A Phase IV, Open-label, Single Arm, Multicentre Trial of Grazoprevir/Elbasvir for Genotype 1 or 4 in People With Chronic Hepatitis C Virus Infection and Recent Injecting Drug Use or Receiving Opioid Substitution Therapy
Phase: PHASE4
Conditions: Hepatitis C
Sponsor: Kirby Institute

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 1 of 38 
 
Scale-up of treatment for hepatitis C infection among people who inject drugs: 
 
A phase IV, open-label, single arm, multicentre trial of elbasvir/grazoprevir for 
genotype 1 or 4 in people with chronic hepatitis C virus infection and recent 
injecting drug use or receiving opioid substitution therapy 
 
Protocol number: 
VHCRP1510 
Protocol version: 
5.0 
Protocol date:  
12 December 2017 
Name of sponsor: 
UNSW Australia 
 
 
 
The Kirby Institute 
 
 
 
Wallace Wurth Building (C27) 
 
 
 
Sydney, NSW 2052 
 
 
 
Australia 
 
Title and name of Co-Coordinating Principal Investigators (CPI): 
 
Coordinating Co-Principal Investigators (CPI):  
 
Medical Monitor: 
Professor Gregory Dore 
Professor Jason Grebely 
A/Professor Gail Matthews 
The Kirby Institute  
The Kirby Institute  
The Kirby Institute  
UNSW Australia 
UNSW Australia 
UNSW Australia  
Wallace Wurth Building (C27) 
Wallace Wurth Building (C27) 
Wallace Wurth Building (C27) 
Sydney NSW 2052 
Sydney NSW 2052 
Sydney NSW 2052 
Australia 
Australia 
Australia 
E: gdore@kirby.unsw.edu.au 
E: jgrebely@kirby.unsw.edu.au 
E: gmatthews@kirby.unsw.edu.au 
P: +61 2 9385 0900 
P: +61 2 9385 0957 
P: +61 2 9385 0877 
F: +61 2 9385 9214 
F: +61 2 9385 9214 
F: +61 2 9385 9214 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 2 of 38 
Table of contents 
Protocol Synopsis ............................................................................................................................................ 4 
Schedule of Assessments............................................................................................................................... 11 
1. 
Background and rationale ................................................................................................................ 12 
2. 
Study objectives ................................................................................................................................ 14 
3. 
Participant population ...................................................................................................................... 14 
4. 
Study design ...................................................................................................................................... 16 
5. 
Treatment of participants ................................................................................................................. 17 
5.1 Dosage and administration ............................................................................................................... 17 
5.2 Elbasvir/grazoprevir prior and concomitant medications ................................................................ 17 
6. 
Study procedures .............................................................................................................................. 19 
6.1 Visits and Procedures ....................................................................................................................... 19 
6.2 Study Questionnaires........................................................................................................................ 22 
6.3 Linkage of data.................................................................................................................................. 23 
7. 
Recording and reporting Adverse Events (AEs) ................................................................................ 23 
7.1 Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events .............................. 23 
7.1.1 Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events .............................. 23 
7.1.2 Definition of Serious Adverse Events (Including Serious Adverse Drug Reactions) ......................... 23 
7.2 Assessment of Serious Adverse Events ............................................................................................ 24 
7.2.1 Assessment of Causality for Study Drugs and Procedures ............................................................... 24 
7.2.2 Assessment of Severity ..................................................................................................................... 24 
7.3 Reporting Requirements................................................................................................................... 25 
7.3.1 Adverse Events ................................................................................................................................. 25 
7.3.2 Serious Adverse Events ..................................................................................................................... 25 
7.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................................. 26 
8. 
Packaging, labeling, storage and accountability of clinical trial supplies ......................................... 26 
8.1 Formulation ...................................................................................................................................... 27 
8.2 Packaging and Labelling .................................................................................................................... 27 
8.3 Storage and handling ........................................................................................................................ 27 
9. 
Biological samples ............................................................................................................................. 27 
9.1 Laboratory supplies and sample processing ..................................................................................... 27 
9.2 Shipping of biological samples .......................................................................................................... 28 
9.3 Future use of biological samples ...................................................................................................... 29 
10. 
Statistics ............................................................................................................................................ 29 
11. 
Data Safety and Monitoring Board (DSMB). ..................................................................................... 31 
12. 
Data collection, source documents and record retention ............................................................... 31 
12.1 Submission of data ........................................................................................................................... 31 
12.2 Linkage of data.................................................................................................................................. 32 
12.3 Retention of Data Linkage Records .................................................................................................. 32 
12.4 Archiving ........................................................................................................................................... 33 
13. 
Ethics committee/regulatory approval and informed consent ........................................................ 33 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 3 of 38 
14. 
Confidentiality of data ...................................................................................................................... 34 
14.1 Confidentiality of participant records............................................................................................... 34 
14.2 Confidentiality of study data ............................................................................................................ 35 
15. 
Governance ....................................................................................................................................... 36 
16. 
Quality Control (QC) and Quality Assurance (QA) ............................................................................ 35 
17. 
Publication Policy .............................................................................................................................. 35 
18. 
List of References.............................................................................................................................. 36 
19. 
Abbreviations List ............................................................................................................................. 38 
 
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 4 of 38 
Protocol Synopsis 
 
Title 
Scale-up of treatment for hepatitis C infection among people who inject 
drugs: A phase IV, open-label, single arm, multicentre trial of 
elbasvir/grazoprevir for genotype 1 or 4 in people with chronic hepatitis 
C virus infection and recent injecting drug use or receiving opioid 
substitution therapy (OST). 
 
Protocol registration no. 
 
NCT02940691 
Background and rationale 
 
 
People who inject drugs (PWID) account for the majority of new (80%) 
and existing (60%) cases of HCV in high-income countries1,2. Development 
of chronic HCV infection may lead to progressive hepatic fibrosis, 
cirrhosis, and complications of liver failure or hepatocellular carcinoma3. 
The ageing cohort of PWID populations means that liver disease-related 
mortality is increasing4-7. However, treatment can attenuate HCV-related 
disease consequences, including all-cause mortality8. HCV transmission 
also continues to occur among PWID9. Estimated HCV incidence among 
PWID ranges from 5-45% per annum10. The risk of HCV infection is 
highest among recent initiates into injecting drug use. Harm reduction 
strategies, such as needle syringe programs (NSP) and opioid substitution 
treatment (OST) have been successful for HIV prevention among PWID, 
but have been less effective for HCV prevention11-15. In many countries, 
low coverage of NSP and OST further hinders HCV prevention efforts16. 
Given that HCV transmission continues to occur among PWID and there is 
no HCV vaccine, strategies to achieve HCV elimination among PWID must 
be explored.   
 
Data from mathematical modelling suggests that substantial reductions 
in HCV prevalence and incidence could be achieved among PWID with 
modest increases in treatment uptake with interferon-free HCV 
regimens17. Given the potential prevention benefits, HCV treatment 
among PWID is also cost-effective18, 19. In fact, combining interferon-free 
HCV therapies with high coverage OST and NSP may lead to even greater 
reductions in HCV prevalence20. As such, combination prevention 
strategies including “HCV Treatment as Prevention”, OST and NSP are 
critical for achieving reductions in HCV prevalence/transmission to very 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 5 of 38 
low levels18. Targeted treatment to those at risk of transmission could be 
used as an HCV “Treatment as Prevention” strategy to reduce onward 
transmission. 
 
One of the most important breakthroughs in clinical medicine in recent 
decades is the advent of well-tolerated, simple, short-course interferon-
free direct acting antiviral (DAA) HCV regimens with cure rates >95%21. 
The interferon-free dual DAA regimen of elbasvir 50 mg once-daily (NS5A 
inhibitor) and grazoprevir 100 mg once-daily (NS3/4A protease inhibitor) 
has demonstrated high efficacy (95% SVR12 overall, 97% SVR12 in those 
with cirrhosis) with a treatment duration of 12 weeks in treatment-naïve 
patients with HCV genotypes 1 or , 4 infection22, including those with HIV 
co-infection (95% SVR12)24. Elbasvir/grazoprevir was also the first DAA 
regimen to be evaluated in a phase III program among a study population 
of people on opioid substitution (OST) treatment, including those with 
ongoing drug use. Results from the CO-STAR study demonstrated 99% of 
patients had >90% adherence to elbasvir/grazoprevir or placebo and the 
overall SVR12 in the full analysis set was 92%. These data suggest that 
interferon-free treatments, such as elbasvir/grazoprevir, will be feasible 
for the treatment of PWID with recent injecting drug use or receiving 
OST.  
 
 
One limitation of the CO-STAR study is that inclusion in this study 
required participants being on stable OST therapy prior to study entry. As 
such, only 59% of the total study population tested positive for illicit 
drugs at the time of treatment initiation. Among people enrolled in the 
3YFU study, injecting drug use in the past 6 months was only reported by 
25% of participants. Further, this study used an innovative adherence 
reminder device, which may have led to improved outcomes in this 
population. As such, further data is needed on responses to 
elbasvir/grazoprevir among recent PWID and people receiving OST in the 
“real-world”. In addition, long-term follow-up to better characterize HCV 
reinfection in those with recent injecting drug use and successful therapy 
is essential.    
 
Australia is an ideal setting for a study to evaluate elbasvir/grazoprevir 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 6 of 38 
therapy among recent PWID and people receiving OST. First, Australia 
has a strong foundation of health services for HCV testing (>80% of PWID 
have been HCV tested and diagnosed) and care among PWID. Second, 
there is a well-established network of clinical sites experienced in clinical 
trial research. Third, Australia has a high coverage of NSP and OST 
services for PWID, which could act in combination with HCV treatment 
scale-up to achieve greater prevention benefits. Lastly, Australia is the 
first country in the world to have broad access to government-funded 
interferon-free DAA HCV therapies without disease-based and drug and 
alcohol use-based restrictions and including specialist and general 
practitioner prescribing. Within the context of an HCV treatment scale-up 
project, this would enable the evaluation of elbasvir/grazoprevir for 
people with HCV genotype 1 or 4 and recent injecting drug use or 
receiving OST. 
 
Drug and alcohol clinics and primary health care clinics are logical venues 
for expanding HCV care, given the large burden of HCV and an existing 
framework for the provision of care for PWID. These settings are ideal for 
a study to evaluate HCV treatment scale-up among PWID with recent 
injecting drug use or receiving OST in the tertiary, drug and alcohol and 
primary health care settings. This project will build on the existing clinical 
capacity at these clinics and utilize the internationally leading Kirby 
Institute Viral Hepatitis Clinical Research Program expertise and clinical 
research operational capacity. 
 
Study objectives 
Hypothesis 
Interferon-free 
and 
ribavirin-free 
DAA 
HCV 
therapy 
with 
elbasvir/grazoprevir will lead to SVR12 >90% among PWID with recent 
injecting drug use or receiving OST and chronic HCV genotype 1 or 4 
infection. 
 
Primary Objective 
To evaluate the proportion of patients with undetectable HCV RNA at 12 
weeks post end of treatment (SVR12) following interferon-free and 
ribavirin-free DAA therapy with elbasvir/grazoprevir among PWID with 
recent injecting drug use or receiving OST and chronic HCV genotype 1 or 
4 infection and evaluate demographic and clinical predictors of non-
response. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 7 of 38 
Secondary Objective 
To evaluate the rate of HCV reinfection up to three years following 
interferon-free and ribavirin-free DAA therapy with elbasvir/grazoprevir. 
 
Exploratory Objectives 
1) To evaluate factors associated with SVR12 (e.g. drug use at 
baseline and during therapy, adherence);  
2) To evaluate the adherence to therapy and associated factors; 
3) To evaluate safety and tolerability; 
4) To evaluate injecting risk behaviours during and following HCV 
treatment; 
5) To evaluate HCV phylogenetic clustering and molecular 
epidemiology; 
6) To 
evaluate 
the 
prevalence 
of 
resistance 
associated 
substitutions; 
7) To determine the sensitivity and specificity of the Xpert® HCV 
Viral Load assay for HCV RNA detection in samples collected by 
finger-stick capillary whole-blood. 
 
Participant population  
A total of 150 participants will be recruited from tertiary, drug and 
alcohol and primary health care services in Sydney, Australia. 
 
Inclusion criteria 
1) Participants have voluntarily signed the informed consent form. 
2) Be ≥18 years of age on day of signing informed consent form. 
3) Have chronic HCV genotype 1 or 4 infection (defined as detectable 
HCV RNA).  
4) Recent injecting drug use (previous 6 months) or receiving opioid 
substitution therapy (OST). 
5) HIV-1 infected subjects enrolled in the study must meet the 
following criteria: 
a) Have HIV infection documented by any licensed rapid HIV test 
or HIV enzyme or chemiluminescence immunoassay (E/CIA) 
test kit at any time prior to study entry (Baseline) and 
confirmed by a licensed Western blot or a second antibody 
test by a method other than the initial rapid HIV and/or E/CIA, 
or by HIV-1 p24 antigen, or plasma HIV-1 RNA viral load. 
b) Be on HIV Antiretroviral Therapy (ART) for at least 4 weeks 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 8 of 38 
prior to study entry using an ART regimen that is allowable 
with the intended DAA regimen as determined by the current 
PI 
and 
the 
Liverpool 
drug 
interaction 
website 
(http://www.hiv-druginteractions.org/) or current prescribing 
guidelines for elbasvir/grazoprevir OR be naive to treatment 
with any antiretroviral therapy (ART) with a baseline CD4 
count of >200 and have no plans to initiate ART treatment 
while participating in this study and through to at least 
Follow-up Week 4. 
6) Negative pregnancy test at screening and baseline (females of 
childbearing potential only). 
7) All fertile males and females must be using effective contraception 
during treatment and during 14 days after treatment end.  
 
Exclusion criteria 
The subject must be excluded from participating in the trial if the subject: 
1) Is taking or plans to take any prohibited medications as per DAA 
Product Information or herbal supplements, including but not 
limited to St. John’s Wort (Hypericum perforatum) within 2 weeks 
of Baseline. 
2) Is currently using or intends to use barbiturates.  
3) Is a female and is pregnant or breast-feeding, or expecting to 
conceive or donate eggs from Baseline and continue throughout 
treatment, and after the last dose of study medication (as per the 
regimen requirements), or longer if dictated by local regulations. 
4) Has any condition or pre-study laboratory abnormality, ECG 
abnormality or history of any illness, which, in the opinion of the 
investigator, might confound the results of the study or pose 
additional risk in administering the study drugs to the subject. 
5) Had a life-threatening SAE during the screening period. 
6) Has exclusionary laboratory values as listed below: 
Laboratory Assessment 
Value 
Haemoglobin 
< 9.5 g/dL for both males and 
females 
Platelets 
< 75 x 103 /µL 
Serum albumin 
< 3.0 g/dL 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 9 of 38 
9) Has Child Pugh-B or C decompensated cirrhosis. 
10) Has previous HCV treatment-experience. 
11) Has ongoing severe psychiatric disease as judged by the treating 
physician.  
12) Has frequent injecting drug use that is judged by the treating 
physician to compromise treatment safety. 
14) Is unable or unwilling to provide informed consent or abide by the 
requirements of the study. 
15) Is Hepatitis B surface antigen (HBsAg) positive. 
 
Study design 
The study will be conducted as a phase IV, open-label single arm 
multicentre trial. 
 
A total of 150 participants with chronic hepatitis C virus infection 
genotype 1 or 4 with recent injecting drug use or receiving OST will be 
enrolled.  
 
The study consists of a treatment phase of 12 weeks and a follow up 
phase of up to 3 years. Participants will be followed up every 3 months 
for the first year and every 6 months in year’s 2-3 to evaluate treatment 
response and reinfection. 
 
Treatment of participants 
Participants with chronic hepatitis C infection genotype 1 or 4 will receive 
12 weeks of open-label elbasvir/grazoprevir (50mg/100mg) in a once 
daily fixed combination.  
 
Study procedures 
Refer to the Schedule of Assessments and Study Procedures (Section 6) 
 
Statistics 
Primary Objective: To evaluate the proportion of patients with 
undetectable HCV RNA at 12 weeks post end of treatment (SVR12) 
following elbasvir/grazoprevir therapy among PWID with recent injecting 
drug use or receiving OST and chronic HCV genotype 1 or 4 infection and 
evaluate demographic and clinical predictors of non-response. 
 
Assuming an overall SVR of 90% (135 of 150), the 95% confidence interval 
around this estimate will be 84.0% to 94.3%. This study will have robust 
power to examine the effect of treatment setting on SVR: e.g. 80% power 
to detect an odds ratio of 0.39 or 2.59 or more extreme (with alpha=0.05) 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 10 of 38 
for a variable that is 50% prevalent. 
 
Secondary Objective: Estimate incidence and predictors of HCV 
reinfection after successful elbasvir/grazoprevir. 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 11 of 38 
Schedule of Assessments 
 
Assessment / Procedure 
Screen 
Baseline 
W4 
Safety 
Study 
Treatment 
(weeks) 
Follow-up (weeks) 
Study weeks 
-6 to 0 
0 
4 
8 
12 
(ETR) 
24 
(SVR12) 
36 
(FU1) 
48 
(FU2) 
60 
(FU3) 
84 
(FU4) 
108 
(FU5) 
132 
(FU6) 
156 
(FU7) 
Study Days 
-42 to 0 
0 
28 
56 
84 
168 
252 
336 
420 
588 
756 
924 
1092 
Visit Window (Days) 
 
 
+/- 7 
+/- 7 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
+/- 14 
Informed consent, medical history 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs & physical measurements 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
HCV-RNA testing (Local Laboratory) 
xa 
 
xa 
 
x 
x 
xd 
HCV genotyping (Local Laboratory) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Behavioural survey 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated behavioural survey 
 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Adherence survey and pill count 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
Health outcomes survey (EQ-5D) 
x 
 
 
 
x 
x 
 
 
 
 
 
 
 
Liver function tests/ Full blood count/ Biochemistry 
x 
x 
 
xc 
x 
x 
 
 
 
 
 
 
 
HIV & HBV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Fibroscan 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
x 
x 
x 
x 
x 
xf 
 
 
 
 
 
 
 
Serious Adverse Events 
 
x 
x 
x 
x 
xe 
 
 
 
 
 
 
 
Concomitant medication 
x 
x 
 
 
x 
 
 
 
 
 
 
 
 
Research Sample (10 mL EDTA plasma and Whole Blood)  
xb 
xb 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HCV sequencing/resistance testing (tested at Central lab using 
10ml of research sample) 
xg 
Finger-stick point-of-care HCV RNA testing (sub-study sites 
only) 
x 
x 
x 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
 a must be quantitative HCV RNA, b 4ml whole Blood and 20mL EDTA at Screening and Baseline only, c ALT only, d as per standard of care, e to week 16  only, f at 14 days post end of treatment (home test allowed) g To evaluate the 
prevalence of resistance associated substitutions and for relapse or reinfection as needed  

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 12 of 38 
1. Background and rationale 
People who inject drugs (PWID) account for the majority of new (80%) and existing (60%) cases of HCV in 
high-income countries1, 2. Development of chronic HCV infection may lead to progressive hepatic fibrosis, 
cirrhosis, and complications of liver failure or hepatocellular carcinoma3. The ageing cohort of PWID 
populations means that liver disease-related mortality is increasing4-7. However, treatment can attenuate 
HCV-related disease consequences, including all-cause mortality8. HCV transmission also continues to 
occur among PWID9. Estimated HCV incidence among PWID ranges from 5-45% per annum10. The risk of 
HCV infection is highest among recent initiates into injecting drug use. Harm reduction strategies, such as 
needle syringe programs (NSP) and opioid substitution treatment (OST) have been successful for HIV 
prevention among PWID, but have been less effective for HCV prevention11-15. In many countries, low 
coverage of NSP and OST further hinders HCV prevention efforts16. Given that HCV transmission continues 
to occur among PWID and there is no HCV vaccine, strategies to achieve HCV elimination among PWID 
must be explored.   
 
Data from mathematical modelling suggests that substantial reductions in HCV prevalence and incidence 
could be achieved among PWID with modest increases in treatment uptake with interferon-free HCV 
regimens17. Given the potential prevention benefits, HCV treatment among PWID is also cost-effective18, 
19. In fact, combining interferon-free HCV therapies with high coverage OST and NSP may lead to even 
greater reductions in HCV prevalence20. As such, combination prevention strategies including “HCV 
Treatment as Prevention”, OST and NSP are critical for achieving reductions in HCV 
prevalence/transmission to very low levels18. Targeted treatment to those at risk of transmission could be 
used as an HCV “Treatment as Prevention” strategy to reduce onward transmission. 
 
One of the most important breakthroughs in clinical medicine in recent decades is the advent of well-
tolerated, simple, short-course interferon-free direct acting antiviral (DAA) HCV regimens with cure rates 
>95%21. The interferon-free dual DAA regimen of elbasvir 50 mg once-daily (NS5A inhibitor) and 
grazoprevir 100 mg once-daily (NS3/4A protease inhibitor) has demonstrated high efficacy (95% SVR12 
overall, 97% SVR12 in those with cirrhosis) with a treatment duration of 12 weeks in treatment-naïve 
patients with HCV genotypes 1 or , 4 infection22, including those with HIV co-infection (95% SVR12)24. 
Elbasvir/grazoprevir was also the first DAA regimen to be evaluated in a phase III program among a study 
population of people on opioid substitution (OST) treatment, including those with ongoing drug use. 
Results from the CO-STAR study demonstrated 99% of patients had >90% adherence to 
elbasvir/grazoprevir or placebo and the overall SVR12 in the full analysis set was 92%. These data suggest 
that interferon-free treatments, such as elbasvir/grazoprevir, will be feasible for the treatment of PWID 
with recent injecting drug use and people receiving OST.  

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 13 of 38 
However, treatment failure due to resistance associated substitutions (RASs) has been described 
following therapy with elbasvir and grazoprevir 25. In particular, reduced response to HCV therapy has 
been observed in certain sub-groups of patients, specifically HCV genotype 1a, with pre-existing RASs, 
such as M28L/T/V, Q30H/L/R, L31M, or Y93C/H/N/S26-30 More recently, the Australian product 
information for elbasvir/grazoprevir and the Australian Recommendations for the Management of 
Hepatitis C Infection have no recommendation for resistance testing prior to initiation of 
elbasvir/grazoprevir given the low prevalence of resistance mutations in the Australian population.  
 
 
One limitation of the CO-STAR study is that inclusion in this study required participants being on stable 
OST therapy prior to study entry. As such, only 59% of the total study population tested positive for illicit 
drugs at the time of treatment initiation. Among people enrolled in the 3YFU study, injecting drug use in 
the past 6 months was only reported by 25% of participants. Further, this study used an innovative 
adherence reminder device, which may have led to improved outcomes in this population. As such, 
further data is needed on responses to elbasvir/grazoprevir among recent PWID and people receiving OST 
in the “real-world”. In addition, long-term follow-up to better characterize HCV reinfection in those with 
recent injecting drug use and successful therapy is essential.    
 
Australia is an ideal setting for a study to evaluate elbasvir/grazoprevir therapy among recent PWID. First, 
Australia has a strong foundation of health services for HCV testing (>80% of PWID have been HCV tested 
and diagnosed) and care among PWID and people receiving OST. Second, there is a well-established 
network of clinical sites experienced in clinical trial research. Third, Australia has a high coverage of NSP 
and OST services for PWID, which could act in combination with HCV treatment scale-up to achieve 
greater prevention benefits. Lastly, Australia is the first country in the world to have broad access to 
government-funded interferon-free DAA HCV therapies without disease-based and drug and alcohol use-
based restrictions and including specialist and general practitioner prescribing. Within the context of an 
HCV treatment scale-up project, this would enable the evaluation of elbasvir/grazoprevir for people with 
HCV genotype 1 or 4 and recent injecting drug use or receiving OST. 
 
Drug and alcohol clinics and primary health care clinics are logical venues for expanding HCV care, given 
the large burden of HCV and an existing framework for the provision of care for PWID. These settings are 
ideal for a study to evaluate HCV treatment scale-up among PWID with recent injecting drug use or 
receiving OST in the tertiary, drug and alcohol and primary health care settings. This project will build on 
the existing clinical capacity at these clinics and utilize the internationally leading Kirby Institute Viral 
Hepatitis Clinical Research Program expertise and clinical research operational capacity. 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 14 of 38 
2. Study objectives 
Primary Hypothesis 
Interferon-free and ribavirin-free DAA HCV therapy with elbasvir/grazoprevir will lead to SVR12 >90% 
among PWID with recent injecting drug use or receiving OST and chronic HCV genotype 1 or 4 infection. 
 
Secondary Hypothesis  
The incidence of HCV reinfection following successful interferon-free and ribavirin-free DAA therapy with 
elbasvir/grazoprevir will be <8 per 100 p-yrs among people with recent injecting drug use or receiving 
OST. 
 
Primary Objective 
To evaluate the proportion of patients with undetectable HCV RNA at 12 weeks post end of treatment 
(SVR12) following interferon-free and ribavirin-free DAA therapy with elbasvir/grazoprevir among PWID 
with recent injecting drug use or receiving OST and chronic HCV genotype 1 or 4 infection and evaluate 
demographic and clinical predictors of non-response. 
 
Secondary Objective 
To evaluate the rate of HCV reinfection up to three years following interferon-free and ribavirin-free DAA 
therapy with elbasvir/grazoprevir. 
 
Exploratory Objectives 
1) To evaluate factors associated with SVR12 (e.g. drug use at baseline and during therapy, 
adherence);  
2) To evaluate the adherence to therapy and associated factors; 
3) To evaluate safety and tolerability; 
4) To evaluate injecting risk behaviours during and following HCV treatment; 
5) To evaluate HCV phylogenetic clustering and molecular epidemiology; 
6) To evaluate the prevalence of resistance associated substitutions; 
7) To determine the sensitivity and specificity of the Xpert® HCV Viral Load assay for HCV RNA 
detection in samples collected by finger-stick capillary whole-blood. 
3. Participant population 
Participants will be recruited from tertiary, drug and alcohol and primary health care services in Sydney, 
Australia. 
 
All patients must be eligible for PBS treatment with elbasvir/grazoprevir as per the prescribing guidelines. 
In addition the following inclusion and exclusion criteria apply.  

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 15 of 38 
 
Inclusion criteria 
1) Participants have voluntarily signed the informed consent form. 
2) Be ≥18 years of age on day of signing informed consent form. 
3) Have chronic HCV genotype 1 or 4 infection (defined as detectable HCV RNA).  
4) Recent injecting drug use (previous 6 months) or receiving opioid substitution therapy. 
5) HIV-1 infected subjects enrolled in the study must meet the following criteria: 
a) Have HIV infection documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry (Baseline) 
and confirmed by a licensed Western blot or a second antibody test by a method other than 
the initial rapid HIV and/or E/CIA, or by HIV-1 p24 antigen, or plasma HIV-1 RNA viral load. 
b) Be on HIV Antiretroviral Therapy (ART) for at least 4 weeks prior to study entry using an ART 
regimen that is allowable with the intended DAA regimen as determined by the current PI and 
the Liverpool drug interaction website (http://www.hiv-druginteractions.org/) or current 
prescribing guidelines for elbasvir/grazoprevir OR be naive to treatment with any antiretroviral 
therapy (ART) with a baseline CD4 count of >200 and have no plans to initiate ART treatment 
while participating in this study and through to at least Follow-up Week 4. 
6) Negative pregnancy test at screening and baseline (females of childbearing potential only). 
7) All fertile males and females must be using effective contraception during treatment and during 14 
days after treatment end.  
 
Exclusion criteria 
The subject must be excluded from participating in the trial if the subject: 
1) Is taking or plans to take any prohibited medications as per DAA Product Information or herbal 
supplements, including but not limited to St. John’s Wort (Hypericum perforatum) within 2 weeks of 
Baseline. 
2) Is currently using or intends to use barbiturates.  
3) Is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs from Baseline 
and continue throughout treatment, and after the last dose of study medication (as per the 
regimen requirements), or longer if dictated by local regulations. 
4) Has any condition or pre-study laboratory abnormality, ECG abnormality or history of any illness, 
which, in the opinion of the investigator, might confound the results of the study or pose additional 
risk in administering the study drugs to the subject. 
5) Had a life-threatening SAE during the screening period. 
 
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 16 of 38 
 
6) Has exclusionary laboratory values as listed below: 
Laboratory Assessment 
Value 
Haemoglobin 
< 9.5 g/dL for both males and females 
Platelets 
< 75 x 103 /µL 
Serum albumin 
< 3.0 g/dL 
 
9) Has Child Pugh-B or C decompensated cirrhosis. 
10) Has previous HCV treatment-experience. 
11) Has ongoing severe psychiatric disease as judged by the treating physician.  
12) Has frequent injecting drug use that is judged by the treating physician to compromise treatment 
safety. 
13) Is unable or unwilling to provide informed consent or abide by the requirements of the study. 
15) Is Hepatitis B surface antigen (HBsAg) positive. 
4. Study design 
The primary objective of this project is to evaluate the proportion of patients with undetectable HCV RNA 
at 12 weeks post end of treatment (SVR12) following therapy with elbasvir/grazoprevir among PWID with 
recent injecting drug use or receiving OST and chronic HCV genotype 1 or 4 infection and evaluate 
demographic and clinical predictors of non-response. The secondary objective of this project is to 
evaluate the rate of HCV reinfection up to three years following treatment among PWID with recent 
injecting drug use. 
 
A prospective, observational cohort design will be used to enrol patients with chronic HCV and recent 
injecting drug use (injecting drug use in the previous six months) attending tertiary, drug and alcohol and 
primary health care services. Persons with chronic HCV genotype 1 or 4 and recent injecting drug use (in 
the previous 6 months) or receiving OST will receive therapy with elbasvir/grazoprevir.  
 
The study consists of a treatment phase (12 weeks) and a follow-up phase (up to 3 years) where 
participants will be followed every 3 months for the first year and every 6 months in years 2-3 to evaluate 
treatment response and reinfection. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 17 of 38 
5. Treatment of participants 
It is estimated that a total 150 participants with HCV genotype 1 or 4 will be treated (approximately 100 in 
2017 and 50 in 2018). All participants will be treated with a ribavirin-free regimen of elbasvir/grazoprevir 
for 12 weeks (all treatment-naïve) as per the recommended indication.  
 
Therapy with elbasvir/grazoprevir will be administered within indication utilising PBS drug therefore a 
Clinical Trials Notification (CTN) is not required.  
5.1 
Dosage and administration 
Elbasvir/grazoprevir is to be administered once daily with or without food. Each subject must be given 
instructions to maintain approximately the same daily dosing interval between study drug doses. Subjects 
should be instructed to swallow the study medication tablet whole. Subjects should be instructed to only 
remove the tablet immediately prior to dosing.  
 
For a missed dose of study medication, subjects should be instructed to take the missed dose of study 
medication as soon as possible during the same day. However, no more than the daily dose of 
elbasvir/grazoprevir should be taken on any calendar day. Subjects should be cautioned never to double 
the next dose with a missed dose of study drug under any circumstances.  
 
Participants will be required to complete a monthly adherence questionnaire and unused medication will 
be returned for a pill count. 
 
Elbasvir/grazoprevir is contraindicated in patients with moderate or severe hepatic impairment (Child-
Pugh B or C) due to the expected significantly increased grazoprevir plasma concentration and increased 
risk of alanine aminotransferase (ALT) elevations. 
5.2 
Elbasvir/grazoprevir prior and concomitant medications 
Elbasvir/grazoprevir is contraindicated with organic anion transporting polypeptides 1B1/3 (OATP1B1/3) 
inhibitors, strong inducers of cytochrome P450 3A (CYP3A), and efavirenz. See Table 2 for details.  
 
 
 
 
 
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 18 of 38 
Table 2: Drugs that are contraindicated with elbasvir/grazoprevir 
Drug Class 
Drug(s) within Class that are 
Contraindicated 
Clinical Comment* 
Anticonvulsants 
Phenytoin  
Carbamazepine 
May lead to loss of virologic response 
to 
elbasvir/grazoprevir 
due 
to 
significant decreases in elbasvir and 
grazoprevir plasma concentrations 
caused by strong CYP3A induction. 
Antimycobacterials 
Rifampin 
May lead to loss of virologic response 
to 
elbasvir/grazoprevir 
due 
to 
significant decreases in elbasvir and 
grazoprevir plasma concentrations 
caused by strong CYP3A induction. 
Herbal Products 
St. John’s Wort (Hypericum 
perforatum) 
 
May lead to loss of virologic response 
to 
elbasvir/grazoprevir 
due 
to 
significant decreases in elbasvir and 
grazoprevir plasma concentrations 
caused by strong CYP3A induction. 
HIV Medications 
Efavirenz† 
May lead to loss of virologic response 
to 
elbasvir/grazoprevir 
due 
to 
significant decreases in elbasvir and 
grazoprevir plasma concentrations 
caused by CYP3A induction. 
HIV Medications 
Atazanavir 
Darunavir 
Lopinavir 
Saquinavir 
Tipranavir 
May 
increase 
the 
risk 
of 
ALT 
elevations 
due 
to 
a 
significant 
increase in grazoprevir plasma 
concentrations caused by OATP1B1/3 
inhibition. 
Immunosuppressants 
Cyclosporine 
May 
increase 
the 
risk 
of 
ALT 
elevations 
due 
to 
a 
significant 
increase in grazoprevir plasma 
concentrations caused by OATP1B1/3 
inhibition.  
*This table is not a comprehensive list of all drugs that inhibit OATP1B1/3 or strongly induce CYP3A. 
†Efavirenz is included as a strong CYP3A inducer in this table, since co-administration reduced grazoprevir 
exposure by ≥80%. 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 19 of 38 
Should any participant need to initiate treatment with an excluded concomitant medication during the 
study, the Medical Monitor, A/Prof Gail Matthews must be consulted prior to the initiation of any 
excluded medication. In the event that an excluded medication is initiated prior to discussion with A/Prof 
Gail Matthews, she must be made aware of the use of the excluded medication as soon as possible. 
A/Prof Gail Matthews’ contact details are listed on the cover of this protocol. 
6. Study procedures 
6.1 
Visits and Procedures 
The following assessments must be conducted at study visits as per the schedule of assessments: 
Vital 
signs 
& 
physical 
measurements 
Sitting systolic and diastolic blood pressure, heart rate, body weighta, 
heighta 
Fibroscan 
Within 12 months prior to screening 
Biochemistry 
Creatinine, glucose, sodium, chloride, and potassium 
Liver Function Tests 
ALT, AST, GGT, total bilirubin, albumin, alkaline phosphatase, total 
protein 
Full Blood Count 
Haemoglobin, haematocrit , White Blood Cells, platelets, neutrophils 
HCV RNA 
Must be quantitative at Screening (within 12 weeks prior to Screening) 
and Week 4 
HCV Genotype 
Within 12 weeks prior to screening 
HBV Serology 
Anti-HBc, HBsAg and Anti-HBs testing (within 6 months prior to 
Screening) 
HIV Serology 
HIV antibody (within 6 months prior to Screening) 
HCG Pregnancy Test 
For women of childbearing potential, a negative urine (or serum) HCG 
test at screening, baseline, weeks 4, 8, week 12 (ETR) and week 14 
(home test allowed at week 14) 
Questionnaires 
Behavioural survey, abbreviated behavioural survey, adherence 
questionnaire and EQ-5D 
Finger-stick 
point-of-care 
HCV RNA testing (POC) 
At sub-study sites only 
a at screening only 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 20 of 38 
The following assessments and procedures must be performed at each visit as specified below: 
Initial screening period (Week -6 to Week 0) 
• 
Informed consent 
• 
Medical history  
• 
Vital signs and physical measurements 
• 
Quantitative HCV RNA and genotype (Local Laboratory) 
• 
LFTs, FBC and biochemistry 
• 
HIV & HBV serology 
• 
Fibroscan 
• 
Pregnancy test (females of child bearing potential only)  
• 
Concomitant medication 
• 
Study questionnaires (Behavioural and EQ-5D) 
• 
Research specimen collection (EDTA plasma & whole blood) 
• 
Finger-stick point-of-care HCV RNA testing (Sub-study sites only) 
 
Baseline visit (Week 0) 
• 
Vital signs and physical measurements 
• 
LFTs, FBC and biochemistry 
• 
Pregnancy test (females of child bearing potential only)  
• 
Serious Adverse Events 
• 
Concomitant medication 
• 
Study questionnaires (Abbreviated Behavioural)  
• 
Research specimen collection (EDTA plasma & whole blood) 
• 
Finger-stick point-of-care HCV RNA testing (Sub-study sites only) 
 
On-Treatment Visits  
Week 4 (+/- 7 days) 
• 
Quantitative HCV RNA (Local laboratory) 
• 
Pregnancy test (females of child bearing potential only)  
• 
Serious Adverse Events 
• 
Research specimen collection (EDTA plasma)  
• 
Study questionnaire (Adherence) 
• 
Finger-stick point-of-care HCV RNA testing (Sub-study sites only) 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 21 of 38 
Week 8 (+/- 7 days) 
• 
LFTs – ALT only 
• 
Pregnancy test (females of child bearing potential only) 
• 
Serious Adverse Events 
• 
Research specimen collection (EDTA plasma) 
• 
Study questionnaire (Adherence) 
 
End of Treatment (ETR) - Week 12 (+/-14 days) 
• 
Qualitative HCV RNA (where available, otherwise quantitative), (Local laboratory) 
• 
LFTs, FBC and biochemistry 
• 
Pregnancy test (females of child bearing potential only)  
• 
Serious Adverse Events 
• 
Concomitant medication 
• 
Study questionnaires (Abbreviated Behavioural, Adherence, and EQ-5D) 
• 
Research specimen collection (EDTA plasma)  
 
Post Treatment Follow-up Visits 
Post Treatment Week 12 (SVR12) - Week 24 (+/- 14 days) 
• 
Qualitative HCV RNA (Where available, otherwise quantitative) (Local laboratory) 
• 
LFTs, FBC and biochemistry 
• 
Pregnancy test (females of child bearing potential only) (at 14 days post end of treatment 
– home test allowed) 
• 
Serious Adverse Events (up to week 16 (SVR4) only) 
• 
Study questionnaires (Abbreviated Behavioural and EQ-5D) 
• 
Research specimen collection (EDTA plasma) 
• 
Finger-stick point-of-care HCV RNA testing (Sub-study sites only) 
 
Post Treatment Weeks 36 (FU1), 48 (FU2), 60 (FU3), 84 (FU4), 108 (FU5), 132 (FU6) and 156 (FU7) (+/- 14 
days)  
• 
Qualitative HCV RNA (Where available, otherwise quantitative)  (Local laboratory)  
• 
Study questionnaires (Abbreviated Behavioural) 
• 
Research specimen collection (EDTA plasma) 
• 
Finger-stick point-of-care HCV RNA testing (Sub-study sites only) 
If a patient has suspected viral relapse or HCV reinfection HCV RNA sequencing will be performed. No 
additional sample is required.   
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 22 of 38 
Monitoring of HBV reactivation  
At screening, all patients will be tested for evidence of current (Hepatitis B surface antigen positive) and 
prior (anti-Hepatitis B core antibody positive) HBV infection before initiation of treatment. Patients with 
current HBV infection will be excluded. Patients with evidence of prior HBV infection only will be enrolled.  
 
Patients with evidence of prior HBV infection will be monitored for HBV reactivation and hepatitis flare 
during HCV treatment and post-treatment follow-up. LFTs will be performed 4-weekly during treatment. 
In the setting of a clinically significant ALT elevation or symptoms and signs of acute hepatitis, HBV DNA 
testing will be performed to assess for reactivation. Appropriate management for HBV infection will be 
initiated by the site investigator as clinically indicated.  
 
Sites should advise patients of the risk of HBV reactivation and instruct patients on the signs and 
symptoms of reactivation (such as lethargy, nausea, jaundice). Patients should be encouraged to report 
any signs or symptoms. 
6.2 
Study Questionnaires 
All subjects will undertake a number of study questionnaires at screening, baseline, and selected follow-
up visits.  
The Behavioural Questionnaire  
The study staff will assist participants to complete this questionnaire. The behavioural survey will collect 
information on the following: 
• 
Demographics 
• 
HIV and drug treatment history  
• 
Drug and alcohol usage  
• 
Treatment acceptance and willingness (prior to treatment commencement only) 
• 
Attitudes and behaviours associated with HCV reinfection 
• 
Injecting risk behaviours (including information about injecting sharing partners and 
equipment sharing) 
 
An abbreviated behavioural questionnaire (follow-up) will be administered at subsequent time points 
during the study. 
Health Outcomes Survey (EQ-5D) 
The EQ-5D health questionnaire provides a simple descriptive profile and a single index value for health 
status. This information can then be translated into a health utility, which can be used for cost-
effectiveness analyses. 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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Adherence Survey 
Adherence to elbasvir/grazoprevir will be assessed by a four-weekly structured self-report adherence 
questionnaire and four-weekly pill count.  
6.3 
Linkage of data (optional) 
Participants are invited to consent to link their data collected during the DARLO-C study with routinely 
collected data from a range of population Health and Incarceration databases and registers. 
 
The collection of participant names, date of birth, sex, and post code in DARLO-C is essential for accurate 
data linkage. Participant data will be linked to a variety of health variables including information on 
hepatitis C notifications, HIV/AIDS notifications, use of hepatitis services, use of prescription medication 
(including hepatitis C treatment), OST, incarceration, hospitalizations, emergency department use, cancer, 
and mortality through the New South Wales Centre for Health Record Linkage (www.cherel.org.au), and 
the Australian Institute of Health and Welfare (www.aihw.gov.au). Linkage will be both retrospective and 
prospective, with the time period covered dependent on the properties of the specific data set. Approval 
from the NSW Population and Health Services Research Ethics Committee, and all other required Human 
Research Ethics Committees will be sought prior to any data linkage being performed. 
  
Participants are given the option to opt out of the health and incarceration data linkage component of 
this study on the Participant Consent Form. Participants not wishing to have their data used in the data 
linkage studies may still enroll in DARLO-C.   
7. Recording and reporting Adverse Events (AEs) 
7.1 
Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events 
7.1.1 
Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events 
The medications for this study are supplied via the PBS. Adverse events and adverse drug reactions will be 
reported to the Therapeutic Goods Administration as per standard practice for PBS prescribed 
medications. Only serious adverse events will be reported as detailed below. 
7.1.2 
Definition of Serious Adverse Events (Including Serious Adverse Drug Reactions) 
The definition of a SAE is any untoward medical occurrence that at any dose:  
• 
Results in death 
• 
Is life-threatening 
(Note: the term “life-threatening” in the definition of “serious” refers to an event/reaction in 
which the participant was at risk of death at the time of event/reaction; it does not refer to an 
event/reaction which hypothetically might have caused death if it were more severe) 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 24 of 38 
• 
Requires in-patient hospitalisation or prolongation of existing hospitalisation 
• 
Results in persistent or significant disability/incapacity 
• 
Is a congenital anomaly/birth defect 
• 
Results in a medically important event or reaction (includes infections from contaminated 
medicinal product/s). Other important medical events that may not result in death, not be life 
threatening, or not require hospitalization may be considered a serious adverse experience when, 
based upon appropriate medical judgment, the event may jeopardize the subject/patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above.  
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that did not require 
hospitalization, or development of drug dependency or drug abuse. 
• 
Is an overdose of study medication (whether accidental or intentional) 
• 
Cancer (that is not the condition under the study)* 
 
All Serious Adverse Events, regardless of causal relationship to the investigational product, must be 
forwarded to Merck Worldwide Product Safety via fax (+1 215 993-1220) within 2 working days of the 
investigator becoming aware of the event and no later than 3 calendar days. 
Medical and scientific judgment should be exercised in deciding whether other situations should be 
considered serious e.g. important medical events that may not be immediately life-threatening or result 
in death or hospitalisation, but may jeopardise the participant or may require intervention to prevent one 
of the outcomes listed in the definition above.  
 
Serious adverse events are collected from screening through to 4 weeks post end of treatment (SVR4). 
7.2 
Assessment of Serious Adverse Events 
7.2.1 
Assessment of Causality for Study Drugs and Procedures  
The investigator or designee must assess each adverse event for the following: 
Relationship 
Unlikely: 
An adverse event that is unlikely to be related to the use of the drug or procedures 
Possibly: 
 An adverse event that might be related to the use of the drug or procedures 
Probably: 
 An adverse event that is likely to be related to the use of the drug or procedures 
7.2.2 
Assessment of Severity 
The investigator or designee must assess each adverse event for the following: 
Severity 
Mild: 
 
 
Discomfort noticed but no disruption of normal daily activity 
Moderate: 
 
Discomfort sufficient to reduce or affect normal daily activity 
Severe:  
 
Incapacitating with inability to work or perform normal daily activity 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 25 of 38 
Life threatening: 
Represents an immediate threat to life 
7.3 
Reporting Requirements 
7.3.1 
Adverse Events  
An adverse event means any unfavourable and unintended change in the structure, function, or chemistry 
of the body temporally associated with any use of the Merck product whether or not considered related 
to the use of the product.  Any worsening (i.e., any clinically significant adverse change in frequency 
and/or intensity) of a pre-existing condition which is temporally associated with the use of the product, is 
also an adverse experience. 
 
Adverse events and adverse drug reactions will be reported to the Therapeutic Goods Administration as 
per standard practice for PBS prescribed medications. 
7.3.2 
Serious Adverse Events  
All serious adverse events (SAEs) should be reported within TWO (2) WORKING DAYS of becoming aware 
of the event to the Kirby Institute and Merck by fax on the Serious Adverse Event Reporting Form. The 
appropriate Serious Event form should be used. Reports should be followed promptly by detailed, written 
follow-up reports when all information is not included in the initial report. Follow-up reports should be 
reported within TWO (2) WORKING DAYS also. The immediate and follow up reports should identify 
participants by unique code numbers assigned to study participants rather than personal identification. 
The investigator must also comply with all applicable ethical and regulatory requirement/s relating to the 
reporting of serious adverse events.  
 
Any serious adverse event that is ongoing at the post-study follow-up visit must be followed until 
resolution or until the event stabilizes (for those events that will not resolve). 
 
For deaths, the Principal Investigator will supply the sponsor and the IRB/IEC with any additional 
requested information (e.g. death certificate, autopsy reports and medical reports). 
 
Merck (Attn: Worldwide Product Safety; FAX +1 215 993-1220) will be provided with copies of all serious 
adverse experiences regardless of causality to use of a Merck product within two working days.  
Additionally, any pregnancy occurring in association with use of a Merck Product will be reported (Attn: 
Worldwide Product Safety; FAX +1 215 993-1220). 
 
A copy of all 15 Day Reports is submitted as required by local regulators by the investigator. This 
submission will be cross referenced according to local regulations to the Merck Investigational Compound 
Number (IND, CSA, etc.) at the time of submission.  Additionally, a copy of these reports will be submitted 
to Merck (Attn: Worldwide Product Safety; FAX +1 215 993-1220) at the time of submission to local 
regulator. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 26 of 38 
 
SAE reports must be submitted to BOTH the Kirby Institute AND Merck: 
Kirby Institute:  
 
 
Fax: 
+61 2 9385-9214. 
Merck Worldwide Product Safety:  
Fax:  
+1 215 993 1220 
7.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
The Project Team in collaboration with the Medical Officer will review and identify all serious events 
which fit the criteria of a SUSAR and requiring expedited reporting to relevant parties.  
 
The definition of a SUSAR is a serious adverse event which is both suspected as being related to the drug 
(i.e. has a reasonable suspected causal relationship) and is unexpected) whereby the nature and severity 
is not consistent with known information (e.g. the Investigator’s Brochure).  
 
The sponsor must expedite the reporting of all SUSARs to all concerned investigators/institutions, 
IRB/IEC/s, and regulatory authorities within the reporting timeframe. Reports must comply with the 
applicable regulatory requirements and ICH Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting.  
 
Researchers must inform the IRB/IEC and regulatory authorities of all SUSARs that occur during the study 
that may affect the conduct of the study or the safety of the participants or their willingness to continue 
participation in the study. Researchers must inform the IRB/IEC as soon as possible of any new 
information from other published or unpublished studies which may have an impact on the continued 
ethical acceptability of the study or which may indicate the need for amendments to the study protocol. 
 
All SAEs and SUSARs will be reported to the approving Human Research Ethics Committee as per local 
policy.  
 
Coding 
Serious Adverse Events will be assigned preferred terms and categorised into system organ classes 
according to the Medical Dictionary for Drug Regulatory Affairs (MedDRA) classification of the WHO 
terminology. 
8. Packaging, labeling, storage and accountability of clinical trial supplies 
All study drugs will be supplied via PBS following PBAC listing. The drugs should be dispensed under the 
supervision of the investigator or a qualified member of the investigational staff, or by a hospital/clinic 
pharmacist.  
 
Medications must be stored, and dispensed according to PBS regulations as per standard practice.  

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 27 of 38 
8.1 
Formulation  
The elbasvir/grazoprevir (50mg/100mg) tablets are beige, oval-shaped, film-coated, debossed with “770” 
on one side and plain on the other. In addition to the active ingredients the tablets also contain the 
following inactive ingredients: colloidal silicon dioxide, copovidone, croscarmellose sodium, hypromellose, 
lactose monohydrate, magnesium stearate, mannitol, microcrystalline cellulose, sodium chloride, sodium 
lauryl sulfate, and vitamin E polyethylene glycol succinate. 
8.2 
Packaging and Labelling 
The tablets are packaged into a carton (NDC 0006-3074-02) containing two (2) 14-count child-resistant 
dose packs for a total of 28 tablets. 
8.3 
Storage and handling 
Elbasvir/grazoprevir packs should be stored in the original packs at controlled room temperature until 
required for administration. Elbasvir/grazoprevir should be stored at 20°C to 25°C (68°F to 77°F); 
excursions are permitted between 15°C and 30°C (59°F to 86°F).  
 
Subjects should be counselled to store elbasvir/grazoprevir blister packs at room temperature not in the 
refrigerator. 
  
All drug products should be stored in a securely locked area, assessable only to authorized site personnel. 
To ensure the stability of the study drug and to ensure proper product identification, the drug product 
should not be stored in a container other than the container in which they are supplied. 
9. Biological samples 
9.1 
Laboratory supplies and sample processing 
Laboratory supplies for collection of research specimens (plasma and whole blood) will be supplied by the 
Kirby Institute.  
 
The following blood samples will be collected as time point specified in the schedule of assessments: 
1. 10 mL EDTA plasma for HCV RNA testing and future HCV related research (20 mL will be 
collected at Screening and Baseline visits); 
2. 4mL whole blood for human genomic DNA analysis collected at the screening and baseline 
visits only. 
 
Samples will be collected by sites and then processed and stored at -70°C at the site local laboratory for 
bulk shipment to the Kirby Institute laboratory. Detailed sample processing instructions will be provided 
in the laboratory manual. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 28 of 38 
 
EDTA plasma samples will be used for study endpoint analysis. HCV viral load will be measured using in-
house and commercial assays. Sequencing of the viral genome will also be performed as a more accurate 
means of genotyping. Data generated from the sequencing may also be used to distinguish relapse from 
reinfection and to examine the prevalence of mixed infection.   
 
HCV sequencing/resistance testing 
Sanger sequencing will be performed on a pre-treatment sample on all participants. Complementary RNA 
will be generated using SuperScript® VILO™ cDNA Synthesis Kit (Life Technologies, Carlsbad, CA) with 
random hexamers. Sequencing of NS5A will be performed on all participants.  A fragment of the HCV 
genome covering Core, Envelope-1, hypervariable region-1 and beginning of Envelope-2 (E2) will be 
amplified using a method previously described. Sequencing of NS3/4, NS5A, NS5B, and full-length next 
generation sequencing may also be performed. Purified amplicons will be sequenced using the Sanger 
method and sequence chromatograms processed using RECall: a fully automated sequence analysis 
pipeline. Subtypes will be determined using the Oxford HCV Automated Subtype Tool. Reverse 
transcription, PCR and sequencing reaction and thermal cycling conditions will be performed as previously 
described. Further, Sanger sequencing and next generation sequencing will be performed among samples 
with persistent infection at risk of HCV mixed infection (e.g. treatment non-response). Lastly, Sanger 
sequencing and next generation sequencing will be performed among samples with HCV recurrence to 
distinguish HCV reinfection from viral relapse (detectable HCV RNA following HCV virological suppression).  
 
HCV RNA point of Care testing (sub-study sites only) 
Point of care testing for HCV RNA detection will be performed at each visit at selected sub study sites 
using the Xpert® HCV Viral Load assay for samples collected by finger-stick capillary whole-blood as 
described below. This point of care testing will be undertaken in addition to the standard of care (local 
laboratory).  
 
The capillary whole-blood sample is collected from participants via a finger-stick [MiniCollect® Safety 
Lancet (Order Number 450429), Greiner Bio-One, Monroe, Frickenhausen, Germany] using procedures 
recommended by the World Health Organization31 and collected into a 100µL minivette collection tube 
[Minivette® POCT 100µl (Order number 17.2111.100), Sarstedt, Nümbrech, Germany]. 
9.2 
Shipping of biological samples 
Samples must only be shipped to the Kirby Institute laboratory on the instruction from the Study 
Coordinator.  
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 29 of 38 
It is the responsibility of each site Principal Investigator to ensure that all site staff handling, packaging, 
and/or shipping biological samples understand and comply with International Air Transport Association 
(IATA) regulations relating to the handling and shipping of hazardous goods and/or diagnostic specimens. 
9.3 
Future use of biological samples 
After the samples have been analysed for the study endpoints as specified in the protocol, remaining 
samples will be stored for use in future Human Research Ethics Committee approved hepatitis C related 
research. Additional consent will not be sought for this storage and future use. It is not optional. Subjects 
not wishing to have their samples stored or used in future hepatitis C related research will not be eligible 
to participate in this study. 
10. 
Statistics 
The statistical team and investigators at the Kirby Institute will be responsible for analysing the study 
data. 
 
Primary Objective: To evaluate the proportion of patients with undetectable HCV RNA at 12 weeks post 
end of treatment (SVR12) following elbasvir/grazoprevir therapy among PWID with recent injecting 
drug use or receiving OST and chronic HCV genotype 1 or 4 infection and evaluate demographic and 
clinical predictors of non-response. 
 
Hypothesis: Elbasvir/grazoprevir therapy will lead to SVR12 >90% among PWID with recent injecting drug 
use or receiving OST and chronic HCV genotype 1 or 4 infection. 
 
Outcome: The primary endpoint for this aim is the proportion of participants with a treatment response 
(measured by SVR, undetectable HCV RNA 12 weeks after the completion of therapy).  
 
Statistical analysis: The proportion of people with a response to HCV therapy will be evaluated. Factors 
associated with treatment response (as measured by SVR) will be assessed by univariate and multivariate 
logistic regression analyses. Factors hypothesized to be associated with HCV treatment response will be 
assessed including: sociodemographic factors (housing and education), injecting behaviours (recent 
injecting drug use prior to and during therapy and type of drug injected), and clinical factors (opioid 
substitution treatment, HCV genotype, fibrosis stage). 
 
Sample Size: Assuming an overall SVR of 90% (135 of 150), the 95% confidence interval around this 
estimate will be 84.0% to 94.3%. This study will have robust power to examine the effect of treatment 
setting on SVR: e.g. 80% power to detect an odds ratio of 0.39 or 2.59 or more extreme (with alpha=0.05) 
for a variable that is 50% prevalent. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
Page 30 of 38 
Secondary Objective: Estimate incidence and predictors of HCV reinfection after successful 
elbasvir/grazoprevir. 
 
Hypothesis 2.1: The incidence of HCV reinfection following successful elbasvir/grazoprevir therapy will be 
<8 per 100 p-yrs among people with recent injecting drug use or receiving OST. 
Hypothesis 2.2: HCV reinfection will be associated with ongoing >daily injecting drug use, and needle and 
syringe borrowing. OST and high-coverage access to needle and syringes will be associated with reduced 
HCV reinfection. 
 
Outcome: Incidence of HCV reinfection following successful elbasvir/grazoprevir therapy.  
 
Statistical analysis: Rates of HCV reinfection will be calculated using person-time of observation. The 
estimated date of reinfection will be calculated as the midpoint between the dates of the last 
undetectable HCV RNA test and the first detectable HCV RNA test at the time of HCV reinfection. Time at 
risk will commence at the date of undetectable HCV RNA at end of treatment and end at the first of 
estimated date of re-infection, death, loss-to-follow up or end of study. Confidence intervals for rates will 
be calculated using a Poisson distribution.  
 
Cox proportional hazards analyses (or other appropriate regression models) will be used to estimate 
crude and adjusted hazard ratios and corresponding 95%CI to evaluate factors associated with 
reinfection. Factors hypothesised to be associated with reinfection include demographic factors (age, 
sex), injecting behaviours (current injecting drug use, daily injecting, type of drug injected, injecting 
equipment borrowing), use of needle and syringe programs, and opioid substitution treatment with time-
updated co-variates.  
 
Sample Size: Overall, based on previous reports of HCV reinfection among current PWID32, and assuming 
loss to follow-up is 20% per year, it is estimated that the overall reinfection rate will be 8/100 p-yrs 
(95%CI 5.3, 11.4; 337 p-yrs of follow-up; 27 reinfections). Overall (135 with successful therapy, 27 
reinfections), we will have 80% power to detect a hazards ratio (HR) of 2.94 or greater (with alpha=0.05) 
for a variable 50% prevalent (e.g. ongoing injecting drug use).  
 
Collateral research 
Evaluation of HCV phylogenetics  
All participants enrolled in this study with available plasma samples at screening or baseline (HCV RNA 
detectable) will be sequenced for HCV RNA for evaluation of HCV phylogenetics.  
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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Evaluation of HCV re-infection  
All participants with an ETR will be followed for up to three years post-ETR to assess HCV reinfection. 
Participants with viral recurrence (detectable HCV RNA following HCV virological suppression, reinfection 
rate: 8/100 person years, estimated n=27 x 2 samples=54 total samples) will be identified and available 
follow-up plasma samples assessed for re-infection. 
 
The sensitivity and specificity of the Xpert® HCV Viral Load point-of-care test for detection of HCV RNA in 
plasma samples collected via venepuncture and capillary whole-blood samples collected by finger-stick 
will be assessed using both detectable and quantifiable thresholds (limit of quantification >10 IU/mL) for 
each assay compared to the local laboratory HCV RNA assay in plasma as the gold standard. A Bland-
Altman difference plot will be generated to assess bias and agreement measurements, including limits of 
agreement, between the quantification of HCV by Xpert® HCV Viral Load both sample types, compared to 
the local laboratory HCV RNA assay in plasma. 
11. 
Data Safety and Monitoring Board (DSMB). 
A Data Safety Monitoring Board will not be used for this study as the drug is being prescribed and 
supplied according to indication via the PBS.  
 
The study Medical Monitor, A/Prof Gail Matthews will oversee all serious adverse events for DARLO-C. 
A/Prof Matthews is independent of the study project management team and Protocol Steering 
Committee. A/Prof Matthews is also a clinician at St Vincent’s Hospital which is one of the recruiting sites. 
Should an SAE occur in a patient under A/Prof Matthews’s care the project team will seek an independent 
review of the SAE from a suitably qualified independent Infectious Diseases Specialist or Hepatologist.  
12. 
Data collection, source documents and record retention 
The Principal Investigator and the institution where the study will be conducted will permit study-related 
monitoring, audits, ethics committee review and regulatory inspection providing direct access to source 
documents. 
 
Data will be collected on study specific electronic or paper copy case record forms. The Principal 
Investigator is responsible for ensuring the data collected are complete, accurate and recorded in a timely 
manner.  
12.1 Submission of data 
Electronic CRFs: following each participant visit the designated site staff will complete the visit specific 
eCRF. Once all required information is received the eCRF shall be considered complete. Project Team staff 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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will then monitor the data for completeness and accuracy. Any eCRF discrepancies, either manual or 
automatic, will be addressed with the site staff for clarification. 
 
The site Principal Investigator is responsible for ensuring the completion of accurate source 
documentation to support data collected on case report forms. Source documents include all recordings 
of observations or notations of clinical activities and all reports and records necessary for the evaluation 
and reconstruction of the trial. Source documents include, but are not limited to; participant medical 
records, laboratory reports, ECG tracings, X-rays, radiologist reports, participant diaries, biopsy reports, 
ultrasound images, participant progress notes, pharmacy records and any other reports or records of 
procedures performed in accordance with the protocol.  
 
It is not acceptable for the CRF to be the only record of study participation and progress must also be 
recorded in the each person’s medical record. This is to ensure that anyone accessing the medical record 
has adequate knowledge that the person is a clinical trial participant. 
 
Any document that acts as a source document (the point of the initial recording of a piece of data) should 
be signed and dated by the person recording or reviewing the data for issues of medical significance (for 
example the review of laboratory reports). Persons signing the source documents must be listed as a site 
staff member. 
 
The sponsor’s monitor will visit sites to conduct source document verification. The number of visits will 
depend upon study complexity and recruitment rate; however, the monitor will conduct a minimum of 
two source data verification visits during the study. These should occur shortly after randomization of the 
first participant(s) and following completion of all study visits. 
 
The Principal Investigator is responsible for retaining all essential documents listed in ICH Good Clinical 
Practice guidelines. These must be organised in a comprehensive filing system that is accessible to study 
monitors and other relevant personnel. 
12.2 Linkage of data  
Study data will be periodically linked with public registries, for example the National Notifiable Diseases 
Database, hospital morbidity databases, cancer and death registries. Ethics approval from the Population 
Health Ethics Committee, and all other required Human Research Ethics Committees will be obtained 
prior to any linkage study being performed.  
12.3 Retention of Data Linkage Records  
All datasets relating to the project will be held at CHeRel and AIHW for at least 12 months following the 
last update so that the linkage can be recreated should a problem with the linkage be identified at the 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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time of analysis. The electronic data files will be retained by the Kirby Institute for 7 years after the 
publication of the study results. At the end of this period, the Kirby Institute Information Technology staff 
will follow standard operating procedures to delete the archived electronic records. 
12.4 Archiving  
The Principal Investigator is responsible for ensuring all study documents are retained for a minimum of 
15 years following completion and publication of the study. 
13. 
Ethics committee/regulatory approval and informed consent 
The sponsor is responsible for ensuring regulatory approval for the study is obtained where required. 
 
The site Principal Investigator is responsible for obtaining IRB/EC approval for the protocol and participant 
information and informed consent form in compliance with local regulatory requirements prior to 
entering any participant into the study. The approval letter/document must clearly identify the protocol 
and all documents approved by the IRB/IEC including version number & date of the protocol and 
participant information and consent form. A copy of the approval document must be sent to the study 
sponsor.  
 
The site Principal Investigator must also obtain approval for any amendments to the protocol or 
participant information and informed consent form. The Principal Investigator must comply with all 
IRB/IEC reporting requirements for all adverse events, annual updates and end of study reports and must 
agree to abide by any IRB/IEC conditions of approval. 
 
The site Principal Investigator (or designee) is responsible for ensuring freely-given consent is obtained 
from each potential participant prior to the conduct of any protocol-specific procedures. The Principal 
Investigator may delegate the task of obtaining consent to appropriately qualified Sub-investigator(s). 
Consent must be documented by the participant’s dated signature on the participant information and 
consent form together with the dated signature of the person conducting the consent discussion.  
 
If the participant is illiterate, an impartial witness should be present during the entire consent discussion. 
Once the discussion is complete, the participant must sign and date the informed consent form, if 
capable. The impartial witness must also sign and date the consent form along with the person who 
conducted the consent discussion. 
 
If the participant is legally incompetent (i.e. under 18 years of age or mentally incapacitated) the written 
consent of a parent, guardian or legally authorised representative must be obtained. 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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A copy of the signed and dated participant information and consent form must be given to the person 
prior to study participation. The participant or their legally authorised representative must be informed in 
a timely manner of any new information that becomes available during the course of the study that may 
affect his/her willingness to continue study participation. 
 
This study shall be conducted in accordance with the ethical principles laid out in the Declaration of 
Helsinki (most current issued version) and the National Statement on Ethical Conduct in Research 
Involving Humans (most current issued version). 
14. 
Confidentiality of data 
14.1 Confidentiality of participant records 
By signing the Clinical Trial Agreement, the site Principal Investigator agrees that the sponsor, IRB/IEC or 
regulatory authorities may consult and/or copy study documents to verify information in the case report 
form. By signing the consent form the participant agrees to these processes. The following wording may 
be included in the protocol. 
 
Participant confidentiality will be maintained at all times and no documents containing the participant’s 
name or other identifying information will be collected by the sponsor. It may be necessary for the 
sponsor’s representatives, the IRB/IEC and regulatory authority representatives to have direct access to 
the participant’s medical records. If study documents need to be photocopied during the process of 
verifying case report form data, the participant will be identified by a unique code only; full names and 
other identifying information will be masked.  
 
Confidentiality of Personal Information for Data Linkage  
The Kirby Institute has a strict participant data confidentiality policy. An independent Data Custodian will 
be appointed for this study to manage the identifiable data required for data linkage. The Data Custodian 
will not be involved in the conduct of the study, and in most cases, will be a Data Manager. The role of the 
Data Custodian is to ensure that identifiable information is collected, used, accessed, stored and 
destroyed in line with HREC approval and in accordance with the participant data confidentiality policy 
and the NHMRC National Statement on Ethical Conduct in Research Involving Humans (2007). The Data 
Custodian will be responsible for the exchange of information with data linkage services, and for provision 
of de-identified linked records back to the person/s who requested the data linkage. Once the linked data 
file is received by the Data Custodian at the Kirby Institute, all study data will be transferred to a secure 
network protected by a firewall and individual files will also be password-protected. All results will be 
published in a form that will not allow individuals to be identified, that is, in tabular, aggregate form only; 
no individual results will be disclosed. 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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14.2 Confidentiality of study data 
By signing the Clinical Trial Agreement, the site Principal Investigator affirms to the sponsor that 
information provided to them by the sponsor will be maintained in confidence and divulged only as 
necessary to the ethics committee and institution employees directly involved in the study. Both ethics 
committee members and employees must also understand the confidentiality requirements for any 
information divulged to them. The data generated by this study will be considered confidential, except 
where it is included in a publication as agreed in the publication policy of this protocol.  
15. 
Governance 
The study is sponsored by UNSW and coordinated through the Kirby Institute. It is funded by the 
University of New South Wales (UNSW) and Merck Sharpe and Dohme. The Kirby Institute has established 
governance and implementation structures which use resources efficiently to deliver program objectives 
on schedule. 
16. 
Quality Control (QC) and Quality Assurance (QA) 
The sponsor agrees to be responsible for implementing and maintaining quality control and quality 
assurance systems with written standard operating procedures to ensure the study is conducted and data 
are generated, documented and reported in compliance with the protocol, Good Clinical Practice 
standards and all applicable local laws and regulations relating to the conduct of a clinical trial. 
17. 
Publication Policy 
The results of this study may be published and presented at scientific meetings. Publication of data 
derived from this protocol will be governed by the Protocol Steering Committee. All published data will be 
non-identifiable grouped data.  

DARLO-C Protocol version 5.0 dated 12 December 2017 
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18. 
List of References 
1. 
Nelson, P.K. et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: 
results of systematic reviews. Lancet 378, 571-83 (2011). 
2. 
Hajarizadeh, B., Grebely, J. & Dore, G.J. Epidemiology and natural history of HCV infection. Nat 
Rev Gastroenterol Hepatol (2013). 
3. 
Seeff, L.B. The history of the "natural history" of hepatitis C (1968-2009). Liver Int 29 Suppl 1, 89-
99 (2009). 
4. 
Amin, J., Law, M.G., Bartlett, M., Kaldor, J.M. & Dore, G.J. Causes of death after diagnosis of 
hepatitis B or hepatitis C infection: a large community-based linkage study. Lancet 368, 938-45 
(2006). 
5. 
Grebely, J. et al. Impact of hepatitis C virus infection on all-cause and liver-related mortality in a 
large community-based cohort of inner city residents. J Viral Hepat 18, 32-41 (2011). 
6. 
Deans, G.D. et al. Mortality in a large community-based cohort of inner-city residents in 
Vancouver, Canada. CMAJ Open 1, E68-E76 (2013). 
7. 
Walter, S.R. et al. Trends in mortality after diagnosis of hepatitis B or C infection: 1992-2006. J 
Hepatol 54, 879-86 (2011). 
8. 
van der Meer, A.J. et al. Association between sustained virological response and all-cause 
mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA 308, 2584-
93 (2012). 
9. 
Grebely, J. & Dore, G.J. Can hepatitis C virus infection be eradicated in people who inject drugs? . 
Antiviral Research In Press (2014). 
10. 
Grebely, J. & Dore, G.J. Prevention of hepatitis C virus in injecting drug users: a narrow window of 
opportunity. J Infect Dis 203, 571-4 (2011). 
11. 
Hagan, H., Pouget, E.R. & Des Jarlais, D.C. A systematic review and meta-analysis of interventions 
to prevent hepatitis C virus infection in people who inject drugs. J Infect Dis 204, 74-83 (2011). 
12. 
Sacks-Davis, R., Horyniak, D., Grebely, J. & Hellard, M. Behavioural interventions for preventing 
hepatitis C infection in people who inject drugs: a global systematic review. Int J Drug Policy 23, 
176-84 (2012). 
13. 
Turner, K.M. et al. The impact of needle and syringe provision and opiate substitution therapy on 
the incidence of hepatitis C virus in injecting drug users: pooling of UK evidence. Addiction 106, 
1978-88 (2011). 
14. 
Palmateer, N. et al. Evidence for the effectiveness of sterile injecting equipment provision in 
preventing hepatitis C and human immunodeficiency virus transmission among injecting drug 
users: a review of reviews. Addiction 105, 844-59 (2010). 
15. 
Van Den Berg, C., Smit, C., Van Brussel, G., Coutinho, R. & Prins, M. Full participation in harm 
reduction programmes is associated with decreased risk for human immunodeficiency virus and 
hepatitis C virus: evidence from the Amsterdam Cohort Studies among drug users. Addiction 102, 
1454-62 (2007). 
16. 
Mathers, B.M. et al. HIV prevention, treatment, and care services for people who inject drugs: a 
systematic review of global, regional, and national coverage. Lancet 375, 1014-28 (2010). 
17. 
Martin, N.K. et al. Hepatitis C virus treatment for prevention among people who inject drugs: 
Modeling treatment scale-up in the age of direct-acting antivirals. Hepatology 58, 1598-609 
(2013). 
18. 
Williams, R. et al. Addressing liver disease in the UK: a blueprint for attaining excellence in health 
care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, 
obesity, and viral hepatitis. Lancet 384, 1953-97 (2014). 
19. 
Martin, N.K. et al. Cost-effectiveness of hepatitis C virus antiviral treatment for injection drug user 
populations. Hepatology 55, 49-57 (2012). 
20. 
Martin, N.K., Hickman, M., Hutchinson, S.J., Goldberg, D.J. & Vickerman, P. Combination 
interventions to prevent HCV transmission among people who inject drugs: modeling the impact 
of antiviral treatment, needle and syringe programs, and opiate substitution therapy. Clin Infect 
Dis 57 Suppl 2, S39-45 (2013). 
21. 
Dore, G.J. & Feld, J.J. Hepatitis C virus therapeutic development: in pursuit of perfectovir. Clin 
Infect Dis (2015). 

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22. 
Zeuzem, S. et al. in International Liver Congress (Vienna, Austria, 2015). 
23. 
Kwo, P. et al. in International Liver Congress (Vienna, Austria, 2015). 
24. 
Rockstroh, J.K. et al. in International Liver Congress (Vienna, Austria, 2015). 
25. 
Komatsu, T.E. et al. Regulatory Analysis of Effects of Hepatitis C Virus NS5A Polymorphisms on 
Efficacy of Elbasvir and Grazoprevir. Gastroenterology. 
26. 
Sarrazin, C. The importance of resistance to direct antiviral drugs in HCV infection in clinical 
practice. Journal of Hepatology 64, 486-504 (2016). 
27. 
Pawlotsky, J.-M. Hepatitis C Virus Resistance to Direct-Acting Antiviral Drugs in Interferon-Free 
Regimens. Gastroenterology. 
28. 
Dore, G.J. et al. Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving 
Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med (2016). 
29. 
Forns, X. et al. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after 
failure of combination therapy containing a direct-acting antiviral agent. Journal of Hepatology 
63, 564-572 (2015). 
30. 
Zeuzem, S. et al. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and 
Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection A Randomized 
Trial. Annals of Internal Medicine 163, 1-13 (2015). 
31. 
WHO. in 7. Capillary sampling (World Health Organization, Geneva, 2010). 
32. 
Aspinall, E.J. et al. Treatment of hepatitis C virus infection among people who are actively 
injecting drugs: a systematic review and meta-analysis. Clin Infect Dis 57 Suppl 2, S80-9 (2013). 
 
 
 
 
 

DARLO-C Protocol version 5.0 dated 12 December 2017 
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19. Abbreviations List 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
DAA 
Direct Acting Antiviral 
End of treatment 
Date of last dose of treatment 
ETR 
End of Treatment Response, undetectable HCV RNA at the completion of 
treatment 
FBC 
Full Blood Count (haemoglobin, WCC including differentials, platelets) 
HCV 
Hepatitis C Virus 
IDUs 
Injection Drug Users 
IEC 
Institutional Ethics Committee (Human Research Ethics Committee) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board (Human Research Ethics Committee) 
LFTs 
Liver Function Tests – albumin, ALT, AST, alkaline phosphatase, GGT, total 
bilirubin, total protein 
LLOQ 
Lower Limit Of Quantification 
GGT 
Gamma Glutamic Transpeptidase 
Hgb 
Haemoglobin 
OST 
Opioid Substitution Therapy 
PEG-IFN 
Pegylated interferon alfa 2a 
PWID 
People Who Inject Drugs 
POC 
Point of Care 
RAS 
Resistant Associated Substitutions 
Reinfection  
Detection of infection with an HCV strain which was distinct from the primary 
infecting strain among participants with either spontaneous or treatment-
induced HCV virological suppression (≤15 IU/ml on Roche TaqMan). 
SVR12 
Sustained Virological Response, HCV RNA undetectable 12 weeks post-
treatment 
SVR24 
Sustained Virological Response, HCV RNA undetectable 24 weeks post-
treatment 
Undetectable HCV 
RNA 
HCV RNA results that are <15 IU/ml (non-quantifiable), but “detectable” will be 
considered as undetectable HCV RNA  
WCC 
White Cell Count