Clinical trial NCT03236506
Conditions: Hepatitis C
Keywords: Illicit drug Injecting drug
Sponsor: University of Dundee
Start date: 2018-01-19; Completion date: 2020-10-28
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV infection is intravenous drug use. As HCV is highly infectious by the blood borne route through needle sharing, it can infect the person who injects drugs (PWID) early in their habit.

Around two thirds of people who are infected are unaware of it, and often show no symptoms over a long period of time. While there is presently no vaccination for Hepatitis C, improved treatments with shorter duration are now available. This raises the possibility of using therapy as prevention, turning the epidemic off at source, by targeting active PWID who are the main source of new infections. Modelling work illustrates the startling possibility and impact of treating drug users to reduce the prevalence of HCV.

The focus of this trial will be to ascertain whether oral treatment regimens are effective in the treatment as prevention scenario in an active PWID population where illicit drug taking and poor adherence may reduce treatment efficacy. The investigators will trial 3 different methods of delivering treatment and will trial an unlicensed combined treatment against HCV genotype 3 infection of shortened duration since current regimens for this genotype are limited.

The investigators will recruit 135 participants and randomise them to one of three arms: daily, directly observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of drugs with a psychological adherence intervention. Randomisation will be stratified according to HCV genotype. Participants will be treated for 12 or 8 weeks depending on genotype and followed up 12 weeks post treatment for the measurement of sustained viral response (SVR). The primary outcome measure will be SVR at 12 weeks post treatment (SVR12), as this measure of cure is the determinant of sufficient compliance and efficacy within the 3 treatment arms. Analysis will be by modified intention to treat of all participants who receive one dose of therapy, to show non-inferiority fortnightly dispensing is easier to deliver than daily dispensing.

Detailed description:
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV infection is intravenous drug use. As HCV is highly infectious by the blood borne route through needle sharing, it can infect the PWID early in their habit. With the advent of more effective therapies of shortening duration, it raises the possibility of using therapy as prevention, turning the epidemic off at source, by targeting active infected drug users who are the main source of new infections.

The modelling work of Martin et al, raises the startling possibility of the profound impact of treating small numbers of drug users on the prevalence of HCV, the work shows that treating as few as 10-20 per 1000 drug users per year can reduce HCV prevalence by 50-90% over 10 years. This has generated in the HCV field, the concept of treatment as prevention. The scale of the benefit is exponentially related to prevalence of HCV in the population, the lower the prevalence the bigger the impact. The model has some limitations, it groups all drug users together and assumes a similar risk of infection for those on methadone and those actively injecting and assumes a high rate of turn over from methadone back to active injecting and further assumes treatment is only possible during the opiate substitution phase.

Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now the standard of care in conventional treatment populations. The medication should be taken daily to optimise therapeutic success, and if adherence is poor in the actively injecting population it is possible that the effectiveness of the new oral drugs will be reduced. It is key to know if all oral directly acting antivirals (DAA) regimens are robust and maintain SVR rates in this population. The real world SVR rate combined with drug cost, re-infection rate and emergence of viral resistance will determine if this treatment as prevention model is cost-effective with DAAs. Directly observed therapy (DOT) is the ultimate adherence aid, but it is more costly and draconian so that it may discourage participants, especially this group, from taking up therapy. Therefore the investigators need to demonstrate that treatment uptake and adherence is sufficient to maintain the SVR rate at a level which makes treatment as prevention cost effective. Three means of delivery will be compared: daily DOT vs fortnightly pick up of therapy vs. fortnightly pick-up of therapy with a psychological intervention for adherence. The DOT method of treatment has not been explored in this difficult to find and engage population previously. Contingency management in the form of protein drinks for successful completion of each fortnight of treatment will be provided in all three arms of the trial. A comparison of the three pathways mentioned above will show which pathway shows best acceptability to participants and greatest compliance

The advent of DAAs with their reduced side effect profiles, shorter treatment duration and high SVR rates have the potential to reduce the burden of treatment providing high levels of adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to achieve the required levels of adherence. In addition, the use of DAAs will not address the psychosocial factors known to influence adherence. This trial will therefore investigate the effectiveness of a nurse-led educational intervention for adherence to DAAs in a PWID population.

Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype 1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown that the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week treatment for HCV genotype 3, resulting in high SVR rates. Whilst all 3 drugs are licensed for treatment of HCV, the combination is not yet licensed. This combination will be used to treat HCV genotype 3 infections in this trial.

Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate and therefore forms large numbers of genetically-distinct viral variants. The investigators will investigate whether participants who do not achieve SVR are infected with a drug resistant strain of HCV by sequencing the NS3 and NS5A regions of viral nonstructural (NS) protein present within their blood. The proteins of these genes are targeted by the DAA medications and if their structure is altered the DAA may no longer be effective.

The trial will also explore whether the taking of illicit drugs affects the efficacy of treatment. While the main effect is likely to be via adherence, it is also possible that some of the illicit drugs may interact with the DAAs. A log of illicit drugs used by the participants will be kept and used to identify any candidate interactions for further investigation.

This is a randomised, un-blinded trial which will be conducted in the needle exchange services and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of DAA therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three different routes:

1. DOT,
2. Fortnightly pick-up
3. Fortnightly pick-up with psychological intervention.

Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm HCV infection, polymerase chain reaction (PCR) test to confirm active infection and will currently be using illicit drugs, as confirmed by the participant. Drug screening (by urine sample) will not be tested at that time.

Participants will be stratified by the genotype of their HCV infection; genotype 1 vs genotype 3 and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly pick-up with psychological adherence intervention.

All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside. Upon receipt of a reactive DBS test, potential participants will be briefed about the trial by the specialist nurse or other trained member of staff and given a participant information sheet (PIS) informing them of what is involved. Willing individuals will provide written informed consent and will then have safety bloods drawn to determine eligibility to proceed.

Participants in all three arms of the trial will attend a baseline visit, a randomisation visit either one (genotype 3) or two (genotype 1) visits during treatment, an end of treatment visit and an SVR visit.

All participants will be given incentives to continue with their treatment in the trial. These will consist of protein drinks and will be given at each study visit.

Psychological intervention Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse, prior to beginning their treatment, which will cover the educational intervention designed to aid their compliance with the drug regimen. The intervention will be based on the Information-Motivation-Behavioural (IMB) Skills Model of Adherence12 which was originally developed to explain adherence behaviour in HIV. Recent research suggests this model may have applicability in understanding the facilitator and barriers to adherence in HCV patients. The model suggests that provision of medication information, enhancing personal and social motivation and developing behavioural skills that are key determinants of adherence and may improve adherence in this group. The intervention will involve a structured interview in which the trial nurse and participant will develop an action plan that includes personalised information, sources of motivation for adherence and a treatment routine configured to be compatible with the participant's lifestyle. Anticipating barriers to adherence and problem-solving will be included in the treatment routine. The intervention will take place at the randomisation visit and last approximately one hour. During the intervention, participants will be guided by their trial nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet contains general and personalised information on Hepatitis C, exercises designed to explore and enhance personal and social motivation for treatment adherence and a behavioural action plan (the skills element of the IMB model). The booklet uses the principles of node-link mapping to structure the intervention. Node link mapping use a set of visual tools to structure and guide therapeutic conversation and has been shown to enhance memory and compliance with treatment in substance misusers. Participants in the other two arms of the trial, who are not receiving the psychological intervention, will be given the current National Health Service (NHS) Tayside hepatitis information booklet ("Living with Hepatitis C") which provides generalised information about HCV without personalised information or specific strategies to enhance motivation and behavioural skills.

Reinfection follow up. Trial participants will be invited to also consent for access to information from their annual clinic visits and HCV testing at any other contact with clinical services for up to 5 years, to detect re-infection.

Illicit drug monitoring Illicit drug use will be recorded at baseline and at end of treatment (week 8 for genotype 3, week 12 for genotype 1). One sample of urine for toxicology will be taken during treatment. Those participants who fail to achieve SVR will be compared to successful participants for any correlation with particular substance use. For any candidate substance associated with failure to achieve SVR not explained by lack of adherence, biological samples will be analysed for biological mechanisms.

Adherence monitoring Adherence of those participants randomised to DOT will be documented on a daily log. Those randomised to fortnightly collection of medication will receive Zepatier tablets in blister packaging. They will return their packets of medication every two weeks and any remaining tablets will be counted. Participants infected with HCV genotype 3 will additionally receive bottles containing Sovaldi tablets. These bottles will be fitted with adherence aid caps that record time and date of each cap opening.

Arms: arm 1: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a daily, observed basis by either the nurse or a community pharmacist. arm 2: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. arm 3: Patients with active hepatitis C infection genotype 1 will receive 12 weeks treatment with Zepatier at one tablet per day. Patients with active hepatitis C infection genotype 3 will receive 8 weeks treatment with Zepatier pill plus Sofosbuvir pill at one of each tablets per day. These tablets will be given to patients on a fortnightly basis by the nurse. In addition, this group will receive a one-off interview with the researcher to complete a psychological intervention designed to improve adherence to the medication regimen.
Interventions: intervention 1: Elbasvir/Grazoprevir 50 MG-100 MG Oral Tablet intervention 2: Psychological intervention intervention 3: Sofosbuvir 400 MG
Intervention descriptions: intervention 1: Drugs will be given to participants to treat hepatitis C infection intervention 2: Participants randomised to fortnightly pick-up with psychological intervention will have an interview with the study nurse designed to aid their compliance with the drug regimen. During the intervention participants will be guided by their trial nurse in the completion of a personalised booklet, "Hepatitis C and Me". The booklet uses the principles of node-link mapping to structure the intervention. intervention 3: Drugs will be given along with Zepatier to participants to treat genotype 3hepatitis C infection

Protocol documents:
SAP_002.pdf: 
 
 
A Direct obserVed therApy vs fortNightly CollEction Study for 
HCV Treatment – ADVANCE HCV Study 
 
 
Statistical Analysis Plan 
 
 
 
TRIAL FULL TITLE 
A Direct obserVed therApy vs fortNightly CollEction Study 
for HCV Treatment – ADVANCE HCV Study 
Trial Acronym 
ADVANCE HCV 
Sponsor 
NHS Tayside/University of Dundee  
Sponsor R&D Number 
2016GA03 
Funder 
Merck  
Chief Investigator 
Professor John Dillon 
EudraCT Number 
2017-001039-38  
CTA Number 
41692/0019/001-0001 
REC Number 
17/ES/0089 
Clinicaltrials.gov Number 
NCT03236506 
SAP VERSION 
V1 
SAP VERSION DATE 
29/07/2019 
 
 
 
Name 
Signature 
Date  
TRIAL CHIEF INVESTIGATOR 
 
Prof John Dillon 
 
29/09/2020 
TRIAL 
STATISTICIAN, 
SAP 
AUTHOR 
Dr Adrian Hapca 
A Hapca 
29/09/2020 
 
 
 
 
 
 


TABLE OF CONTENTS 
 
1 
INTRODUCTION ........................................................................................................ 5 
 
BACKGROUND ............................................................................................... 5 
 
RATIONALE FOR TRIAL ................................................................................. 5 
2 
TRIAL OBJECTIVES AND OUTCOMES .................................................................. 7 
2.1.1 
Primary Outcomes ................................................................................. 7 
2.1.2 
Secondary Outcomes ............................................................................ 7 
3 
TRIAL DESIGN .......................................................................................................... 8 
 
TRIAL DESCRIPTION ..................................................................................... 8 
4 
TRIAL POPULATION .............................................................................................. 10 
 
NUMBER OF PARTICIPANTS ...................................................................... 10 
 
INCLUSION CRITERIA .................................................................................. 10 
 
EXCLUSION CRITERIA ................................................................................ 10 
5 
PARTICIPANT RANDOMISATION ......................................................................... 11 
5.1.1 
Randomisation ..................................................................................... 11 
5.1.2 
Treatment Allocation ............................................................................ 12 
6 
DATA COLLECTION& MANAGEMENT ................................................................. 12 
 
Data Collection ............................................................................................... 12 
 
Data Management SysteM ............................................................................ 12 
7 
STATISTICS AND DATA ANALYSIS ..................................................................... 13 
 
SAMPLE SIZE CALCULATION ..................................................................... 13 
 
PROPOSED ANALYSES ............................................................................... 13 
 
Missing data ................................................................................................... 15 
7 
DOCUMENT HISTORY ................................. ERROR! BOOKMARK NOT DEFINED. 
8 
REPORTING CONVENTIONS ...................... ERROR! BOOKMARK NOT DEFINED. 
9 
TECHNICAL DETAILS .................................. ERROR! BOOKMARK NOT DEFINED. 
10 
STATISTICAL REPORT ................................ ERROR! BOOKMARK NOT DEFINED. 
 
 
 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
Page 3 of 19 
 
LIST OF ABBREVIATIONS 
 
BBV 
Blood Borne Virus 
CI 
Chief Investigator 
CNORIS 
Clinical Negligence and Other Risks Scheme 
CRF 
Case Report Form 
DAA 
Direct Acting Antivirals 
DBS 
Dried Blood Spot 
DMC 
Data Monitoring Committee 
DOT 
Directly Observed therapy 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase  
GP 
General Practitioner 
HCV 
Hepatitis C Virus 
IMB 
Information-Motivation-Behavioural 
ISF 
Investigator Site File 
LFT 
Liver Function Test 
MEMS® 
medication event monitoring system 
NESI 
Needle Exchange Service Initiative 
PCR 
Polymerase Chain Reaction 
Peg IFN 
Pegylated Interferon 
PHQ-9 
The Patient Health Questionnaire 
PWID 
Person Who Injects Drugs 
PT 
Prothrombin Time 
QC 
Quality Control 
RSI 
Reference Safety Information 
 RBV 
Ribavirin 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SVR 
Sustained Viral Response 
SVR12 
Sustained Viral Response at 12 weeks 
TCTU 
Tayside Clinical Trials Unit 
TMF 
Trial Master File 
TMG 
Trial Management Group 
U&Es 
Urea & Electrolytes 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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SUMMARY 
 
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 
Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV 
infection is intravenous drug use. As HCV is highly infectious by the blood borne route through 
needle sharing, it can infect the person who injects drugs (PWID) early in their habit. 
 
The outcome of HCV infection varies considerably between individuals. Some (up to 25%) are 
able to clear the infection spontaneously, whilst the remaining 75% become chronically 
infected. Within the subpopulation of chronically infected patients, some will develop serious 
liver disease, including cirrhosis and hepatocellular carcinoma, within a few years1.  
 
The focus of this trial will be to ascertain whether oral treatment regimens are effective in the 
treatment as prevention scenario in an active PWID population where illicit drug taking and poor 
adherence may reduce treatment efficacy. We will trial 3 different methods of delivering 
treatment and determine which is most successful in this population. Additionally, we will trial 
an unlicensed combined treatment against HCV genotype 3 infection of shortened duration 
since current regimens for this genotype are limited.  
 
We will recruit 135 participants and randomise them to one of three arms: daily, directly 
observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of drugs with a 
psychological adherence intervention. Randomisation will be stratified according to HCV 
genotype. Participants will be treated for 12 weeks and followed up 12 weeks post treatment 
for the measurement of sustained viral response (SVR). 
The primary outcome measure will be SVR at 12 weeks post treatment (SVR12), as this 
measure of cure is the determinant of sufficient compliance and efficacy within the 3 treatment 
arms. 
Analysis will be by modified intention to treat of all participants who receive one dose of therapy, 
to show non-inferiority fortnightly dispensing is easier to deliver than daily dispensing.  
 
 
 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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1 
 
INTRODUCTION 
  BACKGROUND 
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 
Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV 
infection is intravenous drug use. As HCV is highly infectious by the blood borne route through 
needle sharing, it can infect the PWID early in their habit. With the advent of more effective 
therapies of shortening duration, it raises the possibility of using therapy as prevention, turning 
the epidemic off at source, by targeting active infected drug users who are the main source of 
new infections. 
 
 RATIONALE FOR TRIAL 
Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now the 
standard of care in conventional treatment populations. The medication should be taken daily 
to optimise therapeutic success, and if adherence is poor in the actively injecting population it 
is possible that the effectiveness of the new oral drugs will be reduced.  It is key to know if all 
oral directly acting antivirals (DAA) regimens are robust and maintain SVR rates in this 
population. Directly observed therapy (DOT) is the ultimate adherence aid, but it is more costly 
and draconian so that it may discourage participants, especially this group, from taking up 
therapy. 
 
The advent of DAAs with their reduced side effect profiles, shorter treatment duration and high 
SVR rates have the potential to reduce the burden of treatment providing high levels of 
adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to 
achieve the required levels of adherence. In addition, the use of DAAs will not address the 
psychosocial factors known to influence adherence. To maximise participant outcomes, it will 
therefore be necessary to promote adherence. Finally, none of the studies investigated 
adherence in PWID or with DAA treatments only and therefore the effectiveness of such 
interventions in this population with newer treatment approaches is unknown. This trial will 
therefore investigate the effectiveness of a nurse-led educational intervention for adherence to 
DAAs in a PWID population. 
 
Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype 
1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown 
that the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week 
treatment for HCV genotype 3, resulting in high SVR rates11. Whilst all 3 drugs are licensed for 
treatment of HCV, the combination is not yet licensed. We will use this combination to treat 
HCV genotype 3 infections in this trial.  


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
Page 6 of 19 
 
 
Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate and 
therefore forms large numbers of genetically-distinct viral variants. We will investigate whether 
participants who do not achieve SVR are infected with a drug resistant strain of HCV by 
sequencing the NS3 and NS5A regions of virus present within their blood. The proteins of these 
genes are targeted by the DAA medications and if their structure is altered the DAA may no 
longer be effective.  
 
The trial will also explore whether the taking of illicit drugs affects the efficacy of treatment. 
While the main effect is likely to be via adherence, it is also possible that some of the illicit drugs 
may interact with the DAAs. A log of illicit drugs used by the participants will be kept and used 
to identify any candidate interactions for further investigation. 
 
 
 
 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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2 
TRIAL OBJECTIVES AND OUTCOMES 
 
 
2.1.1 
Primary Outcomes 
 
To compare using SVR rates the efficacy and compliance of DAAs in 135 new HCV 
positive individuals randomised to one of three groups; DOT, fortnightly therapy and 
fortnightly therapy with psychological adherence intervention.  
The data for these outcomes will be generated directly from the CRFs from the clinical and 
laboratory data recorded therein.  
 
2.1.2 
Secondary Outcomes 
 
To compare patient progression through the different trial pathway stages. 
 
Compare adherence to therapy rates of subjects randomised to either DOT, 
fortnightly therapy or fortnightly therapy with psychological adherence intervention - 
treatment of HCV. Adherence rates will be obtained from the daily log data in the 
DOT group, and from pill counting and MEMs caps data in the two fortnightly therapy 
groups. 
 
Assess reinfection rates in the PWID population and treated using all oral DAA 
regimes. The data for reinfection rates will be will generated from the annual follow up 
and retesting for chronic HCV infection of all participants treated. This will be from 
routine clinical follow data and consent will be sought to access this. The analysis is 
simple, requiring only simple descriptive statistics. 
 
Assess viral resistance patterns in participants who do not achieve SVR. These data 
will be obtained by analysing samples for resistance associated variants (RAVs) 
using standard clinical laboratory assays.  
 
Assess the types of illicit drugs taken by trial participants and identify any interaction 
with the DAAs and possible effect on adherence. This data will be generated by the 
adverse event reporting mechanism within the trial. The particular interest will be 
around interactions of the trial medication with drugs of misuse. Concomitant drug use 
during the trial will be recorded in the CRF at baseline and end of treatment and 
supported by urine toxicology from a urine sample that will be collected during 
treatment. Data will be recorded in the CRF.  
 
 
 
 
 
 


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3 
TRIAL DESIGN 
 TRIAL DESCRIPTION 
This is a randomised, un-blinded trial which will be conducted in the needle exchange services 
and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of DAA 
therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three different 
routes:  
1. DOT,  
2. Fortnightly pick-up  
3. Fortnightly pick-up with psychological intervention. 
 
Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm HCV 
infection, PCR to confirm active infection and will currently be using illicit drugs, as confirmed 
by the participant. Drug screening (by urine sample) will not be tested at that time. 
 
Participants will be stratified by the genotype of their HCV infection; genotype 1 vs genotype 3 
and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly pick-up with 
psychological adherence intervention. 
  
All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside. 
Upon receipt of a reactive DBS test, potential participants will be briefed about the trial by the 
specialist nurse or other trained member of staff and given a participant information sheet (PIS) 
informing them of what is involved. Willing individuals will provide written informed consent and 
will then have safety bloods drawn to determine eligibility to proceed. A full list of 
inclusion/exclusion criteria is detailed in section 4.  
 
Participants in all three arms of the trial will attend a baseline visit, a randomisation visit, either 
one (genotype 3) or two (genotype 1) visits during treatment, an end of treatment visit and an 
SVR visit, as detailed in Appendix 2.  
All participants will be given incentives to continue with their treatment in the trial. These will 
consist of protein drinks and travel expenses, in the form of a local return bus fare and will be 
given at each study visit. 
 
Psychological intervention 
Participants randomised to fortnightly pick-up with psychological intervention will have an 
interview with the study nurse, prior to beginning their treatment, which will cover the 
educational intervention designed to aid their compliance with the drug regimen. The 
intervention will be based on the Information-Motivation-Behavioural (IMB) Skills Model of 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
Page 9 of 19 
 
Adherence12 which was originally developed to explain adherence behaviour in HIV. Recent 
research suggests this model may have applicability in understanding the facilitator and barriers 
to adherence in HCV patients8. The model suggests that provision of medication information, 
enhancing personal and social motivation and developing behavioural skills that are key 
determinants of adherence and may improve adherence in this group. The intervention will 
involve a structured interview in which the trial nurse and participant will develop an action plan 
that includes personalised information, sources of motivation for adherence and a treatment 
routine configured to be compatible with the participant’s lifestyle. Anticipating barriers to 
adherence and problem-solving will be included in the treatment routine. The intervention will 
take place at the randomisation visit and last approximately one hour. During the intervention, 
participants will be guided by their trial nurse in the completion of a personalised booklet, 
“Hepatitis C and Me”. The booklet contains general and personalised information on Hepatitis 
C, exercises designed to explore and enhance personal and social motivation for treatment 
adherence and a behavioural action plan (the skills element of the IMB model). The booklet 
uses the principles of node-link mapping to structure the intervention. Node link mapping use a 
set of visual tools to structure and guide therapeutic conversation and has been shown to 
enhance memory and compliance with treatment in substance misusers (e.g 13,14). 
Participants in the other two arms of the trial, who are not receiving the psychological 
intervention, will be given the current NHS Tayside hepatitis information booklet (“Living with 
Hepatitis C”) which provides generalised information about HCV without personalised 
information or specific strategies to enhance motivation and behavioural skills.  
 
Reinfection follow up.  
Trial participants will be invited to also consent for access to information from their annual clinic 
visits and HCV testing at any other contact with clinical services for up to 5 years, to detect re-
infection.  
 
Illicit drug monitoring 
Illicit drug use will be recorded at baseline and at end of treatment (week 8 for genotype 3, 
week 12 for genotype 1). One sample of urine for toxicology will be taken during treatment. 
Those participants who fail to achieve SVR will be compared to successful participants for any 
correlation with particular substance use. For any candidate substance associated with failure 
to achieve SVR not explained by lack of adherence, biological samples will be analysed for 
biological mechanisms. 
 
Adherence monitoring 
Adherence of those participants randomised to DOT will be documented on a daily log. Those 
randomised to fortnightly collection of medication will receive Zepatier tablets in blister 
packaging. They will return their packets of medication every two weeks and any remaining 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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tablets will be counted. Participants infected with HCV genotype 3 will additionally receive 
bottles containing Sovaldi tablets. These bottles will be fitted with adherence aid caps that 
record time and date of each cap opening. 
4 
TRIAL POPULATION 
 NUMBER OF PARTICIPANTS 
This trial aims to treat 135 active PWID with active HCV infection in Tayside over a two year 
period. Due to the nature of this trial, trial dropouts are a trial endpoint and will not be replaced. 
 
 INCLUSION CRITERIA 
 
Male or Female. (Age limit 18-70) 
 
HCV PCR confirmed active infection, genotype 1 or 3. 
 
If female, must have negative urine test results for pregnancy during initial screening 
period (for trial inclusion) and be advised of limited safety data in pregnancy. 
 
Current illicit drug use established through participant history.  
 
Able to provide informed consent, agreeing to trial and clinical monitoring criteria  
 
 EXCLUSION CRITERIA 
 
Aggressive or violent behaviour. 
 
Unwilling to consent to GP being informed of their participation in the trial 
 
Platelet count < 75 x 10 9 /l 
 
Alanine transaminase > 350U/l 
 
Inability to provide informed consent. 
 
Clinical history or abnormal valves for albumin< 30 g/l, Bilirubin >35 umol/l or PT >1.5 
consistent with decompensated liver failure Childs-Pugh B or C 
 
Clinical history of primary hepatocellular carcinoma 
 
Pregnancy or breast feeding.  
 
Participation in a drug trial within the previous 30 days 
 
Hepatitis B surface antigen positive 
 
HIV infection. 
 
Hypersensitivity to elbasvir and grazoprevir  
 
Hypersensitivity to sofosbuvir (genotype 3 infected-participants ony) 
 
Currently being treated with an inhibitor of organic anion transporting polypeptide 1B, 
e.g. rifampicin, atazanavir, daruavir, lopinavir, saquinavir, tipranavir, cobicistat or 
ciclosporin. 


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 
Currently being treated with inducers of cytochrome P450 3A or P-glycoprotein, such 
as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St John’s 
Wort (Hypericum perforatum) 
 
Currently being treated with amiodarone (Participants infected with genotype 3 HCV 
only) 
 
5 
PARTICIPANT RANDOMISATION 
5.1.1 
Randomisation 
After successful screening for eligibility and safety, participants will be randomised to either 
DOT, fortnightly pick up or fortnightly pick up with psychological intervention.  
PWID who are eligible for this trial have unpredictable and chaotic lives. It is therefore possible 
that an individual will consent to take part, provide baseline information and have blood taken 
for safety and eligibility checking. If eligible they may be randomised. They may then not be 
seen at the needle exchange for a number of weeks or even months. It is standard clinical 
practice that pretreatment bloods are valid for a period of 6 months and therefore we will 
consider baseline bloods taken for the study to be valid for 6 months unless there is a clinical 
indication to repeat within that period. Any clinical decision on whether bloods need to be 
repeated within 6 months will be made by the CI. If a consented participant reappears after a 
period longer than 6 months has elapsed, a documented verbal check will be made to confirm 
that the individual continues to consent to taking part in the study. The bloods will be re-taken 
and eligibility will be based on the results of these new blood tests. The blood tests taken closest 
to the date of treatment initiation will be considered as the baseline data.The viral genotype will 
not be retested as NHS lab policy is to redo this test only after 5 years have elapsed. After 6 
months the baseline CRF will also be repeated to provide up-to-date pretreatment information. 
In this case, the information originally collected in the baseline CRF will be filed but will not be 
entered into the electronic data management system (Openclinica) and will not form part of the 
analysed dataset. To ensure that the correct, most up-to-date baseline data is entered into 
Openclinica, baseline data will be entered once each participant has started their treatment.  
 
As this is an un-blinded trial, the nurse, or delegated member of staff, and participant will be 
aware of which arm they are allocated to. Randomisation to each of the three trial groups will 
be stratified by genotype so that the proportion of genotype 1 vs genotype 3 infected 
participants will be the same in each group. The Tayside Clinical Trials Unit (TCTU) GCP-
compliant online randomisation system, TRuST, will be used by the specialist nurse or 
delegated, trained member of staff to perform the randomisation. 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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5.1.2 
Treatment Allocation 
Eligible participants infected with genotype 1 HCV will receive Zepatier treatment for 12 weeks. 
Zepatier contains a combination of Grazoprevir and Elbasvir. Merck will supply GMP ready 
investigational medical product (IMP) for use in the trial. Those infected with genotype 3 HCV 
will receive commercial stock sofosbuvir off the shelf in addition to Zepatier for 8 weeks. 
Treatment regimens for treatment naïve and treatment experienced participants enrolled in the 
trial will be the same. Zepatier tablets are film-coated and each contains 50 mg Elbasvir and 
100 mg Grazoprevir. Sovaldi is provided as a single 400mg tablet.  
 
For participants in group 1, medication will be dispensed daily at the needle exchange. The 
pharmacist or trial nurse will observe the participant taking the medication and this will be noted 
in a daily log. Participants will be provided with sufficient tablets for the weekend and other days 
that the needle exchange is closed. Participants in groups 2 and 3 will fortnightly receive two 
week’s supply of medication from the trial staff.  Participants infected with Genotype 1 HCV will 
be instructed to take one tablet daily from the blister pack. Those infected with Genotype 3 HCV 
will be instructed to take one tablet daily from the blister pack and one tablet daily from the 
bottle. The bottle will be fitted with an electronic adherence measuring aid.  
 
6 
DATA COLLECTION& MANAGEMENT 
 DATA COLLECTION 
Data management will be conducted in compliance with TASC SOPs on Data Management. 
The data will be principally collected by the nurses appointed to the trial and supported by other 
trial appointed staff. The data sources will include the CRF, medical notes, laboratory reports 
and trial specific questionnaires.  
Trial-specific data will be collected at baseline, randomisation, week 4, week 8 (HCV genotype 
1), end of treatment and 12 weeks post treatment. 
Most of this data will be entered directly into the CRFs without being routinely recorded in 
clinical data sources. Participants will be asked to consent to information being collected at 
routine annual clinic visits for up to 5 years to check for reinfection.   
 
 DATA MANAGEMENT SYSTEM  
The data management system provided by TCTU will be OpenClinica. Development and 
validation of the trial database with QC and extraction of data will be done according to TCTU 
procedures. The DMS will be based on the protocol and case report form (CRF) for the trial and 
individual requirements of the investigators. The CRF will collect only information that is 
required to meet the aims of the trial and to ensure the eligibility and safety of the participant. 
The CI may delegate CRF completion but is responsible for completeness, plausibility and 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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consistency of the CRF. Any queries will be resolved by the CI or delegated member of the trial 
team. The trial database will be compliant with TASC SOPs on Creating and Managing 
Databases. Extracts for analysis will be based on the dummy data tables provided by the trial 
team. 
 
 
 
7 
STATISTICS AND DATA ANALYSIS 
 SAMPLE SIZE CALCULATION 
Statistical analysis will be conducted in compliance with TASC SOPS. 
 
We propose to conduct this project as a randomised trial to show that DAA therapy in very 
active PWIDs administered fortnightly with or without adherence intervention is non-inferior to 
DOT. We will compare pathways sequentially comparing DOT vs fortnightly delivery and then 
DOT verses fortnightly pickup with adherence intervention. Fortnightly pick up will be more cost 
effective than the other two options so long as adherence and efficacy matches that of the DOT 
and fortnightly plus adherence intervention. If we assume a 95% SVR rate (based on published 
studies) in the DOT arm of the trial in this population and a non-inferiority limit of 14% (which 
would be likely to maintain cost-effectiveness) then at a 5% significance level and 90% power 
we would need a sample size of 42 in each group 126 in total. To allow for drop-outs we will 
aim to recruit 135 individuals, 45 per group. 
 
A Statistical Analysis Plan (SAP) will be prepared for analysis of primary and secondary 
outcomes and will include a plan for handling missing data 
 
 PROPOSED ANALYSES 
Analyses will be conducted according to the principles of intention to treat (ITT) and comply 
with the ICH E9 ‘Statistical Principles for Clinical Trials’ and carried out by the UKCRC 
registered Tayside Clinical Trials Unit (TCTU). A 2 sided p value of <0.05 will be taken as 
significant for all analyses. 
 
As part of descriptive statistics, continuous variables will be summarised by the number of 
observations, number of missing values, mean, median, standard deviation (SD). Categorical 
variables will be summarised by the number of observations, number of missing values and 
number and percentage in each category. Summaries will be provided at baseline and at each 
subsequent time point and for the change from baseline by intervention group where 
appropriate. 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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The primary outcome of SVR will be assessed as a binary outcome for subjects and so will 
utilise logistic regression modelling. The numerator will be the number of subjects achieving 
SVR and the denominator will be total number of patients randomised to each arm. Additionally 
results will be expressed as a proportion of the estimated HCV infected subjects in needle 
exchange. The estimated number of infected patients will be based on national survey data and 
the empirical rate discovered in the trial (allowing for patients who refuse testing). As all patients 
will have either achieved SVR or not and we will assume that drop-outs / lost to follow-up are 
failures, there will be no missing data in the primary outcome. Over-dispersion will be examined 
in the logistic model and if present alternative modelling such as negative binomial models will 
be considered. This will also be adjusted by therapy and genotype; the two factors are 
interdependent determining length of therapy. 
 
Secondary Outcomes 
 
To compare patient progression through the different trial pathway.  A study flow chart will be 
constructed starting with the number of patients tested, the number tested positive, the number 
consenting, the number initiating treatment in each of the 3 arms and the number completing 
therapy.  Secondary binary outcomes will be analysed using the same procedure, initially as 
intention to treat with all eligible patients as the denominator. The numerator being sequentially 
the number initiating treatment in each of the 3 arms and the number completing therapy, 
Multiple logistic regression modelling will explore the patient and pathway characteristics that 
are associated with the secondary outcomes and primary outcome. Patient outcomes 
considered will be age, gender, deprivation, employment, comorbidity, and the psycho-social 
variables assessed. 
  
Adherence: to compare the longitudinal evolution of adherence to the prescribed regimen 
between the fortnightly dispensed groups and the DOT group. For each patient, daily 
adherence will be defined using a binary variable Z it indicating whether yes (=1) or no (=0) the 
subject has taken their medication on day t. This longitudinal binary variable will be directly 
generated from the patient electronically compiled dosing history. Comparison of binary time 
series is realized using a logistic regression where dependence among observations from a 
given patient over time is taken into account. The effect of pathway on overall adherence will 
be tested using the above-described model by testing if either the group coefficient or the 
interaction between the group and time are significantly different from zero.  
 
The remaining 3 secondary outcomes will be ad hoc analyses performed after the study report 
as they are dependent on numbers of treatment failures and will be irrelevant if small or 
dependent on long term follow up.  


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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 
Assess reinfection rates in the PWID population and treated using all oral DAA regimes. 
The data for reinfection rates will be will generated from the annual follow up and 
retesting for chronic HCV infection of all participants treated. This will be from routine 
clinical follow data and consent will be sought to access this. The analysis is simple, 
requiring only simple descriptive statistics. 
 
Assess viral resistance patterns in participants who do not achieve SVR. These data 
will be obtained by analysing samples for resistance associated variants (RAVs) using 
standard clinical laboratory assays.  
 
Assess the types of illicit drugs taken by trial participants and identify any interaction 
with the DAAs and possible effect on adherence. This data will be generated by the 
adverse event reporting mechanism within the trial. The particular interest will be 
around interactions of the trial medication with drugs of misuse. Concomitant drug use 
during the trial will be recorded in the CRF at baseline and end of treatment and 
supported by urine toxicology from a urine sample that will be collected during 
treatment. Data will be recorded in the CRF.  
 
 
 MISSING DATA 
The nature of this trial is to assess the applicability of this model in the real world, so incomplete 
data that impacts the primary outcome will be assumed to be to consistent with failure of therapy 
and drop-outs won’t be replaced. However every effort will be made to obtain missing data and 
as the primary outcomes are not time point critical a wide latitude for admissibility of data will 
be employed. We will accept measures of SVR up to 12 weeks after the due SVR12 date. 
 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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Table 1: Summary of Objectives, outcomes, proposed statistical analysis. 
Objectives/ Research question 
Outcome measure
Statistical analysis / variables
Primary
To compare using SVR rates the 
efficacy and compliance of DAAs 
in135 new HCV positive individuals 
randomised to one of three groups; 
DOT, 
fortnightly 
therapy 
and 
fortnightly 
therapy 
with 
psychological 
adherence 
intervention 
SVR12 rates of participants in the DOT, fortnightly pick-up or fortnightly 
pick-up with a psychological adherence intervention group 
 
Logistic regression models
Secondary
To compare patient progression 
through the different trial pathway. 
The number initiating treatment in each of the 3 arms and the number 
completing therapy in each arm 
Logistic regression models
Compare adherence to therapy 
rates of subjects randomised to 
either DOT, fortnightly therapy or 
fortnightly 
therapy 
with 
psychological 
adherence 
intervention -  
Adherence of daily directly observed therapy group from daily logs
Adherence measured by counting tablets returned after each 2 week 
treatment period (fortnightly pickup groups). 
Adherence of participants infected with genotype 3 and treated with 
Sovaldi measured using MEMS® cap. 
 
Logistic regression models
To assess reinfection rates in active 
PWIDs treated with oral DAA 
regimes 
Hepatitis C viral load from PCR
ad hoc analyses performed after the study report as 
dependent on long term follow up. 
To assess resistance profiles in those 
who do not achieve SVR. 
Profiles of the HCV viral resistance proteins, NS5a and NS3
ad hoc analyses performed after the study report as 
they are dependent on numbers of treatment failures 
and will be irrelevant if small numbers. 
To assess the types of illicit drugs 
taken by trial participants and 
identify any interaction with the 
DAAs. 
Drug misuse history
Urine toxicology 
ad hoc analyses performed after the study report as 
they are dependent on numbers of treatment failures 
and will be irrelevant if small numbers.  


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
Page 17 of 19 
 
 
Table 2: Summary of Outcome measure and Variable source. 
Objectives
Outcome
Variable description / collection pointy
Variable name
Variable location
Primary
P1 - SVR rates at 12 months
12 weeks post treatment completion
SVR12
pCRF/OC – SVR Visit
‘PCR for HCV 
detectable, yes/no?’ 
Secondary
S1 patient progression through the different 
trial pathway 
The number initiating treatment in each of 
the 3 arms and the number completing 
therapy in each arm 
Treatment initiation
Did participant complete 
treatment? 
pCRF/OC – Visit 2 
attended, yes/no? 
 
pCRF/OC – End of 
study form ‘yes/no?’ 
S2 Adherence of daily directly observed 
therapy group from daily logs. 
Daily log completed daily, adherence 
calculated at end of treatment 
Adherence – total number of 
tablets remaining from total of 4 
(G3) or 6 (G1) periods for zepatier 
and sovaldi (G3 only) 
pCRF/OC – Daily Log
S2 Adherence measured by counting tablets 
returned after each 2 week treatment 
period (fortnightly pickup groups). 
Calculated at end of treatment
Adherence – total number of 
tablets returned at study visit or 
week. 
Study visit 3 and week 2&6 for G3 – 
Zepatier and Sovaldi 
Study visits 3&4 and week 2,6&10 
for G1 – Zepatier only 
pCRF/OC –
Fortnightly Visit Log 
S2 Adherence of participants infected with 
genotype 3 and treated with Sovaldi 
measured using MEMS® cap 
Calculated at end of treatment
Adherence
Excel spreadsheet 
downloaded from 
MEMS® software 
S3 Hepatitis C viral load from PCR
Annually at clinic visits
HCV PCR viral load
ICE – online clinical 
results system 


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S4 Profiles of the HCV viral resistance 
proteins, NS5a and NS3 
Blood collected at baseline, end of 
treatment and SVR12 
HCV Viral Resistance (if required)
ICE – online clinical 
results system 
S5 Drug misuse history
Baseline, end of treatment (genotype 1 
infection = week12, genotype 3 infection= 
week8) 
When did you last inject?
pCRF/OC – baseline 
and end of treatment 
– Illicit drugs 
S5 Urine toxicology
Once during treatment
Drug-drug interaction with 
medication (if required) 
ICE – online clinical 
results system 
Explanatory 
variables 
Therapy, genotype, age, gender, 
deprivation, employment, comorbidity, and 
the psycho-social variables assessed 
Baseline
Demographics, social history, 
medical history 
Therapy = genotype 
Genotype 1 = 12 weeks Zepatier 
Genotype 3 = 8 weeks 
Zepatier/Sovaldi 
pCRF/OC – baseline 
(screening) 
 
 
pCRF/OC – baseline 
(blood test results 
screening) 
 
 
 
 


ADVANCE SATATISTICAL ANALYSIS PLAN V01 
 
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8 
DOCUMENT HISTORY 
This is document was developed following the study protocol V5  
The final version of Statistical Analysis Plan for all analyses of Advance trial is dated 06 
September 2019. 
 
9 
REPORTING CONVENTIONS 
P-values ≥0.001 will be reported to 3 decimal places; p-values less than 0.001 will be reported 
as “<0.001”. The mean, standard deviation, and any other statistics other than quantiles, will 
be reported to one decimal place greater than the original data. Quantiles, such as median, or 
minimum and maximum will use the same number of decimal places as the original data. 
Estimated parameters, not on the same scale as raw observations (e.g. regression coefficients) 
will be reported to 3 significant figures. 
 
10 TECHNICAL DETAILS 
All analysis will be performed using SAS 9.4. All data, analysis programs and output will be kept 
on the TCTU Server and backed up according to the internal IT SOPs.  
 
The analysis programs for outcomes will be reviewed by a second statistician, and any 
irregularities within the programs will be investigated and fixed and date of finalised analysis 
programs will be signed and recorded. 
 
 
11 STATISTICAL REPORT 
A statistical report will be created with all analyses according to the SAP. This will form the 
basis of any future paper or report and will be assessed for consistency. 
 

Prot_000.pdf: 
 
 
 
 
 
Trial Protocol 
 
A Direct obserVed therApy vs fortNightly CollEction Study for HCV Treatment – ADVANCE 
HCV Study 
 
 
 
 
 
 
 
 
 
 
 
 
Trial Acronym 
ADVANCE HCV 
Sponsor 
NHS Tayside/University of Dundee  
Sponsor R&D Number 
2016GA03 
Funder 
Merck  
Chief Investigator 
Professor John Dillon 
EudraCT Number 
2017-001039-38  
CTA Number 
41692/0019/001-0001 
REC Number 
17/ES/0089 
Clinicaltrials.gov Number 
NCT03236506 
Version Number and Date 
Version 5.0  02/04/2018 


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Contents 
1 
INTRODUCTION ........................................................................................................ 7 
1.1 
BACKGROUND ............................................................................................... 7 
1.2 
RATIONALE FOR TRIAL ................................................................................. 8 
2 
TRIAL OBJECTIVES AND OUTCOMES .................................................................. 9 
3 
TRIAL DESIGN ........................................................................................................ 10 
3.1 
TRIAL DESCRIPTION ................................................................................... 10 
3.2 
TRIAL FLOWCHART ..................................................................................... 12 
3.3 
TRIAL MATRIX .............................................................................................. 12 
4 
TRIAL POPULATION .............................................................................................. 12 
4.1 
NUMBER OF PARTICIPANTS ...................................................................... 12 
4.2 
INCLUSION CRITERIA .................................................................................. 13 
4.3 
EXCLUSION CRITERIA ................................................................................ 13 
5 
PARTICIPANT SELECTION AND ENROLMENT ................................................... 14 
5.1 
IDENTIFYING PARTICIPANTS ..................................................................... 14 
5.2 
CONSENTING PARTICIPANTS .................................................................... 14 
5.3 
SCREENING FOR ELIGIBILITY .................................................................... 14 
5.4 
INELIGIBLE AND NON-RECRUITED PARTICIPANTS ................................ 15 
5.5 
RANDOMISATION ......................................................................................... 15 
5.5.1 
Randomisation ..................................................................................... 15 
5.5.2 
Treatment Allocation ............................................................................ 16 
5.5.3 
Withdrawal procedures ........................................................................ 16 
 
INVESTIGATIONAL MEDICINAL PRODUCT ........................................................ 17 
6 
17 
 
TRIAL DRUG ................................................................................................. 17 
6.1 
17 
6.1.1 
Trial Drug Identification ........................................................................ 17 
6.1.2 
Trial Drug Manufacturer ....................................................................... 17 
6.1.3 
Marketing Authorisation Holder ........................................................... 17 
6.1.4 
Labelling and Packaging...................................................................... 18 
6.1.5 
Storage ................................................................................................ 18 
6.1.6 
Reference Safety Information .............................................................. 18 
6.1.7 
Accountability procedures.................................................................... 18 
 
DOSING REGIME .......................................................................................... 18 
6.2 
18 
6.3 
DOSE CHANGES .......................................................................................... 19 
6.4 
PARTICIPANT COMPLIANCE ...................................................................... 19 
6.5 
OVERDOSE ................................................................................................... 19 
6.6 
OTHER MEDICATIONS ................................................................................ 19 


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6.6.1 
Permitted Medications ......................................................................... 19 
6.6.2 
Prohibited Medications ........................................................................ 19 
6.6.3 
Concomitant Medications .................................................................... 20 
7 
TRIAL ASSESSMENTS .......................................................................................... 20 
7.1 
TRIAL ASSESSMENTS ................................................................................. 20 
7.2 
SAFETY ASSESSMENTS ............................................................................. 20 
8 
DATA COLLECTION& MANAGEMENT ................................................................. 21 
 
Data Collection ............................................................................................... 21 
8.1 
21 
 
Data Management SysteM ............................................................................ 21 
8.2 
21 
9 
STATISTICS AND DATA ANALYSIS ..................................................................... 21 
 
SAMPLE SIZE CALCULATION ..................................................................... 21 
9.1 
21 
9.2 
PROPOSED ANALYSES ............................................................................... 22 
9.2.1 
Primary Outcomes ............................................................................... 22 
9.2.2 
Secondary Outcomes .......................................................................... 22 
9.3 
Missing data ................................................................................................... 24 
9.4 
TRANSFER OF DATA ................................................................................... 24 
 
ADVERSE EVENTS................................................................................................. 24 
10 
24 
10.1 
DEFINITIONS ................................................................................................ 24 
10.2 
RECORDING AND REPORTING AEs AND SAEs........................................ 24 
 
REGULATORY REPORTING REQUIREMENTS.......................................... 25 
10.3 
25 
10.4 
ANNUAL REPORTING REQUIREMENTS .................................................... 25 
10.5 
URGENT SAFETY MEASURES.................................................................... 26 
11 
PREGNANCY .......................................................................................................... 26 
11.1 
CONTRACEPTIVE ADVICE TO PARTICIPANTS ......................................... 26 
12 
TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS ............................ 27 
12.1 
TRIAL MANAGEMENT GROUP .................................................................... 27 
12.2 
TRIAL MANAGEMENT .................................................................................. 27 
12.3 
TRIAL STEERING COMMITTEE ................................................................... 27 
12.4 
DATA MONITORING COMMITTEE .............................................................. 27 
12.5 
INSPECTION OF RECORDS ........................................................................ 27 
12.6 
RISK ASSESSMENT ..................................................................................... 27 
12.7 
TRIAL MONITORING .................................................................................... 28 
 
Potential Risks ..................................................................................... 28 
12.7.1 
28 
 
Minimising Risk .................................................................................... 28 


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12.7.2 
28 
13 
GOOD CLINICAL PRACTICE ................................................................................. 28 
13.1 
ETHICAL CONDUCT OF THE TRIAL ........................................................... 28 
13.1.1 
Confidentiality ...................................................................................... 28 
13.1.2 
Data Protection .................................................................................... 28 
 
Insurance and Indemnity ..................................................................... 29 
13.1.3 
29 
14 
TRIAL CONDUCT RESPONSIBILITIES ................................................................. 29 
14.1 
PROTOCOL AMENDMENTS ........................................................................ 29 
14.2 
PROTOCOL DEVIATIONS, BREACHES AND WAIVERS ............................ 29 
 
TRIAL RECORD RETENTION ...................................................................... 30 
14.3 
30 
14.4 
END OF TRIAL .............................................................................................. 30 
14.5 
CONTINUATION OF DRUG FOLLOWING THE END OF TRIAL ................. 30 
15 
REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS ................... 30 
15.1 
AUTHORSHIP POLICY ................................................................................. 30 
15.2 
PUBLICATION ............................................................................................... 30 
15.3 
PEER REVIEW .............................................................................................. 31 
16 
REFERENCES ......................................................................................................... 32 
17 
APPENDIX ............................................................................................................... 34 
 
Appendix 1: Trial FLOW CHART ................................................................... 34 
17.1 
34 
 
34 
17.2 APPENDIX 2: TRIAL MATRIX ................................................................................... 36 
 
 


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PROTOCOL APPROVAL 
ADVANCE HCV 
EudraCT number 2017-001039-38 
Signatures 
By signing this document I am confirming that I have read, understood and approve the protocol 
for the above trial. 
 
Prof John Dillon 
 
 
 
Chief Investigator 
Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
 
BBV 
Blood Borne Virus 
CI 
Chief Investigator 
CNORIS 
Clinical Negligence and Other Risks Scheme 
CRF 
Case Report Form 
DAA 
Direct Acting Antivirals 
DBS 
Dried Blood Spot 
DMC 
Data Monitoring Committee 
DOT 
Directly Observed therapy 
FBC 
Full Blood Count 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase  
GP 
General Practitioner 
HCV 
Hepatitis C Virus 
IMB 
Information-Motivation-Behavioural 
ISF 
Investigator Site File 
LFT 
Liver Function Test 
MEMS® 
medication event monitoring system 
NESI 
Needle Exchange Service Initiative 
PCR 
Polymerase Chain Reaction 
Peg IFN 
Pegylated Interferon 
PHQ-9 
The Patient Health Questionnaire 
PWID 
Person Who Injects Drugs 
PT 
Prothrombin Time 
QC 
Quality Control 
RSI 
Reference Safety Information 
 RBV 
Ribavirin 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SVR 
Sustained Viral Response 
SVR12 
Sustained Viral Response at 12 weeks 
TCTU 
Tayside Clinical Trials Unit 
TMF 
Trial Master File 
TMG 
Trial Management Group 
U&Es 
Urea & Electrolytes 


ADVANCE V5.0 02/04/2018 
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SUMMARY 
 
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 
Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV 
infection is intravenous drug use. As HCV is highly infectious by the blood borne route through 
needle sharing, it can infect the person who injects drugs (PWID) early in their habit. 
 
The outcome of HCV infection varies considerably between individuals. Some (up to 25%) are 
able to clear the infection spontaneously, whilst the remaining 75% become chronically 
infected. Within the subpopulation of chronically infected patients, some will develop serious 
liver disease, including cirrhosis and hepatocellular carcinoma, within a few years1.  
 
Around two thirds of people who are infected are unaware of it 2, and often show no symptoms 
over a long period of time. While there is presently no vaccination for Hepatitis C, improved 
treatments with shorter duration are now available. This raises the possibility of using therapy 
as prevention, turning the epidemic off at source, by targeting active PWID who are the main 
source of new infections. The modelling work of Martin et al3, illustrates the startling possibility 
and impact of treating drug users to reduce the prevalence of HCV. 
 
The focus of this trial will be to ascertain whether oral treatment regimens are effective in the 
treatment as prevention scenario in an active PWID population where illicit drug taking and poor 
adherence may reduce treatment efficacy. We will trial 3 different methods of delivering 
treatment and determine which is most successful in this population. Additionally we will trial 
an unlicensed combined treatment against HCV genotype 3 infection of shortened duration 
since current regimens for this genotype are limited.  
 
We will recruit 135 participants and randomise them to one of three arms: daily, directly 
observed therapy; fortnightly dispensing of drugs; fortnightly dispensing of drugs with a 
psychological adherence intervention. Randomisation will be stratified according to HCV 
genotype. Participants will be treated for 12 weeks and followed up 12 weeks post treatment 
for the measurement of sustained viral response (SVR). The primary outcome measure will be 
SVR at 12 weeks post treatment (SVR12), as this measure of cure is the determinant of sufficient 
compliance and efficacy within the 3 treatment arms. Analysis will be by modified intention to 
treat of all participants who receive one dose of therapy, to show non-inferiority fortnightly 
dispensing is easier to deliver than daily dispensing.  
 
 
 
 


ADVANCE V5.0 02/04/2018 
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1 
 
INTRODUCTION 
  BACKGROUND 
Hepatitis C is a blood borne virus that can seriously damage the liver. An estimated 50,000 
Scots have been infected with Hepatitis C virus (HCV). The main driver for spread of HCV 
infection is intravenous drug use. As HCV is highly infectious by the blood borne route through 
needle sharing, it can infect the PWID early in their habit. With the advent of more effective 
therapies of shortening duration, it raises the possibility of using therapy as prevention, turning 
the epidemic off at source, by targeting active infected drug users who are the main source of 
new infections. 
Current treatment pathways focus on populations drawn from those known to drug problem 
services and former drug users. Some older periodic drug users are tested for HCV and are 
offered accelerated access into opiate substitution programs and early antiviral therapy. This 
treatment activity will reduce the health consequences of HCV infection but will have little impact 
on the group with active acquisition of HCV and hence the prevalence of HCV will remain the 
same, as any participants cured with anti-virals are more than replaced with new infections.  
The modelling work of Martin et al3, raises the startling possibility of the profound impact  of 
treating small numbers of drug users on the prevalence of HCV, the work shows that treating 
as few as 10-20 per 1000 drug users per year can reduce HCV prevalence by 50-90% over 10 
years. This has generated in the HCV field, the concept of treatment as prevention. The scale 
of the benefit is exponentially related to prevalence of HCV in the population, the lower the 
prevalence the bigger the impact. The model has some limitations, it groups all drug users 
together and assumes a similar risk of infection for those on methadone and those actively 
injecting and assumes a high rate of turn over from methadone back to active injecting and 
further assumes treatment is only possible during the opiate substitution phase. 
To test the feasibility of the model of Martin et al3 we ran the “Eradicate C” trial. This trial focuses 
on treating those drug users outside services where the impact on prevalence could be even 
more impressive, for such a relatively small investment. This group had never been previously 
targeted for therapy as it was believed to be too difficult to achieve the required adherence to 
therapy. The aim was to treat 20-40 highly active injecting drug users per year, recruited from 
Needle Exchange services. This trial showed that it was possible to treat this participant group 
with interferon based regimens +/- telaprevir, with SVRs that matched the conventional 
treatment trial outcomes. Adherence is crucial to therapy success and supervised interferon 
injections make therapy robust and may cover for lesser adherence to the ribavirin and protease 
inhibitor. The Eradicate C trial demonstrated that it is possible to deliver interferon based 
therapies to very active drug users and achieve cure rates that will power treatment as 
prevention.  
 


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 RATIONALE FOR TRIAL 
Oral anti-HCV regimens that are interferon free and have virtually no side-effects are now the 
standard of care in conventional treatment populations. The medication should be taken daily 
to optimise therapeutic success, and if adherence is poor in the actively injecting population it 
is possible that the effectiveness of the new oral drugs will be reduced.  It is key to know if all 
oral directly acting antivirals (DAA) regimens are robust and maintain SVR rates in this 
population. The real world SVR rate combined with drug cost, re-infection rate and emergence 
of viral resistance will determine if this treatment as prevention model is cost-effective with 
DAAs. Directly observed therapy (DOT) is the ultimate adherence aid, but it is more costly and 
draconian so that it may discourage participants, especially this group, from taking up therapy. 
Therefore we need to demonstrate that treatment uptake and adherence is sufficient to maintain 
the SVR rate at a level which makes treatment as prevention cost effective. We will compare 
three means of delivery: daily DOT vs fortnightly pick up of therapy vs. fortnightly pick-up of 
therapy with a psychological intervention for adherence. The DOT method of treatment has not 
been explored in this difficult to find and engage population previously. Contingency 
management in the form of protein drinks for successful completion of each fortnight of 
treatment will be provided in all three arms of the trial. A comparison of the three pathways 
mentioned above will show which pathway shows best acceptability to participants and greatest 
compliance  
 
The advent of DAAs with their reduced side effect profiles, shorter treatment duration and high 
SVR rates have the potential to reduce the burden of treatment providing high levels of 
adherence can be maintained. However, the use of DAAs alone are unlikely to be sufficient to 
achieve the required levels of adherence. In addition, the use of DAAs will not address the 
psychosocial factors known to influence adherence. To maximise participant outcomes, it will 
therefore be necessary to design interventions to promote adherence. One factor consistently 
cited as essential to treatment adherence is the provision of educational interventions regarding 
HCV, treatment of the condition and prognosis. However, these interventions (e.g.4,5,6) have 
not been shown to be effective in improving treatment adherence7. Several possible reasons 
exist for this discrepancy. First, the studies were generally of low quality with evidence of 
systematic bias (e.g. non-randomisation) and varied considerably in the structure and content 
of the intervention delivered. Second, none of the studies described a clear theoretical model 
of adherence behaviour upon which the interventions were based. Third, all interventions 
utilised generic education information about HCV. Evidence suggests that individualised and 
personalised information is essential in the promotion of adherence (e.g.8,9,10). All the factors 
likely limited the ability of the education to influence adherence in these studies. Finally, none 
of the studies investigated adherence in PWID or with DAA treatments only and therefore the 
effectiveness of such interventions in this population with newer treatment approaches is 
unknown. This trial will therefore investigate the effectiveness of a nurse-led educational 
intervention for adherence to DAAs in a PWID population. 


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Whilst the combination of Grazoprevir and Elbasvir is licensed for treatment of HCV genotype 
1, treatment of HCV genotype 3 is more problematic. The C-SWIFT trial has recently shown 
that the combination of Grazoprevir, Elbasvir and Sofosbuvir is an effective and safe 8 week 
treatment for HCV genotype 3, resulting in high SVR rates11. Whilst all 3 drugs are licensed for 
treatment of HCV, the combination is not yet licensed. We will use this combination to treat 
HCV genotype 3 infections in this trial.  
 
Hepatitis C virus is prone to develop resistance to DAAs since it has a high replication rate and 
therefore forms large numbers of genetically-distinct viral variants. We will investigate whether 
participants who do not achieve SVR are infected with a drug resistant strain of HCV by 
sequencing the NS3 and NS5A regions of virus present within their blood. The proteins of these 
genes are targeted by the DAA medications and if their structure is altered the DAA may no 
longer be effective.  
 
The trial will also explore whether the taking of illicit drugs affects the efficacy of treatment. 
While the main effect is likely to be via adherence, it is also possible that some of the illicit drugs 
may interact with the DAAs. A log of illicit drugs used by the participants will be kept and used 
to identify any candidate interactions for further investigation. 
 
2 
TRIAL OBJECTIVES AND OUTCOMES 
Table 1: Primary Objectives and Outcome Measures 
Primary Objective: 
Outcome Measure: 
Time point of outcome  
measured 
To compare the efficacy of DAAs 
in HCV positive, active PWIDs, 
administered via DOT, fortnightly 
pick-up or fortnightly pick-up with 
a psychological adherence 
intervention.   
SVR12 rates of participants in the 
DOT, fortnightly pick-up or 
fortnightly pick-up with a 
psychological adherence 
intervention group  
 
 
12 weeks post 
treatment completion 
 
 
 
 
 
 
 
 
 


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Table 2: Secondary Objectives and Outcome Measures 
Secondary Objective: 
Outcome Measure: 
Timepoint of outcome  
measured 
To demonstrate that the achieved 
SVR rates in HCV PWID 
participants with DAA treatment 
are similar to RCT results and 
therefore a cost-effective 
treatment  
Adherence of daily directly 
observed therapy group from daily 
logs 
Daily log completed 
daily, adherence 
calculated at end of 
treatment 
Adherence measured by counting 
tablets returned after each 2 week 
treatment period (fortnightly 
pickup groups) 
Calculated at end of 
treatment 
Adherence of participants infected 
with genotype 3 and treated with 
Sovaldi measured using MEMS® 
cap. 
Calculated at end of 
treatment 
To assess reinfection rates in 
active PWIDs treated with oral 
DAA regimes 
Hepatitis C viral load from PCR 
Annually at clinic visits 
To assess resistance profiles in 
those who do not achieve SVR. 
Profiles of the HCV viral resistance 
proteins,  NS5a and NS3 
Blood 
collected 
at 
baseline, 
end 
of 
treatment and SVR12 
To assess the types of illicit drugs 
taken by trial participants and 
identify any interaction with the 
DAAs. 
Drug misuse history 
Baseline, end of 
treatment (genotype 1 
infection = week12, 
genotype 3 infection= 
week8) 
Urine toxicology 
Once during treatment 
 
3 
TRIAL DESIGN 
 TRIAL DESCRIPTION 
This is a randomised, un-blinded trial which will be conducted in the needle exchange services 
and pharmacies across Tayside, designed to evaluate the efficacy and feasibility of DAA 
therapy, in HCV positive, genotype 1 and 3, active PWIDs, administered via three different 
routes:  
1. DOT,  
2. Fortnightly pick-up  
3. Fortnightly pick-up with psychological intervention. 
 


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Participants included in the trial will have a reactive Dry Blood Spot (DBS) test to confirm HCV 
infection, PCR to confirm active infection and will currently be using illicit drugs, as confirmed 
by the participant. Drug screening (by urine sample) will not be tested at that time. 
 
Participants will be stratified by the genotype of their HCV infection; genotype 1 vs genotype 3 
and randomised to one of three groups; DOT, fortnightly pick-up, or fortnightly pick-up with 
psychological adherence intervention. 
  
All PWID are encouraged to have a DBS test annually as part of clinical practice in Tayside. 
Upon receipt of a reactive DBS test, potential participants will be briefed about the trial by the 
specialist nurse or other trained member of staff and given a participant information sheet (PIS) 
informing them of what is involved. Willing individuals will provide written informed consent and 
will then have safety bloods drawn to determine eligibility to proceed. A full list of 
inclusion/exclusion criteria is detailed in section 4.  
 
Participants in all three arms of the trial will attend a baseline visit, a randomisation visit either 
one (genotype 3) or two (genotype 1) visits during treatment, an end of treatment visit and an 
SVR visit, as detailed in Appendix 2.  
All participants will be given incentives to continue with their treatment in the trial. These will 
consist of protein drinks and will be given at each study visit. 
 
Psychological intervention 
Participants randomised to fortnightly pick-up with psychological intervention will have an 
interview with the study nurse, prior to beginning their treatment, which will cover the 
educational intervention designed to aid their compliance with the drug regimen. The 
intervention will be based on the Information-Motivation-Behavioural (IMB) Skills Model of 
Adherence12 which was originally developed to explain adherence behaviour in HIV. Recent 
research suggests this model may have applicability in understanding the facilitator and barriers 
to adherence in HCV patients8. The model suggests that provision of medication information, 
enhancing personal and social motivation and developing behavioural skills that are key 
determinants of adherence and may improve adherence in this group. The intervention will 
involve a structured interview in which the trial nurse and participant will develop an action plan 
that includes personalised information, sources of motivation for adherence and a treatment 
routine configured to be compatible with the participant’s lifestyle. Anticipating barriers to 
adherence and problem-solving will be included in the treatment routine. The intervention will 
take place at the randomisation visit and last approximately one hour. During the intervention, 
participants will be guided by their trial nurse in the completion of a personalised booklet, 
“Hepatitis C and Me”. The booklet contains general and personalised information on Hepatitis 
C, exercises designed to explore and enhance personal and social motivation for treatment 
adherence and a behavioural action plan (the skills element of the IMB model). The booklet 


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uses the principles of node-link mapping to structure the intervention. Node link mapping use a 
set of visual tools to structure and guide therapeutic conversation and has been shown to 
enhance memory and compliance with treatment in substance misusers (e.g 13,14). 
Participants in the other two arms of the trial, who are not receiving the psychological 
intervention, will be given the current NHS Tayside hepatitis information booklet (“Living with 
Hepatitis C”) which provides generalised information about HCV without personalised 
information or specific strategies to enhance motivation and behavioural skills.  
 
Reinfection follow up.  
Trial participants will be invited to also consent for access to information from their annual clinic 
visits and HCV testing at any other contact with clinical services for up to 5 years, to detect re-
infection.  
 
Illicit drug monitoring 
Illicit drug use will be recorded at baseline and at end of treatment (week 8 for genotype 3, 
week 12 for genotype 1). One sample of urine for toxicology will be taken during treatment. 
Those participants who fail to achieve SVR will be compared to successful participants for any 
correlation with particular substance use. For any candidate substance associated with failure 
to achieve SVR not explained by lack of adherence, biological samples will be analysed for 
biological mechanisms. 
 
Adherence monitoring 
Adherence of those participants randomised to DOT will be documented on a daily log. Those 
randomised to fortnightly collection of medication will receive Zepatier tablets in blister 
packaging. They will return their packets of medication every two weeks and any remaining 
tablets will be counted. Participants infected with HCV genotype 3 will additionally receive 
bottles containing Sovaldi tablets. These bottles will be fitted with adherence aid caps that 
record time and date of each cap opening. 
 
 
TRIAL FLOWCHART 
Please refer to Appendix 1 (section 17.1) 
 
 
TRIAL MATRIX 
Please refer to Appendix 2 (section 17.2).  
 
4 
TRIAL POPULATION 
 NUMBER OF PARTICIPANTS 
 


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This trial aims to treat 135 active PWID with active HCV infection in Tayside over a two year 
period. Due to the nature of this trial, trial dropouts are a trial endpoint and will not be replaced. 
 
 INCLUSION CRITERIA 
 
Male or Female. (Age limit 18-70) 
 
HCV PCR confirmed active infection, genotype 1 or 3. 
 
If female, must have negative urine test results for pregnancy during initial screening 
period (for trial inclusion) and be advised of limited safety data in pregnancy. 
 
Current illicit drug use established through participant history.  
 
Able to provide informed consent, agreeing to trial and clinical monitoring criteria  
 
 EXCLUSION CRITERIA 
 
Aggressive or violent behaviour. 
 
Unwilling to consent to GP being informed of their participation in the trial 
 
Platelet count < 75 x 10 9 /l 
 
Alanine transaminase > 350U/l 
 
Inability to provide informed consent. 
 
Clinical history or abnormal valves for albumin< 30 g/l, Bilirubin >35 umol/l or PT >1.5 
consistent with decompensated liver failure Childs-Pugh B or C 
 
Clinical history of primary hepatocellular carcinoma 
 
Pregnancy or breast feeding.  
 
Participation in a drug trial within the previous 30 days 
 
Hepatitis B surface antigen positive 
 
HIV infection. 
 
Hypersensitivity to elbasvir and grazoprevir  
 
Hypersensitivity to sofosbuvir (genotype 3 infected-participants ony) 
 
Currently being treated with an inhibitor of organic anion transporting polypeptide 1B, 
e.g. rifampicin, atazanavir, daruavir, lopinavir, saquinavir, tipranavir, cobicistat or 
ciclosporin. 
 
Currently being treated with inducers of cytochrome P450 3A or P-glycoprotein, such 
as efavirenz, phenytoin, carbamazepine, bosentan, etravirine, modafinil or St John’s 
Wort (Hypericum perforatum) 
 
Currently being treated with amiodarone (Participants infected with genotype 3 HCV 
only) 
 


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5 
PARTICIPANT SELECTION AND ENROLMENT 
 IDENTIFYING PARTICIPANTS 
 
Individuals will be identified via the current DBS testing pathway in Needle Exchange 
centres sited in health care hubs by specialist nurse or other trained member of staff.  
 
In addition, known HCV positive participants with reactive dry blood spot test attending 
needle exchange with status having previously been established elsewhere will be 
approached in Needle Exchange centres or other suitable venues by specialist nurse 
or other trained member of staff. 
 
Potential participants (above) will be given a participant information sheet (PIS) and 
any questions they have about the trial will be answered by the trial team. 
 
 CONSENTING PARTICIPANTS 
Potential participants will be approached by research nurses but they may delegate to other  
individuals who are trained in dried blood spot testing and are part of the managed care network 
and have right of referral to treatment services. Any such delegation will be recorded on the 
trial Delegation Log and be authorised by the CI. Potential participants will be provided with 
information on the trial verbally and via the PIS and be given at least 24 hours to consider 
participation in line with prevailing TASC SOP. At their return visit for screening they will be 
interviewed by the trial research nurse and asked to sign an informed consent form once they 
are satisfied that they have had adequate explanation from the member of staff explaining the 
trial to them.  
 
Where a participant requests to speak with a physician from the trial team the consent process 
will not be completed until the participant had spoken to the physician and had all their questions 
answered to their satisfaction. 
Once a participant has consented to take part a GP letter will be sent to their GP to inform them 
that their patient is in a clinical trial. If the individual is not registered with a GP they will be 
encouraged to do so. In the meantime, any acute medical problems will be handled by the 
hepatitis C clinical team.  
 
 SCREENING FOR ELIGIBILITY 
Following informed consent, blood will be taken from the participants to assess their liver 
function and to confirm that they have active infection with HCV genotype 1 or 3 and not with 
HIV or hepatitis B. Active illicit drug use will be confirmed by participant. Urine sample will be 
taken from female potential participants and a pregnancy test carried out to confirm that they 
are not pregnant. Any prescribed medication will be checked for drug-drug interactions with trial 
medication. 
 


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 INELIGIBLE AND NON-RECRUITED PARTICIPANTS  
Ineligible or non-recruited participants will be thanked for their interest in the trial and be given 
a clear explanation as to why they are ineligible. If a clinically significant abnormality is detected 
relevant clinical management will be instigated and the participants GP informed if the patient 
consents. 
 
 RANDOMISATION 
5.5.1 
Randomisation 
After successful screening for eligibility and safety, participants will be randomised to either 
DOT, fortnightly pick up or fortnightly pick up with psychological intervention.  
PWID who are eligible for this trial have unpredictable and chaotic lives. It is therefore possible 
that an individual will consent to take part, provide baseline information and have blood taken 
for safety and eligibility checking. If eligible they may be randomised. They may then not be 
seen at the needle exchange for a number of weeks or even months. It is standard clinical 
practice that pretreatment bloods are valid for a period of 6 months and therefore we will 
consider baseline bloods taken for the study to be valid for 6 months unless there is a clinical 
indication to repeat within that period. Any clinical decision on whether bloods need to be 
repeated within 6 months will be made by the CI. If a consented participant reappears after a 
period longer than 6 months has elapsed, a documented verbal check will be made to confirm 
that the individual continues to consent to taking part in the study. The bloods will be re-taken 
and eligibility will be based on the results of these new blood tests. The blood tests taken closest 
to the date of treatment initiation will be considered as the baseline data.The viral genotype will 
not be retested as NHS lab policy is to redo this test only after 5 years have elapsed. After 6 
months the baseline CRF will also be repeated to provide up-to-date pretreatment information. 
In this case, the information originally collected in the baseline CRF will be filed but will not be 
entered into the electronic data management system (Openclinica) and will not form part of the 
analysed dataset. To ensure that the correct, most up-to-date baseline data is entered into 
Openclinica, baseline data will be entered once each participant has started their treatment.  
 
As this is an un-blinded trial, the nurse, or delegated member of staff, and participant will be 
aware of which arm they are allocated to. Randomisation to each of the three trial groups will 
be stratified by genotype so that the proportion of genotype 1 vs genotype 3 infected 
participants will be the same in each group. The Tayside Clinical Trials Unit (TCTU) GCP-
compliant online randomisation system, TRuST, will be used by the specialist nurse or 
delegated, trained member of staff to perform the randomisation. 
 


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5.5.2 
Treatment Allocation 
Eligible participants infected with genotype 1 HCV will receive Zepatier treatment for 12 weeks. 
Zepatier contains a combination of Grazoprevir and Elbasvir. Whilst it is a licensed medication, 
Merck will supply GMP ready investigational medical product (IMP) for use in the trial. Those 
infected with genotype 3 HCV will receive commercial stock sofosbuvir off the shelf in addition 
to Zepatier for 8 weeks. Treatment regimens for treatment naïve and treatment experienced 
participants enrolled in the trial will be the same. Zepatier tablets are film-coated and each 
contains 50 mg Elbasvir and 100 mg Grazoprevir. Sovaldi is provided as a single 400mg tablet.  
 
For participants in group 1, medication will be dispensed daily by the participant’s community 
pharmacist or at the needle exchange. The pharmacist or trial nurse will observe the participant 
taking the medication and this will be noted in a daily log. Participants will be provided with 
sufficient tablets for the weekend and other days that the pharmacy/needle exchange is closed. 
Participants in groups 2 and 3 will fortnightly receive two week’s supply of medication from the 
trial staff.  Participants infected with Genotype 1 HCV will be instructed to take one tablet daily 
from the blister pack. Those infected with Genotype 3 HCV will be instructed to take one tablet 
daily from the blister pack and one tablet daily from the bottle. The bottle will be fitted with an 
electronic adherence measuring aid.  
 
5.5.3 
Withdrawal procedures 
Participants will be informed that they have the right to withdraw from the trial at any time without 
giving reasons and without prejudicing further treatment.  The right to refuse to participate 
without reasons will be respected.  After the participant has entered the trial the clinician 
remains free to give alternative treatment to that specified in the protocol at any stage if he/she 
feels that it is in the participant’s best interest but, reasons for doing so will be recorded.  In 
these cases the participants remain within the trial for the purposes of follow-up and data 
analysis.   
 
Although a participant is not obliged to give reason(s) for withdrawing prematurely, if the 
participant appears lost to follow up, the CI will make a reasonable effort to ascertain the 
reason(s), while fully respecting the individual’s rights, and will demonstrate that everything 
possible was done in an attempt to find any participant lost to follow-up. Those lost to follow-up 
or withdrawn will be identified and a descriptive analysis of them provided, including the reasons 
for their loss and its relationship to treatment and outcome. 
 


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6 
INVESTIGATIONAL MEDICINAL PRODUCT 
 TRIAL DRUG 
6.1.1 
Trial Drug Identification 
Genotype 1 infection will be treated with Zepatier (100mg Grazoprevir and 50mg of Elbasvir) 
supplied as one film-coated tablet to be taken once per day with or without food for 12 weeks. 
This is a licensed medication but the drug supplied by the manufacturer will be IMP.  
 
Genotype 3 infection will be treated with Zepatier as above plus Sovaldi (Sofosbuvir 400mg, 
licensed product), taken as one film-coated tablet once daily with food for 8 weeks. The 
combination of Zepatier plus Sovaldi has been successfully trialled for treatment of genotype 3 
hepatitis C infection (C-SWIFT11 and C-ISLE15 trials) but this combination of drugs is not 
licensed for treatment of HCV genotype 3 infection. 
 
6.1.2 
Trial Drug Manufacturer 
Merck (Zepatier) 
Gilead (Sovaldi) 
 
6.1.3 
Marketing Authorisation Holder 
Zepatier is manufactured by: 
Merck Sharp & Dohme Limited 
Hertford Road 
Hoddesdon EN11 9BU 
United Kingdom 
MA number: EU/1/16/1119/001. As stated above, the manufacturer will supply us with IMP 
product. 
 
Sovaldi is manufactured by:  
Gilead Sciences International Ltd 
Flowers Building  
Granta Park Abington  
Cambridge  
CB21 6GT  
United Kingdom 
MA number: EU/1/13/894/001 (for 1 bottle of 28 tablets) and EU/1/13/894/002 (for 3 bottles of 
28 tablets). 
 


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6.1.4 
Labelling and Packaging 
Zepatier tablets are packaged in a carton containing two cardboard cards, each containing 2 
strips of 7 sealed blisters. Participants randomised to the DOT arm will receive one tablet per 
day. Those randomised to the fortnightly collection of medication will receive one cardboard 
card, containing 2 strips of 7 blisters, making 14 blisters in total.  
 
Participants randomised to the DOT arm will receive one Sovaldi tablet per day. Those 
randomised to the fortnightly collection of medication will receive one bottle containing 14 
tablets every 14 days. Commercially available medication event monitoring system (MEMS®) 
caps will be used on the bottles of Sovaldi to enable measurement of adherence in the 
participants with genotype 3 infection.  
 
6.1.5 
Storage 
Drugs will be stored in the Clinical Trial Pharmacy (Ninewells Hospital, Dundee). Following 
receipt of a prescription, a participant’s drug will be dispensed from there to the community 
pharmacy or needle exchange centre. A drug accountability log will be held in the Clinical Trial 
Pharmacy. There are no special storage conditions required for either Zepatier or Sovaldi as 
per their Summary of Product Characteristics (SmPC). 
 
6.1.6 
Reference Safety Information (RSI) 
Zepatier SmPC and Sovaldi  SmPC  will be held in the Trial Master File -  specifically in 
Pharmacy Site File (PSF) and Investigator Site File (ISF). The SmPCs will be reviewed at least 
annually and where there have been any changes to the RSI from the SmPC version approved 
by MHRA, an amendment will be submitted for regulatory approval. Other changes to the SmPC 
will not require an amendment. 
 
6.1.7 
Accountability procedures 
This will be overseen by the Clinical Trials Pharmacist in the Clinical Trials Pharmacy 
Department (Ninewells). This will be documented as such in the TMF and Accountability Logs 
will be held in the PSF.  
 
 DOSING REGIME 
Following randomisation, participants in the DOT group will be issued with their first dose of 
medication. Those with genotype 1 infection will be given one Zepatier tablet whilst those with 
genotype 3 will get one Zepatier tablet and one Sovaldi tablet. Participants in each of the 
fortnightly dosing regimens will be given two week’s supply of medication. No per body weight 
dose adjustment is required and participants with genotype 1 will be treated for 12 weeks, those 
with genotype 3 for 8 weeks.12 weeks following the end of treatment blood will be taken from 


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participants in order to establish whether they have achieved SVR12. Participants will be asked 
to consent to being followed up annually for five years to enable us to establish reinfection rates. 
Participants will be asked to use adequate contraception (see section 11.1).  
 
 DOSE CHANGES 
No dose change is planned in this trial protocol. If the participant is taken off the trial, their GP 
and consultant will be informed of the reason for stopping trial medication. The participant will 
remain in the trial for the entire duration even if the trial medications are stopped, subject to 
their agreement.  
 
 PARTICIPANT COMPLIANCE 
Adherence to the dosing regime is a secondary outcome of this trial. It will be checked and 
documented in each of the 3 arms of the trial.  Those in the DOT arm will have adherence 
documented by the pharmacist or staff member, while those in the other two arms will be asked 
about adherence at each trial visit and, for participants being treated for genotype 3 HCV 
infection, the MEMS® caps records will be analysed. Should compliance be poor, the participant 
will be advised by the trial nurse or delegated individual on the importance of correct 
compliance. If any subject misses more than 7 consecutive doses they will be withdrawn from 
treatment but still followed up to the SVR 12 visit. 
 
 OVERDOSE 
Experience of human overdose with these drugs is limited. When tested in healthy volunteers, 
adverse reactions were similar in frequency and severity to those reported in the placebo 
groups.  
In the event of an overdose, it is recommended that the participant be monitored for any 
signs/symptoms of adverse reactions and appropriate symptomatic treatment instituted.  
 
 OTHER MEDICATIONS 
6.6.1 
Permitted Medications 
Medications will be permitted as long as they do not interact with the trial drugs. The SmPC 
and Liverpool HEP interactions website (http://www.hep-druginteractions.org) will be used to 
identify drugs with potential interactions. 
 
6.6.2 
Prohibited Medications 
Prohibited medications are those identified by the SmPC and Liverpool HEP interactions 
website (http://www.hep-druginteractions.org) as having potential interactions with the trial 


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drugs. GPs will be informed that their patient is participating in the study and will check 
compatibility prior to prescribing new drugs.  
 
6.6.3 
Concomitant Medications 
Details of all concurrent medications will be recorded in the CRF.     
 
7 
TRIAL ASSESSMENTS 
 TRIAL ASSESSMENTS 
See participant trial matrix: Appendix 2 
 
Participants who are randomised to the DOT arm of the trial will undergo daily review by their 
dispensing pharmacist or delegated member of staff.   
 
Participants who are randomised to the fortnightly pick-up with psychological intervention will 
receive a less than one-hour individual session with a research nurse exploring their motivation 
and skills to adhere to their treatment regime. The intervention is described in section 3.1 and 
will involve a structured interview in which the trial nurse and participant will develop an action 
plan that includes personalised information, sources of motivation for adherence and a 
treatment routine configured to be compatible with the participant’s lifestyle. During the 
intervention, participants will be guided by their trial nurse in the completion of a personalised 
booklet, “Hepatitis C and Me”.  
 
 
 SAFETY ASSESSMENTS 
For adverse event reporting see section 10 below.  
Safety bloods to assess liver and kidney function including liver function tests (LFTs), urea and 
electrolytes (U&Es) Full blood count (FBC), and prothrombin time (PT) will be assessed prior 
to the onset of treatment to ensure that the participant can tolerate DAA therapy and at the end 
of treatment (week 8 for genotype 3 infection, week 12 for genotype 1 infection). LFTs will be 
measured at week 8 of treatment in all participants due to rare flare in alanine aminotransferase 
levels. 
Female participants will have a urine pregnancy test prior to beginning treatment to ensure that 
they are not pregnant.  
 


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8 
DATA COLLECTION& MANAGEMENT 
 DATA COLLECTION 
Data management will be conducted in compliance with TASC SOPs on Data Management. 
The data will be principally collected by the nurses appointed to the trial and supported by other 
trial appointed staff. The data sources will include the CRF, medical notes, laboratory reports 
and trial specific questionnaires.  
Trial-specific data will be collected at baseline, randomisation week 4, week 8 (HCV genotype 
1), end of treatment and 12 weeks post treatment. 
Most of this data will be entered directly into the CRFs without being routinely recorded in 
clinical data sources. Participants will be asked to consent to information being collected at 
routine annual clinic visits for up to 5 years to check for reinfection.   
 
 DATA MANAGEMENT SYSTEM  
The data management system provided by TCTU will be OpenClinica. Development and 
validation of the trial database with QC and extraction of data will be done according to TCTU 
procedures. The DMS will be based on the protocol and case report form (CRF) for the trial and 
individual requirements of the investigators. The CRF will collect only information that is 
required to meet the aims of the trial and to ensure the eligibility and safety of the participant. 
The CI may delegate CRF completion but is responsible for completeness, plausibility and 
consistency of the CRF. Any queries will be resolved by the CI or delegated member of the trial 
team. The trial database will be compliant with TASC SOPs on Creating and Managing 
Databases. Extracts for analysis will be based on the dummy data tables provided by the trial 
team. 
 
9 
STATISTICS AND DATA ANALYSIS 
 SAMPLE SIZE CALCULATION 
Statistical analysis will be conducted in compliance with TASC SOPS. 
 
We propose to conduct this project as a randomised trial to show that DAA therapy in very 
active PWIDs administered fortnightly with or without adherence intervention is non-inferior to 
DOT. We will compare pathways sequentially comparing DOT vs fortnightly delivery and then 
DOT verses fortnightly pickup with adherence intervention. Fortnightly pick up will be more cost 
effective than the other two options so long as adherence and efficacy matches that of the DOT 
and fortnightly plus adherence intervention. If we assume a 95% SVR rate (based on published 
studies) in the DOT arm of the trial in this population and a non-inferiority limit of 14% (which 
would be likely to maintain cost-effectiveness) then at a 5% significance level and 90% power 


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we would need a sample size of 42 in each group 126 in total. To allow for drop-outs we will 
aim to recruit 135 individuals, 45 per group. 
 
A Statistical Analysis Plan (SAP) will be prepared for analysis of primary and secondary 
outcomes and will include a plan for handling missing data 
 
 PROPOSED ANALYSES 
9.2.1 
Primary Outcomes 
 
To compare using SVR rates the efficacy and compliance of DAAs in135 new HCV 
positive individuals randomised to one of three groups; DOT, fortnightly therapy and 
fortnightly therapy with psychological adherence intervention.  
The data for these outcomes will be generated directly from the CRFs from the clinical and 
laboratory data recorded therein.  
 
9.2.2 
Secondary Outcomes 
 
Compare adherence to therapy rates of subjects randomised to either DOT, 
fortnightly therapy or fortnightly therapy with psychological adherence intervention - 
treatment of HCV. Adherence rates will be obtained from the daily log data in the 
DOT group, and from pill counting and MEMs caps data in the two fortnightly therapy 
groups. 
 
Assess reinfection rates in the PWID population and treated using all oral DAA 
regimes. The data for reinfection rates will be will generated from the annual follow up 
and retesting for chronic HCV infection of all participants treated. This will be from 
routine clinical follow data and consent will be sought to access this. The analysis is 
simple, requiring only simple descriptive statistics. 
 
Assess viral resistance patterns in participants who do not achieve SVR. These data 
will be obtained by analysing samples for resistance associated variants (RAVs) 
using standard clinical laboratory assays.  
 
Assess the types of illicit drugs taken by trial participants and identify any interaction 
with the DAAs and possible effect on adherence. This data will be generated by the 
adverse event reporting mechanism within the trial. The particular interest will be 
around interactions of the trial medication with drugs of misuse. Concomitant drug use 
during the trial will be recorded in the CRF at baseline and end of treatment and 
supported by urine toxicology from a urine sample that will be collected during 
treatment. Data will be recorded in the CRF.  
9.2.3 
Statistical analysis 
Outcomes Data Analysis plan: Analysis of the trial will follow the principles outlined in the ICH 
E9 ‘Statistical Principles for Clinical Trials’ and carried out by the UKCRC registered Tayside 


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Clinical Trials Unit (TCTU). Prior to data lock an agreed Statistical Analysis Plan (SAP) will be 
finalised covering the pre-specified statistical analysis.  
The primary outcome of SVR will be assessed as a binary outcome for subjects and so will 
utilise logistic regression modelling. The numerator will be the number of subjects achieving 
SVR and the denominator will be total number of patients randomised to each arm. Additionally 
results will be expressed as a proportion of the estimated HCV infected subjects in needle 
exchange. The estimated number of infected patients will be based on national survey data and 
the empirical rate discovered in the trial (allowing for patients who refuse testing). A test of 
interaction between contingency and pathway will be carried out and if not significant 
contingency will be assessed independently. If significant then the effect of contingency will be 
assessed by each pathway separately. As all patients will have either achieved SVR or not and 
we will assume that drop-outs / lost to follow-up are failures, there will be no missing data in the 
primary outcome. Extra- binomial variability or over-dispersion will be examined in the logistic 
model and if present alternative modelling such as negative binomial models will be considered. 
This will also be adjusted by therapy and genotype; the two factors are interdependent 
determining length of therapy. 
Secondary binary outcomes will be analysed in the same procedure, initially as intention to treat 
with all eligible patients as the denominator and then to explore the steps in the pathway by per 
protocol analysis in particular to analyse on treatment success: 
a) Proportion of HCV tested.  
b) Proportion who start HCV treatment within the duration of the study of those identified with 
HCV.  
c) Adherence:  to compare the longitudinal evolution of adherence to the prescribed regimen 
between the conventional pathway and the pharmacy led pathway. For each patient, daily 
adherence will be defined using a binary variable Z it indicating whether yes (=1) or no (=0) the 
subject has taken their medication on day t. This longitudinal binary variable will be directly 
generated from the patient electronically compiled dosing history. Comparison of binary time 
series is realized using a logistic regression where dependence among observations from a 
given patient over time is taken into account. The effect of pathway and contingency 
management on overall adherence will be tested using the above-described model by testing 
if either the group coefficient or the interaction between the group and time are significantly 
different from zero.  
d) Proportion who complete the course of those initiating treatment. 
Multiple logistic regression modelling will explore the patient and pathway characteristics that 
are associated with the secondary outcomes and primary outcome. Patient outcomes 
considered will be age, gender, deprivation, employment, comorbidity, and the psycho-social 
variables assessed. 
 


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 MISSING DATA 
The nature of this trial is to assess the applicability of this model in the real world, so incomplete 
data that impacts the primary outcome will be assumed to be to consistent with failure of therapy 
and drop-outs won’t be replaced. However every effort will be made to obtain missing data and 
as the primary outcomes are not time point critical a wide latitude for admissibility of data will 
be employed. We will accept measures of SVR up to 12 weeks after the due SVR12 date. 
 
 TRANSFER OF DATA 
No participant identifiable data will be transferred off site. Data will be stored, identified by trial 
number, with a separately held key to link trial number to identifiers that could be used for record 
linkage.  
 
10 ADVERSE EVENTS 
 DEFINITIONS 
An adverse event (AE) is any untoward medical event affecting a clinical trial participant. Each 
initial AE will be considered for severity, causality or expectedness and may be reclassified as 
a serious event or reaction based on prevailing circumstances. 
An adverse reaction (AR) is where it is suspected that an AE has been caused by a reaction 
to a trial drug 
A serious adverse event (SAE), serious adverse reaction (SAR) or suspected unexpected 
serious adverse reaction (SUSAR) is any AE, AR or UAR that at any dose: 
 
results in death 
 
is life threatening  
 
requires hospitalisation or prolongation of existing hospitalisation 
 
results in persistent or significant disability or incapacity 
 
is a congenital anomaly or birth defect 
 
Or is otherwise considered serious 
 
 RECORDING AND REPORTING AES AND SAES 
All AEs and SAEs will be recorded from the time a participant consents to join the trial until the 
last trial visit. Participants with unresolved AEs at their last trial visit will be followed up until 
resolution or 30 days after their last trial visit whichever is sooner. SUSARS will be followed 
until resolution. 
 
The CI or delegate will ask about the occurrence of AEs and hospitalisations at every trial visit. 
AEs will be recorded on the AE Log in the CRF. SAEs will be submitted on an SAE form to the 
Sponsor Pharmacovigilance Section (pharmacovigilance.tayside@nhs.net) within 24 hours of 


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becoming aware of the SAE except as described below and to MSD Global Safety group within 
2 business days of the study team becoming aware of the event. SAEs will be assessed for 
expectedness and causality by the Investigator. The evaluation of expectedness will be made 
based on the knowledge of the reaction and the relevant product information (SmPC or IB). 
Refer to TASC SOP “Identifying, Recording and Reporting Adverse Events for CTIMPs”. 
Causality will be assessed by the Sponsor 
Hospitalisations for treatment planned prior to randomisation and hospitalisation for elective 
treatment of a pre-existing condition will not be considered as an SAE. However any adverse 
events occurring during such hospitalisation will be recorded. 
 
Due to the large amount of comorbid disease and very high levels of illness and AEs that are 
expected to be present in this population, we will record as AEs/SAEs, but not report as SAEs 
to Sponsor Pharmacovigilance Section within 24 hours but will provide as line listings only to 
be included in the annual Development Safety Update Report (DSUR), in following the 
categories:  
 
Any death or hospitalisation for assault or accidental injury 
 
Hospitalisation for abscesses due to drugs use 
 
Hospitalisation for wound management due to drugs use 
 
Any death or hospitalisation due to infection 
 
Hospitalisation for elective or planned investigation or treatment 
 
Any death or hospitalisation for deteriorating renal function, high or low potassium 
levels 
 
Any hospitalisation due to nausea, vomiting, constipation or diarrhea 
All other SAEs will be reported to Sponsor Pharmacovigilance Section within 24 hours and to 
MSD’s Drug Surveillance Department within 2 business days of becoming aware of the event.  
 
 REGULATORY REPORTING REQUIREMENTS 
The Sponsor, together with the CI, is responsible for reporting SUSARs to the competent 
authority, the MHRA, the Research Ethics Committee (REC) and any other competent 
authorities. Fatal or life threatening SUSARs will be reported within 7 days and non-fatal and 
non-life threatening SUSARs within 15 days. 
 
 
 ANNUAL REPORTING REQUIREMENTS 
The following reports will be submitted each year as a condition of the authorisation to 
undertake a clinical trial or as a condition of a favourable opinion from a REC. 
  
The DSUR will be prepared jointly by the Sponsor Pharmacovigilance Section and CI and 
submitted to the MHRA on the anniversary of date of Clinical Trial Authorisation (CTA). 


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An NRES CTIMP Safety Report Form will be sent to REC along with the DSUR. A NRES Annual 
Progress Report for CTIMPs will be prepared and submitted by the CI to REC, and copied to 
Sponsor, on the anniversary date of the REC favourable opinion. 
 
Reports of SUSARs in the UK, urgent safety measures and any other safety reports submitted, 
for example, reports of a data monitoring committee, will also be accompanied by a Safety 
Report Form.  
 
 
 URGENT SAFETY MEASURES 
The CI or other clinician may take appropriate immediate urgent safety measures in order to 
protect the participants of a CTIMP against any immediate hazard to their health or safety. The 
MHRA, REC and Sponsor will be notified in writing within three days. 
 
11 PREGNANCY 
Pregnancy is not considered an AE or SAE, however an abnormal outcome would be. If a 
pregnancy occurs, the CI or delegate must collect pregnancy information for female trial 
participants, who will be advised to stop trial medication immediately.  
 
The CI or delegate should complete the TASC Pregnancy Notification Form and submit to the 
Sponsor Pharmacovigilance section within 14 days of being made aware of the pregnancy.   
Any pregnancy should be followed to outcome. Pregnancy follow up information must be 
recorded on the TASC Pregnancy Follow up form and submitted to the Sponsor 
Pharmacovigilance section.   
 
 CONTRACEPTIVE ADVICE TO PARTICIPANTS   
All participants will be given contraceptive advice. With the aim of avoiding pregnancy during 
treatment. Avoiding getting pregnant by not having sex at all is obviously effective. If participants 
follow this strictly, no contraception is needed. If not, the following are effective types of 
contraception:   
• 
Combined Oral Contraceptive Pill   
• 
EVRA-oestrogen and progestogen: ‘Transdermal Patch’   
• 
Progestogen only pill: ‘mini pill’   
• 
Depoprovera injection (medroxyprogesterone acetate)   
• 
Implanon Implant (Etonogestrel)   
• 
Mirena Coil (Intra-Uterine System)   
• 
IUD-copper containing intrauterine device   
• 
Female sterilisation   


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• 
‘Barrier methods’ such as the condom, diaphragm or cap, with or without 
spermicide, may also be used.    
 
Male vasectomy is also a good form of contraception but only if the procedure has been 
confirmed afterwards by a physician to make sure it has worked.   No contraception method is 
100% reliable by itself. Even surgical sterilisation in men and women has been known to fail 
very occasionally therefore participants will be advised to use additional contraception from the 
start of the trial if they or their partner is of child bearing potential.    
 
12 TRIAL MANAGEMENT AND OVERSIGHT ARRANGEMENTS 
 TRIAL MANAGEMENT GROUP 
The trial will be co-ordinated by a Trial Management Group, who will meet regularly and co-opt 
co-investigators and the research nurses to the meeting as required.  
 
 TRIAL MANAGEMENT 
A Trial Manager will support the chief investigator (CI) in managing the trial, they will have the 
support of a trial Coordinator who will work closely with the research nurses. The research 
Nurses will oversee the trial and will be accountable to the CI.  
A trial-specific Delegation of Responsibilities & Signature Log will be prepared for each Site, 
detailing the responsibilities of each member of staff working on the trial.  
 
 TRIAL STEERING COMMITTEE 
The trial management group (TMG) will carry out the duties of the trial steering committee. 
 
 DATA MONITORING COMMITTEE 
Since the drugs being used in this trial are licensed an independent Data Monitoring Committee 
will not be required.  
 
 INSPECTION OF RECORDS 
The CI will permit trial related monitoring, audits, REC review, and regulatory inspection(s). In 
the event of an audit, the CI will allow the Sponsor, representatives of the Sponsor or regulatory 
authorities direct access to all trial records and source documentation. 
 
 RISK ASSESSMENT 
A trial risk assessment was carried out by the Sponsor Research Governance Manager prior 
to Sponsorship approval being granted. 


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 TRIAL MONITORING 
The Sponsor will determine the appropriate extent and nature of monitoring for the trial and will 
appoint appropriately qualified and trained monitors.
 
12.7.1 Potential Risks  
Potential adverse reactions to Zepatier and Sovaldi are as outlined in the SmPC.  
Having blood taken may cause some mild bruising.  
 
12.7.2 Minimising Risk 
Participants will be monitored closely throughout the trial and adverse event monitoring will be 
undertaken as required. Every precaution will be taken to minimise discomfort whilst taking 
bloods, only trained and delegated members of staff will perform this procedure.  
 
13 GOOD CLINICAL PRACTICE 
 ETHICAL CONDUCT OF THE TRIAL 
The trial will be conducted in accordance with the principles of good clinical practice (GCP). 
In addition to Sponsorship approval, a favorable ethical opinion will be obtained from an 
appropriate REC. Authorisation from the MHRA  and appropriate NHS R&D permissions will be 
obtained prior to commencement of the trial. 
 
13.1.1 Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records will be identified in a 
manner designed to maintain participant confidentiality. All records will be kept in a secure 
storage area with limited access to trial staff only. Clinical information will not be released 
without the written permission of the participant, except as necessary for monitoring and 
auditing by the Sponsor, its designee or Regulatory Authorities. The CI and trial staff involved 
with this trial will not disclose or use for any purpose other than performance of the trial, any 
data, record, or other unpublished, confidential information disclosed to those individuals for 
the purpose of the trial. Prior written agreement from the Sponsor or its designee will be 
obtained for the disclosure of any said confidential information to other parties. 
 
13.1.2 Data Protection 
The CI and trial staff involved with this trial will comply with the requirements of the Data 
Protection Act 1998 with regard to the collection, storage, processing and disclosure of personal 
information and will uphold the Act’s core principles. The CI and trial staff will also adhere, if 
appropriate, to the current version of the NHS Scotland Code of Practice on Protecting Patient 


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Confidentiality.  Access to collated participant data will be restricted to the CI and appropriate 
trial staff. 
Computers used to collate the data will have limited access measures via user names and 
passwords. 
Published results will not contain any personal data that could allow identification of individual 
participants. 
 
13.1.3 Insurance and Indemnity 
The University of Dundee and Tayside Health Board are Co-Sponsoring the trial. 
 
Insurance. – The University of Dundee will obtain and hold Professional Negligence Clinical 
Trials Insurance cover for legal liabilities arising from the trial. 
 
Tayside Health Board will maintain its membership of the Clinical Negligence and Other Risks 
Insurance Scheme (“CNORIS”) which covers the legal liability of Tayside in relation to the trial. 
 
Where the trial involves University of Dundee staff undertaking clinical research on NHS 
patients, such staff will hold honorary contracts with Tayside Health Board which means they 
will have cover under Tayside’s membership of the CNORIS scheme. 
 
Indemnity. Co-Sponsors do not provide trial participants with indemnity in relation to 
participation in the Trial but have insurance for legal liability as described above. 
 
 
14 TRIAL CONDUCT RESPONSIBILITIES 
 PROTOCOL AMENDMENTS 
The CI will seek Sponsor approval for any amendments to the Protocol or other trial documents. 
Amendments to the protocol or other trial docs will not be implemented without approval from 
the Sponsor and subsequent approval from the appropriate REC and/or MHRA, as appropriate, 
and NHS R&D Office.  
 
 PROTOCOL DEVIATIONS, BREACHES AND WAIVERS 
The CI will not implement any deviation from the protocol without agreement from the Sponsor, 
except where necessary to eliminate an immediate hazard to trial participants. In the event that 
the CI needs to deviate from the protocol, the nature of and reasons for the deviation will be 
recorded in the CRF, documented in a TASC Deviation & Breach Log and notified to the 
Sponsor. If this necessitates a subsequent protocol amendment, this will be submitted to the 
Sponsor for approval and then to the appropriate REC, Regulatory Authority and local NHS 


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R&D for review and approvals as appropriate. It is Sponsor policy that waivers to the Protocol 
will not be approved. 
 
In the event that a serious breach of the protocol or GCP is suspected, this will be reported to 
the Sponsor immediately using the form “Notification to Sponsor of Potential Serious Breach or 
Serious Deviation”.  
 
 TRIAL RECORD RETENTION  
Archiving of trial documents will be carried out as specified in TASC SOPs (unless otherwise 
agreed with the Sponsor and by contract). As the data from this trial does not form part of an 
application for a Marketing Authorisation (MA) all trial documentation will be kept for at least 5 
years.  
 
 END OF TRIAL 
The end of trial is defined as datalock. The Sponsor and CI have the right at any time to 
terminate the trial for clinical or administrative reasons.  
 
The end of the trial will be reported to the Sponsor, REC, MHRA and NHS R&D Office within 
90 days, or 15 days if the trial is terminated prematurely. The CI will ensure that any appropriate 
follow up is arranged for all participants. 
 
A final report of the trial will be provided to the Sponsor, REC and MHRA within 1 year of the 
end of the trial. 
 
 CONTINUATION OF DRUG FOLLOWING THE END OF TRIAL 
This is not appropriate as the drugs being issued are only to be taken for 12 weeks during the 
trial.  
 
15 REPORTING, PUBLICATIONS AND NOTIFICATION OF RESULTS 
 AUTHORSHIP POLICY 
Ownership of the data arising from this trial resides with the trial team and their respective 
employers. On completion of the trial, the trial data will be analysed and tabulated, and a clinical 
trial report will be prepared.  
 
 PUBLICATION 
The clinical trial report will be used for publication and presentation at scientific meetings. 
Investigators have the right to publish orally or in writing the results of the trial. Summaries of 


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results will also be made available to Investigators for dissemination within their clinical areas 
(where appropriate and according to their discretion). 
 
The clinical trial report will be used for publication and presentation at scientific meetings. 
Investigators have the right to publish orally or in writing the results of the trial. The International 
Committee of Medical Journal Editors recommendation on Authorship and Contributor-ship will 
be adhered to when presenting papers for publication or acknowledging public responsibility 
for appropriate portions of the content.  
 
Abstracts will be presented at European Association for the Study of the Liver and American 
Association for the Study of Liver Diseases annual meetings, 4 papers are anticipated and 
target journals include Hepatology, J Hepatology and Gut, within 3 years of trial start. 
 
The clinical trial report will be used for publication and presentation at scientific meetings. Trial 
investigators have the right to publish orally or in writing the results of the trial. 
Summaries of results will also be made available to Investigators for dissemination within their 
clinical areas (where appropriate and according to their discretion). 
 
 PEER REVIEW 
Peer review of the protocol will occur via the Sponsorship Committee and of the resulting 
publication by the referees of the journal to which the paper (and its protocol) will be submitted.  
 
This trial has been funded by MERCK/MSD who have peer reviewed the grant application.  
 
 
 


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16 REFERENCES 
1. The Hepatitis C Trust. http://www.hepctrust.org.uk Jun 2012.  
2. Hepatitis C in the UK 2011. London: Health Protection Agency, Colindale July 2011. 
3. Can antiviral therapy for hepatitis C reduce the prevalence of HCV among injecting 
drug user populations? A modeling analysis of its prevention utility. Martin NK, 
Vickerman P, Foster GR, Hutchinson SJ, Goldberg DJ, Hickman M. J Hepatol. 2011 
Jun;54(6):1137-44.  
4. Cacoub et al. (2008). Patient education improves adherence to peg-interferon and 
ribavirin in chronic type 2 or 3 hepatitis C virus infection: A prospective, real-life, 
observational study. World Journal of Gasteroenterology, 14, 6195-203. 
5. Lugeba et al. (2013). Formal hepatitis C education enhances HCV care coordination, 
expedites HCV treatment and improves antiviral response. Liver International, 33, 999-
1007.  
6. Merck, Sharp and Doume (2007). Compliance of HCV genotype 1 infected patients 
receiving PegIntron/Rebetol and a patient assistance program. (Study P04671). 
7. Zhou et al. (2016). Interventions to optimise the care continuum for chronic viral 
hepatitis: A systematic review and meta-analyses. Lancet Infectious Diseases, 16, 
1409-22. 
8. Evon et al. (2015). Adherence during antiviral treatment regimens for chronic hepatitis 
C: a qualitative study of patient reported facilitators and barriers. Journal of Clinical 
Gasteroenterology, 49, e41-e50. 
9. Sublette et al. (2015). Listening to both sides: A qualitative comparison between 
patients with hepatitis C and their healthcare professionals’ perception of the facilitators 
and barriers to hepatitis C treatment adherence and completion. Journal of Health 
Psychology, 1-12. 
10. Sublette et al. (2016). The Hepatitis c treatment experience: Patients’ perceptions of 
the facilitators of and barriers to uptake, adherence and completion. Psychology & 
Health, 30, 987-1004.  
11. Lawitz E, Poordad F, Gutierrez JA, et al (2017). Short-duration treatment with 
elbasvir/grazoprevir and sofosbuvir for hepatitis C: A ranomised trial. Hepatology 
65(2):439-450. doi 10.1002/hep.28877  
12. Fisher et al. (2006) An Information-Motivation-Behavioral Skills model of adherence to 
antiretroviral therapy. Health Psychology, 25, 462-473. 
13. Dansereau, D. F. (2005). Node-link mapping principles for visualizing knowledge and 
information. In Knowledge and information visualization (pp. 61-81). Springer Berlin 
Heidelberg.  
14. Knight, D. K., Dansereau, D. F., Joe, G. W., & Simpson, D. D. (1994). The role of node-
link mapping in individual and group counseling. The American journal of drug and 
alcohol abuse, 20(4), 517-527.  


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15. Foster GR, Agarwal K, Cramp M, et al.(2016) C-ISLE: Grazoprevir/Elbasvir plus 
Sofosbuvir in Treatment-naive and Treatment-experienced HCV GT3 Cirrhotic Patients 
Treated for 8, 12 or 16 weeks. 67th Meeting of the American Association for the Study 
of 
Liver 
Diseases: 
Liver 
Meeting 
2016. 
 
Abstract 
74. 
http://www.natap.org/2016/AASLD/AASLD_15.htm 
 
 


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17 APPENDIX 
 APPENDIX 1: TRIAL FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fortnightly Pick-up Groups 
DOT Group n=45 
• 
Daily visit to pharmacy for 
therapy.  
• 
AE/SAE review 
• 
ConMeds Review 
• 
Compliance 
• 
Incentives. 
Fortnightly Pick-up Group + 
Pysch Intervention n=45 
• 
Fortnightly visit to needle 
exchange 
centre 
for 
therapy.  
• 
AE/SAE review 
• 
ConMeds Review 
• 
Compliance 
• 
Incentives 
• 
Motivational/psychological 
interview.  
Fortnightly 
Pick-up 
Group 
n=45  
• 
Fortnightly visit to needle 
exchange 
centre 
for 
therapy.  
• 
AE/SAE review 
• 
ConMeds Review 
• 
Compliance 
• 
Incentives. 
Daily Observational Therapy Group 
End of Treatment (Week 12) 
• 
Safety Bloods and PCR 
• 
AE/SAE and ConMeds Review 
PCR bloods for SVR 12 weeks after end of treatment 
Opportunistic 
recruitment 
at 
Needle 
Exchange Centre or other suitable venue.  
• 
Invited to participate if: DBS test positive 
• 
Meets all inclusion criteria. 
Excluded: Declined 
to participate. 
Excluded: Did not 
meet 
inclusion 
criteria.  
Baseline Visit: ICF, Safety bloods, PCR, CRF population.  
Randomisation Visit; check inc/exc criteria, AE/SAE review, ConMeds Review, 
randomise to one of the 3 arms, supply medication 


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17.2 APPENDIX 2: TRIAL MATRIX 
Participants infected with genotype 1 HCV 
Activity 
Visit 1 
Baseline 
Visit 2 
Randomisation 
 
Visit 3 
 
Visit 4 
 
Visit 5 
End of treatment 
SVR12 
DV / USV 
 
Day 0 
Week 2 
Week 4 
(-7 to+14 
days) 
Week 6 
Week 8  
(-7 to +14days) 
Week 
10 
Week 12 
(-7 to +14days) 
Week 24 
(+12weeks) 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Check Inc/Exc Criteria 
X 
X 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Drug Misuse History 
X 
 
 
 
 
 
 
X 
 
X 
Urine test for illicit 
drugs 
 
 
* 
* 
* 
* 
* 
* 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
Blood tests; U&Es, 
FBC, PT 
X 
 
 
 
 
 
 
X 
 
X 
Blood tests; LFTs 
X 
 
 
 
 
X 
 
X 
 
 
Blood test; PCR  
X 
 
 
 
 
 
 
X 
X 
 
Research Blood 
X 
 
 
 
 
 
 
X 
X 
X 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
 
 
Adverse Event 
Assessment 
 
X 
 
X 
 
X 
 
X 
X 
X 
Record or Review 
Con Meds 
X 
X 
 
X 
 
X 
 
X 
X 
X 


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Check Drug 
Compliance 
 
 
 
X 
 
X 
 
X 
 
 
Antiviral Drug 
Administration 
 
X 
X 
X 
X 
X 
X 
 
 
 
Psychological 
interview for those 
randomised to this 
intervention 
 
X 
 
 
 
 
 
 
 
 
 
1. Discontinued Visits (DV) and Unscheduled Visits (USV). Additional Standard of Care sampling including LFT’s, U&E’s, FBC, 
and PT, (as a minimum), should be performed where the USV is in relation to an AE/SAE which may be attributable.   
2. Unscheduled Visits / DOT daily visits - Adverse Event and check for concomitant medications should be performed at any 
unscheduled visit. 
* One urine sample will be taken during treatment for analysis of illicit drug taking. 


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Participants infected with genotype 3 HCV 
 
 
 
1. Discontinued Visits (DV) and Unscheduled 
Visits (USV).  Additional Standard of Care 
sampling including LFT’s, U&E’s, FBC, and 
PT, (as a minimum), should be performed 
where the USV is in relation to an AE/SAE 
which may be attributable.   
2. Unscheduled Visits / DOT daily visits - 
Adverse Event and check for concomitant 
medications should be performed at any 
unscheduled visit. 
* One urine sample will be taken during 
treatment for analysis of illicit drug taking. 
 
Activity 
Baseline 
Randomi
sation 
 
Visit 3 
 
Visit 4 
End of 
treatment 
SVR12 
DV / 
USV 
 
Day 0 
Week 
2 
Week 4  
(-7 to 
+14 
days ) 
Week 6 
Week 8  
(-7 to+14 
days ) 
Week 20 
(+12weeks) 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Check Inc/Exc Criteria 
X 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Drug Misuse History 
X 
 
 
 
 
X 
 
X 
Urine test for illicit drugs 
 
 
* 
* 
* 
* 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Blood tests; U&Es, FBC, 
PT 
X 
 
 
 
 
X 
 
X 
Blood tests; LFTs 
X 
 
 
 
 
X 
 
 
Blood  test; PCR  
X 
 
 
 
 
X 
X 
 
Research Blood 
X 
 
 
 
 
X 
X 
X 
Urine pregnancy test 
X 
 
 
 
 
 
 
 
Adverse Event 
Assessment 
 
X 
 
X 
 
X 
X 
X 
Record or Review Con 
Meds 
X 
X 
 
X 
 
X 
X 
X 
Check Drug Compliance 
 
 
 
X 
 
X 
 
 
Antiviral Drug 
Administration 
 
X 
X 
X 
X 
 
 
 
Psychological interview 
for those randomised to 
this intervention 
 
X