Conditions: Hepatitis C
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 222
Healthy volunteers: no

Brief summary:
The aim of the study is to determine if treatment for recently acquired hepatitis C infection (with or without HIV coinfection) can be shortened when treating with the interferon-free therapy sofosbuvir/velpatasvir (SOF/VEL).

SOF/VEL is a new treatment for hepatitis C called direct acting antiviral which targets the hepatitis C virus replication cycle and has been shown in phase II studies in chronic HCV to be highly effective (SVR12 \>95%) when given for 12 weeks.

Data has shown that treatment can be shortened when treating recently acquired HCV with interferon containing treatments. It is not known whether treatment with SOF/VEL can be shortened.

This study aims to find out if treatment for 6 weeks with open-label SOF/VEL is equivalent to treatment for 12 weeks with SOF/VEL in participants with recently acquired hepatitis C infection. The project is a randomised study where both participants and investigators would not find out the treatment duration of the participants until week 6 of treatment.

Detailed description:
Globally, 3-4 million new HCV infections are estimated to occur annually. People who inject drugs (PWID) represent one of the groups at highest risk of transmitting and acquiring infection with the majority of new (60%) and existing (80%) infections in developed countries occur in this population with HCV antibody prevalence estimated at 67% (60-80%). HIV-positive men-who-have-sex-with-men (MSM) are another high risk group for HCV acquisition.

Direct acting antivirals (DAA) has changed the treatment landscape for individuals with chronic HCV infection with interferon-free therapy offering high effectiveness and tolerability, even in "difficult-to-treat" populations.

Given the burden of HCV-related disease among PWID and HIV-positive MSM, strategies to enhance HCV assessment, treatment and prevention in these groups are urgently needed. Much of what is known about the timing of treatment initiation, regimen choice and duration of therapy in acute HCV infection comes from small observational studies and randomized controlled (randomly assigned into one or other of the different treatment groups)trials in selected populations with limited data on treatment in PWID and HIV co-infection. With recent rapid advances in HCV treatments, management strategies for acute HCV will evolve rapidly over the next few years.

The REACT study will compare the efficacy and safety of open-label SOF/VEL administered for 6 or 12 weeks in individuals with recent HCV infection. Participants will be randomised into receiving 6 weeks or 12 weeks treatment. Both investigators and participants will be blinded to the treatment duration until week 6 of treatment. The role and activity of DAA regimens in acute HCV infection requires evaluation, with the potential to be given as highly effective, short course interferon-sparing regimens, maximising acceptability to patients, encouraging uptake of treatment, limiting further transmission and preventing progression to chronic liver disease.

Arms:
arm 1: Open-label SOF/VEL 400mg/100mg co-formulated tablet once daily will be given to participants who are randomised into the short treatment duration arm (A) for 6 weeks. arm 2: Open-label SOF/VEL 400mg/100mg co-formulated tablet once daily will be given to participants who are randomised into the standard treatment duration arm (B) for 12 weeks.

Interventions: intervention 1: SOF/VEL for 6 weeks intervention 2: SOF/VEL for 12 weeks
Intervention descriptions: intervention 1: Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm A (6 weeks short treatment duration). intervention 2: Open-label SOF/VEL 400mg/100mg once daily to be given to participants randomised to Arm B (12 weeks standard treatment duration).

Protocol document:
Prot_000.pdf: 
 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 1 of 54 
 
 
 
 
 
 
 
 
 
 
 
 
A randomised study of interferon‐free treatment for recently acquired 
hepatitis C in people who inject drugs and people with HIV coinfection 
(REACT) 
 
 
Protocol number: 
VHCRP1401 
 
Protocol version: 
5.0 
 
 
Protocol date:   
 04 June 2019 
 
 
Name of sponsor: 
The Kirby Institute  
 
 
 
UNSW Australia  
 
 
 
Wallace Wurth Building (C27) 
 
 
 
Sydney NSW 2052 
 
 
 
Australia 
 
 
Coordinating Co‐Principal Investigators (CPI):  
Medical Monitor: 
Associate Prof Gail Matthews 
Professor Gregory Dore 
The Kirby Institute  
The Kirby Institute  
UNSW Australia  
UNSW Australia 
Wallace Wurth Building (C27) 
Wallace Wurth Building (C27) 
Sydney NSW 2052 
Sydney NSW 2052 
Australia 
Australia 
E: gmatthews@kirby.unsw.edu.au   
E: gdore@kirby.unsw.edu.au 
P: +61 2 9385 0900 
P: +61 2 9385 0898 
F: +61 2 9385 9214 
F: +61 2 9385 9214 
 
 
 
 
 
 
 
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 2 of 54 
 
 
 
 
 
 
 
 
  
Table of contents 
1 
Background and rationale ................................................................................................................. 15 
1.1 
Incidence and risk factors for HCV acquisition .............................................................................. 15 
1.2 
Management of chronic HCV infection ‐ directly acting antiviral therapy .................................... 16 
1.3 
Management of recent HCV infection ........................................................................................... 17 
1.3.1 
Treatment of acute HCV mono‐infection .............................................................................. 17 
1.3.2 
Treatment of recent HCV infection in PWID ......................................................................... 17 
1.3.3 
Treatment of recent HCV infection in HIV co‐infection......................................................... 18 
1.3.4 
Duration of treatment ........................................................................................................... 19 
1.3.5 
Directly‐acting antiviral therapy for acute HCV infection ..................................................... 19 
1.3.6 
Reinfection following acute HCV infection ............................................................................ 19 
1.4 
ATAHC I, ATAHC II, DARE‐C I and DARE‐C II studies....................................................................... 20 
1.5 
REACT rationale ............................................................................................................................. 21 
2 
Study objectives ................................................................................................................................. 21 
2.1 
Hypothesis ..................................................................................................................................... 21 
2.2 
Primary objective ........................................................................................................................... 21 
2.3 
Secondary objective(s) .................................................................................................................. 22 
3 
Participant population ....................................................................................................................... 22 
3.1 
Number of Participants and Participant Selection ........................................................................ 22 
3.2 
Inclusion criteria ............................................................................................................................ 23 
3.3 
Exclusion criteria ............................................................................................................................ 24 
3.4 
Definitions used to calculate Estimated Date of Infection ............................................................ 26 
4 
Study design ...................................................................................................................................... 26 
4.1 
Summary of study design .............................................................................................................. 26 
4.2 
Visit Schedule ................................................................................................................................ 27 
4.3 
Treatment Discontinuation Criteria............................................................................................... 28 
5 
Treatment of participants.................................................................................................................. 28 
5.1 
Sofosbuvir/velpatasvir dosage and administration ....................................................................... 28 
5.2 
Study Drug Adherence and Drug Accountability ........................................................................... 28 
5.3 
Prior and Concomitant Medications.............................................................................................. 28 
6 
Study procedures ............................................................................................................................... 31 
6.1 
Visits and Procedures .................................................................................................................... 31 
6.2 
Prevention of Pregnancy ............................................................................................................... 35 
6.2.1 
Definitions of Childbearing Potential .................................................................................... 35 
6.2.2 
Female Participants ............................................................................................................... 35 
6.2.3 
Male Participants ................................................................................................................... 35 
6.3 
Study Questionnaires .................................................................................................................... 35 
7 
Reinfection follow‐up ........................................................................................................................ 36 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 3 of 54 
 
 
 
 
 
 
 
 
7.1 
Schedule of Assessments – Reinfection ........................................................................................ 37 
8 
Recording and reporting Adverse Events (AEs) ................................................................................. 37 
8.1 
Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events............................... 37 
8.1.1  Adverse Event Definition ................................................................................................................... 37 
8.1.2  Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions)........................................ 38 
8.1.3  Special Situation Report (SSR) ........................................................................................................... 38 
8.2 
Assessment of Adverse Events and Serious Adverse Events ............................................................. 38 
8.2.1  Assessment of Causality for Study Drugs and Procedures ................................................................ 38 
8.2.2  Assessment of Severity ...................................................................................................................... 38 
8.3 
Reporting Requirements ................................................................................................................... 39 
8.3.1  Adverse Events .................................................................................................................................. 39 
8.3.2  Serious Adverse Events...................................................................................................................... 39 
8.3.3  Special Situation Reports ................................................................................................................... 39 
8.3.4  Suspected Unexpected Serious Adverse Reaction (SUSAR) .............................................................. 40 
9 
Packaging, labeling, storage and accountability of clinical trial supplies .......................................... 40 
9.1 
Formulation ................................................................................................................................... 40 
9.2 
Packaging and Labelling ................................................................................................................. 41 
9.3 
Storage and handling ..................................................................................................................... 41 
9.4 
Dosage and administration ........................................................................................................... 41 
10 
Biological samples ............................................................................................................................. 41 
10.1 
Laboratory supplies and sample processing.................................................................................. 41 
10.2 
Shipping of biological samples ...................................................................................................... 42 
10.3 
Future use of biological samples ................................................................................................... 42 
11 
Statistics ............................................................................................................................................. 42 
11.1 
Sample size .................................................................................................................................... 42 
11.2 
Assessments of Safety and Efficacy ............................................................................................... 42 
11.3 
Analyses ......................................................................................................................................... 43 
12 
Data Safety and Monitoring Board (DSMB) ....................................................................................... 44 
13 
Data collection, source documents and record retention ................................................................ 45 
13.1 
Submission of data ........................................................................................................................ 45 
13.2 
Linkage of data ‐ Applicable to Australian Sites Only .................................................................... 45 
13.3 
Archiving ........................................................................................................................................ 46 
14 
Ethics committee/regulatory approval and informed consent ......................................................... 46 
15 
Confidentiality of data ....................................................................................................................... 46 
16 
Governance ....................................................................................................................................... 47 
17 
Quality Control (QC) and Quality Assurance (QA) ............................................................................. 47 
18 
Publication Policy ............................................................................................................................... 47 
19 
List of References .............................................................................................................................. 47 
20 
Abbreviations List .............................................................................................................................. 54 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 4 of 54 
 
 
 
 
 
 
 
 
 
 
Protocol Synopsis 
 
Title 
A randomised study of interferon‐free treatment for recently acquired 
hepatitis C in people who inject drugs and people with HIV coinfection 
(REACT) 
Protocol registration 
number: 
NCT 02625909 
 
Background and rationale 
 
 
Globally, 3‐4 million new hepatitis C virus (HCV) infections are estimated 
to occur annually (1).  People who inject drugs (PWID) represent one of 
the groups at highest risk of transmitting and acquiring infection with the 
majority  of  new  (60%)  and  existing  (80%)  infections  in  developed 
countries  occur  in  this  population  with  HCV  antibody  prevalence 
estimated at 67% (60‐80%) (2, 3).  HIV‐positive men‐who‐have‐sex‐with‐
men (MSM) are another high risk group for HCV acquisition.   
 
The advent of DAAs has changed the therapeutic landscape for individuals 
with chronic HCV infection with IFN‐free therapy offering high efficacy 
and tolerability, even in “difficult‐to‐treat” populations (4‐11).  Multiple 
agents  in  different  classes  have  been  approved  in  Australia  by  the 
Therapeutic  Goods  Administration  (TGA),  the  European  Union  by  the 
European  Medicines  Agency  (EMA),  the  US  by  the  Food  and  Drug 
Administration (FDA), and in Canada by Health Canada   
 
Given the burden of HCV‐related disease among PWID and HIV‐positive 
MSM, strategies to enhance HCV assessment, treatment and prevention 
in these groups are urgently needed.  Much of what is known about the 
timing of treatment initiation, regimen choice and duration of therapy in 
acute  HCV  infection  comes  from  small  observational  studies  and 
randomized controlled trials in selected populations with limited data on 
treatment in PWID and HIV co‐infection.  With recent rapid advances in 
HCV  therapeutics,  management  strategies  for  acute  HCV  will  evolve 
rapidly over the next few years.   
 
The  REACT  study  will  compare  the  efficacy  and  safety  of 
sofosbuvir/velpatasvir administered for 6 or 12 weeks in individuals with 
recent HCV infection.  The role and activity of potent DAA regimens in 
acute HCV infection requires evaluation, with the potential to be given as 
highly  efficacious,  short  course  IFN‐sparing  regimens,  maximising 
acceptability  to  patients,  encouraging  uptake  of  treatment,  limiting 
further transmission and preventing progression to chronic liver disease.   
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 5 of 54 
 
 
 
 
 
 
 
 
Refer to Section 1.0 for complete background and rationale. 
Study objectives 
Hypothesis 
Six weeks treatment with sofosbuvir/velpatasvir is non‐inferior to twelve 
weeks  treatment  with  sofosbuvir/velpastavir  as  assessed  by  sustained 
virological response at 12 weeks post treatment in the intention‐to‐treat 
population (SVR12). 
 
Primary objective 
The primary objective is to evaluate the proportion of patients with HCV 
RNA below the level of quantitation (target not detected [TND] or target 
detected, not quantifiable [TDnq]) at 12 weeks post end of treatment 
(SVR12)  following  sofosbuvir/velpatasvir  therapy  for  6  weeks  (short 
treatment  duration)  as  compared  with  12  weeks  (standard  treatment 
duration) in people with recent HCV infection (duration of infection ≤12 
months).  
 
Secondary objectives 
1 
To evaluate the proportion of participants with HCV RNA below the 
level of quantitation (TND or TDnq) at the end of treatment (ETR), 4 
weeks  after  treatment  completion  (SVR4)  and  24  weeks  after 
treatment completion (SVR24); 
 
2 
To  evaluate  the  proportion  of  participants  with  undetectable  HCV 
RNA through 2 years post treatment; 
 
3 
To  evaluate  the  levels  of  adherence,  factors  associated  with 
suboptimal  adherence  including  HIV  status,  and  the  impact  of 
suboptimal adherence on therapeutic response; 
 
4 
To  evaluate  the  impact  of  treatment  on  illicit  drug  use,  injecting 
behaviour  and  sexual  risk  taking  behaviour  (behavioural  survey) 
during treatment; 
 
5 
To evaluate safety and tolerability 
 
6 
To evaluate the change in HIV RNA and CD4 (on‐treatment and end 
of treatment); 
 
7 
To evaluate the rate and risk factors for reinfection during and up to 
2 years following treatment; 
 
8 
To  evaluate  the  immunological  factors  associated  with  treatment 
induced clearance and reinfection  
 
9 
To  evaluate  patient  interest  and  attitudes  towards  long  acting 
parenteral  hepatitis  C  therapy  (Long‐Acting  Hepatitis  C  Therapy 
Questionnaire) 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 6 of 54 
 
 
 
 
 
 
 
 
 
Participant population  
A total of 250 participants with recent HCV infection will be enrolled from 
drug and alcohol clinics, tertiary liver and infectious diseases clinics and 
community  health  centres  across  Australia,  Canada,  Germany,  New 
Zealand,  Switzerland,  The  Netherlands,  the  United  Kingdom  and  the 
United States. The Kirby Institute may close or suspend screening prior 
to  reaching  250  participants  in  order  to  manage  the  total  study 
enrolment numbers.  
 
The  number  of  participants  with  HCV/HIV  coinfection  enrolled  to  the 
study will be capped at 70% (or less than 175 participants) of the total 
study  population.    In  addition,  the  number  of  participants  with  HCV 
reinfection enrolled to the study will be capped at 20% (or less than 50 
participants) of the total study population. 
 
Inclusion Criteria 
Subjects must meet all of the following inclusion criteria to be eligible to 
participate in this study.  
1 
Participants have voluntarily signed the informed consent form. 
2 
18 years of age or older. 
3 
Detectable HCV RNA at screening (>10,000 IU/ml), and in the opinion 
of  the  investigator  is  unlikely  to  demonstrate  spontaneous  viral 
clearance  
4 
HCV genotypes 1‐6. 
5 
HBsAg negative 
6 
Negative  pregnancy  test  at  screening  and  baseline  (females  of 
childbearing potential only). 
7 
Male  subjects  and  female  subjects  of  childbearing  potential  who 
engage  in  heterosexual  intercourse  must  agree  to  use  protocol 
specified method(s) of contraception 
8 
Medically stable on the basis of physical examination, medical history 
and vital signs 
9 
Adequate  literacy  to  provide  reliable  responses  to  the  study 
questionnaires 
10 All fertile males and females must be using effective contraception 
during treatment and during the 30 days after treatment end. 
11 Recently acquired HCV infection (estimated duration of infection ≤12 
months)* 
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 7 of 54 
 
 
 
 
 
 
 
 
Recently acquired HCV infection as defined by: 
A)  
i) First anti‐HCV Ab or HCV RNA positive within the previous 6 months  
and  
ii) Documented anti‐HCV Ab negative within the 12 months prior to anti‐
HCV antibody positive result  
 
OR  
 
B)  
i) First anti‐HCV Ab or HCV RNA positive within the previous 6  months  
and 
ii) Acute clinical hepatitis (jaundice or ALT> 10 X ULN) within the previous 
6months prior to first positive HCV antibody or HCV RNA, with no other 
cause of acute hepatitis identifiable 
 
OR 
 
C) For cases of recent HCV reinfection the following criteria are required: 
i) Documented prior HCV antibody positive with HCV RNA negative on at 
least 2 occasions 6 months apart  
and 
ii) new HCV RNA positive within the previous 6 months  
*Estimated  duration  of  infection  based  on  midpoint  between  last 
antibody negative or HCV RNA and first antibody positive or HCV RNA in 
the case of seroconversion and 6 weeks prior to date of maximum ALT in 
the case of acute hepatitis. 
See  Section  3.4  for  ‘Definitions  used  to  calculate  Estimated  Date  of 
Infection’. 
 
If  co‐infection  with  HIV  is  documented,  the  subject  must  meet  the 
following criteria: 
1 
Antiretroviral (ARV) untreated for >8 weeks preceding screening visit 
with CD4 T cell count >500 cells/mm3 
OR 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 8 of 54 
 
 
 
 
 
 
 
 
2 
On a stable ARV regimen for >8 weeks prior to screening visit, with 
CD4 T cell count >200 cells/mm3 and an undetectable plasma HIV RNA 
level. 
 
Suitable ARV include:   
o Nucleos(t)ide  reverse  transcriptase  inhibitors:    Tenofovir 
disoproxil  fumarate  (TDF),  tenofovir  alafenamide  (TAF), 
emtricitabine 
(FTC)Non‐nucleoside 
reverse 
transcriptase 
inhibitors: Rilpivirine 
o Protease inhibitors: Atazanavir, darunavir, lopinavir, ritonavir 
o Integrase 
inhibitors: 
Dolutegravir, 
raltegravir, 
elvitegravir/cobicistat 
 
Contraindicated ARV include: 
o Efavirenz 
 
50% reduction in velpatasvir (GS‐5816) exposure 
o Didanosine 
o Zidovudine 
o Tipranavir 
Other  ARV  agents  may  be  permissible  at  the  time  of  study 
commencement  pending  further  drug‐drug  interaction  studies;  please 
discuss with the Medical Monitor.   
 
 
 
 
Exclusion criteria 
Subjects who meet any of the exclusion criteria are not to be enrolled in 
this study. 
1 
History of any of the following: 
a. Clinically significant illness (other than HCV) or any other major 
medical  disorder  that  may  interfere  with  the  participant 
treatment,  assessment  or  compliance  with  the  protocol; 
participants currently under evaluation for a potentially clinically 
significant illness (other than HCV) are also excluded. 
b. History of chronic pulmonary disease associated with functional 
limitation, severe cardiac disease, major organ transplantation or 
other  evidence  of  severe  illness,  malignancy,  or  any  other 
conditions which would make the patient, in the opinion of the 
investigator, unsuitable for the study 
c. Solid organ transplant 
d. Malignancy within 5 years prior to screening, with exception of 
specific cancers that may have been cured by surgical resection 
(basal  cell  skin  cancer,  etc.).  Subjects  under  evaluation  for 
possible malignancy are also excluded. 
e. Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2 
Subject has a known or documented prior history of  cirrhosis   


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 9 of 54 
 
 
 
 
 
 
 
 
3 
Subject  shows  evidence  of  significant  liver  disease  in  addition  to 
hepatitis C, which may include but is not limited to drug‐ or alcohol‐
related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s 
disease,  non‐alcoholic  steatohepatitis  (NASH),  or  primary  biliary 
cirrhosis 
4 
Any of the following lab parameters at screening: 
a. Direct bilirubin > 1.5 x ULN 
b. Platelets < 50,000/μL 
c. Creatinine clearance (CLcr) < 50 mL/min  
d. Haemoglobin < 10 g/dL  
e. Albumin < 30g/L 
f. 
International Normalised Ratio (INR) >1.5 (unless subject is on a 
stable anticoagulant regimen or has known coagulopathy) 
5 
Pregnant or nursing female. 
6 
Use of prohibited concomitant medications as described in section 
5.2 
7 
Chronic use of systemically administered  immunosuppressive agents 
(e.g. prednisone equivalent > 10 mg/day) 
8 
Known  hypersensitivity  to  velpatasvir,  sofosbuvir  or  formulation 
excipients. 
9 
Therapy with any anti‐neoplastic or immunomodulatory treatment 
(including  supraphysiologic  doses  of  steroids  and  radiation)  ≤6 
months prior to the first dose of study drug. 
10 Any investigational drug ≤6 weeks prior to the first dose of study drug. 
11 Previous failure of therapy with sofosbuvir or an NS5A inhibitor prior 
to the first dose of study drug. 
12 Ongoing  severe  psychiatric  disease  as  judged  by  the  treating 
physician.  
13 Frequent injecting drug use that is judged by the treating physician to 
compromise treatment safety. 
14 Inability or unwillingness to provide informed consent or abide by the 
requirements of the study. 
15 Prior enrolment within this study. 
 
Study design 
This study will be conducted as a phase III randomised, open‐label, non‐
inferiority multicentre international trial. 
A total of 250 people with recently acquired hepatitis C will be enrolled 
and randomised. 
The  study  consists  of  a  screening  phase  (‐12  to  ‐4  weeks),  treatment 
commencement from baseline, randomisation between week 5 and 6, 
treatment for another 6 weeks for those randomised to standard therapy 
(12 weeks of treatment) or end of treatment for those randomised to 
shortened treatment (6 weeks of treatment). Randomisation will be using 
blocks and will be stratified by study site and HIV status.  


 
REACT Protocol Version 5.0 dated 04 June 2019 
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All participants will then enter the follow‐up phase (96 weeks) to evaluate 
treatment response and reinfection.  
Participants  who  become  re‐viraemic  following  an  end  of  treatment 
response will be followed monthly for six months. After completing the 
monthly  follow‐up  visits,  participants  will  continue  to  attend  three 
monthly follow‐up visits up to two years. Please see section 7 ‘Reinfection 
follow‐up’ for more details. 
Treatment of participants 
Participants  will  receive  six  or  twelve  12  weeks  of  open‐label 
sofosbuvir/velpatasvir (400mg/100mg daily) in an oral once‐daily fixed 
dose combination. Dose modifications are prohibited.  
 
Study procedures 
All  participants  will  complete  screening,  on‐treatment  and  post‐
treatment  assessments  as  outlined  in  the  Schedule  of  Assessments  in 
Section 6.0. 
 
Screening  assessments  must  be  completed  within  12  weeks  prior  to 
baseline. There must be a minimum of 4 weeks between screening and 
baseline.  
 
Following  screening,  eligible  participants  will  commence  treatment  at 
baseline.  Between week 5 and week 6, participants will be randomised 
to the shortened or standard treatment duration.  On‐treatment visits will 
be conducted at weeks 1, 2, 4 and 6 (end of treatment for participants on 
shortened  treatment  duration),  weeks  8  and  10  (for  participants  on 
standard treatment duration only). Participants on standard treatment 
duration will attend end of treatment at week 12.  
For participants randomised to shortened treatment, follow‐up visits will 
be conducted at week 10 (SVR4), week 18 (SVR12), week 30 (SVR24), 
week 42 (FU1), week 54 (FU2), week 66 (FU3), week 78 (FU4), week 90 
(FU5) and week 102 (Termination).   
For participants randomised to standard treatment, follow‐up visits will 
be conducted at week 16 (SVR4), week 24 (SVR12), week 36 (SVR24), 
week 48 (FU1), week 60 (FU2), week 72 (FU3), week 84 (FU4), week 96 
(FU5) and week 108 (Termination). 
 


 
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Statistics 
The primary objective of this trial is to establish the non‐inferiority of 
short duration treatment (6 weeks) to the standard duration treatment 
(12 weeks).   
 
Assuming an expected SVR of 90% in the control arm, 113 participants per 
arm will be required to give 80% chance that the two sided confidence 
interval of the difference between regimens has a lower limit greater than 
‐12%.   
 
A  total  of  250  subjects  enrolled  and  randomised  will  comprise  the  
intention‐to‐treat (ITT) population and will form the study population for 
evaluation of the primary and secondary endpoints.  
 
Primary endpoint: 
The  primary  endpoint  is  the  proportion  of  participants  with  HCV  RNA 
below  the  level  of  quantitation  (target  not  detected  [TND]  or  target 
detected, not quantifiable [TDnq]) at 12 weeks post end of treatment 
(SVR12) 
 
Secondary endpoints: 
 
 
Secondary virological endpoints 
o The proportion of participants with: 
 
ETR  defined  as  HCV  RNA  below  the  level  of 
quantitation at end of therapy 
 
SVR  4  defined  as  HCV  RNA  below  the  level  of 
quantitation 4 weeks post therapy 
 
SVR  24  defined  as  HCV  RNA  below  the  level  of 
quantitation 24 weeks post therapy  
 
HCV RNA below the level of quantitation through 2 
years post treatment 
Results  will  be  stratified  by  HCV  genotype  and  HIV‐
coinfection.  
 
80/80 adherence: Defined as the receipt of >80% of scheduled doses 
for >80% of the scheduled treatment period.  
 
90/90 adherence: Defined as the receipt of >90% of scheduled doses 
for >90% of the scheduled treatment period.  
 
100/100 adherence: Defined as the receipt of 100% of scheduled 
doses for 100% of the scheduled treatment period.  
 
On‐treatment adherence: Calculated by subtracting the number of 
missed doses from the total number of doses of scheduled treatment 
and dividing by the total intended therapy duration. This measures 
the proportion of doses received from the time that treatment was 
initiated until treatment was discontinued or completed. 
 
Toxicity:  Proportion  of  participants  with  at  least  one  severe  or 
potentially life threatening (grade 3 or 4) adverse event. 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 12 of 54 
 
 
 
 
 
 
 
 
 
Early treatment discontinuation: Discontinuation of therapy prior to 
the per‐protocol planned end of treatment (6 or 12 weeks depending 
on study arm).  
 
Resistance  associated  variants  (RAVs):  The  proportion  of  treated 
subjects with development of RAVs following virological relapse or 
breakthrough. 
 
Reinfection rate: Rates of HCV reinfection will be calculated using 
person‐time of observation during and up to 48 months following 
end of treatment. 
 
Baseline  characteristics,  on‐treatment  adherence,  risk  behaviours 
and toxicity will be evaluated among subjects withdrawing prior to 
randomisation.   


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 13 of 54 
 
 
 
 
 
 
 
 
Schedule of Assessments 
Arm A: Short – 6 weeks 
Assessment/Procedure 
Screening# 
Baseline  Study Treatment (weeks) 
Follow‐up (weeks) 
Study week 
‐12 to ‐4 
0 
1 
2 
 
4 
 
6 
(ETR) 
10 
(SVR4) 
18 
(SVR12) 
30 
(SVR24) 
42 
(FU1) 
54 
(FU2) 
66 
(FU3) 
78 
(FU4) 
90 
(FU5) 
102 
(Termination) 
Visit Window (Days) 
 
 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 14 
+/‐ 14 
+/‐ 28 
+/‐ 28  +/‐ 28 
+/‐ 28  +/‐ 28  +/‐ 28 
Informed consent, medical history, physical examination  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs & physical measurements 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisationg  
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
FibroScan® 
x 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Anti‐HCV antibody 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV‐RNA testing (local lab.) 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
HCV Genotype 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver function tests/Full blood count/Biochemistry 
x 
x 
x 
x 
x 
x 
x 
x 
xf 
xf 
xf 
xf 
xf 
xf 
xf 
Clotting (INR)  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVa, HBV & HAV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4/CD8 & HIV viral loadb 
x 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (serum or urine)c 
x 
x 
 
 
x 
 
x 
 
 
 
 
 
 
 
 
Behavioural questionnaire 
x 
x 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adherence questionnaire 
 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Pill count 
 
 
 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Health outcomes survey (EQ‐5D) 
x 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Long‐Acting Hepatitis C Therapy Questionnaire 
 
xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Specimen Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDTA plasma (10ml)  
xd 
xd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Whole blood (4ml) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACD Plasma / PBMCs (60ml) 
x 
x 
x 
x 
x 
x 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
# Minimum wait period between screening and baseline visit is 4 weeks, a HIV negative individuals only, b HIV positive individuals only, c Females of child bearing potential only, d20ml collected at screening and 
baseline, e To be collected in patients with suspected relapse/reinfection, f Liver function tests only, g randomisation will occur between week 5 and 6, h Currently enrolled participants will complete questionnaire 
at their next scheduled visit 
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 14 of 54 
 
 
 
 
 
 
 
 
Arm B: Standard – 12 weeks 
Assessment/Procedure 
Screening# 
Baseline  Study Treatment (weeks) 
Follow‐up (weeks) 
Study week 
‐12 to ‐4 
0 
1 
2 
4 
6 
8 
10 
12 
(ETR) 
16 
(SVR4) 
24 
(SVR12) 
36 
(SVR24) 
48 
(FU1) 
60 
(FU2) 
72 
(FU3) 
84 
(FU4) 
96 
(FU5) 
108 
(Termination
) 
Visit Window (Days) 
 
 
+/‐ 3  +/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 14 
+/‐ 14 
+/‐ 28 
+/‐ 28 
+/‐ 28 
+/‐ 28 
+/‐ 28  +/‐ 28 
Informed consent, medical history, physical 
examination  
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Patient demographics 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs & physical measurements 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomisation  
 
 
 
 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
FibroScan® 
x 
 
 
 
 
 
 
 
 
 
x 
x 
x 
x 
x 
x 
x 
x 
Anti‐HCV antibody 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HCV‐RNA testing (local lab.) 
x 
x 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
HCV Genotype 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liver function tests/Full blood count/Biochemistry 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
xf 
xf 
xf 
xf 
xf 
xf 
xf 
Clotting (INR) 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIVa, HBV & HAV serology 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4/CD8 & HIV viral loadb 
x 
 
 
 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Pregnancy test (serum or urine)c 
x 
x 
 
 
x 
 
x 
 
x 
x 
 
 
 
 
 
 
 
 
Behavioural questionnaire 
x 
x 
 
 
 
x 
 
 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Adherence questionnaire 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Pill count 
 
 
 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Health outcomes survey (EQ‐5D) 
x 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
 
Concomitant medications 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
Long‐Acting Hepatitis C Therapy Questionnaire 
 
xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Research Specimen Collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EDTA plasma (10ml)  
xd 
xd 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Whole blood (4ml) 
x 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ACD Plasma / PBMCs (60ml) 
x 
x 
x 
x 
x 
x 
 
 
x 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
x e 
# Minimum wait period between screening and baseline visit is 4 weeks, a HIV negative individuals only, b HIV positive individuals only, c Females of child bearing potential only, d20ml collected at screening and 
baseline, e To be collected in patients with suspected relapse/reinfection, f Liver function tests only, g randomisation will occur between week 5 and 6, h Currently enrolled participants will complete questionnaire 
at their next scheduled visit 
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 15 of 54 
 
 
 
 
 
 
 
 
1 Background and rationale 
1.1 Incidence and risk factors for HCV acquisition 
Globally, 3‐4 million new hepatitis C virus (HCV) infections are estimated to occur annually (1).  People who 
inject drugs (PWID) represent one of the groups at highest risk of transmitting and acquiring infection with 
the majority of new (60%) and existing (80%) infections in developed countries occur in this population with 
HCV antibody prevalence estimated at 67% (60‐80%) (2, 3).  HIV‐positive men‐who‐have‐sex‐with‐men 
(MSM) are another high risk group for HCV acquisition.   
 
In the United States, HCV incidence fell between 2006 and 2010, although subsequently rose to 0.6 per 
100,000 in 2012 (12, 13).  However, US surveillance relies upon passive reporting (with the exception of 6 
US  jurisdictions  funded  for  enhanced  surveillance  between  2006–2011)  (13)  thus  leading  to  a  marked 
underestimate of the true incidence.  Mathematical modelling suggests that the incidence of new HCV 
infections  is  in  the  region  of  5‐10  times  greater  than  reported.    Recent  estimates  following  enhanced 
surveillance  suggest  that  17,100‐21,870  new  infections  occur  annually  in  the  US  (approximately  12.3 
infections per reported case) (13, 14).   
 
In Europe, 7.3–8.8 million people (1.1–1.3%) were estimated to be living with chronic HCV infection (15), 
with injecting drug use (IDU) accounting for the majority (60–90%) of prevalent cases (16).  Incident cases 
were estimated at 6.2 per 100,000 people in 2005 (15), though significant regional variation existed with 
many countries in Eastern Europe documenting a recent increase in IDU with an associated rise in HCV 
incidence and prevalence (17).   
 
In Australia, approximately 5000 newly acquired cases are notified each year through national surveillance 
systems  (18),  with  90%  of  these  cases  occurring  as  a  result  of  unsafe  injecting  practices  (18,  19).  
Mathematical models estimate that the true number of new HCV infections peaked at 14,000 cases per 
annum in 1999 (20) before falling to 5,400‐8,790 cases in 2013 for an incidence of 0.04 per 100,000 (18, 
21).  The decline in incidence was largely attributed to a reduction in IDU.   
 
Although overall HCV incidence is falling in many countries, high incidence persists in specific populations, 
including young adult PWID (12, 13, 18, 22‐24), incarcerated PWID (25) and HIV‐positive MSM.  Over the 
last decade, an international epidemic of acute HCV infection has been observed in HIV‐positive men‐who‐
have‐sex‐with‐men (MSM), largely associated with sexual and non‐IDU behaviour (26‐33).  In the Swiss 
Cohort Study, HCV incidence increased 18‐fold in MSM between 1998‐2011, while it declined in PWID and 
remained <1 per 100 py in heterosexuals (27).  As compared with PWID, risk factors for HCV acquisition in 
MSM include unprotected anal intercourse, higher number of sexual partners, group sex, ulcerogenital 
sexually  transmitted  diseases  (notably  syphilis  and  lymphogranuloma  venereum)  and  sexual  acts  that 
involve  trauma  and  bleeding  (27,  32,  33).    However,  while  non‐IDU  is  associated  with  this  epidemic, 
concurrent IDU remains an important mode of HCV acquisition (26) and places this population at greater 
risk.  In a cohort study of HIV‐infected MSM, significantly higher incidence was documented among PWID 
as compared with non‐PWID (4.7 per 100 py [95% CI: 2.7, 7.5] vs 0.6 per 100 py [95% CI: 0.4, 0.8]; HR 8.7 
[95% CI: 4.6, 16.6]; p <0.001) (31).   
 


 
REACT Protocol Version 5.0 dated 04 June 2019 
Page 16 of 54 
 
 
 
 
 
 
 
 
1.2 Management of chronic HCV infection ‐ directly acting antiviral therapy 
The advent of DAAs has changed the therapeutic landscape for individuals with chronic HCV infection with 
IFN‐free  therapy  offering  high  efficacy  and  tolerability,  even  in  “difficult‐to‐treat”  populations  (4‐11).  
Multiple  agents  in  different  classes  have  been  approved  in  Australia  by  the  Therapeutic  Goods 
Administration (TGA), the European Union by the European Medicines Agency (EMA),  the US by the Food 
and Drug Administration (FDA), and in Canada by Health Canada.   
 
One such agent is the NS5B polymerase inhibitor, sofosbuvir (SOF). This drug belongs to the nucleotide 
analogue class of polymerase inhibitors, which mimics and competes with the natural nucleotides resulting 
in chain termination and prevention of viral replication. SOF targets the highly conserved active site of the 
HCV‐specific NS5B polymerase, an effect that is independent of the viral genotype. As such, it is highly 
potent, has  pan‐genotypic  activity  and  a  high  barrier  to  resistance.  Its  activity  has  been  assessed  in  a 
number of Phase II and III trials in combination with PEG‐IFN, RBV and/or an NS5A inhibitor, including those 
with HIV co‐infection (6, 7, 34‐39). 
 
SOF in combination with velpatasvir (GS‐5816), a 2nd generation NS5A inhibitor, is currently completing 
Phase III evaluation in the ASTRAL program.  As individual agents, SOF and velpatasvir exhibited potent pan‐
genotypic (GT 1a, 1b, 2a, 2b, 3a, 4a, 5a, 6a) anti‐HCV activity with additive antiviral interaction when co‐
adminstered.  The regimen has been well tolerated and is effective.  In an ongoing Phase 2 trial, treatment‐
naïve, non‐cirrhotic individuals with genotypes 1‐6 HCV infection received 12 weeks of SOF plus GS‐5816, 
dosed at either 25 mg or 100 mg daily.  SVR12 was 95% (73/77) in those receiving the 25 mg dose and 96% 
(74/77)  in  those  receiving  the  100  mg  dose  (40).    Shorter  treatment  durations  have  been  studied.  
Treatment‐naïve, non‐cirrhotic individuals with HCV GT 1 and 2 were randomised to SOF+GS‐5816 (25mg 
or 100mg) with or without RBV for 8 or 12 weeks (41).  In those receiving 12 weeks without RBV, SVR12 
was 96‐100% in those with GT 1 (GS‐5816 25mg: 26/27; GS‐5816 100mg: 28/28) and 91‐100% in those with 
GT  2  (GS‐5816  25mg:  10/11;  GS‐5816  100mg:  10/10)  (41).    In  ELECTRON2,  104  treatment‐naïve,  non‐
cirrhotic individuals with GT 3 HCV infection were randomised to SOF+GS‐5816 25 mg, SOF+GS‐5816 25 
mg+RBV, SOF+GS‐5816 100 mg, or SOF+GS‐5816 100 mg+RBV for 8 weeks with SVR 12 100% (27/27), 88% 
(21/24), 96% (26/27) and 100% (26/26), respectively (42).   
 
Reduced  susceptibility  to  SOF  is  associated  with  the  NS5B  substitution  S282T.  However,  the  clinical 
significance of the mutation is limited as the presence of S282T reduces viral replication capacity by 89‐99% 
as compared with wild type virus. In a pooled analysis of subjects who received sofosbuvir in 4 phase III 
clinical trials (SOF + RBV +/‐ PEG), no resistance was detected by deep sequencing in any individual with 
virologic  failure(43).  One  patient  who  relapsed  at  week  4  post‐treatment  following  12  weeks  of  SOF 
monotherapy in the phase II ELECTRON trial demonstrated the S282T mutation. However, by week 12 post‐
treatment, the mutation was no longer detectable by next generation sequencing, consistent with the 
impaired  replicative  capacity  of  the  mutant  strain(44).  Moreover,  retreatment  with  SOF‐containing 
regimens is successful in SOF‐experienced patients (45, 46). No on‐treatment resistance associated viral 
breakthrough has been observed and virtually all patients who have received SOF to date showed a robust 
and rapid response with suppression of HCV viraemia to undetectable levels within 2‐4 weeks.   
 


 
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1.3 Management of recent HCV infection 
1.3.1 
Treatment of acute HCV mono‐infection 
Global  clinical  practice  of  acute  HCV  monoinfection  is  not  standardised  with  significant  uncertainty 
regarding the optimal regimen and treatment duration, particularly as the therapeutic landscape changes 
with the advent of directly‐acting antiviral (DAA) therapy for chronic HCV.  Previous international guidelines 
had  been  in  agreement  regarding  administration  of  16‐24  weeks  of  PEG‐IFN  monotherapy  (47)  (48).  
However, despite the lack of direct evidence, recent amendments to the US guidelines support “the same 
regimens recommended for chronic HCV infection … owing to high efficacy and safety” (class IIa, level C) 
with PEG‐IFN with or without RBV for 16‐24 weeks listed as an alternative regimen (class II, level A) (48). 
 
Early  clinical  trials  evaluating  standard  or  PEG‐IFN  monotherapy  for  acute  HCV  mono‐infection 
demonstrated promising results (largely in symptomatic patients) with SVR 24 rates ranging from 75‐98% 
(49‐52).    The  first  large  prospective  study  evaluated  44  patients  (mean  duration  of  infection  before 
treatment initiation: 89 days; GT 1, 61%) who received daily standard IFN alfa‐2b for 4 weeks, followed by 
thrice weekly IFN for a further 20 weeks with a resultant SVR 24 of 98% (49).  Santantonio et al administered 
24 weeks of PEG‐IFN alfa‐2b to 16 patients with detectable HCV RNA 12 weeks following the onset of acute 
HCV infection with a resultant SVR 24 of 94% (51).  In a larger German prospective trial, 89 patients (median 
duration of infection: 76 days) received PEG‐IFN alfa‐2b for 24 weeks with an SVR 24 of 71% in the ITT 
population (per‐protocol SVR 24 89%) (53).  A meta‐analysis by Corey et al of 22 studies (including 1075 
patients) revealed an overall SVR of 78% for acute HCV treated with standard or PEG‐IFN monotherapy for 
a mean treatment duration of 19.7 weeks (standard deviation, 12.5 weeks) (54).   
 
More recently, Santantonio et al evaluated the efficacy and safety of a 24 week course of PEG‐IFN alfa‐2b 
(group A) versus a 12‐week course of PEG‐IFN alfa‐2b alone (group B) or with RBV (group C) in an open 
randomized  multicentre  trial  involving  130  patients  with  acute  HCV  monoinfection  who  did  not 
demonstrate spontaneous clearance after  12 weeks of observation  (55).   The study protocol excluded 
PWID.  By ITT, the overall SVR 24 was 71.5%; the SVR 24 was 70.5% (31/44), 72.1% (31/43) and 72.1% 
(31/43) in groups A, B and C, respectively (p = 0.898).  By per‐protocol analysis, SVR 24 rose to 81.6% in 
each group.  On multivariate analysis, a rapid virological response (RVR, undetectable HCV RNA at week 4 
of treatment) was associated with SVR, consistent with the evidence available in chronic HCV infection.  No 
other assessed baseline factor (age, gender, HCV genotype, treatment arm) predicted SVR.  
 
The addition of RBV to PEG‐IFN is of uncertain benefit in acute HCV mono‐infection.  The recent study by 
Santantonio et al (55) and others (56) demonstrate no additional advantage.  In the Australian Trial in Acute 
Hepatitis C (ATAHC) trial, the addition of RBV in the HIV co‐infected population improved viral kinetics as 
compared with PEG‐IFN monotherapy in the HCV mono‐infected population (57).  Given the efficacy of RBV 
in chronic HCV infection, the treating clinician may consider adding RBV in an attempt to maximize SVR, in 
the absence of evidence.   
 
1.3.2 
Treatment of recent HCV infection in PWID 
While the majority of HCV transmission in the developed world occurs in the setting of IDU, there are limited 
data on treatment of acute HCV infection in PWID.  In a small Swiss study, 22 patients with acute HCV were 
assessed for treatment and 14 commenced PEG‐IFN alfa‐2b for 24 weeks (58).  By ITT, the SVR 24 was 57%.  
However, adherence was poor with only 8 patients completing more than 80% of the scheduled treatment 


 
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course (SVR by per‐protocol analysis, 88% [7/8]).  De Rosa et al offered 12 weeks of directly observed 
therapy with PEG‐IFN alfa‐2b with a much improved SVR 24 of 74% (17/23) (59).  Adherence was excellent 
with 96% (22/23) completing more than 80% of the scheduled treatment course.   
 
The largest trial to date examining treatment of acute and early chronic HCV infection involving PWID was 
ATAHC, a multicentre prospective cohort study of the natural history and outcomes following treatment 
with PEG‐IFN alfa‐2a with or without RBV (60).  Between 2004 and 2008, 167 subjects were enrolled, of 
whom 111 (76%) with detectable HCV RNA at screening elected to commence treatment.  57% of the 
treated  population  were  GT  1,  85%  had  acquired  HCV  via  IDU  and  the  median  estimated  duration  of 
infection  was  25  weeks.    33%  of  subjects  were  HIV  co‐infected  (predominantly  sexual  [permucosal] 
transmission).  In the cohort of 74 HCV mono‐infected individuals who commenced PEG‐IFN monotherapy, 
the SVR 24 by ITT and per protocol analyses were 55% and 72%, respectively, with 77% (57/74) receiving at 
least 80% of the scheduled treatment course.  While the SVR rate was lower in those who had a history of 
IDU (history of IDU, SVR 24 48% vs no IDU, SVR 24 91%, p = 0.03), after adjusted analysis, the only pre‐
treatment factors associated with treatment failure were poor social functioning and a history of drug 
dependency treatment.   
 
Collectively, these data demonstrate that PWID with recent HCV infection can be treated successfully, but 
that  strategies  to  optimize  adherence  in  socially  marginalized  populations  are  required  to  improve 
outcomes.  
 
While HCV treatment in PWID is feasible and successful across a broad range of multidisciplinary healthcare 
settings (58‐61), treatment uptake remains low with multiple barriers to care at an individual and systems 
level,  driven  in  part  by  concerns  of  adherence,  social  instability,  treatment‐related  adverse  effects, 
psychiatric comorbidity and the perceived risk of HCV reinfection (62).  The availability of IFN‐free, DAA 
therapy will address some of these concerns and may facilitate treatment uptake. 
 
1.3.3 
Treatment of recent HCV infection in HIV co‐infection 
While SVR rates with IFN‐based therapy for chronic HCV in HIV co‐infection have been consistently lower 
than those of HCV monoinfection, treatment efficacy is improved in acute HCV infection.  In the ATAHC 
trial, 35 patients co‐infected with HIV and HCV commenced 24 weeks of PEG‐IFN and RBV with SVR 24 by 
ITT and per protocol analyses of 74% and 75%, respectively, higher than the HCV mono‐infected population 
(60).  The higher SVR among HIV‐positive compared with HIV‐negative individuals may relate to socio‐
demographic  differences  between  these  groups  with  the  majority  of  HIV‐positive  individuals  reporting 
higher levels of education and employment, more stable housing and greater social support than the HIV‐
negative patients, facilitating better adherence.  Acknowledging the predominance of sexual (permucosal) 
transmission (60%), IDU remained an important mode of acquisition in the co‐infected cohort (37%), with 
54% reporting prior or current IDU (60).   
 
Boescke et el demonstrated similar results with administration of either PEG‐IFN alfa‐2a monotherapy or 
PEG‐IFN and RBV for 24‐48 weeks at the investigators discretion (treatment duration 24 weeks: PEG‐IFN 
83%, PEG‐IFN/RBV 70%) (63).  The overall SVR was 64.8%, with no apparent additional benefit of RBV (PEG‐
IFN SVR 69%, PEG‐IFN/RBV SVR 63%).  The European AIDS Treatment Network (NEAT) reviewed nine co‐
infected cohorts, including 170 HIV‐positive individuals who received IFN‐based treatment for acute HCV 
infection (predominantly GT 1) and demonstrated a combined SVR 24 of 60‐80% (64).  Their subsequent 


 
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recommendations involve administration of 24‐48 weeks of PEG‐IFN and RBV, with treatment duration 
based on presence or absence of RVR.   
 
1.3.4 
Duration of treatment 
The enhanced outcomes in early infection mean that IFN‐based therapy at this time can often be simplified, 
and specifically be administered for a shorter duration.  Previous studies have demonstrated the efficacy 
of short course treatment for 4 (SVR 24 87%) (50) and 12 weeks (SVR 24 72–74%) (50, 55, 61, 65, 66).  Short 
duration response guided therapy may be appropriate for many individuals with recent HCV infection (67).  
Shorter  treatment  durations  result  in  fewer  adverse  events,  better  quality  of  life,  less  frequent  dose 
reductions and increased likelihood of optimal adherence (61, 65).   
 
Shortening the duration of therapy with interferon‐free DAA regimens in CHC is supported by recent phase 
II data. In LONESTAR, excellent results (SVR 12 95 – 100%) were obtained in GT 1 infection with 8 – 12 weeks 
of SOF and ledipasvir with or without RBV (4). SYNERGY proved that 6 weeks of triple combination DAA 
therapy is effective, with SVR 12 95% in arm B (SOF/ledipasvir plus GS‐9669, a once‐daily non‐nucleoside 
NS5B inhibitor) and SVR 12 100% in arm C (SOF/ledipasvir plus GS‐9451, a once‐daily HCV NS3/4 protease 
inhibitor)(68). As double or triple DAA‐combination regimens have markedly reduced treatment duration 
in GT 1 CHC as compared with standard of care (48 weeks PEG/RBV), it is postulated that similarly marked 
reductions in duration should be feasible in recently acquired HCV infection.  
 
1.3.5 
Directly‐acting antiviral therapy for acute HCV infection 
Very limited evidence exists for the use of DAA therapy in the setting of acute HCV infection.  Fierer et al 
recently published the results of a pilot study involving administration of PEG‐IFN, RBV and telaprevir in 
HIV‐positive MSM with recent GT 1 HCV infection (69).  Risk factors for acquisition were not reported.  By 
ITT, SVR 12 was 84% (16/19).  Treatment duration was response‐guided; of those who achieved SVR 12, 
most (13/16; 81%) received ≤12 weeks of therapy.  While these results are encouraging, the side‐effect 
profile (70, 71), drug‐drug interactions and treatment complexity seen with triple therapy regimens will 
likely prevent routine use of this strategy.   
 
1.3.6 
Reinfection following acute HCV infection 
The risk of reinfection is often cited as a reason for not offering treatment to current and former PWID, but 
few studies have evaluated the incidence of HCV reinfection following successful treatment in this context.  
The limited evidence would suggest that the reinfection rate is low.  Of 111 subjects treated in the ATAHC 
study, viral recurrence after treatment‐induced suppression was observed in 19% (17/88) with 5 cases of 
reinfection (4.7 cases per 100 py; 95% CI 1.9, 11.2) (72).  Ongoing IDU during follow up was reported by 
38% of participants with treatment‐induced virological suppression, with a higher reinfection rate in this 
subgroup (7.3 per 100 py [95% CI: 2.3, 22.6]).  In the ATAHC Recall study, 50 individuals from the original 
ATAHC cohort were reassessed at a median duration of 7.2 years following primary infection with 37 (74%) 
having received treatment (SVR 24 70%) and 10 (20%) having demonstrated spontaneous clearance (73).  
Only 4 reinfections were identified (with 3 related to ongoing IDU) for an incidence rate of 1.8 per 100 py 
(95% CI: 0.7, 4.8).  Importantly, significant changes were noted in injecting behaviour; 66% (33/50) had 
acquired HCV via IDU, but only 30% (15/50) reported ongoing use.   
 


 
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Two  systematic  reviews  have  examined  the  risk  of  reinfection  in  PWID  after  treatment‐induced  SVR, 
combining studies of acute and chronic HCV infection.  In the first, the pooled estimate of reinfection from 
5 prospective studies was 2.4 per 100 py (95% CI: 0.9, 6.1), rising to 6.4 per 100 py (95% CI: 2.5, 16.7) in 
those reporting ongoing IDU post SVR (74).  The second systematic review and meta‐analysis revealed 
similar findings with viral recurrence (late relapse or reinfection) in the “high risk” group (PWID, prisoners) 
estimated at 2.8 per 100 py (95% CI 2.06, 3.71) (75).  Contrary to this, reinfection rates in predominantly 
young adult PWID who exhibited spontaneous clearance are higher, suggesting that this cohort may be at 
especial risk, though the number of subjects available for assessment was small (76‐79).   
Reinfection rates in HIV‐positive MSM following primary HCV infection are varied, with very high incidence 
reported  in  some  studies  (80).    In  the  aforementioned  meta‐analysis,  viral  recurrence  (late  relapse  or 
reinfection) following SVR in those with HIV co‐infection was 4.78 per 100 py (95% CI 3.97, 5.71) (75) .  
Multiple reinfections in individuals with ongoing high risk behaviour emphasise the need for continuing 
surveillance, education and prevention strategies (81, 82).  In a retrospective analysis of 48 HIV‐positive 
MSM with more than one sexually acquired HCV infection, 11 patients presented with 3 episodes and 1 
patient with four episodes (81).  In another cohort of HIV‐positive MSM, the overall reinfection rate was 
7.8 per 100 py (95% CI: 5.8, 10.5) with 8 individuals reinfected a second time for a secondary reinfection 
rate of 15.5 per 100 py (95% CI: 7.7, 31.0) (82).  
1.4 ATAHC I, ATAHC II, DARE‐C I and DARE‐C II studies 
The Australian Trial in Acute Hepatitis C (ATAHC) was an NIH funded multicentre prospective cohort study 
of the natural history, and outcomes following treatment with PEG (with or without RBV) in individuals with 
acute and early chronic HCV infection, with the final results published in Gastroenterology (60). Between 
2004 and 2008, 167 subjects with acute and early chronic HCV infection were enrolled throughout Australia, 
of whom 111 (76%) subjects with detectable HCV RNA at screening elected to undertake treatment. 57% 
of the treated population were GT 1 and the median estimated duration of infection was 25 weeks, meaning 
that around half the patients had early chronic HCV infection. 33% of subjects were HIV co‐infected. Final 
analysis of treatment outcomes in the 74 HCV mono‐infected subjects who commenced treatment with 
PEG monotherapy demonstrated SVR rates of 55% and 72% by intention‐to‐treat and per‐protocol analysis, 
respectively.  
 
A second study (ATAHC II) was funded by the NIH for 5 years in 2010. One of the primary aims of this 
subsequent study is to explore potential therapeutic strategies aiming to enhance treatment efficacy and 
acceptability in the setting of recently acquired HCV infection (duration of infection <18 months). Within 
this second trial, a strategy of individualised response guided therapy was explored in which duration of 
therapy with PEG and RBV for acute and early chronic HCV infection was based on time to first undetectable 
HCV RNA, with total treatment duration ranging between 8‐48 weeks.  Eighty‐two participants (HIV‐positive 
62%) were enrolled in ATAHC II (treated, n=52).  SVR12 was 71% (37/52) with the majority (56%) receiving 
shortened therapy (8 or 16 weeks) with a combined SVR12 of 93% (unpublished data).  SVR was associated 
with shorter treatment duration (OR 17.55; p=0.001) (unpublished data).   
 
DARE‐C I, a sub‐study of ATAHC II, was established in 2013 to evaluate the safety and efficacy of response 
guided therapy with PEG, weight‐based RBV and telaprevir (TVR) for recently acquired GT1 HCV infection 
(duration of infection 6‐18 months).  Treatment duration was dependent on time to first HCV RNA below 
the limit of detection and ranged between 8‐24 weeks.  Between April 2013 and May 2014, 14 participants 


 
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(79%  HIV‐positive)  were  enrolled.    SVR12  by  ITT  was  71%  (10/14)  (unpublished  data).    By  treatment 
duration, SVR12 was 71% (5/7) in those receiving PEG/RBV/TVR for 8 weeks, 100% (3/3) in those receiving 
PEG/RBV/TVR for 12 weeks and 100% (2/2) in those receiving PEG/RBV/TVR for 12 weeks + PEG/RBV for 12 
weeks (24 weeks) (unpublished data).  In those with HIV, SVR12 was 73% (8/11) (unpublished data). 
 
DARE‐C II is an ongoing pilot study exploring the safety, efficacy and feasibility of the dual interferon‐sparing 
combination of SOF plus RBV in participants with recent HCV infection (duration of infection <12 months).  
The study is closed to recruitment.  Results will be presented at the American Association for the Society of 
Liver Disease (AASLD) meeting in November 2015.  
 
1.5 REACT rationale 
Given the burden of HCV‐related disease among PWID and HIV‐positive MSM, strategies to enhance HCV 
assessment, treatment and prevention in these groups are urgently needed.  Much of what is known about 
the timing of treatment initiation, regimen choice and duration of therapy in acute HCV infection comes 
from small observational studies and randomized controlled trials in selected populations with limited data 
on treatment in PWID and HIV co‐infection.  With recent rapid advances in HCV therapeutics, management 
strategies for acute HCV will evolve rapidly over the next few years.   
 
The REACT study will compare the efficacy and safety of sofosbuvir/velpatasvir administered for 6 or 12 
weeks in individuals with recent HCV infection.  The role and activity of potent DAA regimens in acute HCV 
infection requires evaluation, with the potential to be given as highly efficacious, short course IFN‐sparing 
regimens,  maximising  acceptability  to  patients,  encouraging  uptake  of  treatment,  limiting  further 
transmission and preventing progression to chronic liver disease.   
 
2 Study objectives 
2.1 Hypothesis 
Six  weeks  treatment  with  sofosbuvir/velpastavir  is  non‐inferior  to  twelve  weeks  treatment  with 
sofosbuvir/velpastavir as assessed by sustained virological response at 12 weeks post treatment in the 
intention‐to‐treat population (SVR12). 
 
2.2 Primary objective 
The  primary  objective  is  to  evaluate  the  proportion  of  patients  with  HCV  RNA  below  the  level  of 
quantitation (target not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end 
of treatment (SVR12) following sofosbuvir/velpatasvir therapy for 6 weeks (short treatment duration) as 
compared with 12 weeks (standard treatment duration) in people with recent HCV infection (duration of 
infection ≤12 months).  
 


 
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2.3 Secondary objective(s) 
1 
To evaluate the proportion of participants with HCV RNA below the level of quantitation (TND or TDnq) 
at  the  end  of  treatment  (ETR),  4  weeks  after  treatment  completion  (SVR4)  and  24  weeks  after 
treatment completion (SVR24); 
 
2 
To evaluate the proportion of participants with undetectable HCV RNA through 2 years post treatment; 
 
3 
To  evaluate  the  levels  of  adherence,  factors  associated  with  suboptimal  adherence  including  HIV 
status, and the impact of suboptimal adherence on therapeutic response; 
 
4 
To evaluate the impact of treatment on illicit drug use, injecting behaviour and sexual risk taking 
behaviour (behavioural survey) during treatment; 
 
5 
To evaluate safety and tolerability 
 
6 
To evaluate the change in HIV RNA and CD4 (on‐treatment and end of treatment); 
 
7 
To evaluate the rate and risk factors for reinfection during and up to 2 years following treatment; 
 
8 
To evaluate the immunological factors associated with treatment induced clearance and reinfection  
 
9 
To evaluate patient interest and attitudes towards long acting parenteral hepatitis C therapy (Long‐
Acting Hepatitis C Therapy Questionnaire) 
 
3 Participant population 
3.1 Number of Participants and Participant Selection 
A total of 250 participants with recent HCV infection will be enrolled from drug and alcohol clinics, tertiary 
liver and infectious diseases clinics and community health centres across Australia, Canada, Germany, New 
Zealand, Switzerland, The Netherlands, the United Kingdom and the United States. The Kirby Institute may 
close or suspend screening prior to reaching 250 participants in order to manage the total study enrolment 
numbers.  
 
The number of participants with HCV/HIV coinfection enrolled to the study will be capped at 70% (or less 
than 175 participants) of the total study population.  In addition, the number of participants with HCV 
reinfection enrolled to the study will be capped at 50% (or less than 125 participants) of the total study 
population. 
 
Selection of participants: 
 
Enrolment  into  the  study  is  at  clinician  discretion  providing  participant  satisfies  all  eligibility  criteria. 
However, the following situations should be considered prior to enrolment: 
 
1. It is possible that participants presenting with acute HCV infection may spontaneously clear if followed 
untreated. Clinicians should consider it unlikely that the patient will spontaneously clear based on viral 


 
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load fluctuation before enrolling in this treatment study. It is suggested that a minimum of 4 weeks is 
observed from presentation to exclude this possibility. 
 
2. Acute participants with very high viral loads (>7 log IU/ml) may be at higher risk of treatment failure. It 
is suggested to observe these patients until HCV viral load reduces to <7 log IU/ml before enrolling in 
study. 
 
3.2 Inclusion criteria 
Subjects must meet all of the following inclusion criteria to be eligible to participate in this study.  
1 
Participants have voluntarily signed the informed consent form. 
2 
18 years of age or older. 
3 
Detectable HCV RNA at screening (>10,000 IU/ml), and in the opinion of the investigator is unlikely 
to demonstrate spontaneous viral clearance  
4 
HCV genotypes 1‐6. 
5 
HBsAg negative 
6 
Negative pregnancy test at screening and baseline (females of childbearing potential only). 
7 
Male subjects and female subjects of childbearing potential who engage in heterosexual intercourse 
must agree to use protocol specified method(s) of contraception 
8 
Medically stable on the basis of physical examination, medical history and vital signs 
9 
Adequate literacy to provide reliable responses to the study questionnaires 
10 
All fertile males and females must be using effective contraception during treatment and during the 
30 days after treatment end. 
11 
Recently acquired HCV infection (estimated duration of infection ≤12 months)* 
 
Recently acquired HCV infection as defined by: 
A)  
i) First anti‐HCV Ab or HCV RNA positive within the previous 6 months  
and  
ii) Documented anti‐HCV Ab negative within the 12 months prior to anti‐HCV antibody positive result  
 
OR  
 
B)  
i) First anti‐HCV Ab or HCV RNA positive within the previous 6 months  
and 
ii) Acute clinical hepatitis (jaundice or ALT> 10 X ULN) within the previous 6 months prior to first positive 
HCV antibody or HCV RNA, with no other cause of acute hepatitis identifiable 
 
OR 
 


 
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C) For cases of recent HCV reinfection the following criteria are required: 
i) Documented prior HCV antibody positive with HCV RNA negative on at least 2 occasions 6 months apart 
and  
ii) new HCV RNA positive within the previous 6 months  
 
*Estimated duration of infection based on midpoint between last antibody negative or HCV RNA and first 
antibody positive or HCV RNA in the case of seroconversion and 6 weeks prior to date of maximum ALT in 
the case of acute hepatitis. 
See Section 3.4 for ‘Definitions used to calculate Estimated Date of Infection’. 
 
If co‐infection with HIV is documented, the subject must meet the following criteria: 
1. Antiretroviral (ARV) untreated for >8 weeks preceding screening visit with CD4 T cell count >500 
cells/mm3 
OR 
2. On a stable ARV regimen for >8 weeks prior to screening visit, with CD4 T cell count >200 cells/mm3 
and an undetectable plasma HIV RNA level. 
 
Suitable ARV include:   
o Nucleos(t)ide  reverse  transcriptase  inhibitors:    Tenofovir  disoproxil  fumarate  (TDF), 
tenofovir  alafenamide  (TAF),  emtricitabine  (FTC)Non‐nucleoside  reverse  transcriptase 
inhibitors: Rilpivirine 
o Protease inhibitors: Atazanavir, darunavir, lopinavir, ritonavir 
o Integrase inhibitors: Dolutegravir, raltegravir, elvitegravir/cobicistat 
 
Contraindicated ARV include: 
o Efavirenz 
 
50% reduction in velpatasvir (GS‐5816) exposure 
o Didanosine 
o Zidovudine 
o Tipranavir 
Other ARV agents may be permissible at the time of study commencement pending further drug‐drug 
interaction studies; please discuss with the Medical Monitor.   
 
3.3 Exclusion criteria 
Subjects who meet any of the exclusion criteria are not to be enrolled in this study. 
1. 
History of any of the following: 
a. 
Clinically significant illness (other than HCV) or any other major medical disorder that may 
interfere  with  the  participant  treatment,  assessment  or  compliance  with  the  protocol; 
participants currently under evaluation for a potentially clinically significant illness (other than 
HCV) are also excluded. 
b. 
History  of  chronic  pulmonary  disease  associated  with  functional  limitation,  severe  cardiac 
disease, major organ transplantation or other evidence of severe illness, malignancy, or any 
other conditions which would make the patient, in the opinion of the investigator, unsuitable 
for the study 


 
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c. 
Solid organ transplant 
d. 
Malignancy within 5 years prior to screening, with exception of specific cancers that may have 
been cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for 
possible malignancy are also excluded. 
e. 
Significant drug allergy (such as anaphylaxis or hepatotoxicity). 
2. 
Subject has a known or documented prior history of cirrhosis.  
3. Subject shows evidence of significant liver disease in addition to hepatitis C, which may include but is 
not limited to drug‐ or alcohol‐related cirrhosis, autoimmune hepatitis, hemochromatosis, Wilson’s 
disease, non‐alcoholic steatohepatitis (NASH), or primary biliary cirrhosis 
4 
Any of the following lab parameters at screening: 
a. 
Direct bilirubin > 1.5 x ULN 
b. 
Platelets < 50,000/μL 
c. 
Creatinine clearance (CLcr) < 50 mL/min  
d. 
Haemoglobin < 10 g/dL  
e. 
Albumin < 30g/L 
f. 
International Normalised Ratio (INR) >1.5 (unless subject is on a stable anticoagulant regimen 
or has known coagulopathy) 
5. Pregnant or nursing female. 
6. Use of prohibited concomitant medications as described in section 5.2 
7. Chronic use of systemically administered  immunosuppressive agents (e.g. prednisone equivalent > 10 
mg/day) 
8. Known hypersensitivity to velpatasvir, sofosbuvir or formulation excipients. 
9. Therapy with any anti‐neoplastic or immunomodulatory treatment (including supraphysiologic doses 
of steroids and radiation) ≤6 months prior to the first dose of study drug. 
10. Any investigational drug ≤6 weeks prior to the first dose of study drug. 
11. Previous failure of therapy with sofosbuvir or an NS5A inhibitor prior to the first dose of study drug. 
12. Ongoing severe psychiatric disease as judged by the treating physician.  
13. Frequent injecting drug use that is judged by the treating physician to compromise treatment safety. 
14. Inability or unwillingness to provide informed consent or abide by the requirements of the study. 
15. Prior enrolment within this study. 
 
Subjects will be stratified by genotype/subtype, HIV status and primary or reinfection for analysis. 
 


 
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3.4 Definitions used to calculate Estimated Date of Infection  
The estimated date of HCV infection will be determined using data obtained at the screening visit according 
to the following rules (Table 1):  
 
Table 1. Estimated duration of infection calculation rules 
Category 
Estimated date of HCV infection 
Acute clinical HCV 
6 weeks prior to onset of acute clinical symptoms 
Acute asymptomatic HCV ALT < 400 IU/L 
Mid‐point between last negative HCV antibody or HCV 
RNA and first positive HCV antibody or HCV RNA 
Acute asymptomatic HCV ALT > 400 IU/L 
6 weeks prior to the date of peak ALT unless the estimated 
date of infection is after the date of first HCV antibody 
positive test. Then, 6 weeks prior to the date of the first 
HCV antibody positive test 
HCV antibody negative and HCV RNA 
positive at screening 
6 weeks prior to the screening date  
 
The estimated date of HCV will then be used to determine the estimated duration of HCV infection.  
 
4 Study design 
4.1 Summary of study design 
This study will be conducted as a phase III randomised, open‐label, non‐inferiority multicentre international 
trial. 
A total of 250 people with recently acquired hepatitis C will be enrolled and randomised.  
 
The number of participants with HCV/HIV coinfection enrolled to the study will be capped at 70% (or less 
than 175 participants) of the total study population.  In addition, the number of participants with HCV 
reinfection enrolled to the study will be capped at 20% (or less than 50 participants) of the total study 
population. 
  
The  study  consists  of  a  screening  phase  (‐12  to  ‐4  weeks),  treatment  commencement  from  baseline, 
randomisation between week 5 and 6, treatment for another 6 weeks for those randomised to standard 
therapy (12 weeks of treatment) or end of treatment for those randomised to shortened treatment (6 
weeks of treatment). All participants will then enter the follow‐up phase (96 weeks) to evaluate treatment 
response and reinfection (Figure 1). Randomisation will be using blocks and will be stratified by study site 
and HIV status.  
 
 


 
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Figure 1: Study Schema 
 
Participants who become re‐viraemic following an end of treatment response will be followed monthly for 
six  months.  After  completing  the  monthly  follow‐up  visits,  participants  will  continue  to  attend  three 
monthly follow‐up visits up to two years. Please see section 7 ‘Reinfection follow‐up’ for more details. 
 
4.2 Visit Schedule 
All participants will complete screening, on‐treatment and post‐treatment assessments as outlined in the 
Schedule of Assessments in Section 6.0. 
 
Screening assessments must be completed within in 12 weeks prior to baseline. There must be a minimum 
of 4 weeks between screening and baseline.  
 
Following  screening,  eligible  participants  will  commence  treatment.  Between  week  5  and  week  6  of 
treatment, the participants will be randomised to either the shortened or standard treatment duration.  
On‐treatment visits will be conducted at weeks 1, 2, 4 and 6 (end of treatment for participants on shortened 
treatment duration), weeks 8 and 10 (for participants on standard treatment duration only). Participants 
on standard treatment duration will attend end of treatment at week 12. For participants randomised to 
shortened treatment, follow‐up visits will be conducted at week 10 (SVR4), week 18 (SVR12), week 30 
(SVR24), week 42 (FU1), week 54 (FU2), week 66 (FU3), week 78 (FU4), week 90 (FU5) and week 102 
(Termination).  For participants randomised to standard treatment, follow‐up visits will be conducted at 
week 16 (SVR4), week 24 (SVR12), week 36 (SVR24), week 48 (FU1), week 60 (FU2), week 72 (FU3), week 
84 (FU4), week 96 (FU5) and week 108 (Termination). 


 
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4.3 Treatment Discontinuation Criteria 
Study drug must be discontinued in the following instances: 
 
Unacceptable toxicity 
 
Pregnancy of female subject 
 
Significant protocol violation 
 
Participant request to discontinue for any reason 
 
Discontinuation of the study by the Kirby Institute, regulatory agencies or a Human Research 
Ethics Committee / Research Ethics Committee / Institutional Review Board 
Participants who cease study medication will, wherever possible, continue to be followed up according to 
the  protocol  study  plan.  Participants  may  revoke  consent  for  follow‐up  without  jeopardizing  their 
relationship with either their doctor or the UNSW. If a participant revokes consent then, if possible, all 
assessments scheduled for the final visit should be completed. 
 
5 Treatment of participants 
5.1 Sofosbuvir/velpatasvir dosage and administration 
Participants will receive six or twelve weeks of open‐label sofosbuvir/velpatasvir (400mg/100mg daily) in 
an oral once‐daily fixed dose combination. Dose modifications are prohibited.  
 
5.2 Study Drug Adherence and Drug Accountability 
Therapy will be administered in two‐weekly supply. Participants will be asked to return study medication 
every two weeks.  Study drug will be reconciled using a pill count on all returned drug bottles. 
 
Participants will also be required to complete an adherence questionnaire as described in section 6.2. 
 
5.3 Prior and Concomitant Medications 
Concomitant medication must be recorded in the source documents and eCRF from screening until the last 
dose of study medication. 
The following medications are prohibited from six weeks prior to the baseline visit through to the end of 
treatment:  
 
Haemotologic stimulating agents  (e.g. erythropoiesis‐stimulating agents [ESAs];  granulocyte 
colony stimulating factor [GCSF]; thrombopoietin [TPO] mimetics) 
 
Chronic  systemic  immunosuppressant  use  including,  but  not  limited  to  corticosteroids 
(prednisone equivalent of >10 mg/day for >2 weeks), azathioprine, or monoclonal antibodies 
(e.g. infliximab) 


 
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 
Investigational agents or devices for any indication  
 
Drugs disallowed per prescribing information of SOF 
Concomitant  use  of  certain  medications  or  herbal/natural  supplements  (inhibitors  or  inducers  of  drug 
transporters i.e. P‐gp) with study drug may result in pharmacokinetic interactions resulting in increases or 
decreases in exposure of study drug or these medications.  
Due to decreases in sofosbuvir or velpatasvir exposure, use of sofosbuvir/velpatasvir with potent P‐gp and 
moderate or potent CYP inducers is not recommended (83‐85).   
The use of the ”Disallowed” agents in Table 2 is prohibited from 21 days prior to Baseline through to the 
end of treatment except Amiodarone which is prohibited from 60 days prior to Baseline through to the end 
of treatment.  
 


 
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Examples of representative medication which are prohibited or are used with caution are listed below: 
Table 2:  
List of Disallowed Medications 
Drug Class 
Agents Disallowed 
Use with Caution 
Acid Reducing Agentsa 
 
H2‐Receptor Antagonistsa, Antacidsa , Proton Pump 
Inhibitorsa 
Anticonvulsantsb 
Carbamazepine, Oxcarbazepine, 
Phenobarbital, Phenytoin,  
 
Antimycobacterialsb 
Rifabutin, Rifapentine, Rifampin 
 
Antiretrovirals 
Efavirenz b 
 
Cardiac Medicationsc 
Amiodaronee,  
Bosentan, Digoxinc, Diltiazem, Dronedarone, 
Olmesartan, Quinidine, Ranolazine, Telmisartan, 
Valsartan, Verapamil  
Herbal/Natural Supplementsb 
St. John’s Wort, Echinaccea, Milk 
Thistle (i.e. silymarin), Chinese herb 
Sho‐Saiko‐To (or Xiao‐Shai‐Hu‐Tang) 
 
HMG‐CoA Reductase 
Inhibitorsd 
 
Atorvastatin, Fluvastatin, Lovastatin, Pitavastatin, 
Pravastatin, Rosuvastatin (≤10 mg/day), 
Simvastatin  
Other 
Modafinilb, sulfasalazinec, 
methotrexatec 
 
a H2‐receptor Antagonists must not exceed a dose of 20 mg famotidine or equivalent and can be taken simultaneously with SOF/VEL 
and/or staggered by 12 hours. Antacids that directly neutralize stomach acid (i.e. Tums, Maalox) may not be taken within 4 hours 
(before or after) of SOF/VEL administration.  Proton Pump Inhibitors equivalent to omeprazole 20 mg can be taken simultaneously 
with SOF/VEL in the fed state.   
b May result in a decrease in the concentration of study drugs 
c May result in an increase in the concentration of study drugs and/or concomitant medications; monitor for signs and symptoms 
of digoxin toxicity 
d  Use  with  SOF/VEL  may  result  in  an  increase  in  the  concentration  of  HMG‐CoA  Reductase  Inhibitors.  Monitor  for  signs  and 
symptoms of muscle weakness or myopathy, including rhabdomyolysis.  
e60 day washout period applies. 
 
Refer to http://www.hep‐druginteractions.org/ and product information for further data.  
 
Should any participant need to initiate treatment with any excluded concomitant medication during the 
study,  the  Medical  Monitor,  Prof Greg  Dore  must  be  consulted  prior  to  the  initiation  of  any  excluded 
medication. In the event that an excluded medication is initiated prior to discussion with Prof Greg Dore, 
he must be made aware of the use of the excluded medication as soon as possible. Prof Greg Dore’s contact 
details are listed on the cover of this protocol. 
 
 
 


 
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6 Study procedures 
6.1 Visits and Procedures 
The following assessments must be conducted at study visits as per the schedule of assessments: 
 
Vital 
signs 
& 
physical 
measurements 
body weighta, heighta 
Biochemistry 
 
Creatinine, glucose, sodium, chloride, and potassium, creatine kinase 
Liver Function Tests 
ALT, AST, GGT, total bilirubin, albumin, alkaline phosphatase, total protein 
Full Blood Count 
Haemoglobin, haematocrit , White Blood Cells, platelets, neutrophils 
Clotting 
INR 
HCV RNA 
Must be quantitative at Screening  
HCV Genotype 
Within 12 months prior to screening 
HAV Serology 
Hepatitis A total Ab (IgG), Hepatitis A IgM 
HBV Serology 
Anti‐HBc, HBsAg 
HCG Pregnancy Test 
For women of childbearing potential, a negative urine (or serum) HCG test 
at screening and baseline 
Questionnaires 
Behavioural  survey, 
abbreviated 
behavioural  survey, 
adherence 
questionnaire, Health Outcomes Survey (EQ‐5D), Long‐Acting Hepatitis C 
Therapy Questionnaire 
a at screening only 
 
The following assessments and procedures must be performed at each visit as specified below: 
 
Initial screening period (Week ‐12 to Week ‐4) 
 
Informed consent 
 
Medical history  
 
FibroScan 
 
Vital signs and physical examination 
 
HCV antibody 
 
HCV RNA and genotype (Local laboratory) 
 
LFTs, FBC and biochemistry 
 
Clotting ‐ INR 
 
HIV antibody, HAV & HBV serology 
 
CD4/CD8 & HIV viral load (HIV positive participants only) 
 
Pregnancy test (females of child bearing potential only)  
 
Study behavioural questionnaire 
 
Concomitant medication 
 
Health outcomes survey (EQ‐5D)  
 
Research specimen collection (EDTA plasma, whole blood & ACD Plasma/PBMCs) 
 
 
Baseline visit (Week 0)  


 
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 
Vital signs and physical examination 
 
HCV RNA (Local laboratory) 
 
LFTs, FBC and biochemistry 
 
Pregnancy test (females of child bearing potential only)  
 
Adverse Events 
 
Concomitant medication 
 
Abbreviated Behavioural questionnaire  
 
Long‐Acting Hepatitis C Therapy Questionnaire* 
 
Research specimen collection (EDTA plasma, whole blood & ACD Plasma/PBMCs) 
 
*  The  Long‐Acting  Hepatitis  C  Therapy  Questionnaire aims  to  obtain  participant  interest  and  attitudes 
towards long‐acting parenteral hepatitis C therapy. All currently enrolled participants will complete the 
Long‐Acting Hepatitis C Therapy Questionnaire at their next scheduled visit. 
 
Week 1 (+/‐ 3 days)  
 
LFTs, FBC and biochemistry  
 
Adverse Events 
 
Concomitant medication 
 
Research specimen (EDTA plasma & ACD Plasma/PBMCs) 
 
Week 2 (+/‐ 3 days) 
 
LFTs, FBC and biochemistry  
 
Adherence questionnaire  
 
Adverse Events 
 
Concomitant medication 
 
Research specimen (EDTA plasma & ACD Plasma/PBMCs) 
 
SOF/VEL pill count 
 
Week 4 (+/‐ 3 days) 
 
LFTs, FBC and biochemistry 
 
Pregnancy test (females of child bearing potential only)  
 
Adherence questionnaire  
 
Adverse Events 
 
Concomitant medication 
 
Research specimen (EDTA plasma & ACD Plasma/PBMCs) 
 
SOF/VEL pill count 
 
 
Between Week 5 and Week 6 – RANDOMISATION 
 
Week 6 (+/‐ 3 days)   
 
For participants in the shortened treatment arm – complete the ETR visit. 


 
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For participants in the standard treatment arm complete the following assessments. 
 
LFTs, FBC and biochemistry 
 
Abbreviated Behavioural questionnaire  
 
Adherence questionnaire  
 
Adverse Events 
 
Concomitant medication 
 
Research specimen (EDTA plasma & ACD Plasma/PBMCs) 
 
SOF/VEL pill count 
 
Week 8 (+/‐ 3 days) and Week 10 (+/‐ 3 days) – STANDARD DURATION ONLY 
 
LFTs, FBC and biochemistry 
 
Pregnancy test (females of child bearing potential only) – week 8 only 
 
Adherence questionnaire  
 
Adverse Events 
 
Concomitant medication 
 
Research specimen collection (EDTA plasma) 
 
SOF/VEL pill count 
 
End of Treatment (ETR) – Week 6 (Shortened treatment) or Week 12 (Standard treatment) (+/‐3 days) 
 
HCV RNA (Local laboratory) 
 
LFTs, FBC and biochemistry 
 
CD4/CD8 & HIV viral load (HIV positive participants only) – Standard treatment arm only 
 
Pregnancy test (females of child bearing potential only) – Standard arm treatment only 
 
Adverse Events 
 
Concomitant medication 
 
Abbreviated Behavioural questionnaire 
 
Adherence questionnaire 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs) 
 
SOF/VEL pill count 
 
Post Treatment Follow‐up Visits 
Post Treatment Week 4 (SVR4) ‐ Week 10 (Shortened treatment) or Week 16 (Standard treatment) (+/‐ 3 
days) 
 
LFTs, FBC and biochemistry 
 
Pregnancy test (females of child bearing potential only) 
 
Adverse Events 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs *) 
*To be collected in patients with suspected relapse/reinfection only 
 
Post Treatment Week 12 (SVR12) ‐ Week 18 (Shortened treatment) or Week 24 (Standard treatment) (+/‐ 
14 days) 


 
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 
FibroScan  
 
HCV RNA (Local laboratory) 
 
LFTs, FBC and biochemistry 
 
CD4/CD8 & HIV viral load (HIV positive participants only) 
 
Abbreviated Behavioural questionnaire 
 
Health outcomes survey (EQ‐5D) 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs *) 
*To be collected in patients with suspected relapse/reinfection only 
 
Post Treatment Week 24 (SVR24) ‐ Week 30 (Shortened treatment) or Week 36 (Standard treatment) (+/‐ 
14 days) 
 
FibroScan  
 
HCV RNA (Local laboratory) 
 
LFTs 
 
CD4/CD8 & HIV viral load (HIV positive participants only) 
 
Abbreviated Behavioural questionnaire 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs *) 
*To be collected in patients with suspected relapse/reinfection only 
 
Post Treatment Weeks ‐   42 (FU1), 54 (FU2), 66 (FU3), 78 (FU4) and 90 (FU5) – Shortened treatment or 
 
 
 
 ‐    48 (FU1), 60 (FU2), 72 (FU3), 84 (FU4) and 96 (FU5) – Standard Treatment 
 (+/‐ 28 days) 
 
FibroScan  
 
HCV RNA (Local laboratory) 
 
LFTs 
 
CD4/CD8 & HIV viral load (HIV positive participants only) 
 
Abbreviated Behavioural questionnaire 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs *) 
*To be collected in patients with suspected relapse/reinfection only 
 
Termination Visit   ‐   Week 102 – Shortened treatment or Week 108 – Standard treatment 
 
FibroScan  
 
HCV RNA (Local laboratory) 
 
LFTs 
 
CD4/CD8 & HIV viral load (HIV positive participants only) 
 
Abbreviated Behavioural questionnaire 
 
Research specimen collection (EDTA plasma & ACD Plasma/PBMCs *) 
*To be collected in patients with suspected relapse/reinfection only 
Re‐treatment 
Any participant receiving re‐treatment will have the following parameters collected: 
 
Re‐treatment regimen, dose and duration 
 
Re‐treatment outcome 


 
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6.2 Prevention of Pregnancy 
6.2.1 
Definitions of Childbearing Potential 
 
For the purposes of this study, a female born subject is considered of childbearing potential from menarche 
until becoming post‐menopausal, unless permanently sterile or with medically documented ovarian failure. 
Women are considered to be in a post‐menopausal state when they are > 54 years of age with cessation of 
previously occurring menses for > 12 months without an alternative cause. Permanent sterilization includes 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy in a female subject of any age. 
 
For the purposes of this study, a male born subject is considered fertile after the initiation of puberty unless 
permanently sterile by bilateral orchidectomy or medical documentation. 
 
6.2.2 
Female Participants 
From screening onwards until 30 days after the last dose of SOF/VEL, a female participant and her partner 
must agree to use 2 effective methods of contraception when having sexual intercourse.  
One method must be a non‐hormonal barrier method that prevents transmission of fluids. Acceptable non‐
hormonal barrier methods include male condoms OR female condoms [female and male condoms are not 
to be used both simultaneously as friction between the two can result in damage or breakage of either 
product], diaphragm or cervical cap.  
The other method must be hormonal. Acceptable hormonal contraceptives are the oral contraception pill, 
the hormonal implant, the hormonal injection, the hormonal IUD, the vaginal ring and the transdermal 
contraceptive patch. Other acceptable methods are tubal sterilisation or vasectomy in male partner. 
Systemic  hormonal  contraceptives  (i.e.,  the  pill)  should  be  effective  in  women  taking  SOF/VEL.  No 
significant drug interactions were seen when systemic hormonal contraceptives and SOF or VEL were given 
to women.   
 
6.2.3 
Male Participants 
For a male participant, they must agree not to get a woman pregnant during the study.  A male participant 
who has a female partner of child‐bearing potential must agree to use 2 effective methods of contraception. 
From screening through 30 days after the last dose of SOF/VEL, both the male participant and his female 
partner should use a male condom in combination with another effective method, such as, intrauterine 
device, diaphragm with spermicidal jelly or cervical cap with spermicidal jelly.  
The male participant must agree to inform his sexual partner that he is participating in a research study 
which requires his partner and him to use 2 methods of contraception.   
 
6.3 Study Questionnaires 
All subjects will undertake a number of study questionnaires at screening, baseline, and selected follow‐up 
visits.  
 


 
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The Behavioral Questionnaire  
The study staff will assist participants to complete this questionnaire. The behavioural survey will collect 
information on the following: 
 
Demographics 
 
HIV and drug treatment history  
 
Drug and alcohol usage  
 
Injecting risk behaviours 
 
Sexual risk behaviours   
 
Treatment acceptance and willingness (prior to treatment commencement only) 
 
Attitudes and behaviours associated with HCV reinfection 
An  abbreviated  behavioural  questionnaire  (follow‐up)  will  be  administered  at  subsequent  time  points 
during the study. 
 
Adherence Survey 
Adherence to SOF/VEL will be assessed by two‐weekly structured self‐report adherence questionnaire and 
two‐weekly pill count.  
 
Health Outcomes Survey (EQ‐5D) 
The EQ‐5D health outcome questionnaire provides a simple descriptive profile and a single index value for 
health status. This information can then be translated into a health utility, which can be used for cost‐
effectiveness analyses. 
 
Long‐Acting Hepatitis C Therapy Questionnaire 
The  Long‐Acting  Hepatitis  C  Therapy  Questionnaire  aims  to  obtain  participant  interest  and  attitudes 
towards long‐acting parenteral hepatitis C therapy. The questionnaire collects information on the following 
topics; 
 
Receiving an injection for hepatitis C therapy 
 
Receiving an implant for hepatitis C therapy 
 
Receiving an expanding long acting pill for hepatitis C therapy 
 
Current and past medication use 
 
7 Reinfection follow‐up 
All participants in this study will be followed up to two years for reinfection with three monthly visits. 
Participants who become re‐viraemic following an end of treatment response will be followed monthly for 
six months as per 7.1 Schedule of Assessments ‐ Reinfection. After completing the monthly reinfection 
follow‐up visits, participants will continue to attend three monthly standard follow‐up visits up to two years 
as per the main study Schedule of Assessments.   
 
Please  see  the  following  section  7.1  ‘Schedule  of  Assessments  –  reinfection’  for  study  visits  and 
assessments.  
   


 
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7.1 Schedule of Assessments – Reinfection 
Assessment/Procedure 
Reinfection monthly  follow‐up visits 
Continue 3 monthly FU ‐  
Refer to Arm A or Arm B 
Schedule of Assessments 
Reinfection visit number 
RFU1  RFU2 
RFU3 
RFU4 
RFU5 
RFU6 
Visit Window (Days) 
+/‐ 3  +/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
+/‐ 3 
HCV‐RNA testing (local lab.) 
x 
x 
x 
x 
x 
x 
Liver function tests 
x 
x 
x 
x 
x 
x 
Behavioural questionnaire 
x 
 
x 
 
 
x 
Research Specimen 
Collection 
 
 
 
 
 
 
EDTA plasma (10ml)   
x 
x 
x 
x 
x 
x 
ACD Plasma/PBMCs (60ml) 
x 
x  
x  
x  
x  
x  
 
 
8 Recording and reporting Adverse Events (AEs) 
8.1 Definitions of Adverse Events, Adverse Reactions and Serious Adverse Events  
8.1.1 
Adverse Event Definition 
Adverse events and adverse drug reactions may occur in the course of this study and within the specified 
follow‐up period. These events may also occur in screened participants during the screening period prior 
to enrolment as a result of protocol‐specified interventions. All such events will be recorded at each study 
visit on the adverse event case report form.  
The definition of an adverse event is any untoward medical occurrence in a participant administered with 
a pharmaceutical product which does not necessarily have a causal relationship with the product.  
Pre‐existing conditions or diseases that occur during the study (e.g. seasonal allergies, asthma or recurrent 
headaches) should not be considered as adverse events unless they change in frequency or severity. 
All adverse events encountered during treatment and  for  4 weeks after  drug discontinuation must  be 
reported on the Adverse Event Page of the case report form (CRF). 
Laboratory test abnormalities as such should not be reported as adverse events unless they result in a 
clinically relevant condition including but not limited to modification or discontinuation of study drug. 
Overdoses without clinical sequelae should not be reported as an adverse event. 
 


 
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8.1.2 
Serious Adverse Event (SAE) (including Serious Adverse Drug Reactions) 
The definition of a SAE is any untoward medical occurrence that at any dose:  
1) Results in death 
2) Is life‐threatening 
(Note: the term “life‐threatening” in the definition of “serious” refers to an event/reaction in which 
the  participant  was  at  risk  of  death  at  the  time  of  event/reaction;  it  does  not  refer  to  an 
event/reaction which hypothetically might have caused death if it were more severe) 
3) Requires in‐patient hospitalisation or prolongation of existing hospitalisation 
4) Results in persistent or significant disability/incapacity 
5) Results in a congenital anomaly/birth defect 
6) Results  in  a  medically  important  event  or  reaction  (includes  infections  from  contaminated 
medicinal product/s) 
 
Medical  and  scientific  judgment  should  be  exercised  in  deciding  whether  other  situations  should  be 
considered serious e.g. important medical events that may not be immediately life‐threatening or result in 
death or hospitalisation, but may jeopardise the participant or may require intervention to prevent one of 
the outcomes listed in the definition above.  
8.1.3 
Special Situation Report (SSR) 
Special Situation Reports are defined as:  
a) Pregnancy Reports 
b) Reports of Medication Abuse, Error, Misuse, Off‐label Use or Overdose  
c) Lack of Effect Reports 
d) Reports of AEs in infants following exposure from breastfeeding 
e) Reports of AEs associated with Product Complaints or arising from Occupational Exposure 
 
 
8.2 Assessment of Adverse Events and Serious Adverse Events 
8.2.1 
Assessment of Causality for Study Drugs and Procedures 
The investigator or designee must assess each adverse event for the following: 
 
Relationship 
Unlikely: 
An adverse event that is unlikely to be related to the use of the drug or procedures 
Possibly: 
 An adverse event that might be related to the use of the drug or procedures 
Probably: 
 An adverse event that is likely to be related to the use of the drug or procedures 
  
8.2.2 
Assessment of Severity 
The investigator or designee must assess each adverse event for the following: 
 
Severity 
Mild: 
 
 
Discomfort noticed but no disruption of normal daily activity 
Moderate: 
 
Discomfort sufficient to reduce or affect normal daily activity 


 
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Severe:  
 
Incapacitating with inability to work or perform normal daily activity 
Life threatening: 
Represents an immediate threat to life 
 
8.3 Reporting Requirements 
8.3.1 
Adverse Events  
All adverse events from the date of signing the consent form until four weeks after the last dose of study 
drug administration should be reported on the case report form. 
Coding 
Adverse events will be assigned preferred terms and categorised into system organ classes according to the 
Medical Dictionary for Drug Regulatory Affairs (MedDRA) classification of the WHO terminology. 
 
8.3.2 
Serious Adverse Events  
All serious adverse events (SAEs) should be reported within 24 hours to the Kirby Institute and Gilead DPSH 
by email or fax on the Serious Adverse Event Reporting Form. Reports should be followed promptly by 
detailed, written follow‐up reports when all information is not included in the initial report. Follow‐up 
reports should be reported within ONE WORKING DAY also. The immediate and follow up reports should 
identify  participants  by  unique  code  numbers  assigned  to  study  participants  rather  than  personal 
identification. The investigator must also comply with all applicable ethical and regulatory requirement/s 
relating to the reporting of serious adverse events.  
 
Any serious adverse event that is ongoing at the post‐study follow‐up visit must be followed until resolution 
or until the event stabilizes (for those events that will not resolve). 
 
For deaths, the Principal Investigator will supply the sponsor and the IRB/IEC with any additional requested 
information (e.g. death certificate, autopsy reports and medical reports). 
 
All SAEs must be reported in English and be submitted to BOTH the Kirby Institute AND Gilead: 
Kirby Institute:  Email:   reactvh@kirby.unsw.edu.au 
Fax: 
+61 2 9385‐9214. 
Gilead DSPH:   Email:   Safety_FC@gilead.com 
 
 
Fax:  
+1 650‐522‐5477 
 
8.3.3 
Special Situation Reports 
All SSRs  must be reported  in English  using the SAE  Reporting  Form  and  submitted to BOTH the Kirby 
Institute AND Gilead within 15 calendar days of first becoming aware of any such safety information and 
in accordance with applicable laws, rules, regulations and guidance: 


 
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Kirby Institute:  Email:   reactvh@kirby.unsw.edu.au  
Fax: 
+61 2 9385‐9214 
Gilead DSPH:   Email:   Safety_FC@gilead.com 
 
 
Fax:  
+1 650‐522‐5477 
 
8.3.4 
Suspected Unexpected Serious Adverse Reaction (SUSAR)  
The definition of a SUSAR is a serious adverse event which is both suspected as being related to the drug 
(i.e. has a reasonable suspected causal relationship and is unexpected) and where the nature and severity 
is not consistent with known information (e.g. the Investigator’s Brochure).  
The sponsor must expedite the reporting of all SUSARs to all concerned investigators/institutions, IRB/IEC/s, 
and  regulatory  authorities  within  the  reporting  timeframe.  Reports  must  comply  with  the  applicable 
regulatory requirements and ICH Guideline for Clinical Safety Data Management: Definitions and Standards 
for Expedited Reporting.  
Researchers must inform the IRB/IEC and regulatory authorities of all SUSARs that occur during the study 
that may affect the conduct of the study or the safety of the participants or their willingness to continue 
participation in the study. Researchers must inform the IRB/IEC as soon as possible of any new information 
from  other  published  or  unpublished  studies  which  may  have  an  impact  on  the  continued  ethical 
acceptability of the study or which may indicate the need for amendments to the study protocol. 
 
9 Packaging, labeling, storage and accountability of clinical trial supplies 
All study drugs will be provided by Gilead Sciences, Inc and should be dispensed under the supervision of 
the investigator or a qualified member of the investigational staff, or by a hospital/clinic pharmacist.  
Returned  study  drug  must  not  be dispensed  again, even  to the  same  subject.  Study  drug  may  not  be 
relabeled or reassigned for use by other subjects.  
A designated person at the study site must receive clinical trial supplies. That person must check that the 
supplies are in good condition and are complete as per the shipping records. Drugs must be stored in a 
secure location with limited access. Clinical trial supplies must only be dispensed according to the protocol 
and records must be kept detailing supplies received, dispensed to the participant, returned from the 
participant and returned to the sponsor or destroyed at site, as applicable. Participants will be instructed 
to return all study drug containers (including empty ones) to the site staff during the course of the study 
and all containers must be retained for review by the sponsor’s monitor until the end of the study. 
Study staff responsible for accountability and dispensing must not open and count clinical trial supplies 
prior to dispensing.  
9.1 Formulation  
The SOF/VEL (400mg/100mg) tablets are pink, diamond shaped, film‐coated tablets, debossed with “GSI” 
on one side and “7916” on the other side. In addition to the active ingredient, SOF/VEL tables also contain 
the  following  inactive  ingredients:  copovidone,  microcrystalline  cellulose,  croscarmellose  sodium, 
magnesium stearate, polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and iron oxide red. 


 
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9.2 Packaging and Labelling 
SOF/VEL 400mg/100mg tablets are packaged in bottles of 14 tablets. 
9.3 Storage and handling 
SOF/VEL should be stored at controlled room temperature until required for administration. Controlled 
room temperature is defined at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F to 86°F).  
Subjects should be counselled to store SOF/VEL at room temperature not in the refrigerator.  
All drug products should be stored in a securely locked area, assessable only to authorized site personnel. 
To ensure the stability of the study drug and to ensure proper product identification, the drug product 
should not be stored in a container other than the container in which they are supplied. 
9.4 Dosage and administration 
SOF/VEL is to be administered once daily with or without food. Each subject must be given instructions to 
maintain approximately the same daily dosing interval between study drug doses.  Subjects should be 
instructed to swallow the study medication tablet whole. Subjects should be instructed to only remove the 
tablet immediately prior to dosing.  
For a missed dose of study medication, subjects should be instructed to take the missed dose of study 
medication as soon as possible during the same day. However, no more than the daily dose of SOF/VEL 
should be taken on any calendar day. Subjects should be cautioned never to double the next dose with a 
missed dose of study drug under any circumstances.  
 
10 Biological samples 
10.1 
Laboratory supplies and sample processing 
Laboratory supplies for collection of research specimens (plasma, whole blood and) will be supplied by the 
Kirby Institute.  
The following blood samples will be collected as time point specified in the schedule of assessments: 
1. 10 mL EDTA plasma for HCV RNA testing and future HCV related research (20ml at screening 
and baseline); 
2. 4mL  Whole  Blood  for  human  genomic  DNA  analysis  collected  from  the  screening  and 
baseline EDTA plasma samples; 
3. 60 ml ACD plasma / PBMCs  
Samples will be collected by sites and then processed and stored at ‐80°C (‐200°C for PBMCs) at the site 
local laboratory for bulk shipment to the Kirby Institute laboratory. Detailed sample processing instructions 
will be provided in the laboratory manual. 
 
EDTA plasma samples will be used for study endpoint analysis. HCV viral load will be measured using in‐
house and commercial assays. Sequencing of the viral genome will also be performed as a more accurate 
means of genotyping. Viral sequences may also be used to distinguish relapse from reinfection, to examine 
the  prevalence  of  mixed  infection,  to  look  at  the  prevalence  and  emergence  of  resistance  associated 
variants (RAVs) and for phylogenetic analysis. EDTA plasma may also be used for drug level monitoring.   
 


 
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PBMCs and whole blood samples may be used to examine host factors associated with viral clearance, 
including but not limited to HLA Type, IL28‐B, ISG expression, IP‐10 and other biomarkers.   
10.2 
Shipping of biological samples 
Samples  must  only  be  shipped  to  the  Kirby  Institute  laboratory  on  the  instruction  from  the  Study 
Coordinator.  
 
It is the responsibility of each site Principal Investigator to ensure that all site staff handling, packaging, 
and/or shipping biological samples understand and comply with International Air Transport Association 
(IATA) regulations relating to the handling and shipping of hazardous goods and/or diagnostic specimens. 
10.3 
Future use of biological samples 
After the  samples  have  been analysed  for the  study endpoints as  specified in the protocol, remaining 
samples will be stored for use in future Human Research Ethics Committee approved hepatitis C related 
research. Additional consent will not be sought for this storage and future use. It is not optional. Subjects 
not wishing to have their samples stored or used in future hepatitis C related research will not be eligible 
to participate in this study. 
 
11 Statistics 
11.1 
Sample size 
The primary objective of this trial is to establish the non‐inferiority of short duration treatment (6 weeks) 
to the standard duration treatment (12 weeks).   
 
Assuming an expected SVR of 90% in the control arm, 113 participants per arm will be required to give 80% 
chance that the two sided confidence interval of the difference between regimens has a lower limit greater 
than ‐12%.   
 
A total of 250 subjects enrolled and randomised will comprise the intention‐to‐treat (ITT) population and 
will form the study population for evaluation of the primary and secondary endpoints. 
11.2 
Assessments of Safety and Efficacy 
The primary analysis will summarise study variables when the last patient recruited has completed 12 
weeks follow‐up post treatment. This analysis will be reviewed by the Protocol Steering Committee and 
then presented publicly. Subsequent analyses will be performed up until and at time that the last patient 
has completed study follow up (or discontinued from the study).  
 
This is a multicentre, randomised study aiming to demonstrate non‐inferiority of a 6 week as compared 
with a 12 week course of sofosbuvir/velpatasvir for recent HCV infection.   
 
Primary endpoint: 
The primary endpoint is the proportion of participants with HCV RNA below the level of quantitation (target 
not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12) 
Secondary endpoints: 


 
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 
Secondary virological endpoints 
o The proportion of participants with: 
 
ETR defined as HCV RNA below the level of quantitation at end of therapy 
 
SVR 4 defined as HCV RNA below the level of quantitation 4 weeks post therapy 
 
SVR 24 defined as HCV RNA below the level of quantitation 24 weeks post therapy  
 
HCV RNA below the level of quantitation through 2 years post treatment 
Results will be stratified by HCV genotype and HIV‐coinfection.  
 
80/80  adherence:  Defined  as  the  receipt  of  >80%  of  scheduled  doses  for  >80%  of  the  scheduled 
treatment period.  
 
90/90  adherence:  Defined  as  the  receipt  of  >90%  of  scheduled  doses  for  >90%  of  the  scheduled 
treatment period.  
 
100/100 adherence: Defined as the receipt of 100% of scheduled doses for 100% of the scheduled 
treatment period.  
 
On‐treatment  adherence:  Calculated  by  subtracting  the  number  of  missed  doses  from  the  total 
number of doses of scheduled treatment and dividing by the total intended therapy duration. This 
measures the proportion of doses received from the time that treatment was initiated until treatment 
was discontinued or completed. 
 
Toxicity: Proportion of participants with at least one severe or potentially life threatening (grade 3 or 
4) adverse event. 
 
Early treatment discontinuation: Discontinuation of therapy prior to the per‐protocol planned end of 
treatment (6 or 12 weeks depending on study arm).  
 
Resistance associated variants (RAVs): The proportion of treated subjects with development of RAVs 
following virological relapse or breakthrough. 
 
Reinfection rate: Rates of HCV reinfection will be calculated using person‐time of observation during 
and up to 48 months following end of treatment. 
 
Baseline characteristics, on‐treatment adherence, risk behaviours and toxicity will be evaluated among 
subjects withdrawing prior to randomisation.   
 
11.3 
Analyses 
Efficacy analyses: 
There will be one primary pair‐wise comparison of the efficacy endpoints: shortened duration therapy 
versus  standard  duration  therapy.  Comparisons  will  be  simple,  direct  two‐sample  comparisons  of 
randomised  treatment  groups  unadjusted  for  baseline  covariates.  If  there  is  evidence  of  substantial 
imbalance at baseline in important covariates, further adjusted analyses will also be performed. If any 
randomisation mistakes occur, such that patients incorrectly receive the wrong treatment, then key efficacy 
endpoints will be performed where these patients will be excluded. 
 
The primary analysis will compare randomised treatment groups on an ITT basis including all available data. 
The primary endpoint, SVR12, will be calculated for each patient based on all available data.  Treatment 
arms will be regarded as non‐inferior if the difference in proportion between regimens has a lower limit 
greater than ‐12%.  Secondary analyses will compare randomised treatment groups based on available data 
(per protocol). 
 


 
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Proportions and 95% confidence intervals will be reported for both the primary and secondary virological 
endpoints. These will be provided overall, by treatment duration, by HCV genotype and by HIV status, and 
will be assessed for both the ITT and PP populations. 
 
SVR 4, SVR 12 and SVR 24 rates will be compared to SVR rates demonstrated in historical controls in the 
ATAHC I, ATAHC II, DARE‐C I and DARE‐C II studies. Differences in proportions between studies will be 
summarised as n (%) in each group, with percent difference between cohorts with 95% confidence interval. 
 
Factors associated with ITT study population treatment efficacy will be evaluated by univariate analysis, 
and will include, but are not limited to, the following variables: socio‐demographic factors (age, gender, 
ethnicity); virological factors (baseline HCV viral load, HCV genotype); risk behaviors (injecting drug use, 
sexual behaviour); and HIV co‐infection.  
 
Additional  treatment  efficacy  evaluations  will  be  conducted  among  the  per  protocol  study  population, 
defined as subjects who receive >80% of planned treatment. 
 
The impact of 80/80 adherence, 90/90 adherence, 100/100 adherence, on‐treatment adherence and early 
discontinuation on SVR will also be evaluated.  
 
To  assess  HCV  reinfection,  among  people  with  virological  suppression,  participants  with  HCV  RNA 
recurrence  (detectable  HCV  RNA  following  HCV  virological  suppression)  will  be  identified.  HCV  RNA 
sequencing will be performed on the first available detectable HCV RNA sample and the first available 
detectable HCV RNA sample following HCV RNA recurrence. HCV reinfection will be defined by the detection 
of infection with an HCV strain which was distinct from the primary infecting strain based on previously 
defined genetic distance‐based cut‐offs for HCV reinfection and HCV viral relapse(72), patristic distance‐
based cut‐offs and phylogenetic tree construction (86). Rates of HCV reinfection will be calculated using 
person‐time of observation up to 48 months following the end of treatment. Modified intention‐to‐treat 
analyses will also be performed in which individuals with confirmed reinfection are removed from the 
efficacy analysis.  
 
Immunological and virological assays will also be performed to assess the impact of HCV treatment on 
immune responses during treatment.  
 
A final full statistical analysis plan will be written and signed off by the Protocol Steering Committee prior 
to final study data lock. 
12 Data Safety and Monitoring Board (DSMB) 
A  data  safety  and  monitoring  board  (DSMB)  will  consist  of  at  least  1  statistician  and  2  practicing 
gastroenterologist/infectious diseases specialists. All DSMB members will be independent of the study and 
the Kirby Institute. The meeting will include the interim efficacy and safety analysis which will be performed 
when the first 50 subjects in each arm have either received treatment and completed 12 weeks of follow‐
up post treatment (SVR12) or dropped out of the study. Additional DSMB meetings will be scheduled at a 
frequency commensurate with the risk as determined by the DSMB. 
 


 
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The Principal Investigator and the institution where the study will be conducted will permit study‐related 
monitoring, audits, ethics committee review and regulatory inspection providing direct access to source 
documents. 
Data  will  be  collected  on  study  specific  electronic  or  paper  copy  case  record  forms.  The  Principal 
Investigator is responsible for ensuring the data collected are complete, accurate and recorded in a timely 
manner.  
 
13 Data collection, source documents and record retention 
13.1 
Submission of data 
Electronic CRFs: following each participant visit the designated site staff will complete the visit specific 
eCRF. Once all required information is received the eCRF shall be considered complete. Project Team 
staff will then monitor the data for completeness and accuracy. Any eCRF discrepancies, either manual 
or automatic, will be addressed with the site staff for clarification. 
The site Principal Investigator is responsible for ensuring the completion of accurate source documentation 
to support data collected on case report forms. Source documents include all recordings of observations or 
notations of clinical activities and all reports and records necessary for the evaluation and reconstruction 
of  the  trial.  Source  documents  include,  but  are not  limited  to;  participant  medical  records,  laboratory 
reports, ECG tracings, X‐rays, radiologist reports, participant diaries, biopsy reports, ultrasound images, 
participant progress notes, pharmacy records and any other reports or records of procedures performed in 
accordance with the protocol.  
It is not acceptable for the CRF to be the only record of study participation and progress must also be 
recorded in the each person’s medical record. This is to ensure that anyone accessing the medical record 
has adequate knowledge that the person is a clinical trial participant. 
Any document that acts as a source document (the point of the initial recording of a piece of data) should 
be signed and dated by the person recording or reviewing the data for issues of medical significance (for 
example the review of laboratory reports). Persons signing the source documents must be listed as a site 
staff member. 
The sponsor’s monitor will visit sites to conduct source document verification. The number of visits will 
depend upon study complexity and recruitment rate; however, the monitor will conduct a minimum of two 
source data verification visits during the study. These should occur shortly after enrolment of the first 
participant(s) and following completion of all study visits. 
The Principal Investigator is responsible for retaining all essential documents listed in ICH Good Clinical 
Practice guidelines. These must be organised in a comprehensive filing system that is accessible to study 
monitors and other relevant personnel. 
13.2 
Linkage of data ‐ Applicable to Australian Sites Only 
At a later date, the study data may be linked with public registries such as the National Notifiable Diseases 
Database, hospital morbidity databases, cancer and death registries and future research databases. 
 


 
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13.3 
Archiving  
The Principal Investigator is responsible for ensuring all study documents are retained for a minimum of 15 
years following completion and publication of the study. 
 
14 Ethics committee/regulatory approval and informed consent 
The sponsor is responsible for ensuring regulatory approval for the study is obtained. 
The site Principal Investigator is responsible for obtaining IRB/EC approval for the protocol and participant 
information and informed consent form in compliance with local regulatory requirements prior to entering 
any participant into the study. The approval letter/document must clearly identify the protocol and all 
documents  approved  by  the  IRB/EC  including  version  number  &  date  of  the  protocol  and  participant 
information and consent form. A copy of the approval document must be sent to the study sponsor.  
The site Principal Investigator must also obtain approval for any amendments to the protocol or participant 
information and informed consent form. The Principal Investigator must comply with all IRB/EC reporting 
requirements for all adverse events, annual updates and end of study reports and must agree to abide by 
any IRB/EC conditions of approval. 
The site Principal Investigator (or designee) is responsible for ensuring freely‐given consent is obtained from 
each  potential  participant  prior  to  the  conduct  of  any  protocol‐specific  procedures.  The  Principal 
Investigator  may  delegate  the  task  of  obtaining  consent  to  appropriately  qualified  Sub‐investigator(s). 
Consent must be documented by the participant’s dated signature on the participant information and 
consent form together with the dated signature of the person conducting the consent discussion.  
A copy of the signed and dated participant information and consent form must be given to the person prior 
to study participation. The participant or their legally authorised representative must be informed in a 
timely manner of any new information that becomes available during the course of the study that may 
affect his/her willingness to continue study participation. 
This study shall be conducted in accordance with the ethical principles laid out in the Declaration of Helsinki 
(most current issued version) and the National Statement on Ethical Conduct in Research Involving Humans 
(most current issued version). 
15 Confidentiality of data 
15.1 
Confidentiality of participant records 
By signing the Clinical Trial Agreement, the site Principal Investigator agrees that the sponsor, IRB/EC or 
regulatory authorities may consult and/or copy study documents to verify information in the case report 
form. By signing the consent form the participant agrees to these processes. The following wording may be 
included in the protocol. 
Participant confidentiality will be maintained at all times and no documents containing the participant’s 
name or other identifying information will be collected by the sponsor. It may be necessary for the sponsor’s 
representatives,  the  IRB/EC  and  regulatory  authority  representatives  to  have  direct  access  to  the 
participant’s medical records. If study documents need to be photocopied during the process of verifying 
case  report  form  data,  the  participant  will  be  identified  by  a  unique  code  only;  full  names  and  other 
identifying information will be masked.  


 
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15.2 
Confidentiality of study data 
By signing the Clinical Trial Agreement, the site Principal Investigator affirms to the sponsor that information 
provided to them by the sponsor will be maintained in confidence and divulged only as necessary to the 
ethics committee and institution employees directly involved in the study. Both ethics committee members 
and employees must also understand the confidentiality requirements for any information divulged to 
them. The data generated by this study will be considered confidential, except where it is included in a 
publication as agreed in the publication policy of this protocol. 
 
At sites where regulations restrict the collection of full date of birth and/or initials the following conventions 
will be used: 
 
 
Date of birth will be entered as 01/01/YYYY 
 
Initials will be entered as AA‐AA, BB‐BB, CC‐CC etc.  
 
16 Governance 
The study is sponsored by UNSW and coordinated through the Kirby Institute for infection and immunity in 
society. It is funded by the University of New South Wales (UNSW) and Gilead Sciences Inc. The study drugs 
will be provided by Gilead Sciences Inc. The Kirby Institute has established governance and implementation 
structures which use resources efficiently to deliver program objectives on schedule. 
 
17 Quality Control (QC) and Quality Assurance (QA) 
The  sponsor  agrees  to  be  responsible  for  implementing  and  maintaining  quality  control  and  quality 
assurance systems with written standard operating procedures to ensure the study is conducted and data 
are generated, documented and reported in compliance with the protocol, Good Clinical Practice standards 
and all applicable local laws and regulations relating to the conduct of a clinical trial. 
 
18 Publication Policy 
The results of this study may be published and presented at scientific meetings. Publication of data derived 
from this protocol will be governed by the Protocol Steering Committee. All published data will be non‐
identifiable grouped data.  
 
 
19 List of References 
1. 
Mohd Hanafiah K, Groeger J, Flaxman AD, Wiersma ST. Global epidemiology of hepatitis 
C virus infection: new estimates of age-specific antibody to HCV seroprevalence. Hepatology. 
2013;57(4):1333-42. 
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Nelson PK, Mathers BM, Cowie B, Hagan H, Des Jarlais D, Horyniak D, et al. Global 
epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic 
reviews. Lancet. 2011;378(9791):571-83. 
3. 
Hajarizadeh B, Grebely J, Dore GJ. Epidemiology and natural history of HCV infection. 
Nature reviews Gastroenterology & hepatology. 2013;10(9):553-62. 


 
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4. 
Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, et al. Sofosbuvir and ledipasvir 
fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients 
with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. 
The Lancet. 2014;383(9916):515-23. 
5. 
Poordad F, Hezode C, Trinh R, Kowdley KV, Zeuzem S, Agarwal K, et al. ABT-450/r-
ombitasvir and dasabuvir with ribavirin for hepatitis C with cirrhosis. The New England journal of 
medicine. 2014;370(21):1973-82. 
6. 
Jacobson IM, Gordon SC, Kowdley KV, Yoshida EM, Rodriguez-Torres M, Sulkowski MS, 
et al. Sofosbuvir for hepatitis C genotype 2 or 3 in patients without treatment options. The New 
England journal of medicine. 2013;368(20):1867-77. 
7. 
Osinusi A, Meissner EG, Lee YJ, Bon D, Heytens L, Nelson A, et al. Sofosbuvir and 
ribavirin for hepatitis C genotype 1 in patients with unfavorable treatment characteristics: a 
randomized clinical trial. JAMA : the journal of the American Medical Association. 
2013;310(8):804-11. 
8. 
Forns X, Charlton M, Denning J, McHutchison JG, Symonds WT, Brainard D, et al. 
Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C following liver 
transplantation. Hepatology (Baltimore, Md). 2014. 
9. 
McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, et al. 
Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 
2009;360(18):1827-38. 
10. 
Hezode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and 
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2009;360(18):1839-50. 
11. 
McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, et al. 
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Suryaprasad AG, White JZ, Xu F, Eichler BA, Hamilton J, Patel A, et al. Emerging epidemic 
of hepatitis C virus infections among young nonurban persons who inject drugs in the United States, 
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Muhlberger N, Schwarzer R, Lettmeier B, Sroczynski G, Zeuzem S, Siebert U. HCV-related 
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Maher L, Jalaludin B, Chant KG, Jayasuriya R, Sladden T, Kaldor JM, et al. Incidence and 
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Tracy D, Hahn JA, Fuller Lewis C, Evans J, Briceno A, Morris MD, et al. Higher risk of 
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Hahn JA, Page-Shafer K, Lum PJ, Bourgois P, Stein E, Evans JL, et al. Hepatitis C virus 
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Matthews GV, Pham ST, Hellard M, Grebely J, Zhang L, Oon A, et al. Patterns and 
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Danta M, Brown D, Bhagani S, Pybus OG, Sabin CA, Nelson M, et al. Recent epidemic of 
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Lawitz E, Lalezari JP, Hassanein T, Kowdley KV, Poordad FF, Sheikh AM, et al. Sofosbuvir 
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Gane EJ, Stedman CA, Hyland RH, Ding X, Svarovskaia E, Symonds WT, et al. Nucleotide 
polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C. The New England journal of 
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Lawitz E, Mangia A, Wyles D, Rodriguez-Torres M, Hassanein T, Gordon SC, et al. 
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37. 
Sulkowski M, Rodriguez-Torres M, Lalezari J, Fessel WJ, Mounzer K, Shuhart M, et al. 
All-Oral Therapy With Sofosbuvir Plus Ribavirin For the Treatment of HCV Genotype 1, 2, and 3 
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38. 
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39. 
Wyles DL, Ruane PJ, Sulkowski MS, Dieterich D, Luetkemeyer A, Morgan TR, et al. 
Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. New England Journal of 
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40. 
Everson GT, Tran TT, Towner WJ, Davis MN, Wyles D, Nahass R, et al. Safety and Efficacy 
of Treatment With Interferon-Free, Ribavirin-Free Combination of Sofosbuvir + GS-5816 for 12 
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41. 
Tran TT, Morgan TR, Thuluvath PJ, Etz-korn K, Hinestrosa F, Tong M, et al. Safety and 
Efficacy of Treatment with Sofosbu-vir+GS-5816±Ribavirin for 8 or 12 Weeks in Treatment Naïve 
Patients with Genotype 1-6 HCV Infection [ABSTRACT #80].  The 65th Annual Meeting of the 
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Gane EJ, Hyland RH, An D, McNally J, Brainard DM, Symonds WT, et al. Once Daily 
Sofosbuvir with GS-5816 for 8 Weeks with or without Ribavirin In Patients with HCV Genotype 3 
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The 65th Annual Meeting of the American Association for the Study of Liver Diseases; Boston, 
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Svarovskaia E, Dvory H, Hebner C, Doehle B, Gontcharova V, Martin R, et al. No resistance 
detected in four phase 3 clinical studies in HCV genotype 1–6 of sofosbuvir + ribavirin with or 
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44. 
Svarovskaia ES, Dvory-Sobol H, Gontcharova V, Chiu S, Hebner C, Hyland RH, et al. 
Comprehensive Resistance Testing in Patients Who Relapsed after Treatment with Sofosbuvir (GS-
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45. 
Gane EJ, Hyland RH, An D, Pang PS, Symonds WT, Mchutchison JG, et al. 
Sofosbuvir/ledipasvir fixed dose combination is safe and effective in difficult-to-treat populations 
including genotype-3 patients, decompensation genotype-1 patients and genotype-1 patients with 
prior sofosbuvir treatment experience. Journal of hepatology. 2014;60:S3. 
46. 
Esteban R, Nyberg L, Lalezari J, Ni L, Doehle B, Kanwar B, et al. Successful retreatment 
with sofosbuvir-containing regimens for HCV genotype 2 or 3 infected patients who failed prior 
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of acute hepatitis C with interferon alfa-2b. New England Journal of Medicine. 2001;345(20):1452-
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50. 
Nomura H, Sou S, Tanimoto H, Nagahama T, Kimura Y, Hayashi J, et al. Short-term 
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Santantonio T, Fasano M, Sinisi E, Guastadisegni A, Casalino C, Mazzola M, et al. Efficacy 
of a 24-week course of PEG-interferon alpha-2b monotherapy in patients with acute hepatitis C after 
failure of spontaneous clearance. Journal of hepatology. 2005;42(3):329-33. 
52. 
Delwaide J, Bourgeois N, Gérard C, De Maeght S, Mokaddem F, Wain E, et al. Treatment 
of acute hepatitis C with interferon α-2b: early initiation of treatment is the most effective predictive 
factor of sustained viral response. Alimentary Pharmacology & Therapeutics. 2004;20(1):15-22. 
53. 
Wiegand J, Buggisch P, Boecher W, Zeuzem S, Gelbmann CM, Berg T, et al. Early 
monotherapy with pegylated interferon alpha-2b for acute hepatitis C infection: the HEP-NET 
acute-HCV-II study. Hepatology (Baltimore, Md). 2006;43(2):250-6. 
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Santantonio T, Fasano M, Sagnelli E, Tundo P, Babudieri S, Fabris P, et al. Acute hepatitis 
C: a 24-week course of pegylated interferon alpha-2b versus a 12-week course of pegylated 
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57. 
Grebely J, Hellard M, Applegate T, Petoumenos K, Yeung B, Feld JJ, et al. Virological 
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interferon-alpha therapy are higher in intravenous drug users than in other patients with acute 
hepatitis C. Journal of hepatology. 2005;42(3):323-8. 
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De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Calleri G, et al. Twelve-
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Dore GJ, Hellard M, Matthews GV, Grebely J, Haber PS, Petoumenos K, et al. Effective 
Treatment of Injecting Drug Users With Recently Acquired Hepatitis C Virus Infection. 
Gastroenterology. 2010;138(1):123-35. 
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course of pegylated interferon-alpha in acute HCV hepatitis. Journal of viral hepatitis. 
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62. 
Edlin BR, Kresina TF, Raymond DB, Carden MR, Gourevitch MN, Rich JD, et al. 
Overcoming barriers to prevention, care, and treatment of hepatitis C in illicit drug users. Clinical 
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63. 
Boesecke C, van Assen S, Stellbrink HJ, Baumgarten A, Ingiliz P, Strassburg CP, et al. 
Peginterferon-alfa mono-therapy in the treatment of acute hepatitis C in HIV-infection. Journal of 
viral hepatitis. 2014;21(11):780-5. 
64. 
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hepatitis C in HIV-infected individuals: recommendations from the European AIDS Treatment 
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65. 
Kamal SM, Moustafa KN, Chen J, Fehr J, Abdel Moneim A, Khalifa KE, et al. Duration of 
peginterferon therapy in acute hepatitis C: a randomized trial. Hepatology. 2006;43(5):923-31. 
66. 
De Rosa FG, Bargiacchi O, Audagnotto S, Garazzino S, Cariti G, Raiteri R, et al. Dose-
dependent and genotype-independent sustained virological response of a 12 week pegylated 
interferon alpha-2b treatment for acute hepatitis C. The Journal of antimicrobial chemotherapy. 
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Martinello M, Hellard M, Shaw D, Petoumenos K, Applegate TL, Grebely J, et al. Short 
duration response-guided treatment is effective for most individuals with recent hepatitis C 
infection: the ATAHC II Study. Hepatology (Baltimore, Md). 2014;60:661a-2a. 
68. 
Kohli A, Z S, A N. Combination oral, hepatitis C antiviral therapy for 6 or 12 weeks: final 
results of the SYNERGY trial.  Conference on Retroviruses and Opportunistic Infections; March 3-
6, 2014; Boston2014. 
69. 
Fierer DS, Dieterich DT, Mullen MP, Branch AD, Uriel AJ, Carriero DC, et al. Telaprevir 
in the treatment of acute hepatitis C virus infection in HIV-infected men. Clinical infectious diseases 
: an official publication of the Infectious Diseases Society of America. 2014;58(6):873-9. 
70. 
Hezode C, Fontaine H, Dorival C, Larrey D, Zoulim F, Canva V, et al. Triple therapy in 
treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early 
Access Programme (ANRS CO20-CUPIC) - NCT01514890. Journal of hepatology. 
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71. 
Maasoumy B, Port K, Deterding K, Honer Zu Siederdissen C, Markova AA, Rogalska-
Taranta M, et al. Limited effectiveness and safety profile of protease inhibitor-based triple therapy 
against chronic hepatitis C in a real-world cohort with a high proportion of advanced liver disease. 
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72. 
Grebely J, Pham ST, Matthews GV, Petoumenos K, Bull RA, Yeung B, et al. Hepatitis C 
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73. 
Doyle J, Shaw D, Dore G, Grebely J, Erratt A, Hellard M, et al. Low rates of re-infection 
and reduced injecting long-term following recently acquired HCV in the Australian trial of acute 
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Aspinall EJ, Corson S, Doyle JS, Grebely J, Hutchinson SJ, Dore GJ, et al. Treatment of 
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Hill A, Simmons B, Saleem J, Cooke G. Risk of Late Relapse or Re-infection with Hepatitis 
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Page K, Hahn JA, Evans J, Shiboski S, Lum P, Delwart E, et al. Acute hepatitis C virus 
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20 Abbreviations List 
 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
DAA 
Direct Acting Antiviral 
End of treatment 
Date of last dose of treatment 
ETR 
End  of  Treatment  Response,  undetectable  HCV  RNA  at  the  completion  of 
treatment 
FBC 
Full Blood Count (haemoglobin, WCC including differentials, platelets) 
HCV 
Hepatitis C Virus 
HCV RNA re‐
viraemia  
Detection of the hepatitis C virus again following an end of treatment response  
HIV 
Human Immunodeficiency Virus 
IDUs 
Injection Drug Users 
INR 
International Normalized Ratio 
LFTs 
Liver  Function  Tests  –  albumin,  ALT,  AST,  alkaline  phosphatase,  GGT,  total 
bilirubin, total protein 
LLOQ 
Lower Limit Of Quantification 
GGT 
Gamma Glutamic Transpeptidase 
Hgb 
Haemoglobin 
PEG‐IFN 
Pegylated interferon alfa 2a 
PWID 
People Who Inject Drugs 
Superinfection 
Detection of infection with an HCV strain which was distinct from the primary 
infecting strain in those with HCV virological persistence  
Reinfection  
Detection of infection with an HCV strain which was distinct from the primary 
infecting  strain  among  participants  with  either  spontaneous  or  treatment‐
induced HCV virological suppression (≤15 IU/ml on Roche TaqMan). 
RAV  
Resistance‐associated variants  
RVR 
Rapid Virological Response, HCV RNA undetectable at week 4 of treatment 
vRVR 
Very Rapid Virological Response, HCV RNA undetectable at week 2 of treatment 
SOF 
Sofosbuvir 
SVR4 
Sustained Virological Response, HCV RNA undetectable 4 weeks post‐treatment 
SVR12 
Sustained Virological Response, HCV RNA undetectable 12 weeks post‐treatment 
SVR24 
Sustained Virological Response, HCV RNA undetectable 24 weeks post‐treatment 
TND 
Target not detected (HCV RNA below the level of quantitation) 
TDnq 
Target detected, not quantifiable (HCV RNA detected but not quantifiable) 
Undetectable  HCV 
RNA 
HCV RNA results that are <15 IU/ml (non‐quantifiable), but “detectable” will be 
considered as undetectable HCV RNA  
VEL 
Velpatasvir 
WCC 
White Cell Count 
 
 
 

SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
A randomised study of interferon-free treatment for recently 
acquired hepatitis C in people who inject drugs and people with HIV 
co-infection 
 
Study Title: 
A randomised study of interferon-free treatment for recently 
acquired hepatitis C in people who inject drugs and people with 
HIV co-infection 
Name of Study Drug: 
sofosbuvir/velpatasvir 
Protocol Number: 
VHCRP1401 
Protocol Version: 
5.0 
Protocol Date: 
4 June 2019 
Co-ordinating Principal Investigators: 
A/Professor Gail Matthews 
Name/s of Sponsor: 
UNSW Sydney 
Analysis Type: 
Primary – SVR12  
Analysis Plan Version: 
Final V1.0  
Analysis Plan Date: 
September 2019 
Analysis Plan Author: 
Kathy Petoumenos 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Contents 
LIST OF ABBREVIATIONS ......................................................................................................................... 3 
STUDY DEFINITIONS ................................................................................................................................ 4 
STUDY DESIGN AND OBJECTIVES ............................................................................................................ 5 
Study Objectives ................................................................................................................................. 5 
Hypothesis .......................................................................................................................................... 5 
Study design (Figure 1) ....................................................................................................................... 5 
Sample size and power ...................................................................................................................... 6 
TYPE OF ANALYSIS ................................................................................................................................... 7 
Data Safety and Monitoring Board (DSMB) Analysis ........................................................................ 7 
Primary analysis: Post-treatment week 12 ....................................................................................... 7 
GENERAL CONSIDERATIONS FOR DATA ANALYSES ................................................................................. 8 
Statistical Methods ............................................................................................................................ 8 
Analysis Sets ....................................................................................................................................... 8 
Data Handling Conventions ............................................................................................................... 9 
Missing Data ................................................................................................................................... 9 
Outliers ........................................................................................................................................... 9 
Data Handling Conventions and Transformations .......................................................................... 10 
Visit Windows ................................................................................................................................... 10 
Definition of Study Day ................................................................................................................ 10 
Analysis Windows ........................................................................................................................ 10 
PARTICIPANT DISPOSITION ................................................................................................................... 12 
Recruitment ...................................................................................................................................... 12 
Participant Enrolment and Disposition ........................................................................................... 12 
Protocol violations ........................................................................................................................... 12 
BASELINE DATA ..................................................................................................................................... 16 
Demographic Data and Baseline Characteristics (Table 7 - 11) ...................................................... 16 
STUDY ENDPOINTS ................................................................................................................................ 22 
Primary efficacy endpoint ................................................................................................................ 23 
Secondary efficacy endpoints .......................................................................................................... 23 
Virological endpoints (Table 13 and 14) .......................................................................................... 23 
Primary safety endpoints ................................................................................................................. 23 
Adherence ........................................................................................................................................ 23 
Other secondary outpoints .............................................................................................................. 26 
SAFETY ANALYSES ................................................................................................................................. 28 
Extent of Exposure ........................................................................................................................... 28 
Adverse Events ................................................................................................................................. 28 


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Adverse Event Severity .................................................................................................................... 28 
Relationship of Adverse Events to Study Drug ................................................................................ 28 
Summaries of Adverse Events and Deaths ...................................................................................... 28 
Serious adverse events (SAE) ........................................................................................................... 29 
Laboratory Evaluation ...................................................................................................................... 29 
 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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LIST OF ABBREVIATIONS 
AE 
 
adverse event 
ALT 
 
alanine aminotransferase 
APRI 
 
AST:platelet ratio index 
APTT 
 
activated partial thromboplastin time 
AST 
 
aspartate aminotransferase 
BLoQ 
 
below the lower limit of quantitation 
CI 
 
confidence interval 
CPT 
 
Child-Pugh-Turcotte 
DAA 
 
direct acting antiviral 
ECG 
 
electrocardiogram 
eCRF 
 
electronic case report form 
EOT 
 
end of treatment 
FDC 
 
fixed-dose combination 
FU 
 
follow-up 
GT 
 
genotype 
HCV 
 
hepatitis C virus 
HLGT 
 
high level group term 
HLT 
 
high level term 
INR 
 
international normalized ratio of prothrombin time 
LLOQ 
 
lower limit of quantitation 
LLT 
 
lower level term  
LSM 
 
liver stiffness measurement 
MedDRA 
Medical Dictionary for Regulatory Activities 
MELD  
Model for End-Stage Liver Disease 
PT 
 
preferred term 
Q1 
 
first quartile 
Q3 
 
third quartile 
SAE 
 
serious adverse event 
SAP 
 
statistical analysis plan 
SD 
 
standard deviation 
SOC 
 
system organ class 
SVR 
 
sustained virologic response 
SVRx 
 
sustained virologic response x weeks after stopping study drug 
TD 
 
target detected 
TND 
 
target not detected 
ULN 
 
upper limit of normal 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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STUDY DEFINITIONS 
HCV virological suppression is defined as HCV RNA below the lower limit of quantitation (LLoQ) 
(target not detected [TND] or target detected, not quantifiable [TDnq]).  
 
An end-of-treatment response (ETR) is defined as plasma HCV RNA below the LLoQ (TND or TDnq) at 
the end of treatment.   
 
Sustained virological response at 4 weeks post-treatment (SVR4) is defined as plasma HCV RNA 
below the LLoQ (TND or TDnq) at 4 weeks post cessation of treatment.   
Sustained virological response at 12 weeks post-treatment (SVR12) is defined as plasma HCV RNA 
below the LLoQ (TND or TDnq) at 12 weeks post cessation of treatment.   
Sustained virological response at 24 weeks post-treatment (SVR24) is defined as plasma HCV RNA 
below the LLoQ (TND or TDnq) at 24 weeks post cessation of treatment.   
HCV virologic failure is defined as non-response (failure of virological suppression on-treatment with 
quantifiable HCV RNA at all time points between baseline and end of treatment)  
 
Reinfection is defined by the presence of quantifiable HCV RNA after an ETR and detection of 
infection with an HCV strain that was distinct from the primary infecting strain (heterologous virus 
on sequencing of Core-E2 and/or NS5B regions).   
 
Relapse is defined by recurrent viraemia by SVR12 where reinfection is not confirmed. 
 
The presentation of recent HCV infection at the time of diagnosis is classified as either acute clinical 
or asymptomatic infection. Acute clinical infection includes participants with a documented clinical 
history of symptomatic seroconversion illness (including, but not limited to, the presence of 
jaundice, nausea/vomiting, abdominal pain, fever and hepatomegaly) and those without clinical 
symptoms but with a documented peak ALT >10 times the upper limit of normal (ULN) within the 12 
months prior to diagnosis. Asymptomatic infection includes participants with anti-HCV antibody 
seroconversion but no acute clinical symptoms or documented peak ALT <10x ULN.   
 
The duration of HCV infection at screening and baseline will be calculated from the estimated date of 
infection.  The estimated date of clinical infection is calculated as six weeks before onset of 
seroconversion illness or six weeks before the first ALT >10x ULN. The estimated date of 
asymptomatic infection is calculated as the midpoint between the last negative anti-HCV antibody or 
HCV RNA and the first positive anti-HCV antibody or HCV RNA.  For participants who were anti-HCV 
antibody negative and HCV-RNA positive at screening, the estimated date of infection is six weeks 
before enrolment, regardless of symptom status.   
 
On-treatment adherence will be calculated by subtracting the number of missed doses from the total 
number of doses prescribed for therapy duration and dividing by the total number of doses 
prescribed for therapy duration. By pill count and self-reported questionnaire, compliance with 
sofosbuvir/velpatasvir will be individually calculated at the 80, 90 and 100 adherence levels, defined 
as receipt of ≥80, ≥90 or 100% of scheduled doses.   


REACT Primary Analysis Statistical Final v1.0  
 
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STUDY DESIGN AND OBJECTIVES 
Study Objectives 
 
Primary objective 
The primary objective is to evaluate the proportion of patients with HCV RNA below the level of 
quantitation (target not detected [TND] or target detected, not quantifiable [TDnq]) at 12 weeks 
post end of treatment (SVR12) following sofosbuvir/velpatasvir therapy for 6 weeks (short 
treatment duration) as compared with 12 weeks (standard treatment duration) in people with 
recent HCV infection (duration of infection ≤12 months). 
 
Secondary objectives 
• 
To evaluate the proportion of participants with HCV RNA below the level of quantitation (TND or 
TDnq) at the end of treatment (ETR), 4 weeks after treatment completion (SVR4) and 24 weeks 
after treatment completion (SVR24); 
 
• 
To evaluate the proportion of participants with undetectable HCV RNA through 2 years post 
treatment; 
 
• 
To evaluate the levels of adherence, factors associated with suboptimal adherence including HIV 
status, and the impact of suboptimal adherence on therapeutic response; 
 
• 
To evaluate the impact of treatment on illicit drug use, injecting behaviour and sexual risk taking 
behaviour (behavioural survey) during treatment; 
 
• 
To evaluate safety and tolerability; 
 
• 
To evaluate the change in HIV RNA and CD4 (on‐treatment and end of treatment); 
 
• 
To evaluate the rate and risk factors for reinfection during and up to 2 years following treatment; 
 
• 
To evaluate the immunological factors associated with treatment induced clearance and 
reinfection; 
 
• 
To evaluate patient interest and attitudes towards long acting parenteral hepatitis C therapy 
(Long‐Acting Hepatitis C Therapy Questionnaire). 
 
Hypothesis 
Six weeks treatment with sofosbuvir/velpatasvir is non‐inferior to twelve weeks treatment with 
sofosbuvir/velpastavir as assessed by sustained virological response at 12 weeks post treatment in 
the intention‐to‐treat population (SVR12). 
Study design (Figure 1) 
This is an open label multicentre study. The study consists of a screening phase, treatment phase 
and follow-up phase to evaluate treatment response and reinfection. Participants will be required to 
wait a minimum of four weeks form screening before commencing treatment to assess for 
spontaneous clearance. The maximum wait period allowed between screening and baseline is 12 
weeks. 
 


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Figure 1: Study Schema 
 
Sample size and power 
The primary objective of this trial is to establish the non‐inferiority of short duration treatment (6 
weeks) to the standard duration treatment (12 weeks). Assuming an expected SVR of 90% in the 
control arm, 113 participants per arm will be required to give 80% chance that the two-sided 
confidence interval of the difference between regimens has a lower limit greater than ‐12%. 
A total of 250 subjects enrolled and randomised will comprise the intention‐to‐treat (ITT) population 
and will form the study population for evaluation of the primary and secondary endpoints. 
 


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TYPE OF ANALYSIS 
This document describes the primary statistical analysis for REACT study in accordance with protocol 
version 5.0. 
 
Data Safety and Monitoring Board (DSMB) Analysis  
This study has a DSMB to review the progress and safety of the study.  The DSMB conducted an 
interim safety and adherence analysis when the first 50 participants had either reached post-
treatment week 12 or dropped out of the study and then when a further 10 per arm reached 12 
weeks post treatment. At the second review the DSMB recommended termination of the short arm 
of the study due to inferiority. At the stage of the DSMB recommendation, at total of 196 
participants had been randomised, 192 had completed their randomised treatment, a further 4 were 
randomised to receive 6 weeks and extended to 12 weeks. Therefore, the primary analysis 
population will be based on 192 participants (99 in standard Arm, and 93 in shortened arm). 
 
Primary analysis: Post-treatment week 12 
The analysis for the primary endpoint, SVR12, will be conducted after all participants have 
completed the post-treatment week 12 visit or prematurely discontinue from study.  All the safety 
and efficacy data through to the post-treatment week 12 visit will be cleaned, finalised, and included 
for the analysis. 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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GENERAL CONSIDERATIONS FOR DATA ANALYSES 
Statistical Methods 
Analysis results will be presented using descriptive statistics. For categorical variables, the number 
(n) and percentage of participants in each category will be presented. For continuous variables, the 
number of participants (n), mean and standard deviation (SD), median, interquartile range (IQR, Q1-
Q3), range (minimum, maximum) will be reported; for inclusion in the manuscript, an appropriate 
determination will be made depending on the variable, size and distribution of the population 
studied. 
 
Statistical tests will be 2-sided and performed at the 5% significance level unless specified.   
 
For all efficacy endpoints, means and proportions with two-sided 95% confidence intervals (CI) will 
be determined. For the analysis of categorical outcomes, Chi-squared tests or exact equivalents (for 
small numbers) will be used. For comparison of continuous measures, t tests or non-parametric 
equivalents will be used as appropriate for the observed data distribution. Changes in injecting 
behaviour between screening, end of treatment and post-treatment week 12 will be compared using 
the McNemar test (exact binomial probability). 
 
Analysis Sets 
Analysis sets define the subjects to be included in an analysis. The number of participants eligible for 
each analysis set will be provided. Participants who were excluded from each analysis set will be 
summarised, with reasons for exclusion. 
 
Full Analysis Set (ITT population) 
The FAS includes all enrolled participants who were randomised. This will be the analysis set used for 
the primary efficacy and safety endpoints.  Following the DSMB recommendation to cease the study, 
the primary analysis population will be based on 192 participants (99 in standard Arm, and 93 in 
shortened arm).  
 
Modified Full Analysis Set 
The modified Intention to Treat (mITT) population includes participants in the FAS excluding those 
with non-virological reasons for treatment failure (i.e., death, loss to follow up) and reinfection. 
Participants with confirmed reinfection after achieving an ETR, but prior to the primary efficacy 
endpoint (SVR12), will be excluded from the mITT.   
 
Per-protocol Analysis Set 
The PP population is defined as all participants who received >90% of scheduled treatment for >90% 
of the scheduled treatment period with follow-up virologic data to SVR12.  
 
Safety Population 
The Safety population includes all participants who randomised and will be analysed and presented 
according to the actual on-treatment monitoring arm received during the study.  
 
The ITT population will be used for primary efficacy analyses, and the safety population will be used 
for all safety analyses.   


REACT Primary Analysis Statistical Final v1.0  
 
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Data Handling Conventions 
Missing Data 
For the analyses of categorical HCV RNA data, missing post-treatment HCV RNA data will have the 
missing data imputed. Missing on-treatment HCV RNA will have the missing data imputed up to the 
time of the last dose. 
 
If a data point is missing and is preceded and followed in time by values that are “<LLOQ, TND,” then 
the missing data point will be set to “<LLOQ, TND.”  
 
If a data point is missing, and preceded and followed by values that are “<LLOQ, target detected,” or 
preceded by “<LLOQ, target detected” and followed by “<LLOQ, TND,” or preceded by “<LLOQ, TND” 
and followed by “<LLOQ, target detected,” then the missing value will be set to “<LLOQ, target 
detected.”  
 
If a data point is missing, and preceded and followed by values that are “>LLOQ, target detected,” or 
preceded by “>LLOQ, detected” and followed by “<LLOQ, target detected” or “<LLOQ, TND”, then 
the missing value will be set to “>LLOQ, target detected.”  
 
The following scenarios describe a framework for analysis of the primary endpoint based on various 
anticipated events for the ITT and mITT population:  
i. 
In the event of the participant dying or becoming lost to follow‐up prior to SVR 
12, the participant will be considered to have failed treatment (loss to follow up 
= failure) 
ii. 
If the SVR 12 time-point measure is missing, then the next available measure 
(i.e., SVR 24 or later) will be used. If no future time points are available, the 
participant will be considered a treatment failure. 
 
Where appropriate, safety data for subjects who did not complete the study will be included in 
summary statistics.  
For example:  
• 
If a participant took at least 1 dose of study drug, the subject will be included in a summary 
of adverse events according to the treatment received; otherwise, if the subject is not 
dosed, then they will be excluded from the summary. 
• 
If safety laboratory results for a participant are missing for any reason at a time point, the 
subject will be excluded from the calculation of the summary statistics for that time point.  
 
Values for missing safety laboratory data will not be imputed; however, a missing baseline (day 0) 
result will be replaced with a screening result, if available.  
 
Outliers  
Outliers will be identified during data management and data analysis process, but no sensitivity 
analyses will be conducted. All data will be included in the data analysis. 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Data Handling Conventions and Transformations  
HCV RNA values below the LLOQ for the assay will be set to the lower limit minus 1 for the 
calculation of summary statistics for the actual HCV RNA values and the change from baseline values 
by study visit.  
For selected analyses, HCV RNA data (IU/mL) will be transformed to the logarithmic (base 10) scale 
(log10 IU/mL). 
 
Visit Windows  
Definition of Study Day 
Study day will be calculated from the date of first dose of study drug administration and derived as 
follows:  
• 
For post-dose study days: Assessment Date minus First Dose Date + 1  
• 
For days prior to the first dose: Assessment Date minus First Dose Date  
The last dose date for an individual study drug will be the end date entered in the Treatment 
Termination or Drug Administration eCRF.  
The last dose date of treatment for a given participant will be defined as the maximum of the last 
dose dates of individual study drugs in a treatment group, if applicable.  
If there are participants for whom the date of last study drug is unknown (lost to follow-up and not 
able to be contacted), the date of last dose will be estimated using the maximum of non-missing 
study drug start or stop dates, visit dates, and laboratory collection dates (post-treatment visits and 
unscheduled visits are not included).  
Analysis Windows 
Participant visits might not occur on protocol-specified days. Therefore, for the purposes of analysis, 
observations will be assigned to analysis windows (Table 1 and Table 2).  
In general, the baseline value will be the last non-missing value on or prior to the first dose date of 
study drug.  HCV RNA and safety laboratory data collected up to the last dose date + ≤3 days are 
considered to be on-treatment data. HCV RNA and safety laboratory data collected after the last 
dose date + >3 days are considered post-treatment data.  HCV RNA and safety laboratory data 
collected after the last dose date + >3 days will be assigned to the post-treatment follow-up (FU) 
visits.  Visit windows will be calculated from the last dose date (ie, FU Day = collection date minus 
the last dose date) as shown. 
Table 1. On-treatment visit analysis windows 
Nominal visit 
 
Nominal day 
Lower Limit 
Upper Limit 
Baseline 
1 
NA 
1 
Week 2 
14 
8 
21 
Week 4 
28 
22 
35 
Week 6* 
42 
36 
49 
Week 8 
56 
50 
63 
Week 10 
70 
64 
77 
Week 12 
84 
78 
>85 
*Shortened arm ETR 
 


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Table 2. Post-treatment visit analysis windows 
Nominal FU 
visit 
HCV RNA 
Safety Laboratory Data 
Nominal 
day 
Lower 
Limit 
Upper 
Limit 
Nominal day 
Lower 
Limit 
Upper 
Limit 
PT week 4 
28 
21 
69 
28 
4 
30 
PT week 12 
84 
70 
146 
NA 
NA 
NA 
PT week 24 
168 
147 
NA 
NA 
NA 
NA 
 
 


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PARTICIPANT DISPOSITION 
Recruitment 
The following dates will be presented to define the period of recruitment and follow-up:  
I. 
first and last participant screened 
II. 
first and last participant baselined 
III. 
first and last participant to complete PT week 12 
 
Participant Enrolment and Disposition  
A summary of participant enrolment will be provided- overall and by treatment group (if 
appropriate). The total number of participants who were screened, enrolled and treated will be 
depicted by a flowchart (Figure 2). 
A summary of participant disposition will be provided overall (Table 3).   
Reasons for participant exclusion, including screen failure and loss to follow up, will be summarised 
(Table 4, Table 5).  
 
Protocol violations 
Number, proportion, type and reason for any protocol violations will be described (Table 6).  
 
 
 


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Figure 2.  Participant disposition 
 
 
Screened
Assessed for eligibility  (n)
Randomised (n)
Randomised to treatment or intervention #1 
(n)
Received allocated treatment or intervention 
(n)
Did not recieve allocated treatment or 
intervention (reasons, n)
Lost to follow up (reasons, n)
Discontinued treatment or intervention 
(reasons, n)
Analysed (n)
Excluded from analysis (reasons, n)
ITT (n)
mITT (n)
PP (n)
Randomised to treatment or intervention #2 
(n)
Received allocated treatment or intervention 
(n)
Did not recieve allocated treatment or 
intervention (reasons, n)
Lost to follow up (reasons, n)
Discontinued treatment or intervention 
(reasons, n)
Analysed (n)
Excluded from analysis (reasons, n)
ITT (n)
mITT (n)
PP (n)
Excluded (n)
Reasons for excusion
Not meeting inclusion criteria (n), consent 
withdrawn (n), lost to follow up (n), other (n, 
list)
Commenced treatement but not randomised
(n)
Reasonse not randomised (n)
Enrolment
Allocation 
Follow-Up 
Analysis 


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Table 3.  Recruitment and follow-up 
Participant disposition 
Total 
N (%) 
Standard 
arm 
N(%) 
Shortened arm 
N(%) 
Total participants screened, n 
 
 
 
Participants screened and excluded, n 
 
 
 
Participants allocated to treatment, N  
 
 
 
Commenced allocated treatment, n/N (%)  
 
 
 
Did not commence allocated treatment, n/N 
(%) 
 
 
 
Treated Participants  
 
 
 
Completed allocated treatment course, n (%) 
 
 
 
Discontinued treatment, n (%) 
 
 
 
Lost to study follow-up, n (%) 
 
 
 
Study follow up 
 
 
 
Completed study follow up, n (%) 
 
 
 
Did not complete study follow up, n (%) 
 
 
 
Population for analysis 
 
 
 
ITT, n 
mITT, n 
 
 
 
PP, n 
 
 
 
 
Table 4.  Reasons for screen failure 
Participant disposition 
N (%) 
Total participants screened, n 
 
Participants screened and excluded, n 
 
Screen fail participants who did not meet eligibility criteria 
  List reasons (inclusion and exclusion criteria) 
 
Participants who met eligibility criteria but were not enrolled 
  List reasons for not being enrolled 
    Lost to follow up 
    Withdrew consent 
 
 
Table 5. Reasons for loss to study follow-up 
Study Number 
Date of treatment 
commencement 
Date last 
follow-up 
Reason lost to follow-up 
Standard Arm 
 
Simplified Arm 
 
 
 
 
 
 
 
 
 
 


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Table 6. Protocol violations or deviations 
Protocol violations or deviations 
N (%) 
Total number with protocol violations 
Total number with protocol deviations 
 
Violation of study inclusion or exclusion criteria 
 
Enrolment errors 
 
 
 
 


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BASELINE DATA 
Demographic Data and Baseline Characteristics (Table 7 - 11) 
Demographic and baseline measurements will be summarized using standard descriptive methods. 
Baseline data will be summarised for the total FAS population and by HCV genotype and HIV 
serostatus as: number (n) and proportion for categorical parameters; or n, mean and standard 
deviation (SD), median, Q1, Q3, minimum and maximum for continuous parameters. 
 
Age will be calculated in years at the date of initial study drug administration (baseline).  
 
P values will not be reported for differences between the two groups at baseline, since appropriate 
randomisation methods will have accounted for this.  Any differences identified would be due to 
chance such that a significant p value would in reality be representative of a type 1 error.  Large 
differences at baseline (more than half a SD for continuous variables or 10% for categorical 
variables) will be investigated in a sensitivity analysis.  
 
For pre-specified variables and variables only recorded at screening and not at baseline, screening 
values will be presented in the baseline table. 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 7. Participant demographic and clinical enrolment characteristics 
Enrolment characteristics 
Total study 
population 
(n=XXX) 
Standard 
Arm 
(n=XXX) 
Shortened 
Arm 
(n=xxx) 
Age, mean (SD) or median (IQR) 
 
 
 
Gender, n (%) 
 
 
 
  Male 
 
 
 
  Female 
 
 
 
  Transgender 
 
 
 
Ethnicity, n (%) 
 
 
 
  Caucasian/white 
 
 
 
  Asian  
 
 
 
  Black  
 
 
 
  Other 
 
 
 
BMI, mean (SD) or median (IQR or range) 
 
 
 
HCV genotype/subtype, n (%) 
 
 
 
  Genotype 1 
 
 
 
    1a 
 
 
 
    1b 
 
 
 
    1, not specified 
 
 
 
  Genotype 2 
 
 
 
    2a 
 
 
 
    2b 
 
 
 
  Genotype 3 
 
 
 
    3a 
 
 
 
  Genotype 4 
 
 
 
  Genotype 5 
 
 
 
  Genotype 6 
 
 
 
  Genotype mixed 
 
 
 
    Specify 
 
 
 
  Genotype indeterminate 
 
 
 
HCV RNA, IU/mL 
 
 
 
  Quantitative, mean (SD) or median (IQR or 
range) 
 
 
 
  Log10, mean (SD) or median (IQR or 
range) 
 
 
 
Classification of recent HCV Infection 
 
 
 
Primary  
 
 
 
Reinfection  
 
 
 
Duration of infection, mean (SD) or median 
(IQR or range) 
 
 
 
Acute 
 
 
 
Chronic 
 
 
 
 
 
 


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Table 8. Other baseline demographic and socio-economic characteristics 
Variable 
Total 
Standard arm 
Shortened 
arm 
Sexuality, n (%) 
 
 
 
Source of income, n (%) 
 
 
 
Highest level of education, n (%) 
 
 
 
Accommodation, n (%) 
Rented house/flat; privately owned house/flat; boarding 
house; hostel; psychiatric home; alcohol/drug treatment 
residence; shelter/refuge; prison/detention centre; caravan; 
no usual residence, squat; other 
 
 
 
Social functioning score, mean (SD) or median (IQR) 
 
 
 
Who do you live with? 
Alone; spouse partner; Alone with children; spouse/partner 
and children; other relatives; friends; 
friends/parents/relative and children; other 
Been in prison/juvenile justice, n(%) 
Ever; last 6 months 
Clinician determined mode of HCV exposure, n (%) 
Self-reported mode of HCV exposure, n (%) 
Injecting drug use/ Transfusion of blood products/ 
Occupational (needle stick or other exposure)/ Sexual 
exposure to a known HCV positive person of the same sex/ 
Sexual exposure to a known HCV positive person of the 
opposite sex/ Sexual exposure to persons of unknown HCV 
status of the same sex/ Sexual exposure to persons of 
unknown HCV status of the opposite sex/ Body piercing/ 
Tattoos/ Use of recreational drugs (snorting/inhaling)/ 
Other (please specify) 
PrEP use in past 6 months (among HIV negative), n(%) 
Never/ Yes every day/ Yes every week (4-6 days per 
week)/ Yes every week (1-3 days per week)/ Yes, 
occasionally (the day or two before or after sex) 
Screened for STDs in last 12 months, n (%) 
STD diagnosed in last 12 months prior to HCV diagnosis, 
n(%) 
Listing of STDs among those diagnosed 
 
 
 
 
 
 


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Table 9. Participant viral enrolment characteristics 
Baseline characteristics 
Total study 
population 
N=XXX 
Standard 
Arm 
N=XXX 
Shortened 
Arm 
N=XXX 
HCV 
 
 
 
ALT (U/L), median (IQR) 
  Peak ALT prior to enrolment  
  ALT at baseline 
 
 
 
Prior HCV treatment, n (%) 
  Yes 
  (Specify) 
 
 
 
Response to prior HCV treatment, n/total “Yes” (%) 
  Non-response 
  Breakthrough 
  Relapse 
  Other (specify) 
 
 
 
Fibroscan performed, n (%) 
  Valid Fibroscan, n/N (%) 
 
 
 
Median liver stiffness measurement (Fibroscan®), kPa 
(IQR) 
(in those with valid Fibroscan result only) 
 
 
 
HIV 
 
 
 
HIV infection, n (%) 
  CD4 count (106/L), median (IQR) 
  HIV VL ≤50 at screening, n (%) 
  On cART, n (%) 
 
 
 
HBV 
 
 
 
HBsAg positive, n (%) 
 
 
 
HBcAb positive, n (%) 
 
 
 
HsAb >10 IU/ml, n (%) 
 
 
 
HBV DNA detected, n (%) 
 
 
 
NA therapy for HBV, n (%) 
 
 
 
Abbreviations: Combination antiretroviral therapy (cART); nucleos(t)ide analogue (NA)  
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 10. History of substance use at enrolment 
Substance use characteristics 
Total 
N= 
Standard 
Arm 
N= 
Shortened Arm 
N= 
Injecting drug use, n (%) 
  Ever 
..Recent a 
  Current a 
 
 
 
In those reporting injecting drug use: 
  Age at first injecting, median (range) 
  Last injected within 30 days, n (%) 
  Last injected between 1-6 months ago, n (%) 
  Last injected >6 months ago, n (%) 
 
 
 
If injected in the previous 1 month, frequency (n, %):  
 >3x most days 
.2-3x most days 
.. Daily 
  More than weekly, but less than daily 
  Less than weekly 
 
 
 
Drug injected most in last month, n (%) b 
   Heroine 
.. Cocaine 
.. Methamphetamines 
.. Other opiates 
.. Benzodiazepines 
 
 
 
Opioid substitution therapy, n (%)  
   Never  
.. Ever 
.. Cot currently 
  Current 
 
 
 
Alcohol use, n (%)c 
  None 
Frequency n (%) 
 Monthly or less;  
 2 - 4 times/month 
 2 -3 times/week 
 4 or more times/week 
Standard drinks per day n (%) 
Mean (SD); Median (IQR) 
Frequency of Six or more standard drinks on one occasion n (%) 
Never, less than monthly, monthly, weekly, almost daily/ daily 
AUDIT C Score n (%) 
Number identified as hazardous drinkers n (%) 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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a Recent injecting drug use refers to use within 6 month of screening, and Current injecting within 
the past month; b other drugs not listed that will also be summarised: Oxycodone, methadone, 
buprenorphine, fentanyl, steroids, LSD or other hallucinogens, Ecstasy; c One standard drink = 10 
grams of alcohol 
 
Table 11. Of syringe sharing among Injecting drug users 
Syringe sharing use characteristics a 
Total 
N= 
Standard 
Arm 
N= 
Shortened Arm 
N= 
Use of NEW sterile needle and syringe in last month, n (%) 
  All injections 
..Most of the time a 
  Half of the time 
  Some of the time 
  Not in the last month 
 
 
 
How many times in last month used a needled/syringe after someone 
else, n (%) 
  None 
  One time 
  Two times 
  3 – 5 times 
  More than 5 times 
 
 
 
Who did you share with?, n (%) 
  No-one 
  Regular sex partner 
  Casual sex partner 
  Close friends 
  Acquaintance 
  Other  
 
 
 
How many times in last month has someone used a needled/syringe 
after you, n (%) 
  None 
  One time 
  Two times 
  3 – 5 times 
  More than 5 times 
Who were these people that shared after you?, n (%)  
  No-one 
  Regular sex partner 
  Casual sex partner 
  Close friends 
  Acquaintance 
  Other 
 
 
 
a Denominator – those reporting injecting drug use in last month 
 


REACT Primary Analysis Statistical Final v1.0  
 
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STUDY ENDPOINTS  
 
Table 12. Study endpoints and outcomes 
Primary endpoint 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (ITT population) 
Included in primary analysis 
Secondary endpoints 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (mITT population) 
Included in primary analysis 
Non-inferiority of simplified on-
treatment monitoring to standard on-
treatment monitoring (PP population) 
Included in primary analysis 
Treatment response: ETR, SVR4, SVR24; 
HCV RNA below the level of 
quantification through 2 years post 
treatment 
Included in primary analysis 
Adverse events 
Included in primary analysis 
On-treatment adherence 
Included in primary analysis 
Early treatment discontinuation 
Included in primary analysis 
Relapse and reinfection 
Included in primary analysis 
Resistance associated substitutions (RAS) 
for people who have failed treatment 
Included in primary analysis 
Laboratory abnormalities 
Included in primary analysis 
Change in HIV RNA and CD4 (on 
treatment and end of treatment) 
Included in primary analysis 
 
 
 
 
 
 
 
Included in primary analysis 
Additional pre-
specified outcomes 
Factors associated with on treatment 
efficacy (only if SVR12 is low) 
Included in primary analysis 
Factors associated with sub-optimal 
adherence 
 
Factors associated with re-infection 
Not included in primary analysis 
 
 
 
To evaluate the impact of treatment on 
illicit drug use, injecting behaviour and 
sexual risk-taking behaviour (behavioural 
survey) during treatment 
Not included in primary analysis 
 
To evaluate patient interest and attitudes 
towards long acting parenteral hepatitis C 
therapy (Long‐Acting Hepatitis C Therapy 
Questionnaire) 
Not included in primary analysis 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Primary efficacy endpoint 
The proportion of participants with HCV RNA below the level of quantitation (target not detected 
[TND] or target detected, not quantifiable [TDnq]) at 12 weeks post end of treatment (SVR12) 
 
The primary analysis will compare randomised treatment groups on an ITT basis including all 
available data. The primary endpoint, SVR12, will be calculated for each patient based on all 
available data. Treatment arms will be regarded as non‐inferior if the difference in proportion 
between regimens has a lower limit greater than ‐12%. Secondary analyses will compare randomised 
treatment groups based on available data (per protocol). 
 
Secondary efficacy endpoints 
• 
Virological endpoints 
o The proportion of treated participants with: 
 
ETR (defined as undetectable plasma HCV RNA at the end of treatment) 
 
SVR4 (defined as undetectable plasma HCV RNA at post-treatment week 4) 
 
For virological endpoints, the point estimates and 95% exact confidence intervals will be reported by 
study arm, by HCV genotype and by HIV serostatus.   
 
Virological endpoints (Table 13 and 14) 
The presence of HCV RNA will be assessed at all scheduled clinic study visits using Aptima HCV Quant 
Dx assay, version 2.15.5 (lower limit of quantitation [LLoQ] 10IU/mL; Hologic, Inc., Marlborough, MA, 
USA), with centralised testing performed at St Vincent’s Centre for Applied Medical Research 
(Sydney, NSW, Australia). 
 
Proportions and 95% confidence intervals will be reported for both the primary and secondary 
virological endpoints. Virological endpoints will be assessed in the ITT, mITT and PP populations, 
with results stratified by HCV genotype/subtype and HIV serostatus.  
 
Factors associated with treatment outcome in the ITT population will be evaluated by univariate 
analysis.  Variables assessed will include but are not limited to: demographic factors (age, gender); 
virological factors (baseline HCV RNA, genotype 1 subtype, duration of HCV infection); risk behaviors 
(injecting drug use, sexual behavior, mode of HCV acquisition); HIV co-infection; treatment factors 
(adherence).  
 
Primary safety endpoints 
The primary safety endpoints are: 
• 
Proportion of participants with common adverse events (reported by greater than 5% of the 
study population); 
• 
Proportion of participants with at least one severe or potentially life threatening (grade 3 or 
4) adverse event; 
 
Adherence 
80% adherence: Defined as the receipt of >80% of scheduled doses. 
90% adherence: Defined as the receipt of >90% of scheduled doses. 
100% adherence: Defined as the receipt of 100% of scheduled doses. 


REACT Primary Analysis Statistical Final v1.0  
 
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On-treatment adherence will be calculated by subtracting the number of missed doses from the total 
number of doses of scheduled treatment and dividing by the total intended therapy duration. This 
measures the proportion of doses received from the time that treatment was initiated until 
treatment was discontinued or completed. 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 13. Primary and secondary efficacy endpoints – (ITT) 
Efficacy 
Arm A 
Standard 
treatment 
(N=XX) 
Arm B 
Shortened 
treatment 
(N=XX) 
Difference 
between arms 
(95% CI) 
P value 
ETR, n (%) 
 
 
 
 
SVR 4, n (%) 
 
 
 
 
SVR 12, n (%) 
  Non-response 
  Relapse 
  Reinfection 
  Lost to follow up 
 
 
 
 
SVR 24, n (%) 
 
 
 
 
Virologic failure, n (%) 
  On-treatment failure (non-response, 
breakthrough) 
  Relapse* 
 
 
NA 
 
 
*relapse definition:  
Analysis tables will also be presented for the mITT, and PP populations 
 
Table 14. SVR12 in participant subgroups, ITT population 
Subgroup 
Standard tx arm 
n/N (%; 95% CI) 
Shortened tx arm 
n/N (%; 95% CI) 
HCV mono-infection 
 
 
HIV/HCV co-infection 
 
 
Genotype 1 
 
 
Genotype 1a 
 
 
Genotype 1b 
 
 
Genotype 2 
 
 
Genotype 3 
 
 
Genotype 4 
 
 
Genotype 5 
 
 
Genotype 6 
 
 
 
 
 
 
 
 
 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Other secondary outpoints 
Table 15: Primary reason for premature discontinuation of study drug 
Reason for premature discontinuation, n 
(%) 
Standard tx arm 
(n=XXX) 
Shortened tx arm 
(n=XXX) 
Adverse event 
 
 
Non-compliance 
 
 
Withdrawal of consent 
 
 
Loss to follow up 
 
 
Other 
Specify - list 
 
 
 
Table 16: Reinfection by SVR12 
  
N 
 % 
95% CI 
Standard Arm 
 
 
 
Shortened Arm 
 
 
 
 
Table 17: Relapse by SVR12 
  
N 
 % 
95% CI 
Standard Arm 
 
 
 
Shortened Arm 
 
 
 
 
Table 18. Prevalence of polymorphisms in NS5B and NS5A at baseline 
Polymorphism, n (%) 
Total study 
population 
N=XXX 
Standard duration 
arm 
N=XXX 
Shortened 
duration arm 
N=XXX 
Any NS5B 
N 
N 
N 
[Specify] 
 
 
 
Any NS5A 
N 
N 
N 
M28G/S/T 
L31F/I/M/P/V 
P32A/L/Q/R 
A/C92K/T 
Y93D/H/N/R/S/W 
 
 
 
 
Baseline polymorphisms detected by Sanger sequencing at the following amino acid positions:  
NS5A: 28, 31, 32, 92, 93 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 19. NS5B and NS5A polymorphisms at baseline and virologic failure 
Subject ID 
Genotype and 
subtype 
Virologic failure 
NS5B Variants 
NS5A variants 
Baseline 
Failure 
Baseline 
Failure 
Standard treatment duration (12 weeks), n=XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shortened treatment duration (6 weeks), n=XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 19. Characteristics of participants with virological failure 
Subject ID 
Genotype and 
subtype 
Virologic failure 
Genetic distance % 1 
Baseline 
HCV 
RNA 
(log10) 
Adherent2 
Core-E21 
NS5A 
Standard treatment duration (12 weeks), n=XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shortened treatment duration (6 weeks), n=XXX 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. Reported genetic distance % for Core-E2 and NS5A was the comparison between sequences at 
baseline and post-treatment week 12. Cut-off for homologous virus was <4% for Core-E2 and X% for 
NS5A.  
2. Adherence was defined as receipt of ≥95% of the prescribed treatment course 
 
Table 21. On treatment adherence 
  
N 
 % 
95% CI 
80% adherence 
 
 
 
Standard Arm 
 
 
 
Shortened Arm 
 
 
 
90% adherence 
 
 
 
Standard Arm 
 
 
 
Shortened Arm 
 
 
 
100% adherence 
 
 
 
Standard Arm 
 
 
 
Shortened Arm 
 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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SAFETY ANALYSES 
All participants who receive at least one dose of study drug will be included in the safety analyses. 
Safety analyses will be performed overall and by treatment arm.  Safety will be evaluated by 
assessment of clinical laboratory tests at various time points during the study, and by the 
documentation of AEs.   
 
All safety data collected on or after the first dose of study drug administration up to 30 days after 
the last dose of study drug will be summarised. 
 
Extent of Exposure 
A participant’s extent of exposure to study drug will be generated from the study drug 
administration page of the eCRF. 
 
Adverse Events 
Clinical and laboratory AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA, insert version).  System organ class (SOC), high level group term (HLGT), high level term 
(HLT), preferred term (PT), and lower level term (LLT) will be provided. 
 
Events will be summarised on the basis of the date of onset for the event.  
 
A treatment-emergent AE (TEAE) will be defined as: 
• 
Any AEs with an onset date on or after the study drug start date and no later than 30 days 
after permanent discontinuation of study drug 
• 
Any AEs leading to premature discontinuation of study drug 
 
Adverse Event Severity 
Adverse events are graded by the investigator as mild (Grade 1), moderate (Grade 2), severe (Grade 
3), or life-threatening (Grade 4) according to toxicity criteria specified in the protocol. The severity 
grade of events for which the investigator did not record severity will be categorized as “missing” for 
tabular summaries and data listings, and the most severe will be considered (for sorting purpose 
only) in data presented.  For example, if an adverse event of the same type (PT) is listed more than 
once for an individual, the highest grade will be used to summarise severity.  
 
Relationship of Adverse Events to Study Drug 
Related AEs are those for which the investigator selected “Related” (“Possibly related” or “Probably 
related”) on the AE CRF to the question of “Related to Study Treatment.” Events for which the 
investigator did not record the relationship to study drug will be considered to be related to study 
drug for summary purposes.  
 
Summaries of Adverse Events and Deaths 
The number and percentage of participants overall and in each arm with treatment-emergent 
adverse events will be tabulated by primary MedDRA System Organ Class (SOC) and preferred term 
(PT). The tabulation of the number of participants with treatment-emergent adverse events by 
severity grade and relationship to study drug also will be provided.  
 
Participants reporting more than one adverse event for a given MedDRA PT will be counted only 
once for that term using the most severe grade for the severity grade table and the most related for 


REACT Primary Analysis Statistical Final v1.0  
 
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the relationship to study drug tables.  Participants reporting more than one type of event within a 
SOC will be counted only once for that SOC, but both PTs will be listed.  
 
Summaries of treatment-emergent AEs (by SOC and PT) will be provided for the following: 
• 
All TEAEs 
• 
TEAEs of Grade 3 or above 
• 
All treatment-related TEAEs 
• 
Treatment-related TEAEs of Grade 3 or above 
• 
All SAEs (including death) 
• 
All treatment-related SAEs 
• 
All TEAEs leading to premature discontinuation of the study drug  
• 
TEAEs that occurred in at least 5% of subjects within any treatment group 
 
Adverse event summaries will provide the number and percentage of subjects with treatment-
emergent AEs by SOC and PT, divided by treatment group. 
 
Adverse events will be summarised and listed first in alphabetic order of SOC and then by PT in order 
of descending incidence of the pooled treatment groups within each SOC.  
 
In summaries by severity grade, the most severe grade will be used for those AEs that occurred more 
than once in a participant during the study.  
 
Serious adverse events (SAE) 
The proportion of participants with at least one SAE will be reported overall. Serious adverse events 
will be summarized and relationship between the SAE and study drug will be detailed 
 
Laboratory Evaluation 
Selected laboratory data will be summarised (n, mean, SD, median, IQR, range) by study visit along 
with the corresponding change from Baseline/Day 1 to Post Treatment Week 12. 
 
Depending on sample distribution, parametric or non-parametric tests can be used to compare the 
change in biochemical and haematological indicators over time.  
 
The NIH DAIDS AE Grading Table Version 2.0- November 2014 will be used to grade severity.   
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 22. Safety parameters – adverse events and treatment discontinuation 
Adverse events 
Safety analysis set 
(N=XX) 
Participants reporting any AE up to 30 days after last dose, n (%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
Participants reporting treatment-related AE up to 30 days after 
last dose, n (%) 
  Grades 1-2, n (%) 
  Grade 3, n (%) 
  Grade 4, n (%) 
 
Serious adverse event, n (%) 
 
Treatment-related serious adverse event, n (%) 
 
Treatment discontinuation due to adverse event, n (%) 
 
Death, n (%) 
 
Adverse events 
Common (>10% of study population), n (%) 
  Specify (list) 
 
 
Table 23.  Listing of serious adverse events  
Study 
Arm  
Date 
Onset 
Date 
resolved 
Diagnosis or 
event 
description 
SAE 
criteria‡ 
Outcome§ 
Relationship to 
study drug 
 
 
 
 
 
 
 
Standard 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shortened  
 
 
 
 
 
 
 
 
 
 
 
 
 
‡ Death, hospitalised, life threatening, medically important, congenital anomaly, disability 
§ Recovered, Improved, Unchanged, Worsened, Unknown, Died 
 
Table 24.  Serious adverse events summary 
SAE – event summary 
All 
N=XXX 
Treatment 
arm 1 
N=XXX 
Treatment 
arm 2 
N=XXX 
N of participants experiencing any treatment-emergent SAE by 
MedDRA SOC and Preferred Term, n (%) 
  SOC (alphabetical order) 
    List PT 
 
 
 
 
 
 
 
 
 
 


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Laboratory Evaluation 
Selected laboratory data will be summarised (n, mean, SD, median, IQR, range) by study visit along 
with the corresponding change from Baseline/Day 1. 
Table 25. Summary table for key laboratory evaluations 
Lab parameter 
N 
Mean 
SD 
Min
Q1 
Median 
Q3 
Max
ALT 
 
 
 
 
 
 
 
 
AST 
Glucose 
ALP 
Albumin 
Creatinine 
Haemoglobin 
WBC 
Neutrophils 
Platelets 
Bilirubin 
 
 
 
 
 
 
 
 
*table will be further stratified by Arm and study weeks (Screening, baseline, Week 4, ETR, SVR4) 
 
Table 26. HIV patients only – changes in HIV viral load and CD4 cell count 
Parameter 
Standard Arm 
Shortened arm 
HIV viral load (<20 copies) 
N (%) 
N (%) 
Screening 
 
 
Baseline 
 
 
Week 4 
 
 
SVR12 
 
 
Change in CD4 cell count  
Mean (SD) 
Mean (SD) 
Screening 
 
 
Baseline 
 
 
SVR12 
 
 
 
 
 


REACT Primary Analysis Statistical Final v1.0  
 
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Table 27. Listing of HIV patients with VL > 200 copies at any timepoint, by treatment arm 
Study Arm 
Study ID 
Week first VL >200 copies/mL 
Standard 
Shortened 
 
 
 
 
Table 28. Grading of severity of laboratory measures 
Laboratory evaluation 
Standard Arm 
(N=XX) 
Shortened Arm 
(N=XX) 
Haematological parameters 
Baseline Hb, g/L (mean, SD) 
 
 
Change in Hb at post-treatment week 12, g/L (mean, SD) 
 
 
Haemoglobin #, n (%) 
  Grade 2 
  Grade 3 
  Grade 4 
 
 
Biochemical parameters 
Baseline ALT, U/L (mean, SD) 
 
 
ALT, n (%) 
  Grade 2 (3-5x ULN) 
  Grade ≥3 (>5x ULN) 
 
 
Change in ALT at post-treatment week 12, g/L (mean, SD) 
 
 
Baseline AST, U/L (mean, SD) 
 
 
AST, n (%) 
  Grade 2 (3-5x ULN) 
  Grade ≥3 (>5x ULN) 
 
 
Change in AST at post-treatment week 12, g/L (mean, SD) 
 
 
Baseline total bilirubin, mg/dl or mmol/L (mean, SD) 
 
 
Total bilirubin *, n (%) 
  >2.5-3.0 mg/dl (43 – 51 mmol/L) 
  >3.0 mg/dl (>51 mmol/L) 
 
 
Change in bilirubin at post-treatment week 12, g/L 
(mean, SD) 
 
 
# At any time during treatment and up to 30 days post; each participant should only be included once 
- record most severe grade of anaemia for each participant  
*At any time during treatment and up to 30 days post; add footnote, if bilirubin elevated at 
screening/baseline