 
dosing visit then the subject should return to the site weekly for additional monitoring until 
the values normalize. 
 
 
8.2    Assessing and Recording Adverse Events 
 
 
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 
unfavorable 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. 

 
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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. 
 
8.2.1    Definition of an Overdose for This Protocol and Reporting of Overdose to 
the Sponsor 
 
In this trial, an overdose is any dose higher than any intake in excess of prescribed dose per 
calendar day. 
 
If an adverse event(s) is associated with (“results from”) the overdose of Sponsor's product 
the adverse event(s) is reported as a serious adverse event, even if no other seriousness 
criteria are met. 
 
If a dose of Sponsor's product 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. 
 
8.2.2    Reporting of Pregnancy and Lactation to the Sponsor 
 
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. 
 
 
 
 

 
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8.2.3   Immediate Reporting of Adverse Events to the Sponsor 
 
8.2.3.1 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 11 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 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. 
 
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. 
 
8.2.3.2 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 Binde. 
 
Events of clinical interest for this trial include: 
 
• 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. 

 
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• first instance of ALT or AST >500 IU/L 
• first instance of ALT or AST >3x baseline AND >100 IU/L 
• first instance of alkaline phosphatase >3x ULN 
 
8.2.4 Evaluating Adverse Events 
 
An investigator who is a qualified physician will evaluate all adverse events with respect to 
the elements outlined in Table 9. The investigator’s assessment of causality is required for 
each adverse event.  Refer to Table 9 for instructions in evaluating adverse events.
 
 
 

 
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Table 9:   Evaluating Adverse Events 
 
Maximum 
Intensity 
Mild 
awareness of sign or symptom, but easily tolerated  (for pediatric trials, awareness of symptom, but easily tolerated) 
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); or 
Is a cancer; or 
Is associated with an overdose (whether accidental or intentional).   Any adverse event associated with an overdose is considered a serious adverse 
event. An overdose 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 units 
Action 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  

 
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Relationship 
To Sponsor's 
Product 
(continued) 
The following components are to be used to assess the relationship between the Sponsor's product and the AE:  (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 U.S. CLINICAL 
MONITOR 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.) 

 
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8.2.5 Sponsor Responsibility for Reporting Adverse Events 
 
All Adverse Events will be reported to regulatory authorities, CPP/ANSM and investigators 
in accordance with all applicable global laws and regulations. 
 
 
9. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
 
9.1    Investigational Product 
 
 
EBR is an HCV NS5A inhibitor and GZR is an HCV NS3/4A protease inhibitor which is direct-
acting antiviral agents against the hepatitis C virus. 
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 10 
 
Table 10 : Summary product information 
Route of Administration  
Dosage Form / Strength  
Clinically Relevant 
Nonmedicinal Ingredients 
oral  
Tablet  
50 mg elbasvir and 100 mg 
grazoprevir  
Lactose monohydrate  
For a complete listing see 
Dosage Forms, 
Composition and Packaging 
section. 
 
 
 
9.2 Dosage and Administration  
 
 
EBR/GZR is a two-drug, fixed-dose combination product containing 50 mg of elbasvir and 100 
mg of grazoprevir in a single tablet. The recommended dosage of EBR/GZR is one tablet taken 
orally once daily with or without food [see Clinical Pharmacology (section 2.2.2)]. EBR/GZR is 
used in combination with ribavirin in certain patient populations (see Table 1). When 
administered with EBR/GZR, the recommended dosage of ribavirin in patients without renal 
impairment is weight-based administered in two divided doses with food. For further 
information on ribavirin dosing and dosage modifications, refer to the ribavirin prescribing 
information. 

 
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Treatment Regimen and Duration of Therapy Relapse rates are affected by baseline host and 
viral factors and differ between treatment regimens and durations for certain subgroups [see 
Clinical Studies (section 2.3)]. Table below provides the recommended EBR/GZR treatment 
regimen and duration based on the patient population and genotype in HCV mono-infected 
and HCV/HIV-1 co-infected patients with or without cirrhosis and with or without renal 
impairment including patients receiving hemodialysis. 
 
 
Table 11 : Recommended Dosage Regimens and Durations for EBV/GZR for treatment of HCV 
genotype 1 or 4 in Patients with or without Cirrhosis 
 
PATIENT POPULATION 
TREATMENT 
DURATION 
Genotype 1a : treatment-naïve or PegIFN/RBV-
experienced without baseline NS5A 
polymorphisms
EBR/GZR 
12 weeks 
Genotype 1a : treatment-naïve or PegIFN/RBV-
experienced with baseline NS5A polymorphisms 
EBR/GZR + RBV 
16 weeks 
Genotype 1b : treatment-naïve or PegIFN/RBV-
experienced 
EBR/GZR 
12 weeks 
Genotype 1a or 1b : PegIFN/RBV/Protease 
inhibitor experienced 
EBR/GZR + RBV 
12 weeks 
Génotype 4 : Treatment naïve 
EBR/GZR 
12 weeks 
Génotype 4 : PegIFN/RBV-experienced 
EBR/GZR + RBV 
16 weeks 
 
 
 
9.3    Packaging and Labeling Information 
 
ZEPATIER® (elbasvir and grazoprevir) is a fixed-dose combination tablet for oral 
administration containing 50 mg of elbasvir and 100 mg of grazoprevir. The beige and oval 
shaped film-coated tablets bear the inscription "770" on one side and are smooth on the 
other. ZEPATIER® is available in two blister packs of 28 tablets. 
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory 
requirements.  
 
Subjects will receive Open Label EBR(50mg)/GZR(100mg) at the baseline visit. 
 
 
 
9.4    Clinical Supplies Disclosure 
 
 
This trial is open-label; therefore, the subject, the trial site personnel, the Sponsor and/or 
designee are not blinded. Drug (name, strength) is included in the label text; random 
code/disclosure envelopes or lists are not provided. 
 

 
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9.5    Storage and Handling Requirements 
 
 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. EBR/GZR bottle should be stored at controlled room 
temperature until required for administration. Controlled room temperature is defined as 25 
°C, excursions are permitted between 15°C and 30°C. 
 
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. 
 
 
9.6    Returns and Reconciliation 
 
 
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. 
 
 
9.7 Study drug adherence and drug Accountability 
 
 
Subjects must be instructed to bring back all bottles of study medications in the original 
container at every study visit after Day 1 through the end of treatment. 
Study medications will be reconciled using medication pill count at every study visit after Day 
1 by the investigator or designee in order to monitor the subject’s adherence with the 
medication regimen. 
 
 
9.8 Drug Interactions 
 
 
Co-administration of EBR/GZR and OATP1B inhibitors may significantly increase grazoprevir 
plasma concentrations and is contraindicated.  
The concomitant use of EBR/GZR and strong CYP3A inducers or efavirenz may significantly 
decrease elbasvir and grazoprevir plasma concentrations and may lead to a reduced 

 
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therapeutic effect of study drug. Therefore, the use of EBR/GZR with strong CYP3A inducers or 
efavirenz is contraindicated.  
The concomitant use of EBR/GZR and moderate CYP3A inducers may decrease elbasvir and 
grazoprevir plasma concentrations and may lead to a reduced therapeutic effect of study drug. 
Therefore, the use of EBV/GZR with moderate CYP3A inducers is not recommended.  
The concomitant use of EBR/GZR and strong CYP3A inhibitors increases elbasvir and 
grazoprevir concentrations. Co-administration of EBR/GZR with certain strong CYP3A inhibitors 
is not recommended.  
The plasma concentration of grazoprevir is increased if EBR/GZR is co-administered with 
cyclosporine. Co-administration with cyclosporine is contraindicated.  
 
Co-administration of EBR/GZR with P-gp inhibitors is expected to have a minimal effect on the 
plasma concentrations of EBR/GZR.  
Grazoprevir is a substrate of OATP1B drug transporters. Co-administration of EBR/GZR with 
drugs that inhibit OATP1B transporters may result in a significant increase in the plasma 
EBR/GZR concentration of grazoprevir. As such, co-administration of EBR/GZR with OATP1B 
inhibitors is contraindicated.  
Investigational agents are not permitted. 
The following medications/therapies are contraindicated in this study 
Strong CYP3A/P-gp  inhibitors,  including  but  not  limited  to 
•  Antibiotics: clarithromycin, erythromycin, telithromycin 
•  Antifungals: itraconazole, ketoconazole, voriconazole 
•  Antihypertensives:  nifedipine 
•  nefazodone 
 
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: glibeclamide, glyburide 
•  Lipid lowering agents: gemfibrozil 
•  eltrombopag 
•  lapatinib 
•  grapefruit/grapefruit juice 
All  HMG-CoA  reductase  inhibitors (statins)  
 

 
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In general, CYP3A4 substrates with narrow therapeutic ranges (e.g. warfarin, amiodarone, 
flecainide, propafenone, quinidine, fentanyl, sildenafil or tadalafil when used for the 
treatment of pulmonary arterial hypertension) are not prohibited but their levels can 
potentially be increased by approximately 30% when co-administered with study drugs. 
 
Diet Consideration 
 
EBV/GZR can be taken without regard to food. Intake of grapefruit or grapefruit juice is 
contraindicated during the treatment period of the trial. 
 
 
 
10.STATISTICAL ANALYSIS PLAN 
 
 
10.1 
Sample size estimation 
 
To evaluate the efficacy of of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in 
Treatment-Naïve for HCV GT1b-Infected Patients, with non-severe fibrosis, the sample size 
estimation was performed according to the precision of 95% confidence interval of the primary 
outcome measured by the proportion of subjects with sustained viral response 12 weeks after 
cessation of treatment. Considering an efficacy at 96%, n=120 patients will be able to obtain an 
exact 95% confidence interval with a lower bound greater than 91.5%, which could be 
considered as the minimal efficacy obtained in several works presented recently in literature. 
 
An exploratory interim analysis will be conducted. More precisely, we want to evaluate 
whether after the inclusion of the first 50 patients, the expected SVR12 rate of 96% always 
seems a robust and possible assumption. In order to better estimate the rate of responders 
treated and to ensure that with 120 patients the lower limit of the 95% confidence interval is 
well above 91.5%, it seems reasonable and relevant to consider early intermediate analysis, 
without inflation of type I error. 
 
 
10.2 
Statistical Analysis Plan Summary 
 
 
The analysis set for antiviral activity analyses will be the Full Analysis Set which includes 
subjects who were enrolled and received at least one dose of study drug and have naïve 
chronic genotype 1b HCV infection with non severe fibrosis. 
Statistical analysis will be performed using Stata software (version 13; Stata-Corp, College 
Station, Tex., USA). All statistical tests will be two-sided and p<0.05 will be considered 
significant.  

 
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Qualitative variables will be described in terms of numbers and proportions.  
Quantitative variables will be described in terms of numbers, mean ± standard deviation or 
median [inter-quartile range] according to statistical distribution (normality studied using 
Shapiro-Wilk test).  
Graphic representations will be complete presentations of results. 
Sensitivity analyses will be considered to measure the possible impact of missing data on 
results and the more appropriate imputation method. For the analysis of post-baseline 
categorical efficacy endpoints, if a data point is missing and is immediately preceded and 
followed in time by values that are deemed successes, then the missing data point will be 
termed a success; otherwise the data point will be termed a failure. For example if a data point 
is missing and is preceded and followed in time by values that are <LLOQ target not detected 
(TND), then the missing data point will be set to < LLOQ TND.  
Demographic and baseline measurements will be summarized using standard descriptive 
methods by treatment group and overall. 
Exploratory analyses may be performed to assess the relationship between demographic, 
baseline characteristics, (including baseline viral load, age, sex, baseline ALT level, bodyweight, 
fibrosis score and additional endpoints as necessary) and antiviral activity (HCV RNA reduction, 
proportion of subjects with HCV RNA below the limit of quantification and target not detected 
at various time points during and following discontinuation of study drugs). Predictive factors 
of antiviral activities may be examined using regression type of analysis. 
 
An interim SVR 12 Clinical Study Report (CSR) will be done because SVR12 is suitable as a 
primary end point for regulatory approval. SVR12 and SVR24 measurements were concordant 
in a large population of subjects with HCV infection who participated in clinical trials with 
various treatment regimens and durations (28). Since the protocol continues to Post Treatment 
Week 24 visit, then we provide a SVR 24 CSR wich will be the final CSR. 
 
 
10.3 
Analyses for the primary outcome 
 
 
To evaluate the efficacy of Elbasvir/Grazoprevir Fixed-Dose Combination for 8 Weeks in 
Treatment-Naïve for HCV GT1b-Infected Patients, with non-severe fibrosis as measured by the 
proportion of subjects with sustained viral response 12 weeks after cessation of treatment 
(SVR 12), the proportion of patients presenting a sustained viral response 12 weeks after 
cessation of treatment (HCV RNA < LLOQ 12 weeks after cessation of treatment) will be 
presented with the associated 95% confidence interval estimated using binomial exact 
distribution (exact confidence interval). The lower-bound of the confidence intervals will be 
studied and analyzed regardless assumptions proposed for sample size estimation. 
A detailed description of patients not assume SVR12 will be proposed according to clinical 
relevance using age, gender, BMI, fibrosis score, viral charge and additional endpoints as 
necessary  
 
10.4 
Analyses for the secondary objectives 

 
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Most of secondary analyses will be exploratory and will be performed as described previously 
(i) to evaluate the safety and tolerability of EBR/GZR treatment, (ii) to determine the 
proportion of subjects who attain SVR at 4 and 24 weeks after cessation of treatment (SVR4 
and SVR24), (iii) to evaluate the proportion of subjects with virological failure and (iv) to 
evaluate the emergence of viral resistance to EBR/GZR during treatment and after cessation of 
treatment. Finally, to evaluate the kinetics of circulating HCV RNA during treatment and after 
cessation of treatment, a descriptive statistical analysis will be proposed. This analysis will be 
completed using random-effects models useful to evaluate kinetics taking into account 
between and within patient variability. 
To better understand the potential for Resistance Associated Variants (RAVs) with EBR and/or 
GZR, samples will be retained from Day 1 and viral failure visits and RAVs will be assessed for 
any subject who has detectable virus above 1000 UI/mL and has met a virologic failure criteria. 
Subjects who discontinue the treatment will continue to participate in the scheduled follow-up 
activities including monitoring for resistance. 
Exploratory IL28B genotyping may also be conducted to detect genetic variations associated 
with response to treatment of hepatitis C. A separate siganture will be required to document a 
subject’s agreement to provide additional samples for optional genetic research. 
 
 
11. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
 
 
11.1  Access to source data 
 
 
The sponsor shall be permitted to inspect the investigator center prior to commencement and 
during the course of the study to satisfy itself that the center is suitable and has the necessary 
facilities, staff and capacity to conduct the study. The investigator will ensure that his center 
has the necessary facilities, time and staff for conducting the study, and that these will be 
maintained for the duration of the study. The investigator will co-operate with the sponsor and 
any affiliated person to monitor or supervise the conduct of the study. 
The study may be subjected to auditing by representatives of the sponsor and/or to 
inspection(s) by authorized representatives of local and/or foreign health authorities. In case of 
an audit or inspection, the investigator will be informed in advance. 
The CRFs are to be made available for review by the clinical monitor or auditor or national 
regulatory inspectors. The investigators are required to give access to all source documents 
and study data in accordance with laws and regulations (articles L.1121-3 and R.5121-13 of the 
code of public health). The sponsor will not require the investigator or any member of their 
staff to take any action or be a party to any action which is contrary to the laws of the country 
in which the study is being carried out or to medical ethics. 
 

 
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11.2 
Source documents 
 
 
The investigator agrees to allow direct access to source data of the study during monitoring 
visits, audits or inspections by authorized representatives of local and/or foreign health 
authorities. Source documents (medical records, the original results of laboratory test …) are 
defined as any document proving the existence or the accuracy of a data or a registered event 
during the clinical study. It will be archived for 15 years by the investigator. 
 
 
11.3 
Confidentiality 
 
 
In accordance with GCP and with the national data protection laws, all information concerning 
the subjects in the study must be treated as strictly confidential by all persons involved in the 
study including the clinical, medical and statistical monitor. 
The investigator acknowledge that any information acquired from the sponsor or developed or 
acquired in connection with the study are strictly confidential and that they will not be 
disclosed to any third party nor use them for any purpose without first obtaining the written 
consent of the sponsor.  
People involved in the study and investigators themselves are subject to professional secrecy 
(under the conditions defined by Articles 226-13 and 226-14 of the Penal Code). 
Such consent shall be deemed to have been given for disclosure to any person for whom the 
investigator is responsible at his centre, but only so far as required for the purposes of the 
study, and, in the case of disclosures to staff, only if such staff are bound by obligations of 
confidentiality no less strict than those set out herein. 
 
 
11.4  Archiving 
 
 
The investigator must retain the subject identification codes for at least 15 years after 
completion or discontinuation of the study. Subject files and other source data must be kept 
for the maximum period of time permitted by the hospital, institution or private practice, but 
not less than 10 years, to meet international registration requirements. The investigator must 
produce them or supply copies thereof to the sponsor or to the regulatory authorities upon 
demand, whilst ensuring subject confidentiality at all times. 
 
 
12. QUALITY CONTROL AND QUALITY ASSURANCE 
 
 

 
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The CRFs, containing all the clinical information, will be carefully checked both by the 
Investigators and the Monitors against the source documents according to the Good Clinical 
Practices Guideline (CPMP/ICH/135/95). 
 
 
12.1 Commitment of the investigators and the sponsor 
 
 
The investigators agrees that the study is conducted in accordance with the Public Health law 
N° 2004-806 - 9 August 2004 on biomedical research, the implementing decree N° 2006-477 
from 26/04/2006 amending chapter I of title II of book I of the first part of the code of Public 
Health relating to biomedical research and the applicable orders. 
The Good Clinical Practice (GCP) for biomedical research involving human drugs, referred to 
the Article L.1121-3 of the Code of public Health and the order of November 24, 2006 will also 
apply.  
The study will be conducted in accordance with the ethical principles that have their origins in 
the Declaration of Helsinki (Tokyo 2004, reviewed). 
 
 
 
12.2  
Quality assurance 
 
 
The Clinical research assistant commissioned by the sponsor is responsible for inspection of the 
case report form at regular intervals, according to the monitoring plan of the study, throughout 
the study to ensure adherence to the protocol, compliance with the source documents, data 
consistency, and adherence to regulations on the conduct of clinical research.  
The Clinical research assistant commissioned must have access to subject’s medical file and 
other records related to the study required to verify the case report forms of the study. 
Controls of consistency will be made by computer according to predefined rules. Requests for 
information or queries will be generated when possible errors have been detected. 
 
 
12.3  
Quality control 
 
 
The investigator is responsible for the authenticity of collected data as part of the study and 
accepts the legal provisions allowing the sponsor of the study to develop a quality control. 

 
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The investigator and coordinator agree to make themselves available for the monitoring visits. 
During this visits, the following documents will be reviewed:  
- 
Informed consent 
- 
Compliance with the protocol and procedures defined therein 
- 
Quality of collected data in the case report forms : accuracy, missing data, data consistency 
with the source documents 
- 
Product management 
 
 
12.4  Case Report Form 
 
  
In order to meet regulatory requirements (Guidance for Computerized systems Used in Clinical 
Trials, International Conference on Harmonisation, Good clinical Practice 2001/20/CE), e-Case 
Report Formdesign, data monitoring and database extractions will be performed with 
Clinsight® software package. 
CLINSIGHT meet the FDA recommendations regarding the Computerized systems for clinical 
trial management ("Guidance for computerized systems used in clinical trials") and electronic 
signature ( "21 CFR Part 11" ) and international standards for the health. 
 
 
 
13. ETHICS 
 
 
13.1  Independent ethics committee 
 
 
The protocol and the Subject informed form and consent and case report form will be 
submitted to The Independent Ethics Committee (CPP Sud-Est) and written approval from the 
Chair of the Ethics Committee is required before the initiation of the study. 
The notification of the approval will be forwarded to the French authority ANSM and 
Promotor. A request for authorization will be sent by the Promotor to ANSM before the start 
of the study. 
 
 
13.2  Subject information and consent 
 
 
Subjects will be informed fully and fairly, in understandable terms, about the objectives, the 
constraints of the study, the potentials risks involved, and monitoring measures, security, their 
rights to refuse to participate in the study and the possibility to withdraw at any time. 

 
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The investigator must also inform the subjects of the approval of the ethic committee.  
All these informations must be listed on the informed consent given to the subjects. 
The informed and written consent of the subjects will be collected by the investigator. These 
documents are approved by the competent ethic committee and no other version shall be 
used.  
Three original consents will be co-signed by the investigator and the subject. One will be given 
to the subject, the second retained by the investigator and the third retained by the sponsor in 
a sealed envelope maintaining the confidentiality. This envelope will be archived during the 
legal period of 15 years. 
 
 
13.3  Amendments to the protocol 
 
 
There will be no alterations or changes to the protocol without agreement of all investigators 
and sponsor. If such an agreement, the planned changes will constitute an amendment that 
will be attached to the protocol. Any amendment must be notified to the ethic committee if 
the planned changes affect the ethical or medical-scientific study (evaluation criteria, addition 
of a new center ….). Minor modifications do not require a review of the ethic committee. 
 
13.4  Reimbursement of travel costs 
 
 
Reimbursement of travel costs will be provided for each protocol visit on presentation of 
supporting documents 
 
 
 14. DATA HANDLING AND RECORD KEEPING 
 
 
14.1  Electronic Case Report Forms (e-CRFs): entry and data processing 
 
 
For each subject consented, an eCRF will be completed by an authorized study staff member 
whose training for this function is documented according to study procedures. eCRFs should be 
completed on the day of the subject visit to enable the sponsor to perform central monitoring 
of safety data. 
The Eligibility Criteria eCRF should be completed only after all data related to eligibility have 
been received. Subsequent to data entry, a study monitor will perform source data 
verification within the EDC system. Original entries as well as any changes to data fields will 

 
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be stored in the audit trail of the system. Prior to database lock (or any interim time points 
as described in the clinical data management plan), the investigator will use his/her log in 
credentials to confirm that the forms have been reviewed, and that the entries accurately 
reflect the information in the source documents. The eCRF capture the data required per 
the protocol schedule of events and procedures. System-generated or manual queries will 
be issued to the investigative site staff as data discrepancies are identified by the monitor, 
who routinely review the data for completeness, correctness, and consistency. The site 
coordinator is responsible for responding to the queries in a timely manner, within the 
system, either by confirming the data as correct or updating the original entry, and 
providing the reason for the update (e.g. data entry error). At the conclusion of the trial, 
Promotor will provide the site with a read-only archive copy of the data entered by that site. 
This archive must be stored in accordance with the records retention requirements. 
 
 
14.2  CNIL 
 
 
The data will be processed in accordance with the provisions of the Act of 6 august 2004 about 
protection of individual data with regard to the processing of personal data and amending Act 
of 6 January 1978 relating to computers, files and liberties. 
This change was approved by decision of 5 January 2006. The CHU Clermont-Ferrand, study 
sponsor, signed a commitment to comply with the "Reference Methodology", dated 
15/03/2007. 
 
14.3 
Archiving 
 
 
The following documents will be archived by the name of the study in the CIC of Clermont-
Ferrand to the end of the period of practical use (15 years). 
These documents are:  
- 
Protocol and annexes, any amendments, 
- 
Information and consent forms signed (originals) 
- 
Individual data (authenticated copies of raw data) 
- 
Follow-up documents 
- 
Statistical analysis 
- 
Final report of the study 
 
At the end of the period of practical use, all documents to be archived, as defined in the 
procedure PG.06.005 “Managing the documentation of protocols” of the University Hospital of 
Clermont-Ferrand will be transferred to central archives and will be under the responsibility of 
the Hospital for 15 years after the end of the study according to institutional practices. 

 
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No destruction can be performed without the consent of the sponsor; at the end of the 15 
years, the sponsor will be consulted for destruction. All data, all documents and reports may 
be subject to audit or inspection. 
 
 
15. FINANCING AND INSURANCE 
 
 
15.1  Budget  
 
 
Cf ANNEXE n°2 
 
 
15.2  Insurance  
 
 
The study will be covered under a liability insurance policy n°147161 in accordance with the 
Article L209-7 of the French Code of public health subscribed by the sponsor to Societé 
Hopitalière d’Assurances Mutelles (SHAM) in the case of an adverse event in relation to the 
study. 
The sponsor will support the additional costs of any supplies or tests specifically required by 
the protocol. 
 
 
16. PUBLICATION POLICY 
 
 
Investigator will have full and unrestricted access to the database with all anonymized data. 
It is intended to publish the results of the clinical trial collectively (no individual report or 
publication will be allowed). 
Neither the Investigator nor his agents, consultants, associates or employees shall, directly or 
indirectly, originate, issue or disclose news releases or any type of announcements, whether 
written or oral, or organize any presentation or issue any publications regarding the study, 
and/or any information, data, results, inventions or discoveries made or obtained during the 
study, without the prior written consent of sponsor, which consent shall not be unreasonably 
withheld. 
In order to protect possible intellectual property rights and commercial confidentiality in the 
interest of the sponsor, a waiting period of up to few months after the end of the trial and until 
publication may be agreed between the investigators and the sponsor. 

 
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Sponsor’s representative(s) have the option to be a named co-author(s) of any such 
publications, presentations or news releases. Sponsor retains the exclusive rights over the data 
resulting from the study for any purpose, including data from other participating institutions. 
 
 

 
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with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 24 avr 
2014;370(17):1594‑603.  
15.  Zeuzem S, Jacobson IM, Baykal T, Marinho RT, Poordad F, Bourlière M, et al. Retreatment 
of HCV with ABT-450/r-ombitasvir and dasabuvir with ribavirin. N Engl J Med. 24 avr 
2014;370(17):1604‑14.  
16.  Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-
ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. N Engl J Med. 22 mai 
2014;370(21):1973‑82.  
17.  Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatol Baltim 
Md. juin 2014;59(6):2403‑12.  
18.  Buti M, Esteban R. Hepatitis C virus genotype 3: a genotype that is not « easy-to-treat ». 
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testing, managing, and treating adults infected with hepatitis C virus. Hepatol Baltim Md. 
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Hepatitis C 2015. J Hepatol. juill 2015;63(1):199‑236.  
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interferon-free therapy for hepatitis C virus genotype 1. N Engl J Med. 16 janv 
2014;370(3):222‑32.  
22.  Everson GT, Towner WJ, Davis MN, Wyles DL, Nahass RG, Thuluvath PJ, et al. Sofosbuvir 
With Velpatasvir in Treatment-Naive Noncirrhotic Patients With Genotype 1 to 6 Hepatitis 
C Virus Infection: A Randomized Trial. Ann Intern Med. 1 déc 2015;163(11):818‑26.  
23.  Sulkowski M, Hezode C, Gerstoft J, Vierling JM, Mallolas J, Pol S, et al. Efficacy and safety 
of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-
8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-
infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label 
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24.  Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, et al. Grazoprevir-Elbasvir 
Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With 
Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern 
Med. 7 juill 2015;163(1):1‑13.  
25.  Serfaty L, Zeuzem S, Vierling JM, Howe AY, Hwang P, Robertson M, et al. High Efficacy of 
the Combination HCV Regimen Grazoprevir and Elbasvir for 8 or 12 Weeks With or 
Without Ribavirin in Treatment-Naive, Noncirrhotic HCV GT1b–Infected Patients: An 
Integrated Analysis. Hepatology. 1 oct 2015;62(suppl 1):118A.  
26.  Alberti A. Impact of a sustained virological response on the long-term outcome of 
hepatitis C. Liver Int Off J Int Assoc Study Liver. janv 2011;31 Suppl 1:18‑22.  
27.  High Rate of Sustained Virologic Response With the All-Oral Combination of Daclatasvir 
(NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or Without Ribavirin, in 
Treatment-Naive Patients Chronically Infected With HCV GT 1, 2, or 3 [Internet]. [cité 14 
mars 2016]. Disponible sur: http://www.natap.org/2012/AASLD/AASLD_06.htm 
28. Jianmeng C, Jeffry F, Wendy C, Russel D F, Thomas S H, Pravin R J, Wen Z, Jeffrey M, and 
Debra B. Earlier Sustained Virologic Response End Points for Regulatory Approval and 
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ANNEXE n°1 : Etude C-WORTHY, partie C. 
 
 
 
 
 
 
 

 
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ANNEXE n°2 
 
 

 
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ANNEXE n°3 
 
 
SIGNATURES 
 
 
 
Sponsor's Representative 
  
 
 
 NAME 
SIGNATURE 
DATE 
 
 
 
 
 
 
 
 
 
Investigator 
 
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. 
  
 
 
NAME                         
         SIGNATURE                                   DATE