Clinical trial NCT03420300
Conditions: Hepatitis C
Keywords: Hepatitis C virus Hemodialysis Direct acting antiviral agent
Sponsor: National Taiwan University Hospital
Start date: 2018-06-05; Completion date: 2020-02-03
Enrollment: 40 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hepatitis C virus (HCV) infection is common in patients receiving hemodialysis. The uptake of antiviral therapy for these patients is limited in the era of interferon (IFN) plus ribavirin (RBV), probably because the sustained virologic response (SVR) rates are low and the risk of treatment-related adverse events (AEs) are high. In the era of IFN-free direct acting antiviral agents (DAAs), several studies have indicated high rates of SVR and excellent safety profiles to treat patients with severe renal impairment. With regard to elbasvir/grazoprevir (EBR/GZR) treatment, a phase 3 study (C-SURFER) study has shown 99% of SVR in HCV-1 patients with chronic kidney disease (CKD) stage 4 or 5. Furthermore, most patients tolerated the treatment well. Although the data confirmed the excellent safety and efficacy in HCV-1 patients with severe renal impairment, data regarding the safety and efficacy for Asian HCV-1b patients receiving hemodialysis is lacking. Therefore, we aim to evaluated the safety and efficacy of EBR/GZR for 12 weeks in treatment-naive and treatment-experienced HCV-1b patients receiving hemodialysis.

Detailed description:
Hepatitis C virus (HCV) infection remains a major co-morbidity in hemodialysis patients. The incidence and prevalence rates of HCV infection in hemodialysis patients are much higher than those in the general population, and are attributed to high rates of nosocomial HCV transmission. With regard to HCV genotype distribution, HCV genotype 1 (GT-1) infection is the most prevalent type of infection worldwide and the genotype distribution in HCV-infected individuals receiving hemodialysis (HD) is similar to that observed in HCV-infected individuals with normal renal function. Compared to non-HCV infected hemodialysis patients, HCV-infected patients have increased risks of liver-related morbidity and mortality. Although HCV-infected hemodialysis patients who receive renal transplantation have survival advantages over those who remain on maintenance dialysis, these patients still have poor patient and graft survival, as well as have poor responses to interferon (IFN)-based therapy.In contrast, hemodialysis patients who eradicate HCV infection have improved biochemical, virologic and histologic responses, whether on maintenance dialysis or after renal transplantation.

Approximately one third of hemodialysis patients with chronic HCV infection achieve sustained virological response (SVR) by conventional IFN or peginterferon monotherapy.In addition 18-30% of patients receiving IFN-based monotherapy prematurely discontinued treatment due to adverse events (AEs). Although the addition of ribavirin to IFN further improves the SVR rate in HCV-infected patients with normal renal function, ribavirin has been considered contraindicated to treat HCV-infected hemodialysis patients because of concern for life-threatening hemolytic anemia. Recently, pilot studies have indicated the feasibility of adding low-dose ribavirin (200 mg three times per week to daily 400 mg, adjusted to achieve a target concentration of 10-15 μmol/L), to IFN for treatment of HCV-infected hemodialysis patients. Generally, the SVR rate and the premature discontinuation rate due to null-response, severe anemia, and/or heart failure for combination therapy are 56% and 22%, respectively. Based on these small-scale studies, low-dose ribavirin (daily 200 mg) was approved in August 2011 by the U.S. Food and Drug Administration to treat HCV-infected hemodialysis patients.30 Two recent well-conducted randomized control studies to compare the efficacy and safety of combination therapy with peginterferon alfa-2a (135 μg/week) plus low-dose ribavirin (RBV) (200 mg/day) or monotherapy with peginterferon (135 μg/week) for 48 and 24 weeks in treatment-naïve HCV GT-1 and GT-2 infected individuals receiving hemodialysis showed that the SVR rates of combination therapy groups were greater than those of monotherapy groups (64% versus 34%, p \< 0.001 for HCV GT-1; 74% versus 44%, p \< 0.001 for HCV GT-2), respectively. Although the SVR rate of combination therapy with peginterferon plus low-dose ribavirin is higher than that of peginterferon monotherapy. About 70-75% of these patients experienced clinically significant anemia which needed high dose of erythropoiesis stimulating agents (ESAs) to keep the hemoglobin level within the safety range. Although telaprevir (TVR)-based triple therapy has been used to treat 4 HCV-1 patients receiving hemodialysis who were not responsive to prior peginterferon plus RBV with good efficacy, the added on-treatment adverse events (AEs) and the pill burden precluded the widespread use of this agent.

The recent introduction of IFN-free direct acting antiviral agents (DAAs) has made a paradigm shift with regard to the medical treatment for HCV-infected individuals, based on the excellent efficacy and safety in ordinary patients. Among the various IFN-free DAA regimens, treatment with elbasvir/grazoprevir (EBR/GZR) has been approved in 2016 to treat patients with chronic HCV GT-1 and GT-4 infection. Treatment with EBR/GZR with/without weight-based ribavirin for 12-16 weeks achieved an SVR12 rate of 94-100% in treatment-naïve and PR or protease-inhibitor based treatment-experienced HCV GT-1a, GT-1b or GT-4 patients, respectively (C-EDGE TN, TE, SALVAGE). Furthermore, the SVR12 rates in HIV-coinfected patients with HCV GT-1a, GT-1b and GT-4 were 95.3% and 98.0% by using EBR/GZR for 12 weeks (C-EDGE Coinfection). In addition to high SVR rates by 12-16 weeks of EBR/GZR treatment, the overall safety profiles are excellent, with only 1% of the patients who discontinue treatment due to drug-related adverse event. With regard to constitutional symptoms, treatment with EBR/GZR had comparable rates to the placebo arms. With regard to laboratory abnormalities, about 1% and less than 1% of the treatment patients experience AST/ALT elevation and hyperbilirubinemia. Clinically significant anemia is more commonly encountered in patients receiving EBR/GZR with weight-based ribavirin. Taking together, treatment with EBR/GZR is efficacious and safe for HCV-infected subjects with HCV GT-1 or 4 infection. The post-hoc analyses for potential factors affecting the SVR rates showed that among GT-1a infected patients with baseline NS5A resistant associated variants (RAVs) at position of 28, 30, 31 and 93, the SVR rates will be compromised for those receiving 12 weeks of treatment or without adding RBV. In addition, treatment-experienced HCV GT-4 patients should also receive 16 weeks of EBR/GZR plus RBV to secure the SVR rates. In GT-1a or GT-1b patients who fail prior protease inhibitor-based triple therapy, 12 weeks of GZR/EBR plus RBV are recommended to secure the high SVR rates. For GT-1a treatment-naïve or PR-experienced patients without the presence of baseline NS5A RAVs, GT-1b treatment-naïve or PR-experienced patients or GT-4 treatment-naïve patients, EBR/GZR for 12 weeks offer satisfactory safety and efficacy profiles. Gender, ethnicity, age, interleukin-28B (IL28B) genotype, cirrhosis status and baseline HCV RNA levels do not affect the overall SVR rates in EBR/GZR treatment patients.

The pharmacokinetic (PK) study of elbasvir and grazoprevir was evaluated 16 subjects with severe renal impairment and end-stage renal disease (ESRD) on maintenance hemodialysis and matched healthy controls. Compared to subjects with matched healthy controls, the area under the curves (AUCs) of elbasvir in subjects with severe renal impairment and ESRD were 99% and 86%; the AUCs of grazoprevir in subjects with severe renal impairment and ESRD were 85% and 83%, respectively. The pharmacokinetic study indicated that dose dosage adjustments of EBR/GZR are not needed for patients with severe renal impairment or those who are on maintenance hemodialysis.

The phase 3 C-SUFER study evaluated the safety and efficacy of EBR/GZR BV for 12 weeks in a total of 235 treatment-naïve and treatment-experienced HCV GT-1 patients with severe renal impairment or ESRD.42 About 82% of the patients had chronic kidney disease (CKD) stage 5, and the remaining 18% of the patients had CKD stage 4. The full set and the modified full set analyses for SVR12 in patients receiving 12 weeks of treatment were 94% and 99% respectively. On-treatment undetectable HCV RNA levels at weeks 4 and 12 were 90% and 100%, respectively. In patients with ESRD, the overall SVR12 was 98.9%. No patients discontinued the study drugs due to adverse events. Furthermore, the constitutional and the laboratory abnormalities were mild in grades and were lower in frequency, compared to the control arm. This large-scale study shows that treatment with EBR/GZR is efficacious and safe for HCV-1 patients with severe renal impairment and those with end-stage renal disease.

Although peginterferon monotherapy and combination therapy with peginterferon plus low-dose RBV for 24-48 weeks have been evaluated in many studies, the efficacy for the treatment regimens were only modest (SVR rate about 60%). In addition, the on-treatment AEs and SAEs by IFN-based therapies were frequently encountered in HCV-infected patients receiving hemodialysis. Of note was the pronounced on-treatment hemoglobin level decrease in patients receiving combination therapy by peginterferon plus low-dose RBV, necessitating significant RBV dose reduction and high-dose erythrocyte stimulating agent (ESA) support.

By receiving IFN-free DAA therapies, HCV-infected patients have excellent SVR rates, low on-treatment SAE and AE rates, shorter treatment duration, and low pill burdens. The PK study of EBR/GZR proves the excellent safety profiles and dose adjustment are not needed for EBR/GZR regimen in subjects with various degrees of renal impairment. The C-SURFER study showed the excellent on-treatment and off-therapy antiviral effects in HCV GT-1a and GT-1b infected patients receiving EBR/GZR, respectively. However, the C-SURFER study enrolled only limited patients of Asian ancestry, making the safety and efficacy in this group of patients still to be confirmed. Based on the excellent safety and efficacy profiles of EBR/GZR treatment for HCV GT-1b infected patients with normal renal function, we aim to evaluate the safety and efficacy of EBR/GZR for 12 weeks in treatment-naïve and treatment-experienced HCV GT-1b patients receiving hemodialysis in Asian population, taking HCV GT-1b patients treated by peginterferon plus ribavirin for 48 weeks as the historical control.

Arms: arm 1: Elbasvir/grazoprevir (EBR/GZR 50mg/100mg fixed dose combination \[FDC\]): 1 table per os per day for 12 weeks
Interventions: intervention 1: EBR/GZR
Intervention descriptions: intervention 1: Elbasvir/grazoprevir (EBR/GZR 50mg/100mg fixed dose combination \[FDC\]): 1 table per os per day for 12 weeks

Protocol documents:
Prot_SAP_000.pdf: 
1 
 
Elbasvir/Grazoprevir for Treatment-Naive 
and Treatment-Experienced Patients with 
Hepatitis C Virus Genotype 1b Receiving 
Hemodialysis 
 
 
 
(NCT03420300) 
 
 
 
Protocol Date: 8 August, 2017 


2 
 
Elbasvir/Grazoprevir for Treatment-Naive and Treatment-Experienced 
Patients with Hepatitis C Virus Genotype 1b Receiving Hemodialysis  
 
Version 
1.0 
Protocol Date 
8 August, 2017 
Investigational 
Product 
Elbasvir/Grazoprevir 
Development phase 4 
Study Design 
Prospective, multicenter, open-label, interventional trial 
Sponsor 
 MSD 
Medical Monitor 
Department Ministry of Health and Welfare, Executive Yuan, 
Taiwan 
Taiwan Central Institutional Review Board 
Study Coordinator 
Chen-Hua Liu, MD, PhD 
Contact Information: +886-2-23123456 ext 63572 
E-mail: jacque_liu@mail2000.com.tw 


3 
 
INVESTIGATOR SIGNATURE PAGE 
 
Title: Elbasvir/Grazoprevir for Treatment-Naive and Treatment-Experienced Patients 
with Hepatitis C Virus Genotype 1b Receiving Hemodialysis 
 
I, the undersigned, have reviewed this protocol, and I agree to conduct this study 
with the information contained in this protocol, and in accordance with the principles 
of Declaration of Helsinki and the International Conference on Harmonization for 
Good Clinical Practice. 
 
 
Name:                            Signature:                         
 
Date:                           
 
Affiliation & Address:                                                  
 
                                                                   


4 
 
PROTOCOL SYNOPSIS 
Version 
1.0 
Protocol Date 
8 August, 2017 
Title 
Elbasvir/Grazoprevir for Treatment-Naive and 
Treatment-Experienced Patients with Hepatitis C Virus Genotype 
1b Receiving Hemodialysis 
Diagnosis 
Chronic hepatitis C, genotype 1b 
Participating Center 
National Taiwan University Hospital, Taiwan 
National Taiwan University Hospital, Yun-Lin Branch, Taiwan 
China Medical University Hospital 
Taichung Veterans General Hospital, Taiwan 
Taipei Medical University Hospital, Taiwan 
Far-Eastern Memorial Hospital, Taiwan 
Phase of Trial 
4 
Investigational 
Product 
Elbasvir/Grazoprevir 50mg/100 mg fixed dose combination (FDC) 
Acronym: EBR/GZR FDC 
Dose 
Elbasvir/Grazoprevir 50mg/100 mg fixed dose combination (FDC) 1 
tablet QD 
Duration 
12 weeks 
Treatment 
allocation 
Open-label 
Estimated Sample 
Size 
40 
Main Inclusion 
Criteria 
1. 
20 to 70 yeas of age 
2. 
Male or female 
3. 
Body mass index (BMI) 18.5-35.0 kg/m2 
4. 
Chronic HCV infection, defined as patients who meet as least 
one of the two following criteria:  
• 
Anti-HCV antibody (Abbott HCV EIA 2.0, Abbott 
Laboratories, Abbott Park, Illinois, USA) or HCV RNA > 
1,000 IU/mL for at least 6 months before screening 
• 
Positive HCV RNA > 1,0000 IU/mL (Cobas TaqMan HCV 
Test v2.0, Roche Diagnostics GmbH, Mannheim, 
Germany, low limit of quantification (LLOQ): 25 IU/mL) 
at the time of screening with a liver biopsy consistent 
with chronic HCV infection 
5. 
HCV genotype 1 (HCV GT-1b) infection (Abbott RealTime HCV 


5 
 
genotype II, Abbott Molecular Inc. Illinois, USA) 
6. 
Treatment-naïve or treatment-experienced (including patients 
who relapsed, who had virological breakthrough, or who were 
null-responsive to IFN-based therapies) 
7. 
HCV RNA > 10,000 IU/mL at screening 
8. 
Estimated glomerular filtration (eGFR) rate < 15 
mL/min/1.73m2 as assessed by modified of diet in renal 
disease (MDRD) equation, and receiving regular hemodialysis 
Main Exclusion 
Criteria 
1. 
HCV infection other than HCV GT-1b 
2. 
HBV or HIV coinfection 
3. 
Presence of decompensated cirrhosis (Child-Pugh class B or C) 
4. 
Any primary cause of liver disease other than chronic HCV 
infection, including but not limited to the following 
• Hemochromatosis 
• Alfa-1 antitrypsin deficiency 
• Wilson’s disease 
• Autoimmune hepatitis 
• Alcoholic liver disease 
• Drug-induced hepatitis 
5. 
Screening laboratory analyses showing any of the following 
results 
• Hemoglobin (Hb) level < 10 g/dL 
• Absolute neutrophil count (ANC) < 1,500 cells/μL 
• Platelet count < 70,000 cells/mm3 
• International normalized ratio (INR) > 2.0 
• Albumin (Alb)< 3.0 g/dL 
• Bilirubin (Bil) > 2.0 mg/dL 
• Alanine aminotransferase (ALT) > 10X upper limit of normal 
(ULN) 
• Aspartate aminotransferase (AST) > 10X upper limit of 
normal (ULN) 
• Serum alfa-fetoprotein (AFP) > 100 ng/mL 
6. 
Presence of hepatocellular carcinoma (HCC) on imaging 
studies such as computed tomography (CT) scan or magnetic 
resonance imaging (MRI) 
7. 
History of malignancy (except cutaneous melanoma) within 5 
years at the screening 
8. 
Organ transplantation other than cornea and hair (prior renal 


6 
 
transplantation with graft failure not included) 
9. 
Prior exposure to investigational agents for HCV (direct acting 
antiviral agents, host-targeting agents, or therapeutic 
vaccines) 
10. Pregnancy 
11. Unwilling to have contraception during the study period 
12. Unwilling to provide informed consent 
Primary endpoint 
1. 
Sustained virological response (SVR12): HCV RNA level < low 
limit of quantification (LOQ) 12 weeks after the completion of 
therapy (Cobas TaqMan HCV Test v2.0, Roche Diagnostics 
GmbH, Mannheim, Germany, low limit of quantification 
(LLOQ): 25 IU/mL) 
Secondary endpoint 
1. 
Treatment-emergent adverse event (AE)-related withdrawal 
rate 
2. 
Sustained virological response (SVR24): HCV RNA level < low 
limit of quantification (LOQ) 24 weeks after the completion of 
therapy (Cobas TaqMan HCV Test v2.0, Roche Diagnostics 
GmbH, Mannheim, Germany, low limit of quantification 
(LLOQ): 25 IU/mL) 
3. 
Rapid virological response (RVR): HCV RNA level < low limit of 
quantification (LOQ) at week 4 of treatment (Cobas TaqMan 
HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, 
Germany, low limit of quantification (LLOQ): 25 IU/mL) 
4. 
End-of-treatment virological response (EOTVR): HCV RNA 
level < low limit of quantification (LOQ) at the end of 
treatment (Cobas TaqMan HCV Test v2.0, Roche Diagnostics 
GmbH, Mannheim, Germany, low limit of quantification 
(LLOQ): 25 IU/mL) 
5. 
Fibrosis Index Based on 4 markers (FIB-4): changes of FIB-4 
before treatment and at the end-of-follow-up 
6. 
FibroScan: changes of liver stiffness before treatment and at 
the end-of-follow-up 
Resistance 
1. 
Resistance information will be analyzed for any subjects who 
has sequencing performed on baseline samples:  
• The resistance-associated variants (RAVs) at signature 
amino acid position at baseline identified by population 
nucleotide sequencing and comparison to the appropriate 
prototype reference standard sequence 


7 
 
2. 
Resistance information will be analyzed for subjects who fail 
to achieve SVR12 and who have on-treatment HCV RNA ≥ 
1,000 IU/mL 
• The RAVs at signature amino acid position at baseline 
identified by population nucleotide sequencing 
comparison to the appropriate prototypic reference 
sequence 
• The RAVs in available post-baseline samples identified by 
population and/or clonal nucleotide sequencing and 
comparison to the baseline sequencing 
• The RAVs in available post-baseline samples identified by 
population and/or clonal nucleotide sequencing and 
comparison to the appropriate prototypic reference 
sequence 
3. 
The most prevalent amino acid RAVs identified by population 
sequencing and those emerging or becoming enriched in 
isolates from at least 2 subjects in the study will be 
summarized. Furthermore, the persistence of the detected 
amino acid RAVs will also be reported. 
Proposed Statistical 
Analysis 
Variables/Time Points of Interest: sustained virological response 
(SVR12): HCV RNA level < low limit of quantification (LOQ) 12 weeks 
after the completion of therapy (Cobas TaqMan HCV Test v2.0, 
Roche Diagnostics GmbH, Mannheim, Germany, low limit of 
quantification (LLOQ): 25 IU/mL) 
Statistical Methods:  
• Alfa-error: 0.05, beta-error: 0.10, two-tailed statistics 
• Controlled arm (null-hypothesis): peginterferon alfa-2a 
plus low-dose ribavirin for 48 weeks (SVR24: 64%, 95% CI: 
54%-73%) (Liu CH, et al. Pegylated interferon-α2a with or 
without low-dose ribavirin for treatment-naive patients 
with hepatitis C virus genotype 1 receiving hemodialysis: a 
randomized trial. Ann Intern Med 2013;159:729-38.) 
• EBR/GZR arm: SVR12 estimated to be 95% with lower 95% 
CI bound to be 84% 
• Sample estimation in EBR/GZR arm: 40 


8 
 
Flow Chart 
 
Study Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Procedure 
Screening 
Treatment 
EOT 
Follow-up 
EOF 
Extended follow-up 
Study Week 
-4 to -1 
Day 1 
1 
2 
4 
8 
12 
16 
20 
24 
36 
Study Day 
-28 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
252 
Time window (Day) 
NA 
NA 
±2 
±2 
±2 
±2 
±2 
±7 
±7 
±14 
±14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Demographic 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abdominal US 
X 
 
 
 
 
 
X 
 
 
X 
 
ECG 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Pregnancy test1 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Hemogram2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation profile3 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Biochemistry4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


9 
 
Serology5 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Virology6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Human genetics7 
X 
 
 
 
 
 
 
 
 
 
 
FibroScan or Liver8 
biopsy 
X 
 
 
 
 
 
X 
 
 
X 
 
Resistant variants9 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archive serum sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispense 
 
X 
X 
X 
X 
X 
 
 
 
 
 
EOT: end of treatment, EOF: end of follow-up 
1 For pre-menopausal women with child birth potential, testing for serum beta human chorionic gonadotropin (β-HCG). 
2 Including hemoglobin level, white blood cell count, absolute neutrophil count, platelet count. 
3 Including prothrombin time, activated partial thromboplastin time, international normalized ratio. 
4 Screening visit, visit 1, visit 6, visit 9 and visit 10: include albumin, total bilirubin (T-Bil), direct bilirubin (D-Bil), aspartate aminotransferase (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP), gamma-glutaryl transpeptidase (-GT), creatinine (Cre), blood urea nitrogen (BUN), sodium (Na), potassium (K), fasting glucose (GluAC), 
glycated hemoglobin (HbA1c), triglyceride (TG), cholesterol (CHO), low density lipoprotein (LDL), high density lipoprotein (HDL), iron (Fe), total iron binding capacity (TIBC), 
ferritin. Visit 2-5, visit 7 and visit 8: include albumin, AST, ALT, T-Bil, D-Bil, ALP/r-GT, BUN, Cre. 
5 Screening visit includes anti-HCV, HBsAg, anti-HBs, anti-HBc, anti-HIV and AFP. Visit 1, visit 6, visit 9 and visit 10 include anti-HCV and AFP. 
6 Screening visit includes HCV RNA, HCV genotype/subgenotype. Other visits include HCV RNA. 
7 Including interleukin 28B (IL28B) genotypes. 
8 For patients with failed or unreliable Fibroscan evaluation, liver biopsy to stage the hepatic fibrosis is suggested and is optional. In patients who receive liver biopsy to 
stage the hepatic fibrosis, the EOF liver biopsy is also optional. 
9 All samples tested were stored until the completion of the study. Tests for all subjects for resistant associated variants (RVAs) of interests at NS3 and NS5A regions at the 
screening time point. Others were tested for subjects who fail to achieve SVR12 or who have on-treatment HCV RNA ≥ 1,000 IU/mL. 


10 
 
ABBREVIATIONS 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AFP 
Alfa Fetoprotein 
AIDS 
Acquired Immune Deficiency Syndrome 
ALB 
Albumin 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
ANC 
Absolute Neutrophil Count 
ANTI-HBc 
Hepatitis B Virus Core Antigen Antibody 
ANTI-HBs 
Hepatitis B Virus Surface Antigen Antibody 
ANTI-HCV 
Hepatitis C Virus Antibody 
ANTI-HIV 
Human Immunodeficiency Virus Antibody 
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate aminotransferase 
AUC 
Area Under the Curve 
BIL 
Bilirubin 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BT 
Body Temperature 
Ca 
Calcium 
CBC 
Complete Blood Count 
CHC 
Chronic Hepatitis C 
CHO 
Cholesterol 
CKD 
Chronic Kidney Disease 
CI 
Confidence Interval 
CL 
Chloride 
CRF 
 
Case Report Form 
CT 
Computed Tomography 
CYP 
Cytochrome P 
DAA 
Direct Acting Antiviral 
D-Bil 
Direct Bilirubin 
DDI 
Drug Drug Interaction 
DNA 
Deoxyribonucleic Acid 
EBR 
Elbasvir 
EC 
Ethics Committee 
ECG 
Electrocardiogram 


11 
 
eGFR 
Estimated Glomerular Filtration Rate 
EIA 
Enzyme Immune Assay 
EOF 
End of Follow-up 
EOT 
End of Treatment 
EOTVR 
End-of-treatment Virologic Response 
ESA 
Erythrocyte Stimulating Agent 
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration 
FDC 
Fixed Dose Combination 
FE 
Iron 
GCP 
Good Clinical Practice 
GLUAC 
Fasting Glucose 
GT 
Genotype 
GZR 
Grazoprevir 
Hb 
Hemoglobin 
HbA1c 
Glycated Hemoglobin 
HBsAg 
Hepatitis B Surface Antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HCT 
Hematocrit 
HCV 
Hepatitis C Virus 
HD 
Hemodialysis 
HDL 
High Density Lipoprotein 
HIV 
Human Immunodeficiency Virus 
IFN 
Interferon 
IL28B 
Interleukin 28B 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IU 
International Unit 
K 
Potassium 
L 
Liter 
LDL 
Low Density Lipoprotein 
LLOD 
Lower Limit of Detection 
LLOQ 
Lower Limit of Quantification 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MDRD 
Modified of Diet in Renal Disease Equation 
mg 
Milligram 


12 
 
Mg 
Magnesium 
mL 
Milliliter 
MRI 
Magnetic Resonance Imaging 
NA 
Sodium 
OATP 
Organic Anion Transporter Protein 
P-gp 
P-Glycoprotein 
PI 
Principle Investigator 
PK 
Pharmacokinetics 
PO 
Per Os 
PR 
Pulse Rate 
PT 
Prothrombin Time 
QD 
Once Daily Dose 
RAV 
Resistance Associated Variant 
RBV 
Ribavirin 
RBC 
Red Blood Cell Count 
RNA 
Ribonucleic Acid 
RR 
Relative Risk 
RR 
Respiratory Rate 
RVR 
Rapid Virologic Response 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SUSAR 
Suspected Unexpected Severe Adverse Reaction 
SVR 
Sustained Virologic Response 
T-Bil 
Total Bilirubin 
TG 
Triglyceride 
TIBC 
Total Iron Binding Capacity 
TVR 
Telaprevir 
UA 
Uric Acid 
ULN 
Upper Limit of Normal 
US 
Ultrasonography 
WBC 
White Blood Cell count 
Β-HCG 
Beta Human Chorionic Gonadotropin 
γ-GT 
Gamma-Glutaryl Transpeptidase 
μg 
Microgram 


13 
 
Table of Contents 
TITLE PAGE ………………………………………………………………………………………………………. 
1 
SPONSOR SIGNATURE PAGE ……………………………………………………………………………. 
2 
INVESTIGATOR SIGNATURE PAGE ……………………………………………………………………. 
3 
PROTOCOL SYNOPSIS ………………………………………………………………….…………………… 
4 
FLOW CHARTS …………….…………………………………………………………………………………… 
9 
ABBREVIATIONS ………………………………………………………………………………………………. 
11 
TABLE OF CONTENTS ……………………………………………………………………………………….. 
14 
1. INTRODUCTION …………………………………………………………………………………………. 
18 
1.1 Overview ……………………………………………………………………………………………… 
18 
1.2 Clinical experience of IFN-based Therapy ……………………………..……………. 
18 
1.3 Clinical experience of IFN-free therapy by elbasvir/grazoprevir 
with/without ribavirin in HCV GT-1 patients ………………..…………………………… 
 
19 
1.4 Clinical experience of IFN-free therapy by elbasvir/grazoprevir in HCV 
GT-1 patients with severe renal impairment or end-stage renal disease 
(ESRD) …………………………………………………………………………………..……………………. 
 
 
20 
1.5 Rationale for the study design …………………………………………………………… 
21 
2. STUDY DESIGN …………………………………………………………………………………………… 
23 
2.1 Study population ………………………….…………………………………………………….. 
23 
  2.1.1 Inclusion criteria ………………………………………………….………………………… 
23 
  2.1.2 Exclusion criteria ……….………………………………………………………..………… 
24 
  2.1.3 Definition of the criteria …….……………………….……………………………….… 
25 
2.1.4 Prior or concomitant HCV therapy …………………………………………………. 
26 
2.1.4.1 Prior therapy ………………………………………………………………………….. 
27 
2.1.4.2 Concomitant therapy ……………………………………………………………… 
27 
2.1.4.3 Prohibited therapy ………………………………………………………………… 
27 
2.1.4.4 Concomitant therapy requiring dosage adjustment, altered 
timing or additional monitoring ……………………………………………… 
 
28 
2.2 Intervention ……………………..…………………………………………………………………. 
29 
2.2.1 Identity of investigational drugs ……………………………………………………. 
20 
  2.2.2 Packing and labeling ……………………………………………………………………… 
29 
2.2.3 Storage and disposition of investigational drugs ……………………………. 
29 


14 
 
  2.2.4 Shipment of investigational drugs ……………..………………………………..… 
29 
2.2.5 Blinding …………………………………………………………………………………………. 
30 
  2.2.6 Dispensing of investigational drugs …….……………………….………………… 
30 
  2.2.7 Dosage and duration of interventional drugs ………………………………… 
30 
  2.2.8 Dosage adjustment …………………………………………………………..…………… 
30 
2.2.9 Treatment compliance …………………………………………………………………… 
30 
  2.2.10 Drug accountability ……………………………………………………..………………. 
31 
2.3 Objective …………………………………………….…………………..…….……………………. 
32 
  2.3.1 Primary objectives ………………….…………………………..……………..…….…… 
32 
  2.3.2 Secondary objectives ………………………………………………………………..…… 
32 
  2.3.3 Outcome measures …………………………………………..…….……………………. 
32 
2.4 Study schedule ……………….………………………………..……..…….……………………. 
33 
  2.4.1 Study windows and rounding principles ……….….……………………………. 
33 
  2.4.2 Screening visit …………………………………………………..…….……………………. 
33 
2.4.3 Rescreening visit ……………………………………………………………………………. 
34 
  2.4.4 Treatment visit ……….………………………………………..…….………….…………. 
34 
  2.4.5 Follow-up visit ……….………………………………………..………….………..………. 
35 
2.4.6 End of follow-up visit …………………………………………………………………….. 
35 
  2.4.7 Extended follow-up visit ……….……………………………..…….….……………… 
35 
2.5 Study procedures/evaluations ………………………….…..…….….……….…………. 
36 
2.5.1 Informed consent ………………………………………………………………………….. 
36 
  2.5.2 Demographics, baseline values, medical history ….….………….…………. 
36 
  2.5.3 Clinical evaluations ……………………………..…………..…….….……….…………. 
36 
     2.5.3.1 Vital signs, weight, height ……………………..………………………..……. 
36 
     2.5.3.2 Physical examination …………….………………..…….….……….…………. 
36 
     2.5.3.3 Adverse events ………………..……………………..…….….……….…………. 
37 
  2.5.4 Laboratory evaluations ……………….…………………..…….….……….…………. 
37 
     2.5.4.1 Routine laboratory panels …………………………….….……….…………. 
37 
     2.5.4.2 Human genetic analysis ……………………………….……………………….. 
38 
     2.5.4.3 Virology analyses ……………….…………………..…….….……….…………. 
39 
     2.5.4.4 Abdominal ultrasonography …………………………….…………………… 
40 
2.5.4.5 Electrocardiogram (ECG) ………………………………………………………. 
40 
     2.5.4.6 FibroScan and liver biopsy ………………..……………………..…….….…. 
41 


15 
 
2.5.4.7 Archive serum sample ………………………………………………………….. 
41 
3. ADVERSE EVENT MANAGEMENT & REPORTING ………………….……..….…………. 
45 
 3.1 Adverse event …………………………………………………………….….……….…………. 
45 
 3.2 Serious adverse event ……………………..……………………….….……..……………. 
45 
 3.3 Reporting and classification procedures ……………………..….……….…….…. 
46 
3.3.1 Severity of adverse event ……………………………………………………………. 
46 
3.3.2 Relationship to investigational drug …………………………………………….. 
47 
3.3.3 Pregnancy ……………………………………………………………………………………. 
47 
3.3.4 Toxicity management ………………………………………………………………….. 
48 
3.3.4.1 Grade 1 or 2 adverse events and laboratory abnormalities …. 
48 
3.3.4.2 Grade 3, or higher adverse events and laboratory 
abnormalities ……………………………………………………………………… 
  
48 
3.3.4.3 Management of transaminase elevations …………………………… 
49 
4. DOSE INTERRUPTION, DISCONTINUATION RULES …………..….………….…………. 
51 
 4.1 Dose interruption ……….………………………..…..………..…….….….…….…………. 
51 
 4.2 Dose discontinuation ……….…………………..…….….……………….….….…………. 
51 
 4.3 Subject withdrawal and replacement ……….……………………….…..…………. 
51 
5. PROTOCOL DEVIATION ………………………………………………….…………………………… 
52 
6. STATISTICAL CONSIDERATIONS ……….…………………………..…….….……….…………. 
53 
 6.1 Sample size determination ……….………..…………..…..…….….……….…………. 
53 
 6.2 Definition of primary endpoints ……….……………..……………....…….….…….. 
53 
 6.3 Analyses for primary efficacy endpoint …………………………………………….. 
53 
 6.4 Analysis for primary safety endpoint ………………………………..……..…..…… 
54 
 6.5 Sensitivity analysis for the primary efficacy endpoint ………………..…….. 
54 
6.6 Subgroup analyses …………………………………………………………………………….. 
54 
6.7 Additional efficacy endpoint …………………………………………………………….. 
55 
6.8 Resistance analyses …………………………………………………………………………… 
55 
6.9 Adverse events ………………………………………………………………………………….. 
57 
6.10 Clinical laboratory data ……………………………………………………………………. 
58 
7. STUDY ADMINISTRATION ………………………….……………………….….……….…………. 
59 
 7.1 Regulatory and ethical consideration ……….…………..…….…..…….…………. 
59 
   7.1.1 Institutional review board/ethics committee approval ………………… 
59 
7.1.2 Ethical conduct of the study ………………………………………………………… 
59 


16 
 
   7.1.3 Subject informed consent ……………………………..…….….……….…………. 
60 
 7.2 Data collection …………………………………………………....…….….……….…………. 
61 
7.2.1 Source documents …………………………………………………………………….... 
61 
7.2.2 Case report forms ……………………………………………………………………….. 
61 
 7.3 Record retention ……………………………..……………………..….….……….…………. 
61 
 7.4 Information disclosure ……………………………………………….….……….…………. 
61 
   7.4.1 Confidentiality ……………………………………………….…….….……….…………. 
62 
7.4.2 Completion of the study ……………………………………………………………… 
62 
   7.4.2 Publication policy ………………………………..…………..….….……….…………. 
62 
8. REFERENCES ………..……………………………………………….………..….….……….…………. 
63 
9. APPENDIX ………………………………………………………………………….….……….…………. 
67 
 
 


17 
 
1. INTRODURCTION 
1.1 Overview 
Hepatitis C virus (HCV) infection remains a major co-morbidity in 
hemodialysis patients.1-3 The incidence and prevalence rates of HCV infection 
in hemodialysis patients are much higher than those in the general 
population, and are attributed to high rates of nosocomial HCV 
transmission.4-6 With regard to HCV genotype distribution, HCV genotype 1 
(GT-1) infection is the most prevalent type of infection worldwide and the 
genotype distribution in HCV-infected individuals receiving hemodialysis (HD) 
is similar to that observed in HCV-infected individuals with normal renal 
function.7-9 
Compared 
to 
non-HCV 
infected 
hemodialysis 
patients, 
HCV-infected patients have increased risks of liver-related morbidity and 
mortality.10 Although HCV-infected hemodialysis patients who receive renal 
transplantation have survival advantages over those who remain on 
maintenance dialysis, these patients still have poor patient and graft survival, 
as well as have poor responses to interferon (IFN)-based therapy.11-13 In 
contrast, hemodialysis patients who eradicate HCV infection have improved 
biochemical, virologic and histologic responses, whether on maintenance 
dialysis or after renal transplantation.14,15 
 
1.2 Clinical experience of IFN-based Therapy 
Approximately one third of hemodialysis patients with chronic HCV infection 
achieve sustained virological response (SVR) by conventional IFN or 
peginterferon monotherapy.16-18 In addition 18-30% of patients receiving 
IFN-based monotherapy prematurely discontinued treatment due to adverse 
events (AEs). Although the addition of ribavirin to IFN further improves the 
SVR rate in HCV-infected patients with normal renal function, ribavirin has 
been considered contraindicated to treat HCV-infected hemodialysis patients 
because of concern for life-threatening hemolytic anemia. Recently, pilot 
studies have indicated the feasibility of adding low-dose ribavirin (200 mg 
three times per week to daily 400 mg, adjusted to achieve a target 
concentration of 10-15 μmol/L), to IFN for treatment of HCV-infected 
hemodialysis patients.19-28 Generally, the SVR rate and the premature 


18 
 
discontinuation rate due to null-response, severe anemia, and/or heart failure 
for combination therapy are 56% and 22%, respectively.29 Based on these 
small-scale studies, low-dose ribavirin (daily 200 mg) was approved in August 
2011 by the U.S. Food and Drug Administration to treat HCV-infected 
hemodialysis patients.30 Two recent well-conducted randomized control 
studies to compare the efficacy and safety of combination therapy with 
peginterferon alfa-2a (135 μg/week) plus low-dose ribavirin (RBV) (200 
mg/day) or monotherapy with peginterferon (135 μg/week) for 48 and 24 
weeks in treatment-naïve HCV GT-1 and GT-2 infected individuals receiving 
hemodialysis showed that the SVR rates of combination therapy groups were 
greater than those of monotherapy groups (64% versus 34%, p < 0.001 for 
HCV GT-1; 74% versus 44%, p < 0.001 for HCV GT-2), respectively.31,32 
Although the SVR rate of combination therapy with peginterferon plus 
low-dose ribavirin is higher than that of peginterferon monotherapy. About 
70-75% of these patients experienced clinically significant anemia which 
needed high dose of erythropoiesis stimulating agents (ESAs) to keep the 
hemoglobin level within the safety range. Although telaprevir (TVR)-based 
triple therapy has been used to treat 4 HCV-1 patients receiving hemodialysis 
who were not responsive to prior peginterferon plus RBV with good efficacy, 
the added on-treatment adverse events (AEs) and the pill burden precluded 
the widespread use of this agent.33,34 
 
1.3 Clinical experience of IFN-free therapy by elbasvir/grazoprevir (EBR/GZR) in 
HCV GT-1 patients 
The recent introduction of IFN-free direct acting antiviral agents (DAAs) has 
made a paradigm shift with regard to the medical treatment for HCV-infected 
individuals, based on the excellent efficacy and safety in ordinary patients. 
Among 
the 
various 
IFN-free 
DAA 
regimens, 
treatment 
with 
elbasvir/grazoprevir (EBR/GZR) has been approved in 2016 to treat patients 
with chronic HCV GT-1 and GT-4 infection.35 Treatment with EBR/GZR 
with/without weight-based ribavirin for 12-16 weeks achieved an SVR12 rate 
of 94-100% in treatment-naïve and PR or protease-inhibitor based 
treatment-experienced HCV GT-1a, GT-1b or GT-4 patients, respectively 


19 
 
(C-EDGE TN, TE, SALVAGE).36-39 Furthermore, the SVR12 rates in HIV-coinfected 
patients with HCV GT-1a, GT-1b and GT-4 were 95.3% and 98.0% by using 
EBR/GZR for 12 weeks (C-EDGE Coinfection).40 In addition to high SVR rates by 
12-16 weeks of EBR/GZR treatment, the overall safety profiles are excellent, 
with only 1% of the patients who discontinue treatment due to drug-related 
adverse event. With regard to constitutional symptoms, treatment with 
EBR/GZR had comparable rates to the placebo arms. With regard to 
laboratory abnormalities, about 1% and less than 1% of the treatment 
patients experience AST/ALT elevation and hyperbilirubinemia. Clinically 
significant anemia is more commonly encountered in patients receiving 
EBR/GZR with weight-based ribavirin. Taking together, treatment with 
EBR/GZR is efficacious and safe for HCV-infected subjects with HCV GT-1 or 4 
infection. The post-hoc analyses for potential factors affecting the SVR rates 
showed that among GT-1a infected patients with baseline NS5A resistant 
associated variants (RAVs) at position of 28, 30, 31 and 93, the SVR rates will 
be compromised for those receiving 12 weeks of treatment or without adding 
RBV. In addition, treatment-experienced HCV GT-4 patients should also 
receive 16 weeks of EBR/GZR plus RBV to secure the SVR rates. In GT-1a or 
GT-1b patients who fail prior protease inhibitor-based triple therapy, 12 
weeks of GZR/EBR plus RBV are recommended to secure the high SVR rates. 
For GT-1a treatment-naïve or PR-experienced patients without the presence 
of baseline NS5A RAVs, GT-1b treatment-naïve or PR-experienced patients or 
GT-4 treatment-naïve patients, EBR/GZR for 12 weeks offer satisfactory safety 
and efficacy profiles.35 Gender, ethnicity, age, interleukin-28B (IL28B) 
genotype, cirrhosis status and baseline HCV RNA levels do not affect the 
overall SVR rates in EBR/GZR treatment patients. 
 
1.4 Clinical experience of IFN-free therapy by elbasvir/grazoprevir in HCV GT-1 
patients with severe renal impairment or end-stage renal disease (ESRD) 
The pharmacokinetic (PK) study of elbasvir and grazoprevir was evaluated 16 
subjects with severe renal impairment and end-stage renal disease (ESRD) on 
maintenance hemodialysis and matched healthy controls. Compared to 
subjects with matched healthy controls, the area under the curves (AUCs) of 


20 
 
elbasvir in subjects with severe renal impairment and ESRD were 99% and 
86%; the AUCs of grazoprevir in subjects with severe renal impairment and 
ESRD were 85% and 83%, respectively.41 The pharmacokinetic study indicated 
that dose dosage adjustments of EBR/GZR are not needed for patients with 
severe renal impairment or those who are on maintenance hemodialysis. 
The phase 3 C-SUFER study evaluated the safety and efficacy of EBR/GZR BV 
for 12 weeks in a total of 235 treatment-naïve and treatment-experienced 
HCV GT-1 patients with severe renal impairment or ESRD.42 About 82% of the 
patients had chronic kidney disease (CKD) stage 5, and the remaining 18% of 
the patients had CKD stage 4. The full set and the modified full set analyses 
for SVR12 in patients receiving 12 weeks of treatment were 94% and 99% 
respectively. On-treatment undetectable HCV RNA levels at weeks 4 and 12 
were 90% and 100%, respectively. In patients with ESRD, the overall SVR12 
was 98.9%. No patients discontinued the study drugs due to adverse events. 
Furthermore, the constitutional and the laboratory abnormalities were mild 
in grades and were lower in frequency, compared to the control arm. This 
large-scale study shows that treatment with EBR/GZR is efficacious and safe 
for HCV-1 patients with severe renal impairment and those with end-stage 
renal disease. 
 
1.5 Rationale of the study design 
Although peginterferon monotherapy and combination therapy with 
peginterferon plus low-dose RBV for 24-48 weeks have been evaluated in 
many studies, the efficacy for the treatment regimens were only modest (SVR 
rate about 60%). In addition, the on-treatment AEs and SAEs by IFN-based 
therapies were frequently encountered in HCV-infected patients receiving 
hemodialysis. Of note was the pronounced on-treatment hemoglobin level 
decrease in patients receiving combination therapy by peginterferon plus 
low-dose RBV, necessitating significant RBV dose reduction and high-dose 
erythrocyte stimulating agent (ESA) support. 
By receiving IFN-free DAA therapies, HCV-infected patients have excellent SVR 
rates, low on-treatment SAE and AE rates, shorter treatment duration, and 
low pill burdens. The PK study of EBR/GZR proves the excellent safety profiles 


21 
 
and dose adjustment are not needed for EBR/GZR regimen in subjects with 
various degrees of renal impairment. The C-SURFER study showed the 
excellent on-treatment and off-therapy antiviral effects in HCV GT-1a and 
GT-1b infected patients receiving EBR/GZR, respectively. However, the 
C-SURFER study enrolled only limited patients of Asian ancestry, making the 
safety and efficacy in this group of patients still to be confirmed. Based on the 
excellent safety and efficacy profiles of EBR/GZR treatment for HCV GT-1b 
infected patients with normal renal function, we aim to evaluate the safety 
and efficacy of EBR/GZR for 12 weeks in treatment-naïve and 
treatment-experienced HCV GT-1b patients receiving hemodialysis in Asian 
population, taking HCV GT-1b patients treated by peginterferon plus ribavirin 
for 48 weeks as the historical control. 


22 
 
2. STUDY DESIGN 
2.1 Study population 
We will conduct a phase 4, multicenter, open-label trial at 5 academic centers 
in Taiwan. Treatment-naïve and treatment-experienced HCV GT-1b patients 
who receive maintenance hemodialysis due to ESRD and who are 20-70 years 
old are consecutively enrolled in the study. The protocol will be approved by 
Central Institutional Review Board (C-IRB) of Taiwan and will be conducted in 
accordance with the principles of Declaration of Helsinki and the 
International Conference on Harmonization for Good Clinical Practice. Each 
patient provides written informed consent before enrollment. 
 
2.1.1 Inclusion criteria 
[1] 20 to 70 yeas of age 
[2] Male or female 
[3] Body mass index (BMI) 18.5-35.0 kg/m2 
[4] Chronic HCV infection, defined as patients who meet as least one of the 
two following criteria 
• 
Anti-HCV antibody (Abbott HCV enzyme immunoassay [EIA] 2.0, 
Abbott Laboratories, Abbott Park, Illinois, USA) or HCV RNA > 1,000 
IU/mL for at least 6 months before screening 
• 
Positive HCV RNA > 1,0000 IU/mL (Cobas TaqMan HCV Test v2.0, 
Roche Diagnostics GmbH, Mannheim, Germany, low limit of 
quantification (LLOQ): 25 IU/mL) at the time of screening with a 
liver biopsy consistent with chronic HCV infection 
[5] HCV GT-1b infection (Abbott RealTime HCV genotyping II, Abbott 
Molecular Inc. Illinois, USA) 
[6] Treatment-naïve or treatment-experienced (including patients who 
relapsed, who had virological breakthrough, or who were null-responsive 
to IFN-based therapies) 
[7] HCV RNA > 10,000 IU/mL at screening 
[8] Estimated glomerular filtration (eGFR) rate < 15 mL/min/1.73m2 as 
assessed by modified of diet in renal disease (MDRD) equation, and 
receiving regular hemodialysis 


23 
 
 
2.1.2 Exclusion criteria 
[1] HCV infection other than HCV GT-1b 
[2] HBV or HIV coinfection 
[3] Presence of decompensated cirrhosis (Child-Puge class B or C) 
[4] Any primary cause of liver disease other than chronic HCV infection, 
including but not limited to the following 
• 
Hemochromatosis 
• 
Alfa-1 antitrypsin deficiency 
• 
Wilson’s disease 
• 
Autoimmune hepatitis 
• 
Alcoholic liver disease 
• 
Drug-induced hepatitis 
[5] Screening laboratory analyses showing any of the following results 
• 
Hemoglobin (Hb) level < 10 g/dL 
• 
Absolute neutrophil count (ANC) < 1,500 cells/μL 
• 
Platelet count < 70,000 cells/mm3 
• 
International normalized ratio (INR) > 2.0 
• 
Albumin (Alb)< 3.0 g/dL 
• 
Bilirubin (Bil) > 2.0 mg/dL 
• 
Alanine aminotransferase (ALT) > 10X upper limit of normal (ULN) 
• 
Aspartate aminotransferase (AST) > 10X upper limit of normal (ULN) 
• 
Serum alfa-fetoprotein (AFP) > 100 ng/mL 
[6] Presence of hepatocellular carcinoma (HCC) on imaging studies such as 
computed tomography (CT) scan or magnetic resonance imaging (MRI) 
[7] History of malignancy (except cutaneous melanoma) within 5 years at the 
screening 
[8] Organ transplantation other than cornea and hair (prior renal 
transplantation with graft failure not included) 
[9] Prior exposure to investigational agents for HCV (direct acting antiviral 
agents, host-targeting agents, or therapeutic vaccines) 
[10] Pregnancy 
[11] Unwilling to have contraception during the study period 


24 
 
[12] Unwilling to provide informed consent 
 
2.1.3 Definition of the criteria 
[1] Stage of the hepatic fibrosis: diagnosis of the hepatic fibrosis by one 
of the following methods 
• 
Liver biopsy: graded by METAVIR fibrosis score F0-F4. 
• 
Fibroscan score: F0-F1 (≤ 7.0 KPa), F2 (7.1 to 9.4 KPa), F3 (9.5 to 
12.4 KPa), F4 (≥ 12.5 KPa). 
• 
Subjects with a non-qualifying Fibroscan results (including 
failure to measure [zero valid measurement], unreliable 
measurement [less than 10 valid measurement, a successful 
rate of less than 60% or the interquartile range more than 30% 
of the median FibroScan score]) are suggested to receive liver 
biopsy to confirm the severity of hepatic fibrosis. Liver biopsy is 
optional and is not compulsive. 
[2] Compensated cirrhosis: cirrhotic patients with Child-Pugh score of < 
7 (See below Table). 
[3] Decompensated cirrhosis: cirrhotic patients with Child-Pugh score of 
≥ 7 (See Table below). 
 
Parameter 
Points assigned for Observed Findings 
1 
2 
3 
Total bilirubin (mg/dL) 
< 2 
2-3 
> 3 
Serum albumin (g/dL) 
> 3.5 
2.8-3.5 
< 2.8 
Prothrombin time (INR) 
< 1.7 
1.7-2.3 
> 2.3 
Ascites1 
None 
Mild 
Moderate to severe 
Hepatic encephalopathy2 
Grade 0 
Grade I-II (or suppressed 
with medication)
Grade III-IV (or 
refractory
1 Mild = ascites detectable only by ultrasound examination; moderate to severe = ascites 
manifested by moderate symmetrical distention of the abdomen 
2 Grade 0 = normal consciousness, personality, neurological examination, 
electroencephalogram; grade I = restless, sleep disturbed, irritable/agitated, tremor, 
impaired handwriting, triphasic wave (5 Hz); grade II = lethargic, time-disoriented, 
inappropriate behavior, asterixis, ataxia, slow triphasic wave; grade III = somnolent, 


25 
 
stuporous, place-disoriented, hyperactive reflexes, rigidity, slower triphasic wave; 
grade IV = unarousable coma, no personality/behavior, decerebrate, slow delta wave 
(2-3 Hz) 
[4] Definition of treatment-experienced patients 
• 
Relapser: patients receiving IFN-based therapy (IFN or 
peginterferon with/without RBV) for the treatment of HCV and 
with undetectable HCV RNA at or after the end of treatment, 
but subsequently having detectable HCV RNA within 24 weeks 
of off-therapy follow-up. 
• 
Viral breakthrough: patients receiving IFN-based therapy (IFN 
or peginterferon with/without RBV) for the treatment of HCV 
and 
with 
on-treatment 
undetectable 
HCV 
RNA, 
but 
subsequently having detectable HCV RNA with ongoing 
treatment. 
• 
Null responder: patients receiving at least 12 weeks of 
IFN-based therapy (IFN or peginterferon with/without RBV) for 
the treatment of HCV and failing to achieve at least 2 log HCV 
RNA decline from the baseline to week 12 of therapy, or with 
continuous detectable HCV RNA after 24 weeks of treatment. 
• 
Intolerance: patients who discontinue IFN-based therapy (IFN 
or peginterferon with/without RBV) during the treatment for 
HCV due to intolerance to any of the components of the 
IFN-based therapy. 
 
2.1.4 Prior or concomitant HCV therapy 
Any medication or vaccine (including over-the-counter or prescription 
medicines, vitamins, traditional medicines, and/or herbal medicines) 
taken by the subjects from the timing of signing the informed consent 
through the treatment period and 28 days after the study drugs are 
stopped, must be recorded in the case report form (CRF) along with 
the reason for use, date(s) of administration including the start and 
end dates, and dosage information (including route, dosage and 
frequency). The investigators should review all concomitant 
medications for any potential drug-drug interactions (DDIs). 


26 
 
 
2.1.4.1 Prior therapy 
Treatment-naïve patients must not have prior or current use of 
the investigational or commercially available agents for HCV, 
including IFN, peginterferon, telaprevir, boceprevir, asunaprevir, 
daclatasvir, 
paritaprevir/ritonavir, 
ombitasvir, 
dasabuvir, 
sofosbuvir, ledipasvir, simeprevir, grazoprevir, elbasvir or RBV. 
Treatment-experienced patients must have previously received 
IFN-based therapy, including IFN or peginterferon monotherapy, 
or combination therapy with IFN/peginterferon plus RBV and 
failed treatment. These patients should have documentation of 
the types and duration of prior therapy, as well as the type of 
treatment failure and/or the reason for premature treatment 
discontinuation due to intolerance. 
 
2.1.4.2 Concomitant therapy 
The investigator should confirm than concomitant medications 
can be administered with EBR/GZR. Some medications may 
require dose adjustment due to potential for DDIs. The 
investigator should also review the label(s) for the concomitant 
medication(s) for additional information. 
The 
use 
of 
hepatic 
protective 
medications, 
such 
as, 
ursodeoxycholic acid, glycyrrhizin acid, etc., is allowed, provided 
that the drug does not meet any other exclusion criteria. The 
dose of these drugs should be kept stable while the subjects are 
during the EBR/GZR treatment. 
During the post-treatment period, the investigator should 
reassess concomitant medications and subjects may resume 
previously prohibited medications or revert to pre-study doses 2 
weeks following the last dose of the study drugs, if applicable. 
 
2.1.4.3 Prohibited therapy 
The prohibited therapy in subjects receiving EBR/GZR therapy is 


27 
 
listed below: 
 
Hepatotoxic agents, including but not limited to 
Etofoxine 
Isoniazid 
Nitrofurantoin 
Phenytoin 
 
 
Herbal supplements 
 
 
Strong and moderate cytochrome (CYP) 3A/P-glycoprotein (P-gp) inducers, 
including but not limited to 
Nafcillin 
Rifampin 
Carbamazepine 
Phenytoin 
Phenobarbital 
Bosentan 
Modafinil 
St. John’s Wort 
 
Organic anion transporter protein (OATP) inhibitors, including but not limited to 
Cyclosporine 
Rifampin 
Gemfibrozil 
Eltrombopag 
Lapatinib 
 
HIV medications, including but not limited to 
Efavirenz 
Etravirine 
HIV protease inhibitor 
HMG-CoA reductase inhibitors 
Simvastatin 
Fluvastatin 
Rosuvastatin (> 10 mg) 
Atorvastatin (> 10 mg) 
 
 
 
2.1.4.4 Concomitant therapy requiring dosage adjustment, altered 
timing or additional monitoring 
The concomitant therapy than requires dosage adjustment, 
altered timing, or additional monitoring in subjects receiving 
EBR/GZR therapy is listed below: 
 
Anticoagulants 
 
 
Warfarin 
Heparin 
Aspirin 
Fondaparinux 
Desirudin 
Acenocoumarol 
Anti-hypertensives 
 
 
Enalapril 
Captopril 
Lisinopril 
Ramipril 
Valsartan 
Losartan 
Atenolol 
Metoprolol 
Propranolol 


28 
 
Verapamil 
Diltiazem 
Amlodipine 
Hydralazine 
Clonidine 
Minoxidil 
HMG-CoA reductase inhibitors 
Rosuvastatin 
Atorvastatin 
 
 
2.2 Intervention 
2.2.1 Identity of investigational drugs 
 
Investigational Drugs 
Manufacturer 
Route of 
Administration 
Dosage 
Form 
Strength 
Elbasvir/Grazoprevir 
MSD 
Oral 
Tablet 
50mg/100mg 
 
2.2.2 Packing and labeling 
Elbasvir/grazoprevir (EBR/GZR) fixed-dose combination (FDC) will be 
supplied in boxes containing 14 tablets. Each box will be labeled as 
required by local requirement. 
 
2.2.3 Storage and disposition of investigational drugs 
 
Investigational Drugs 
Storage Condition 
Elbasvir 
15° to 25°C (59°F to 77°F) 
Grazoprevir 
15° to 25°C (59°F to 77°F) 
 
The investigational drugs are for investigational use only and must be 
used within the context of the study. The study drugs supplied for this 
study must be maintained under adequate security and stored under 
appropriate conditions specified on the label until dispensed for subject 
use. 
 
2.2.4 Shipment of the investigational drugs 
A supply of investigational drugs will be sent to each clinical 
pharmacology department of each participating center following the 
approval of the site by Ethic Committee or Institutional Review Board. 


29 
 
Because this is an open-label trial, all the study medications are 
supplied with an open-code. 
 
2.2.5 Blinding 
This is an open-label study. 
 
2.2.6 Dispensing of the investigational drugs 
EBR/GZR FDC tablet is taken Per Os (PO) with food to increase the 
bioavailability. Subjects should comply with the investigators’ 
instructions and receive adequate dosage of the study drugs to secure 
the efficacy and safety. Furthermore, if the subject misses the 
scheduling timing for the study drugs, he/she should replace the dose 
within 12 hours; otherwise he/she should not receive the study drugs 
and be considered as missed dosage. 
 
2.2.7 Dosage and duration of interventional drugs 
[1] Elbasvir/grazoprevir 50 mg/100 mg fixed dose combination 1 tablet 
QD. 
[2] All study drugs should be dosed together and without regard to 
food. 
 
2.2.8 Dosage adjustment 
The dosage and dosing frequency adjustments of the study drugs are 
generally not allowed. The study drugs can be discontinued under 
protocol-defined conditions. 
 
2.2.9 Treatment compliance 
The investigator or his/her designated and qualified representatives will 
administer and dispense investigational drugs for subjects enrolled in 
this study. The study drugs must not be dispensed for reasons other 
than that described in the protocol. Furthermore, all study drugs will be 
dispensed to subjects by study-site personnel under the instruction of 
the investigator. 


30 
 
At the start of the study, each subject should be instructed the 
importance of the dosing adherence to the assigned treatment regimen 
with regard to virologic responses and potential development of 
resistance 
associated 
variants 
(RAVs). 
Subjects 
will 
receive 
investigational drugs from Day 1 visit to the EOT. In addition, subjects 
will be instructed to return all bottles of investigational drugs to the site 
staff at the appropriate visits. During the on-treatment visits, the site 
staff will inspect the content of the bottles and record the status of each 
one as well as the exact number of remaining tablets of investigational 
drugs. 
Investigational drugs should not be interrupted for toxicity management 
or any other reason for more than 7 consecutive days. If investigational 
drugs must be interrupted for more than 7 consecutive days, the 
investigator should note the attributed reason in case report form (CRF), 
and should consider discontinue the subject. 
 
2.2.10 Drug accountability 
The investigator or his/her designated and qualified representatives 
will verify that the investigational drug supplies are well received and 
in the correct amount. An overall accountability of the investigational 
drugs will be performed and verified by monitor throughout the 
treatment period. Final accountability will be verified by the monitor 
at the end of the study drug treatment at each site. 
During the study, should the subject misplace or damage the 
investigational drug bottle, the investigator should contact the study 
coordinator for the replacement of the drugs. An explanation of the 
reason of the misplaced or damaged study drug(s) should be 
documented in CRF. Upon completion of or discontinuation from the 
treatment period, all original investigational drug bottles should be 
counted and destroyed at site. 
The site will maintain the records of the study drugs including the 
amount of drugs received, and return as well as disposal. 
 


31 
 
2.3 Objective 
2.3.1 Primary objectives 
[1] Sustained virological response (SVR12): HCV RNA level < low limit of 
quantification (LOQ) 12 weeks after the completion of therapy 
(Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, 
Germany, low limit of quantification (LLOQ): 25 IU/mL) 
 
2.3.2 Secondary objectives 
[1] Treatment-emergent adverse event (AE)-related withdrawal rate 
[2] Sustained virological response (SVR24): HCV RNA level < low limit of 
quantification (LOQ) 24 weeks after the completion of therapy 
(Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, 
Germany, low limit of quantification (LLOQ): 25 IU/mL) 
[3] Rapid virological response (RVR): HCV RNA level < low limit of 
quantification (LOQ) at week 4 of treatment (Cobas TaqMan HCV 
Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, low limit 
of quantification (LLOQ): 25 IU/mL) 
[4] End-of-treatment virological response (EOTVR): HCV RNA level < 
low limit of quantification (LOQ) at end of treatment (Cobas 
TaqMan HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, 
Germany, low limit of quantification (LLOQ): 25 IU/mL) 
[5] Fibrosis Index Based on 4 markers (FIB-4): changes of FIB-4 before 
treatment and at the end-of-follow-up 
[6] FibroScan: changes of liver stiffness before treatment and at the 
end-of-follow-up 
 
2.3.3 Outcome measures 
[1] Efficacy: sustained virologic response (SVR12), defined as HCV RNA < 
LOQ 12 weeks after the completion of therapy (Cobas TaqMan HCV 
Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, low limit 
of quantification (LLOQ): 25 IU/mL) for subjects who receive at least 
one dose of the study medications. 
[2] Safety: treatment-emergent AE-related withdrawal rate for subjects 
who receive at least one dose of the study drugs. 
 
2.4 Study schedule 


32 
 
2.4.1 Study windows and rounding principles 
The time windows allowed in the study are listed below and should be 
followed unless otherwise specified in this protocol. 
 
Timeframe 
Allowable Windows 
Screening visit 
0 
Rescreening visit 
± 28 days 
Treatment visits 
± 2 days 
Follow-up visits 
± 7 days 
End of follow-up visit 
± 14 days 
Extended follow-up visit 
± 14 days 
 
Data for the analyses will be rounded following the standard 
mathematical or scientific principles where values < 5 will be round 
down whereas values ≥ 5 will be round up to the next significant digit. 
 
2.4.2 Screening visit 
At the screening visit, subjects who provide signed and dated written 
informed consent will undergo the study procedure identified in Section 
2.5 associated with the screening visit. The investigator will evaluate 
whether the subject meets all of the eligibility criteria during the period 
from the screening visit through the start of the treatment period. 
Subjects who meet all eligibility criteria with the exception of 
non-evaluable FibroScan should undergo a liver biopsy. Liver biopsy 
should be performed during the screening period if all the inclusion 
criteria and one of the exclusion criteria are met. The screening visit will 
be conducted up to 28 days before the start of the drug treatment. 
Subjects who fail to fulfill initial screening can have another rescreening 
which would be spanned within 28 days of the first screening. The study 
is 
designed 
to 
enroll 
a 
total 
of 
40 
treatment-naïve 
and 
treatment-experienced eligible subjects to meet the scientific objectives. 
Therefore, if the target number of subjects has been enrolled, there is a 
possibility that additional subjects undergoing screening will not be 


33 
 
enrolled. 
 
2.4.3 Rescreening visit 
Subjects who meet all eligibility criteria with the exception of up to 3 
exclusionary laboratory parameters may rescreen once within the 
28-day screening period. However, subjects with any of the following 
exclusionary values will not be allowed to rescreen: 
[1] Positive hepatitis B surface antigen 
[2] Positive HIV antibody 
[3] Confirmed pregnancy 
Subjects who fail to enroll within 28 days of screening, regardless of the 
reason for falling outside the 28-day screening window, may be allowed 
to rescreen only once. These subjects must be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary 
at the first screening attempt. 
 
2.4.4 Treatment visit 
After meeting the eligibility criteria, a total of 40 treatment-naïve and 
treatment-experienced patients will be enrolled and assigned to 12 
weeks of EBR/GZR treatment. Subjects will receive instructions about 
the investigational drugs and the dosing schedule at the week 0 (i.e. day 
1/baseline) visit. EBR/GZR will be dosed orally once daily as described in 
Section 2.2.7. All subjects will continue to return to the site on an 
outpatient basis up to 12 weeks for the study procedures. Sites should 
ensure that subjects adhere to the study visits listed in the flow chart. 
Subjects who cannot complete the study visits should ensure they do 
not run out of the investigational drugs prior to the next study visit. 
Compliance is critical to ensure adequate drug exposure. Safety and 
tolerability of the treatment will be assessed throughout the study. 
Laboratory tests will include hematology, biochemistry, coagulation 
profiles, virological, serological test, and urinalysis when appropriate. 
Blood samples for the RAVs will be collected as detailed in flow chart. 
Virologic failure criteria will be evaluated and applied by the investigator 


34 
 
as detailed in Section 2.5.4.3. Subjects who prematurely discontinue 
from the treatment should return for a treatment discontinuation visit 
and undergo the study procedures as described (See Section 4.2). 
 
2.4.5 Follow-up visit 
All subjects who receive at least one of investigational drugs after 
treatment visits and either complete treatment or prematurely 
discontinue treatment will be monitored in the post-treatment 
follow-up for safety, efficacy and the emergence and persistence of 
RAVs for additional 24 weeks following the last dose of investigational 
drugs. The post-treatment follow-up will begin the day following the last 
dose of investigational drugs. Subjects with HCV RNA < LOQ at the EOT 
(i.e. end-of-treatment virologic response, EOTVR) and who have a 
confirmed HCV RNA ≥ LOQ at any point in the post-treatment follow-up 
till 12 weeks after the completion of therapy will be considered to have 
relapsed. 
 
2.4.6 End of follow-up visit 
Subjects should return to the site for the end of follow-up visit at week 
12 off-therapy. If the subject prematurely discontinues treatment, then 
he/she should have all end of follow-up visit during the last site visit. 
The site staff should contact the subjects who fail to receive end of 
follow-up visit whining 7 days to confirm the availability of efficacy and 
safety endpoints. 
 
2.4.7 Extended follow-up visit 
Subjects are suggested return to the site for the extended follow-up visit 
at week 24 off-therapy. If the subject prematurely discontinues 
treatment, then he/she should have all end of follow-up visit during the 
last site visit. 
 
2.5 Study procedures/evaluations (See summary Table at the end of the 
section) 


35 
 
The study procedures are outlined and discussed in detail in this section with 
the exception of assessment of concomitant medications (See Section 2.1.4.2), 
monitoring of treatment compliance (See Section 2.2.9), and collection of 
adverse event (AE) information (Section 3). All study data will be recorded in 
the subject’s source documentation and then the appropriate CRF. 
 
2.5.1 Informed consent 
Written informed consent will be obtained from the subject before any 
study procedures are commenced. 
 
2.5.2 Demographics, baseline values, medical history 
Demographics and baseline characteristics including the age, gender, 
race, and medical history will be obtained from each patient who 
provides written informed consent. The medical history will be obtained 
by consulting the subjects. If there is uncertainty with regard to the 
subject’s medical history, he/she may be requested to provide the 
related medical records from the primary care physicians or other 
health-care providers, if appropriate. Methods of contraception, if 
applicable, should also be documented in the source documents. 
 
2.5.3 Clinical evaluations 
2.5.3.1 Vital signs, weight, height 
Vital signs will include ear temperature, pulse rate (PR), 
respiratory rate (RR) and blood pressure (BP). The subject should 
wear lightweight clothing and no shoes during weighing. Height 
will only be measured at screening visit, and the subject will not 
wear shoes. 
 
2.5.3.2 Physical examination 
The site investigators will perform the physical examination for 
each subject at the defined clinic visits. The complete physical 
examination will include examination of all pertinent body 
systems (head & neck, chest, heart, abdomen, genitourinary, 


36 
 
extremities, skin, and nervous system). Furthermore, the site 
investigators should document the specific changes from 
previous medical status. 
 
2.5.3.3 Adverse events 
The site investigators are responsible for the detection and 
documentation of any event meeting the criteria and definition 
of adverse events (AEs) or serious adverse events (SAEs). All AEs 
and SAEs should be recorded by a pre-specific checklist in the 
source documents. The severity of all constitutional AEs is 
graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE), version 4.0. Furthermore, the site 
investigators should assess the causality between the allocated 
treatment and the AEs or SAEs. 
 
2.5.4 Laboratory evaluations 
2.5.4.1 Routine laboratory panels 
Hematology, coagulation profile, biochemistry, serology and 
urinalysis panels performed at the assigned visits will be shown 
below. 
 
Classification 
Item 
Hematology 
Hemoglobin (Hb), hematocrit (HCT), white blood cell 
count (WBC), platelet count (PLT), differential WBC count, 
mean corpuscular volume (MCV), mean corpuscular 
hemoglobin (MCH), mean corpuscular hemoglobin 
concentration (MCHC), red blood cell count (RBC) 
Coagulation profile 
Prothrombin time (PT), activated partial thromboplastin 
time (aPTT), international normalized ratio (INR) 
Biochemistry 
Albumin (ALB), total bilirubin (T-BIL), direct bilirubin 
(D-BIL), 
aspartate 
aminotransferase 
(AST), 
alanine 
aminotransferase (ALT), alkaline phosphatase (ALP), 
gamma-glutaryl 
transpeptidase 
(γ-GT), 
blood 
urea 


37 
 
nitrogen (BUN), creatinine (CRE), sodium (NA), fasting 
glucose 
(GLUAC), 
glycated 
hemoglobin 
(HbA1c), 
triglyceride 
(TG), 
cholesterol 
(CHO), 
low 
density 
lipoprotein (LDL), high density lipoprotein (HDL), iron (FE), 
total iron binding capacity (TIBC), ferritin 
Serology 
Hepatitis B virus surface antigen (HBsAg), hepatitis B virus 
surface antigen antibody(anti-HBs), hepatitis B core 
antigen antibody (anti-HBc), hepatitis C virus antibody 
(Anti-HCV), human immunodeficiency virus antibody 
(Anti-HIV), alfa-fetoprotein (AFP) 
Pregnancy test 
Serum beta human chorionic gonadotropin (β-HCG) 
Fibrosis index based on 4 markers (FIB-4): an index to assess the 
severity of fibrosis stages by using age, platelet count, AST, and 
ALT levels. The formula of FIB-4 is shown as below: 
 
FIB-4 = 
Age (years) 
x AST (IU/L) 
 
 
 
Platelet count (109 cells/L) x 
ALT (IU/L)1/2 
 
FIB-4 ≤ 1.45 denotes a fibrosis stage of < F3 
FIB-4 > 3.25 denotes a fibrosis stage of ≥ F3 
 
2.5.4.2 Human genetic analysis 
Human genetic study will be performed by testing the single 
nucleotide polymorphism (SNP) at the locus of rs8099917 or 
rs12979860 for interleukin 28B (IL28B) gene (ABI TaqMan allelic 
discrimination kit and ABI7900HT Sequence Detection System, 
Applied Biosystems, Life Technologies Corporation, Grand Island, 
NY) at screening visit. Subjects who do not have available but 
who can be reached before the trial completion will be required 
to perform this genetic study. 
 
2.5.4.3 Virology analyses 
Virology analyses performed at the assigned site visits are shown 


38 
 
below. 
 
Classification 
Item 
Virology 
Hepatitis C virus RNA (HCV RNA) 
Virology 
Hepatitis C virus genotype (HCV genotype) 
Virology 
Resistance associated variants (RAVs) 
 
[1] HCV RNA will be tested by Cobas TaqMan HCV Test v2.0, 
(Roche Diagnostics GmbH, Mannheim, Germany, low limit of 
quantification (LLOQ): 25 IU/mL) 
[2] 
HCV genotype will be tested by Abbott RealTime HCV 
genotype II (Abbott Molecular Inc. Illinois, USA) 
[3] 
RAV analysis: specific instruction for preparation and storage 
of samples will be provided by the central laboratory, and 
RAVs will be performed by population-based sequencing at 
sites of interest for HCV NS regions 
The virological responses during treatment and virologic 
outcome are listed below: 
 
Parameter 
Definition 
Very rapid virologic response (vRVR) 
HCV RNA < LOQ at week 2 of treatment 
Rapid virologic response (RVR) 
HCV RNA < LOQ at week 4 of treatment 
End-of-treatment virologic response 
(EOTVR) 
HCV RNA < LOQ at the end of treatment 
(EOT) 
Sustained virologic response (SVR4) 
HCV RNA < LOQ 4 weeks after the 
completion of treatment 
Sustained virologic response (SVR12) 
HCV RNA < LOQ 12 weeks after the 
completion of treatment 
Sustained virologic response (SVR24) 
HCV RNA < LOQ 24 weeks after the 
completion of treatment 
Virologic failure 
Failure to achieve SVR 
Relapse 
HCV RNA < LOQ at the end-of-treatment, but 
becoming detectable after the cessation of 


39 
 
treatment 
Null-response 
Failure to achieve HCV RNA < LOQ by week 8 
Viral breakthrough 
HCV RNA ≥ LOQ (defined as 2 consecutive 
HCV RNA measurement ≥ LOQ) at any time 
point after HCV RNA < LOQ during treatment 
Increased from nadir HCV RNA (defined as 2 
consecutive HCV RNA measurement of > 1 
log10 IU/mL above nadir) at any time point 
during treatment 
Non virologic failure 
Subjects who fail to achieve SVR and who 
cannot be categorized to relapse, null 
response or viral breakthrough 
 
Except for subjects with relapse or subjects who meet the non 
virologic failure, those who meet the criteria for viral 
breakthrough or viral null-response should discontinue study 
treatment. 
 
2.5.4.4 Abdominal ultrasonography 
Gray-scale abdominal ultrasonography (US) will be recorded at 
the time points of screening visit, and EOT and EOF. 
 
2.5.4.5 Electrocardiogram (ECG) 
Resting 12-lead ECG will be recorded at the time points of 
screening visit, day 1 of treatment, EOT, EOF and the extended 
follow-up. 
 
2.5.4.6 FibroScan and liver biopsy 
FibroScan is required at the screening visit for all subjects who 
are willing to participate in the study. Subjects with a 
non-qualifying Fibroscan results (including failure to measure 
[zero valid measurement], unreliable measurement [less than 10 
valid measurement, a successful rate of less than 60% or the 


40 
 
interquartile range more than 30% of the median FibroScan 
score]) are suggested to receive liver biopsy to confirm the 
severity of hepatic fibrosis. Liver biopsy is not optional and is not 
compulsive. Follow-up Fibroscan will be performed at EOT and 
EOF for all subjects who participate in the study, even if the 
subject with non-qualifying FibroScan evaluation at the 
screening visit. Furthermore, liver biopsy to stage the severity of 
hepatic fibrosis at EOF is also optional. 
 
2.5.4.7 Archive serum sample 
Archive serum samples will be collected at the study visits. 
Archive serum samples are being collected for possible 
additional analyses, including but not limited to, study drug or 
metabolite measurements, viral load, safety/efficacy assessment, 
HCV gene sequencing, HCV resistance testing, and other possible 
predictors for treatment responses. 
The preparation, transport, and storage of the archive serum 
samples will be provided by the central laboratory. 


41 
 
Summary Tables for Study Procedures/Evaluations 
 
Study Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Procedure 
Screening 
Treatment 
EOT 
Follow-up 
EOF 
Extended follow-up 
Study Week 
-4 to -1 
Day 1 
1 
2 
4 
8 
12 
16 
20 
24 
36 
Study Day 
-28 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
252 
Time Window (Day) 
NA 
NA 
±2 
±2 
±2 
±2 
±2 
±7 
±7 
±14 
±14 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
Demographic (age, gender, race) 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Abdominal US 
X 
 
 
 
 
 
X 
 
 
X 
 
12-lead ECG 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Pregnancy test 
X 
X 
 
 
X 
X 
X 
X 
 
 
 
FibroScan or Liver biopsy 
X 
 
 
 
 
 
X 
 
 
X 
 


42 
 
Study Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Procedure 
Screening 
Treatment 
EOT 
Follow-up 
EOF 
Extended follow-up 
Study Week 
-4 to -1 
Day 1 
1 
2 
4 
8 
12 
16 
20 
24 
36 
Study Day 
-28 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
252 
Time Window (Day) 
NA 
NA 
±2 
±2 
±2 
±2 
±2 
±7 
±7 
±14 
±14 
Complete blood count 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PT/aPTT 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Alb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T-Bil/D-Bil 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AST/ALT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALP/r-GT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BUN/Cre 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Na/K 
X 
X 
 
 
 
 
X 
 
 
X 
X 
GluAC 
X 
X 
 
 
 
 
X 
 
 
X 
X 
HbA1c 
X 
X 
 
 
 
 
X 
 
 
X 
X 
TG/T-CHO/HDL/LDL 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Fe/TIBC/ferritin 
X 
X 
 
 
 
 
X 
 
 
X 
X 
AFP 
X 
X 
 
 
 
 
X 
 
 
X 
X 
Anti-HCV 
X 
X 
 
 
 
 
X 
 
 
X 
X 
HBsAg/anti-HBs/anti-HBc 
X 
 
 
 
 
 
 
 
 
 
 
Anti-HIV 
X 
 
 
 
 
 
 
 
 
 
 
HCV RNA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


43 
 
Study Visit 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Procedure 
Screening 
Treatment 
EOT 
Follow-up 
EOF 
Extended follow-up 
Study Week 
-4 to -1 
Day 
1 
2 
4 
8 
12 
16 
20 
24 
36 
Study Day 
-28 to -7 
1 
7 
14 
28 
56 
84 
112 
140 
168 
252 
Time Window 
NA 
NA 
±2 
±2 
±2 
±2 
±2 
±7 
±7 
±14 
±14 
HCV genotype 
X 
 
 
 
 
 
 
 
 
 
 
Resistant variants 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Archive serum sample 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug dispense 
 
X 
X 
X 
X 
X 
 
 
 
 
 


44 
 
3. ADVERSE EVENT MANAGEMENT & REPORTING 
3.1 Adverse event  
An adverse event (AE) is defined as any untoward medical occurrence in a 
patient or clinical investigational subject administered a pharmaceutical 
product and which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory tests), symptom, or disease temporally 
associated with the use of a medicinal or investigational product, whether or 
not the event is considered causally related to the use of the product. 
An AE can result from the use of drugs stipulated in the protocol or labeling, 
as well as from accidental or intentional overdose, drug abuse, or drug 
withdrawal. Any worsening of a subject’s pre-existing health status is 
considered an AE. Laboratory abnormalities and changes in vital signs are 
considered to be AEs only if they result in treatment discontinuation or drug 
dosage reduction, necessitate additional medical intervention, and/or if the 
practitioner/investigator considers them to be an AE. 
An elective surgery/procedure scheduled to occur during a study will not be 
considered an AE even if the surgery/procedure is being performed for a 
pre-existing condition and the surgery/procedure has been planned prior to 
the study, and then the deterioration of the condition for which the elective 
surgery/procedure is being done will be considered an AE. 
 
3.2  Serious adverse event 
A serious adverse event (SAE) is any adverse event occurring for treated 
patients during the study period that will results in any of the following 
outcomes: 
[1] Death 
[2] Life-threatening (subject at immediate risk of death) 
[3] In-patients hospitalization or prolongation of existing hospitalization 
[4] Congenital anomaly or birth defect 
[5] Persistent or significant disability or incapacity 
[6] Important medical event requiring medical or surgical intervention to 
prevent serious outcome 


45 
 
For SAEs with the outcome of death, the date and the cause of death will be 
recorded on the appropriate CRF. 
 
3.3 Reporting and classification procedures 
All constitutional and laboratory AEs of the study are graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, which 
can 
be 
available 
by 
visiting 
the 
following 
website 
(http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference
_5x7.pdf). If the subject experiences the same AE with more than one grade 
of intensity, the highest grade of intensity should be recorded in CRF. In 
addition to grade the severity, the investigator should also determine the 
causal-relationship between each AE or SAEs and the administered 
investigational drug(s). When assessing the relationship to the investigational 
drug(s), the most conservative evaluation should be adopted.  
If a SAE occurs during the study period, the investigator should immediately 
notify the Data Monitor and Safety Board (DMSB), Institutional Review Board 
(IRB)/Ethics Committee (EC) and local regulatory authorities. The site 
investigator must complete a SAE Report Form and is responsible to report 
the event to the regulatory authorities mentioned above by faxing the 
required documents. 
 
3.3.1 Severity of adverse event 
The investigator will use the following definition to grade the severity of 
each AE: 
 
Severity* 
Definition 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; 
limiting age-appropriate instrumental activities of daily living (ADL) 
Grade 3 
Severe or medically significant but not immediate life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL 


46 
 
Grade 4 
Life-threatening consequences; urgent intervention indicated 
Grade 5 
Death related to AE 
* Not all grades are appropriate for all AEs. Therefore, some AEs are listed in CTCAE v.4.0 with 
fewer than five options for Grade selection. 
 
3.3.2 Relationship to investigational drug 
The investigator will use the following definition to assess the 
relationship of the AE to the use of EBR/GZR 
 
Relationship 
Definition 
Reasonable possibility 
An AE where there is evidence to suggest a causal 
relationship between the study drug and the AE 
No reasonable possibility 
An AE where there is no evidence to suggest a causal 
relationship between the study drug and the AE 
 
For causality assessments, events assessed as having a reasonable 
possibility of being related to the investigational drug will be considered 
“associated”. Events assessed as having no reasonable possibility of 
being related to the investigational drug will be considered “not 
associated”. An AE will be considered to be associated to the 
investigational drug if the investigator has not reported a causality or 
deemed it not assessable. 
 
3.3.3 Pregnancy 
Subjects and their partners should avoid pregnancy and males should 
avoid sperm donation throughout the course of the study, starting with 
study day 1 and for 14 days after the EOT by EBR/GZR. 
Information regarding a pregnancy occurrence in a study subject and 
the outcome of the pregnancy will be collected for pregnancies 
occurring up to 14 days after the EOT by EBR/GZR. 
Subjects who discontinue investigational drugs due to pregnancy will be 
monitored for SVR in post-treatment period. 
Pregnancy in a study subject is not considered an AE. However, the 


47 
 
medical outcome of an elective or spontaneous abortion, stillbirth or 
congenital anomaly is considered a SAE. 
 
3.3.4 Toxicity management 
For the purpose of medical management, all AEs and laboratory 
abnormalities that occurring during the study must be evaluated by the 
investigator. Toxicity is deemed “clinically significant” based on the 
judgement of the investigator. Laboratory abnormalities will be 
managed as deemed clinically appropriate by the investigator until 
resolved. 
The investigator should avoid interruption investigational drugs for > 7 
consecutive days. The investigator should ensure that the study drug 
interruptions and the associated AEs are promptly entered into 
appropriate CRF. 
 
3.3.4.1 Grade 1 or 2 adverse events and laboratory abnormalities 
Subjects who develop Grade 1 or 2 AEs or laboratory 
abnormalities may continue investigational drugs with follow-up 
per study protocol and in accordance with local standard of care. 
(See Appendix A) 
 
3.3.4.2 Grade 3, or higher adverse events and laboratory abnormalities 
[1] Grade 3, or higher adverse events (severe or serious 
adverse events) 
If a subject experiences a severe or serious AE that the 
investigator considers to be a reasonable possibility of 
relationship to the study drug, investigator should assess 
whether the AE can be managed medically without 
interruption of study drug, or whether study drug should be 
interrupted until it improves, or study drugs should be 
permanently discontinued. If study drugs are interrupted 
and restarted and the AE recurs, then study drug should be 
permanently discontinued. 
If a subject experiences a severe or serious AE that is 
considered unrelated (no reasonable possibility) to the 
study drugs, it is not necessary to interrupt study drugs 
unless an interruption is required because of the nature of 
the event (e.g. unable to take oral medications). If an 


48 
 
interruption is required, it should not exceed 7 days. 
The investigator should ensure that all SAEs are reported to 
DMSB, IRB/EC, local regulatory authorities within 24 hours 
of awareness. SAE follow-up information, including 
associated dose interruption or discontinuation, must also 
be reported to these institutes within 24 hours of 
awareness and the information should be promptly 
recorded in CRF. 
 
[2] Grade 3, or higher laboratory abnormalities (See Appendix 
A) 
With the exception of Grade 3 or higher abnormalities of 
total bilirubin, uric acid, phosphorous, total cholesterol, 
triglyceride, or glucose (in subjects with a diagnosis of 
diabetes mellitus), if the subject a Grade 3 or higher 
laboratory parameter during the treatment period, the 
abnormal laboratory test should be repeated. If the Grade 3 
or higher abnormality is confirmed, the investigator should 
assess whether the abnormality can be managed medically 
without interruption of the study drugs, or whether study 
drugs should be interrupted or permanently discontinued 
and the laboratory parameter followed until it improves. If 
study drugs are interrupted and restarted and the 
abnormality 
recurs, 
then 
study 
drugs 
should 
be 
permanently discontinued. 
Elevations of serum AST or ALT should be managed 
according to the guidance in Section 3.3.4.3. Grade 3 or 
higher 
abnormalities 
of 
total 
bilirubin, 
uric 
acid, 
phosphorus, total cholesterol, triglyceride, or glucose (in 
subjects with a diagnosis of diabetes mellitus) should be 
managed medically as appropriate and do not require 
conformation or study drug interruption unless deemed 
necessary by the investigator. 
 
3.3.4.3 Management of transaminase elevations 
Transient asymptomatic Grade 3 or higher ALT elevations have 
been observed in approximately 1% of subjects receiving 
grazoprevir-containing regimens. If a subject experiences an 


49 
 
increase in ALT > 10X ULN, or to > 5X ULN which was increased 
from previous measurement, the subject should have a 
confirmatory ALT measurement performed in a timely fashion. If 
the ALT increase in confirmed, the management guideline should 
be followed (See Table “Management of Confirmed ALT 
Elevations”).  
 
3.3.4.4 Risk of HBV reactivation 
Given the recent regulatory guidance of US. FDA on the 
potential HBV reactivation in patients with isolated anti-HBc 
seropositivity receiving HCV DAA therapy, periodic surveillance 
of HBV DNA, ALT levels, and HBV serology are needed to early 
detect these patients with potential HBV reactivation and its 
associated clinical events. 
 
Management of Confirmed ALT Elevations 
ALT ≥ 20X ULN 
• 
Permanently discontinue study drugs. 
• 
Manage the subject as medically appropriate. 
ALT ≥ 10X ULN 
or 
ALT ≥ 5X ULN and increased 
from previous measurement 
with symptoms and signs of 
hepatitis present 
• 
Repeat ALT, AST, T-Bil, D-Bil, ALP, and INR, 
preferably within 1 week 
• 
Evaluate for alterative etiology of ALT 
elevation: 
update 
medical 
history 
and 
concomitant medications CRF (if applicable), 
and obtain appropriate testing as appropriate. 
• 
Manage the subject as medically appropriate. 
• 
Permanently discontinue study drugs for any 
of the following: ALT level increase to 20X 
ULN, increasing D-Bil, increasing INR, or new 
symptoms/signs of hepatitis. 
ALT ≥ 5X ULN and increased 
from previous measurement, 
but < 10X ULN and without 
symptoms or signs of hepatitis 
• 
Continue study drugs. 
• 
As soon as possible, measure ALT, AST, T-Bil, 
D-Bil, ALP and INR. Repeat liver chemistry as 
indicated 
until 
resolution. 
Evaluate 
for 
alternative etiology of ALT elevation: update 
medical history and concomitant medications 
CRF (if applicable), and obtain additional 
testing as appropriate. 
• 
Manage the subject as medically appropriate. 


50 
 
• 
Permanently discontinue study drugs for any 
of the following: ALT level increase to 20X 
ULN, increasing D-Bil, increasing INR, or new 
symptoms/signs of hepatitis. 


51 
 
4. DOSE INTERRUPTION, DISCONTINUATION RULES 
4.1 Dose interruption 
If a subject cannot take his/her study drugs according to protocol specific day 
due to AE, the subject should be treated for the event when appropriate. In 
addition, the subject should return to the clinic as soon as possible to receive 
the scheduled dosing within the timeframe (See Section 2.4.1). If the subject 
fails to receive the assigned study drugs within the timeframe, he/she should 
skip this dosing and return to the clinic for the next protocol specific dosing 
day. If an interruption is required, it should not exceed 7 days. 
 
4.2 Dose discontinuation 
Subjects who meet the one of the following criteria will be discontinued from 
the study 
[1] Serious adverse events (SAEs) 
[2] Subjectively wish to discontinue further treatment 
[3] Pregnancy 
[4] Null response to treatment 
[5] Viral breakthrough under treatment 
[6] Subject’s non-compliance with the protocol 
At any time, if the site investigator thinks that the study is no longer in the 
best interest for the patient, then the patients should be discontinued for 
further treatment. 
 
4.3 Subject withdrawal and replacement 
Subjects may withdrawal from the trials at any time for any reasons. Any 
subjects who are withdrawn from the trials are encouraged to receive 
off-therapy study visits to assess the efficacy and safety. The timing and 
reasons for treatment withdrawal should be documented by investigator in 
the CRF. 
Eligible subjects who are scheduled for treatment but who do not receive any 
study drugs will be replaced and will not be considered in the analyses of 
efficacy and safety endpoints. Subjects who receive at least one dose of the 
study drugs and who prematurely discontinue treatment will not be replaced. 


52 
 
5. PROTOCOL DEVIATION 
The investigator should not implement any deviation from the protocol without 
prior review and agreement by the Sponsor and in accordance with EC and local 
regulatory authorities, except when necessary to eliminate an immediate hazard 
to study subjects. When a deviation from the protocol is deemed necessary for 
an individual subject, the investigator must contact the study coordinator. Any 
significant protocol deviations affecting the subject eligibility and/or safety must 
be reviewed and/or approved by IRB/EC and local regulatory authorities, as 
applicable, prior to implementation. 


53 
 
6. STATISTICAL CONSIDERATION 
6.1 Sample size determination 
[1] Treatment-naïve and treatment experienced HCV GT-1b patients:  
We assume a total of 40 patients would provide an SVR rate in HCV GT-1b 
patients who receive 12 weeks of EBR/GZR therapy to be 95% with a 95% lower 
boundary to be 84%, and with a 11% range higher rates than the 95% upper 
boundary to be 73% in the historical SVR rate of 64% in patients who receive 48 
weeks of peginterferon alfa-2a plus low–dose RBV.31 
[2] Estimated timeframe for completing the enrollment: 24 weeks 
 
6.2 Definition of primary endpoints 
[1] Primary efficacy endpoint: SVR12 rate, defined as subjects with serum 
HCV RNA <LOQ 12 weeks after the cessation of treatment by a sensitive 
HCV RNA test (Cobas TaqMan HCV Test v2.0, Roche Diagnostics GmbH, 
Mannheim, Germany, low limit of quantification (LLOQ): 25 IU/mL) 
divided by total enrolled subjects in each arm for subjects who receive at 
least one dose of the study medication. 
[2] Primary safety endpoint: adverse event (AE)-related withdrawal rate for 
subjects who receive at least one dose of the study medication. 
 
6.3 Analyses for primary efficacy endpoint 
The efficacy endpoint is SVR12, and subjects who do not meet the criteria for 
SVR are considered not to achieve SVR12. The clinical scenarios for subjects 
who fail to achieve SVR12 include: virologic failure, including relapse, 
null-response, viral breakthrough, and non virologic failure (See Section 
2.5.4.3). 
Subjects who are categorized as null-response or viral breakthrough are 
considered non-SVR regardless of the availability of the end of follow-up HCV 
RNA data. 
Subjects (except null-response and viral breakthrough) are considered failure 
to achieve SVR12 even if they do not have available end of follow-up HCV RNA 
data. 
To test the hypothesis that the SVR12 rate of treatment-naïve and 
treatment-experienced patients who receive EBR/GZR for 12 weeks is 


54 
 
superior to those who receive peginterferon plus low-dose RBV for 48 weeks, 
the percentages of subjects with SVR12 in patients will be calculated with a 
2-sided 95% confidence interval (CI) using Wilson score method, and the 
lower confidence bound will be compared to the defined threshold. The 
lower confidence bound must be greater than 64% in order for the regimen 
to be considered superior. 
 
6.4 Analysis for primary safety endpoint 
The safety endpoint is treatment-emergent adverse event (AE)-related 
withdrawal rate for subjects who receive at least one dose of the study 
medication. The proportions of AE-related withdrawal rate in the study are 
reported by number (percentage) as appropriate. We will not report the P 
value because the estimated sample sizes in this trial are aimed to detect the 
differences of efficacy endpoint, rather than the differences of safety 
endpoint. 
 
6.5 Sensitivity analysis for the primary efficacy endpoint 
In addition to presenting the primary efficacy endpoint (SVR12), SVR12 will be 
presented using the following other methods to impute missing 
post-treatment virologic results: 
[1] Imputing any missing HCV RNA values in the SVR12 window by carrying 
forward the last non-missing (post-baseline) HCV RNA value prior to the 
SVR12 window 
[2] Imputing as any missing HCV RNA values in the SVR12 window but 
exclude the subjects who are categorized as “prematurely discontinue 
study drugs with no no-treatment virologic failure” and “missing 
follow-up data in the post-treatment period” 
 
6.6 Subgroup analyses 
The SVR12 will be presented in percentage with 2-sided 95% CI in the 
following subgroups: 
[1] Age (< 55 versus ≥ 55 yeas) 
[2] Sex (male versus female) 


55 
 
[3] BMI (< 25 versus ≥ 25 kg/m2) 
[4] Baseline HCV RNA level (< 800,000 versus ≥ 800,000 IU/mL) 
[5] IL28B genotype rs8099917 (TT versus non-TT) or rs12979860 (CC versus 
non-CC) 
[6] Fibrosis stage (< F2 versus ≥ F2, non-F4 versus F4) by FibroScan and/or 
liver biopsy 
[7] Treatment history (naïve versus experienced) 
 
6.7 Additional efficacy endpoint 
[1] 
SVR24: HCV RNA level < low limit of quantification (LOQ) 24 weeks after 
the completion of therapy (Cobas TaqMan HCV Test v2.0, Roche 
Diagnostics GmbH, Mannheim, Germany, low limit of quantification 
(LLOQ): 25 IU/mL) 
[2] 
Rapid virological response (RVR): HCV RNA level < low limit of 
quantification (LOQ) at week 4 of treatment (Cobas TaqMan HCV Test 
v2.0, Roche Diagnostics GmbH, Mannheim, Germany, low limit of 
quantification (LLOQ): 25 IU/mL) 
[3] 
End-of-treatment virological response (EOTVR): HCV RNA level < low 
limit of quantification (LOQ) at the end of treatment (Cobas TaqMan 
HCV Test v2.0, Roche Diagnostics GmbH, Mannheim, Germany, low limit 
of quantification (LLOQ): 25 IU/mL) 
[4] 
Fibrosis index based on 4 markers (FIB-4): changes of FIB-4 before 
treatment and at the end-of-follow-up 
[5] 
FibroScan: changes of liver stiffness before treatment and at the 
end-of-follow-up 
 
6.8 Resistance analyses 
Only samples with an HCV RNA level of ≥ 1,000 IU/mL will undergo 
population sequence analysis in order to allow accurate assessment of the 
product amplification. For subjects who experience virologic failure, the 
sample closest in time after with an HCV RNA level of ≥ 1,000 IU/mL will be 
used if the HCV RNA level at the time of failure is < 1,000 IU/mL. The 
prototype reference strains are 1b-Con1 with its associated GenBank 


56 
 
Accession ID for sequence analyses. 
For EBR/GZR treatment, resistance-associated signature amino acid variants 
will be identified as appropriate. Amino acid positions where RAVs have been 
identified in vitro and/or in vivo in HCV GT-1b are shown: 
 
Direct Acting Antiviral 
Amino Acid Position for HCV GT-1b RAVs 
Grazoprevir (NS3) 
V36A/I/L/M, Q41L/R, F43S, T54A/C/G/S, V55A/I, Y56F, 
Q80L/R, V107I, S122A/G/R, R155E/K/N/Q/S, A156G/S, 
D168E/N/S, V170A/I/T 
Elbasvir (NS5A) 
M28, Q30, L31, P32L, H58D, A92K, Y93 
 
The following definition will be used in the resistance analyses: 
[1] Baseline sample: sample collected before the first dose of EBR/GZR. 
[2] Baseline variant: a variant (by population sequencing) in a baseline 
sample determined by comparison of the amino acid sequence of the 
baseline sample to the appropriate prototypic reference amino acid 
sequence for a given target at the NS3 and NS5A regions. 
[3] Post-baseline variant by population sequencing: an amino acid variant in 
a post-baseline time point sample that is not detected at baseline in the 
subject and is detectable by population sequencing. 
[4] Emerged variant by population sequencing: a post-baseline variant that 
is observed in 2 or more subjects of the same subgenotype by 
population sequencing. 
[5] Linked variant by population sequencing: 2 or more signature or 
emerged amino acid variants identified within a sample by population 
sequencing where at least one of the variants is at a signature position, 
and no mixture amino acids is detected at either position. 
For those samples to be evaluated, a listing by subject of all baseline variants 
relative 
to 
the 
prototypic 
reference 
sequence 
at 
signature 
resistance-associated amino acid positions will be provided for each target of 
EBR/GZR regimen. Furthermore, the HCV amino acid sequence at 
post-baseline time points with an HCV RNA level of ≥ 1,000 IU/mL that are 
analyzed will be compared to the baseline and prototypic reference amino 


57 
 
acid sequences. A listing by subject and time point of all post-baseline 
variants relative to the baseline amino acid sequences will be provided for 
grazoprevir (NS3) and elbasvir (NS5A). In addition, a listing by subject and 
time point of all post-baseline variants at signature resistance-associated 
amino acid positions relative to the prototypic reference amino acid 
sequences will be provided. Furthermore, the number and percentage of 
subjects with emerged variants by amino acid position and variant within a 
DAA target as compared to baseline will be summarized. 
The number and percentage of subjects with linked variants by population 
sequencing within EBR/GZR will be summarized. In addition to a listing of 
linked variants by subject and time point will be provided for each DAA target. 
The persistence of resistance-associated substitutions that emerged for 
EBR/GZR will be assessed by population sequencing at selected 
post-treatment time point. Listing by subject and time point of all 
post-treatment variants relative to the baseline amino acid sequence will be 
provided for each DAA target. 
 
6.9 Adverse events 
The number and percentage of subjects with treatment-emergent AEs after 
initiation of study drugs through 28 days after the last dose of study drugs will 
be tabulated and provided according to definition provided by CTCAE, version 
4.0. In addition, the number and percentage of subjects with SAEs ad the 
number and the number of percentage of subjects with treatment-emergent 
AEs leading to treatment discontinuation will also be provided. 
Subjects with more than one AE defined by CTCAE, version 4.0, will be 
counted only once for that term using the most severe incidence for the 
severity rating table and the most related for the relationship to study drug 
table. 
 
6.10 Clinical laboratory data 
Clinical laboratory tests will be summarized in each study visit. The baseline 
value will be the last measurement prior to the initial dose of study drug. 
Laboratory data values collected during the treatment period will be 


58 
 
categorized as low, normal, or high based on reference ranges of the 
laboratory used in this study. The number and percentage of subjects who 
experience post-baseline changes during treatment in clinical laboratory 
values from low/normal to high and high/normal to low based in the normal 
range will be summarized. 
Additional analyses will be performed if useful and appropriate. 
 


59 
 
7. STUDY ADMINISTRATION 
7.1 Regulatory and ethical consideration 
7.1.1 Institutional review board/ethics committee approval 
It is the investigator’s responsibility to ensure that the protocol is 
reviewed and approved by an appropriate Institutional Review Board 
(IRB) or Ethics Committee (EC). The investigator must also submit the 
informed consent form, any other written documents for the subject, 
and all advertisements that may be used for subject recruitment to 
the IRB/EC for review and approval before commencing study-specific 
activities. If there would be any protocol amendment during the study, 
it is the investigator’s responsibility to submit the related documents 
to 
IRB/EC 
and 
ensure 
to 
obtain 
IRB/EC 
approval 
before 
implementation of any amended procedures. It is also the 
investigator’s responsibility to submit any SAE report, regular progress 
report to IRB/EC, and receive scheduled or un-scheduled monitoring 
from IRB/EC. 
 
7.1.2 Ethical conduct of the study 
The study will be conducted in accordance with the protocol, 
International 
Conference 
on 
Harmonization 
(ICH) 
guidelines, 
applicable regulations and guidelines governing clinical study conduct 
and the ethical principle that have their origin in the Declaration of 
Helsinki. Responsibilities of the clinical investigator are specified as 
followed: 
[1] Conducting the study in accordance with the relevant, current 
protocol, making changes in a protocol only after notifying 
IRB/EC and local regulatory authorities, except when necessary 
to protect the safety, rights or welfare of subjects. 
[2] Personally 
conducting 
or 
supervising 
the 
described 
investigation(s). 
[3] Informing all subjects that the drugs are being used for 
investigational purposes and complying with the requirements 
relating to informed consent and IRB/EC review and approval of 


60 
 
the protocol and amendments. 
[4] Reporting adverse experiences that occur in the course of the 
investigation(s) to the principle investigator, IRB/EC and local 
regulatory authorities. 
[5] Reading the safety information in the protocol, including the 
instructions for use and the potential risks and side effects of the 
investigational product(s). 
[6] Informing all associates, colleagues, and employees assisting in 
the conduct of the study about their obligations in meeting the 
above commitments. 
[7] Maintaining adequate and accurate records of the conduct 
during the study, making those records available for inspection by 
IRB/EC and local regulatory authorities. 
[8] Maintaining records demonstrating that an EC reviews and 
approves the initial clinical investigation and all amendments. 
[9] Reporting promptly, all changes in the research activity and all 
unanticipated problems involving risks to human subjects or 
others, to the appropriate individuals and/or directly to the 
IRB/EC and local regulatory. 
[10] Following the protocol and not make any changes in the research 
without IRB/EC approval, except where necessary to eliminate 
the apparent immediate hazards to human subjects. 
 
7.1.3 Subject informed consent 
Before enrollment, the subject must provide written informed consent 
form to the investigator in accordance to ethical regulations. A copy of 
the informed consent form will be given to the subject and the 
original one will be placed in the subject’s medical record. The 
International Conference on Harmonization (ICH) required elements 
and Health Insurance Portability and Accountability Act (HIPAA) 
authorization in language that is readable an understandable to the 
subject. 
 


61 
 
7.2 Data collection 
7.2.1 Source documents 
Source documents are defined as original documents, data and 
records. This may include hospital records, clinical and office charts, 
laboratory 
data/information, 
evaluation 
checklist, 
pharmacy 
dispensing and other records, recorded data from automated 
instruments, microfiches, photographic negatives, microfilm or 
magnetic media and/or X-rays. Data collected during the study must 
be recorded by the investigator on the appropriate source documents. 
The investigator(s)/institution(s) will permit study-related monitoring, 
IRB/EC audit, and regulatory inspection(s), providing direct access to 
source documents. 
 
7.2.2 Case report forms 
Case report form (CRF) must be completed for each subject screened 
or enrolled in this study. These forms will be used to transmit 
information collected during the study to the local regulatory 
authorities, as applicable. An electronic CRF (eCRF) will be provided for 
the study. All data should be entered into eCRF within 3 days after the 
subject’s visit. After the subject has completed the trial, the principle 
investigator in each site must review the eCRF and sign the signature 
page of the eCRF to confirm he/she has reviewed all the data in eCRF 
that are pertinent to the subject.  
 
7.3 Record retention 
The site should retain a copy of all the study records for the study subjects in 
a secure and accessible location for a minimum of 10 years after the 
completion of the study. Study records will contain the appropriate 
documents which are conformed to the recommendation by International 
Conference on Harmonization for Good Clinical Practice (ICH-GCP). 
 
7.4 Information disclosure 
7.4.1 Confidentiality 


62 
 
The name of each subject will be kept confidential. The subject’s code 
number, subject’s initial, and date of birth will be recorded in eCRF. All 
the findings in the study will be stored in electronic database. Subject 
will be informed that all personal information made available for 
inspection will be protected in strict confidence. 
 
7.4.2 Completion of the study 
The investigator will conduct the study in compliance with the 
protocol. The investigator will provide a final report to the IRB/EC 
following completion of the study. 
 
7.4.3 Publication policy 
The investigators are intended to publish the results in the form of 
interim analysis or final completion report to the conference meeting 
or related journals as appropriate within a reasonable period of time 
after completion of the study.


63 
 
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39. Buti M, Gordon SC, Zuckerman E, et al. Grazoprevir, elbasvir, and ribavirin for 
chronic hepatitis C virus genotype 1 infection after failure of pegylated 
interferon and ribavirin with an earlier-generation protease inhibitor: final 
24-week results from C-SALVAGE. Clin Infect Dis 2016;62:32-6. 
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(MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV 
co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial. 
Lancet HIV 2015;2:e319-27. 
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severe renal impairment (SRI) not on hemodialysis: pharmacokinetic study. 
AASLD 65th Annual Meeting, Boston, MA, 2014. 
42. Roth D, Nelson DR, Bruchfeld A, et al. Grazoprevir plus elbasvir in 
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study): a combination phase 3 study. Lancet 2015;386:1537-45. 


67 
 
9. APPENDIX 
Appendix A: Grading for Laboratory Abnormalities (Adapted from CTCAE, version 4.0) 
 
Hematology 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hemoglobin decreased 
<LLN - 10.0 g/dL 
<LLN - 6.2 mmol/L 
<LLN – 100 g/L 
10.0 - 8.0 g/dL 
6.2 - 4.9 mmol/L 
100 – 80 g/L 
8.0 – 6.5 g/dL 
4.9 – 4.0 mmol/L 
80 – 65 g/L 
< 6.5 g/dL 
< 4.0 mmol/L 
< 65 g/L 
- 
White blood cell count 
decreased 
< LLN – 3,000/mm3 
< LLN – 3.0 x 109/L 
< 3,000 – 2,000/mm3 
< 3.0 x 109 – 2.0 x 109/L 
< 2,000 – 1,000/mm3 
< 2.0 x 109 – 1.0 x 109/L 
< 1,000/mm3 
< 1.0 x 109/L 
- 
Neutrophil count decreased 
< LLN – 1,500/mm3 
< LLN – 1.5 x 109/L 
< 1,500 – 1,000/mm3 
< 1.5 x 109 – 1.0 x 109/L 
< 1,000 – 500/mm3 
< 1.0 x 109 – 0.5 x 109/L 
< 500/mm3 
< 0.5 x 109/L 
- 
Lymphocyte count decreased 
< LLN –800/mm3 
< LLN – 0.8 x 109/L 
< 800 – 500/mm3 
< 0.8 x 109 – 0.5 x 109/L 
< 500 – 200/mm3 
< 0.5 x 109 – 0.2 x 109/L 
< 200/mm3 
< 0.2 x 109/L 
- 
Lymphocyte count increased 
- 
> 4,000 – 20,000/mm3  
> 20,000/mm3 
- 
- 
Platelet count decreased 
< LLN – 75,000/mm3 
< LLN – 75.0 x 109/L 
75,000 – 50,000/mm3 
75.0 x 109 – 50.0 x 109/L 
50,000 – 25,000/mm3 
50.0 x 109 – 25.0 x 109/L 
< 25,000/mm3 
< 25.0 x 109/L 
- 
INR increased 
> 1 – 1.5 x ULN; > 1 – 1.5 
times above baseline if 
on anticoagulation 
> 1.5 – 2.5 x ULN; > 1.5 – 
2.5 times above baseline if 
on anticoagulation 
> 2.5 x ULN; > 2.5 times 
above baseline if on 
anticoagulation 
- 
- 
Activated partial 
thromboplastin time 
prolonged 
> ULN – 1.5 x ULN 
> 1.5 -2.5 x ULN 
> 2.5 x ULN 
- 
- 


68 
 
 
Biochemistry 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Albumin, serum, low 
< LLN – 3 g/dL 
< LLN – 30 g/L 
< 3 - 2 g/dL 
< 30 - 20 g/L 
< 2 g/dL 
< 20 g/L 
Life-threatening 
consequences; urgent 
intervention indicated 
- 
Blood bilirubin increased 
> ULN – 1.5 x ULN 
> 1.5 – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 x ULN 
 
Alanine aminotransferase 
increased 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
- 
Aspartate aminotransferase 
increased 
> ULN – 3.0 x ULN 
> 3.0 – 5.0 x ULN 
> 5.0 – 20.0 x ULN 
> 20.0 x ULN 
- 
Alkaline phosphatase 
increased 
> ULN – 2.5 x ULN 
> 2.5 – 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
- 
r-GT increased 
> ULN – 2.5 x ULN 
> 2.5 – 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
- 
Glucose, serum, low 
< LLN – 55 mg/dL 
< LLN – 3.0 mmol/L 
< 55 – 40 mg/dL 
< 3.0 – 2.2 mmol/L 
< 40 - 30 mg/dL 
< 2.2 – 1.7 mmol/L 
Hospitalization indicated 
< 30 mg/dL 
< 1.7 mmol/L 
Life-threatening 
consequences 
Death 
Glucose, serum, high (fasting) 
> ULN – 160 mg/dL 
> ULN – 8.9 mmol/L 
> 160 - 250 mg/dL 
> 8.9 – 13.9 mmol/L 
> 250 -500 mg/dL 
> 13.9 – 27.8 mmol/L 
Hospitalization indicated 
> 500 mg/dL 
> 27.8 mmol/L 
Life-threatening 
consequences 
Death 
Triglyceride, high (fasting) 
> 150 – 300 mg/dL 
> 300 - 500 mg/dL 
> 500 – 1,000 mg/dL 
> 1,000 mg/dL 
- 


69 
 
> 1.71 -3.42 mmol/L 
> 3.42 -5.7 mmol/L 
> 5.7 -11.4 mmol/L 
> 11.4 mmol/L 
Cholesterol, high 
> ULN – 300 mg/dL 
> ULN – 7.75 mmol/L 
> 300 - 400 mg/dL 
> 7.75 – 10.34 mmol/L 
> 400 - 500 mg/dL 
> 10.34 – 12.92 mmol/L 
> 500 mg/dL 
> 12.92 mmol/L 
- 
Uric acid, serum, high 
> ULN – 10.0 mg/dL (0.59 
mmol/L) without 
physiologic 
consequences 
- 
> ULN – 10.0 mg/dL (0.59 
mmol/L) with physiologic 
consequences 
> 10.0 mg/dL (> 0.59 
mmol/L) 
Life-threatening 
consequences 
- 
Sodium, serum, high 
> ULN – 150 mmol/L 
> 150 – 155 mmol/L 
> 155 – 160 mmol/L 
Hospitalization indicated 
> 160 mmol/L 
Life-threatening 
consequences 
Death 
Sodium, serum, low 
< LLN – 130 mmol/L 
- 
< 130 – 120 mmol/L 
< 120 mmol/L 
Life-threatening 
consequences 
Death 
Potassium, serum, high 
> ULN – 5.5 mmol/L 
> 5.5 – 6.0 mmol/L 
> 6.0 – 7.0 mmol/L 
Hospitalization indicated 
> 7.0 mmol/L 
Life-threatening 
consequences 
Death 
Potassium, serum, low 
< LLN – 3.0 mmol/L 
< LLN – 3.0 mmol/L 
Symptomatic; intervention 
indicated 
< 3.0 – 2.5 mmol/L 
Hospitalization indicated 
< 2.5 mmol/L 
Life-threatening 
consequences 
Death 
Calcium, serum, high 
> ULN – 11.5 mg/dL 
> ULN – 2.9 mmol/L 
> 11.5 – 12.5 mg/dL 
> 2.9 – 3.1 mmol/L 
Symptomatic 
> 12.5 – 13.5 mg/dL 
> 3.1 – 3.4 mmol/L 
Hospitalization indicated 
> 13.5 mg/dL 
> 3.4 mmol/L 
Life-threatening 
Death 


70 
 
consequences 
Calcium, ionized, high 
> ULN – 1.5 mmol/L 
> 1.5 – 1.6 mmol/L 
Symptomatic 
> 1.6 – 1.8 mmol/L 
Hospitalization indicated 
> 1.8 mmol/L 
Life-threatening 
consequences 
Death 
Calcium, serum, low 
< LLN – 8.0 mg/dL 
< LLN – 2.0 mmol/L 
< 8.0 – 7.0 mg/dL 
< 2.0 – 1.75 mmol/L 
< 7.0 – 6.0 mg/dL 
< 1.75 – 1.5 mmol/L 
Hospitalization indicated 
< 6.0 mg/dL 
< 1.5 mmol/L 
Life-threatening 
consequences 
Death 
Calcium, ionized, low 
< LLN – 1.0 mmol/L 
< 1.0 – 0.9 mmol/L 
Symptomatic 
< 0.9 – 0.8 mmol/L 
Hospitalization indicated 
< 0.8 mmol/L 
Life-threatening 
consequences 
Death 
Phosphate, serum, low 
< LLN – 2.5 mg/dL 
< LLN – 0.8 mmol/L 
< 2.5 – 2.0 mg/dL 
< 0.8 – 0.6 mmol/L 
< 2.0 – 1.0 mg/dL 
< 0.6 – 0.3 mmol/L 
< 1.0 mg/dL 
< 0.3 mmol/L 
Life-threatening 
consequences 
Death 
Magnesium, serum, high 
> ULN – 3.0 mg/dL 
> ULN – 1.23 mmol/L 
- 
> 3.0 – 8.0 mg/dL 
> 1.23 – 3.30 mmol/L 
> 8.0 mg/dL 
> 3.30 mmol/L 
Life-threatening 
consequences 
Death 
Magnesium, serum, low 
< LLN – 1.2 mg/dL 
< LLN – 0.5 mmol/L 
< 1.2 – 0.9 mg/dL 
< 0.5 – 0.4 mmol/L 
< 0.9 – 0.7 mg/dL 
< 0.4 – 0.3 mmol/L 
< 0.7 mg/dL 
< 0.3 mmol/L 
Life-threatening 
Death 


71 
 
consequences 
Lipase increased 
> ULN – 1.5 x ULN 
> 1.5 – 2.0 x ULN 
> 2.0 – 5.0 x ULN 
> 5.0 x ULN 
- 
Serum amylase increased 
> ULN – 1.5 x ULN 
> 1.5 – 2.0 x ULN 
> 2.0 – 5.0 x ULN 
> 5.0 x ULN 
- 
Iron overload 
- 
Moderate symptoms; 
intervention not indicated 
Severe symptoms; 
intervention indicated 
Life-threatening 
consequences; urgent 
intervention indicated 
Death 
 
Cardiac Investigation 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Electrocardiogram QT 
corrected interval prolonged 
QTc 450-480 ms 
QTc 481-500 ms 
QTc ≥ 501 ms at least two 
separate ECGs 
QTc ≥ 501 ms and > 60 ms 
change from baseline and 
Torsade de pointes or 
polymorphic ventricular 
tachycardia or 
signs/symptoms of serious 
arrhythmia 
- 
LLN: lower limit of normal; ULN: upper limit of normal