PRO-ACT: Prevention of De Novo HCV With Antiviral HCV Therapy Post-Liver
Phase: PHASE4
Conditions: Hepatitis C, Transplantation Disease Transmission
Sponsor: University of California, San Francisco

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CLINICAL STUDY PROTOCOL 
 
Title: P R O - A C T :  Prevention of De Novo HCV with Antiviral HCV Therapy 
Post-Liver and Post-Kidney Transplant 
 
 
Lead Investigators: 
 
Norah Terrault, MD, MPH 
Gastroenterology/Hepatology 
University of California, San Francisco  
Tel: (415) 476-2227 
Email: Norah.Terrault@ucsf.edu 
 
 
Raymond A. Rubin, MD 
Transplantation 
Piedmont Transplant Institute 
Tel: (888) 605-5888 
Email: Raymond.Rubin@piedmont.org 
 
 
Claus Niemann, MD 
Anesthesia and Perioperative Care 
University of California, San Francisco  
Tel (415) 502-2162 
Email: Claus.Niemann@ucsf.edu 
 
 
 
 
NCT03619837   
Unique Protocol ID: 18-24323

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TABLE OF CONTENTS 
 
Section 
Page 
Table of Contents 
2 
Revision History 
3 
Protocol Synopsis 
4 
Background and Scientific Rationale 
8 
Objectives 
11 
Study Design 
12 
Subject Population 
15 
Investigational Medicinal Product 
16 
Study Procedures 
18 
Adverse Events and Toxicity Management 
26 
Statistical Considerations 
28 
Responsibilities 
31 
References 
35 
Appendix 1-Study Acknowledgement 
39 
Appendix 2-Principal Investigators 
40 
Appendix 3-Schedule of Assessments 
41 
Appendix 3a-Schedule of Assessments for Virologic Failure 
Substudy 
42 
Appendix 4-Child’s Pugh Classification 
43 
 
 

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REVISION HISTORY 
 
Version 1.7, dated 18 January 2018: 
1) HCV viremia is to be confirmed before sofosbuvir/velpatasvir (SOF/VEL) 
EPCLUSA therapy is initiated. Language to reflect this change has been updated 
in the Protocol Synopsis, Study Design (treatment regimen), Study Procedures 
(Clinical evaluations, recipient data in the post-transplant period, study visits), 
and Schedule of Assessments (Appendix 3). 
2) In the event of virologic failure following treatment with SOF/VEL, subjects will 
be 
eligible 
for 
re-treatment 
with 
12 
weeks 
of 
sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) VOSEVI therapy in the 
Virologic Failure Substudy. These subjects must complete their Day 1 visit within 
30 days of documentation of virologic failure. On-treatment visits will occur on 
Weeks 1, 4, 8 and 12. Post-treatment visits will occur at Weeks 4, 12 and 24 after 
last dose of SOF/VEL/VOX. SOF/VEL/VOX is not to be co-administered with 
cyclosporine. Language to reflect this change has been updated in the Protocol 
Synopsis, Background and Scientific Rationale (risk/benefit assessment), Study 
Design (description), Investigational Medicinal Products, Study Procedures, 
Responsibilities (informed consent process), and Schedule of Assessments 
(Appendix 3a). 
 
 

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PROTOCOL SYNOPSIS 
 
Study Title:  
Prevention of De Novo HCV with Antiviral 
HCV Therapy Post-Liver and Post-Kidney 
Transplant 
 
Study Centers Planned: 
 
 
6 
 
Number of Subjects Planned: 
 
30 
 
Target Population: 
HCV negative liver and/or kidney transplant 
recipients who receive an HCV nucleic acid 
test positive deceased donor organ 
 
Duration of Treatment: 
 
 
12 weeks 
 
Duration of Study: 
Up to 40 weeks (up to 1-4 week(s) between 
transplant and start of study medication, 12 
weeks of treatment followed by 24 weeks of 
follow up). The duration for subjects in the 
Virologic Failure Substudy, will be up to an 
additional 36 weeks (12 weeks of treatment 
followed by 24 weeks of follow up). 
 
Objectives: 
1) 
To 
determine 
the 
efficacy 
of 
sofosbuvir/velpatasvir (SOF/VEL) EPCLUSA 
therapy in HCV negative liver and/or kidney 
transplant recipients with HCV nucleic acid 
test (NAT) positive donors. 
 
2) To determine the safety of SOF/VEL 
therapy in HCV negative liver and/or kidney 
transplant recipients with HCV NAT positive 
donors. 
3)  To compare the observed waiting time 
for transplant for HCV negative liver and/or 
kidney transplant recipients with HCV 
NAT positive donors to the expected 
waiting time for transplant with HCV 
negative donors at participating centers. 
 
Study Design: 
An open label, multicenter, proof of concept, 
pilot study evaluating the safety and efficacy 
of SOF/VEL in HCV negative liver and/or 
kidney transplant recipients with HCV NAT 
positive donors 

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Key Inclusion Criteria: 
1) HCV negative adults wait-listed for 
primary liver and/or kidney transplant 
without a suitable living donor; 
 
 
 
2) Donor characteristics: serum HCV NAT 
positive and negative for hepatitis B 
surface antigen  
• For liver transplant: pre-donation 
liver biopsy with no fibrosis (F0) or 
minimal fibrosis (F1) 
• For kidney transplant: kidney donor 
profile index ≤ 85%; 
 
  
 
 
 
 
 
  
 
 
 
3) HCV viremic after transplant 
 
 
 
Key Exclusion Criteria: 
 
1) Recipient or donor HIV infected or 
hepatitis B surface antigen positive; 
2) Liver single organ recipients who 
received hemodialysis ≥ 7 days prior to 
transplant; 
3) Kidney single organ recipients who have 
been on dialysis for > 5 years at time of 
screening, sensitized with panel reactive 
antibody > 80%, or with advanced liver 
fibrosis (Knodell stage 3) or cirrhosis; 
 
 
Study Procedures/Frequency: 
Potential subjects will complete a 3-step 
informed consent process: 1) at pre-
screening, 2) Informed Consent Part 1 at 
screening before they are rendered eligible 
for HCV-viremic organ offers through the 
opt-in mechanism in the allocation system, 
and 3) Informed Consent Part 2 confirming 
their willingness to proceed with HCV 
viremic transplant when they are called in 
for 
transplant. 
Eligible 
subjects 
with 
documented HCV viremia will be started on 
SOF/VEL usually within one week (but up to 
4 weeks per investigator discretion) after 

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transplant. Prior to Day 1, laboratory 
assessment and assessment of severity of 
liver 
disease 
(if 
applicable) 
will 
be 
performed. Day 1 is defined as the day the 
study drug commences. There will be 7 on 
treatment 
study 
visits 
during 
which 
laboratory studies will be sent, concomitant 
medications will be reviewed and adverse 
events (AEs) will be assessed. There will be 
5 on treatment laboratory only visits, which 
may also include a telephone call to verify 
concomitant medications. There will be 1 
end of treatment visit during which 
laboratory studies will be sent, concomitant 
medications will be reviewed and AEs will be 
assessed. There will be 1 post-treatment 
study visit during which laboratory studies 
will be sent, concomitant medications will be 
reviewed and AEs will be assessed. There 
will be 2 post-treatment study visits during 
which laboratory studies will be sent and 
concomitant medications will be reviewed. 
 
Virologic Failure Substudy 
In the event of virologic failure following 
treatment with SOF/VEL, subjects will be 
eligible for re-treatment with 12 weeks of 
sofosbuvir/velpatasvir/voxilaprevir 
(SOF/VEL/VOX) VOSEVI therapy in the 
Virologic Failure Substudy. These subjects 
must complete their Virologic Failure 
Substudy Day 1 visit within 30 days of 
documentation of virologic failure. On-
treatment visits will occur at Weeks 1, 4, 8 
and 12. Post-treatment visits will occur at 
Weeks 4, 12 and 24 after last dose of VOSEVI. 
 
 
  
Test Product: 
SOF/VEL (sofosbuvir 400 mg/ velpatasvir 
100 mg). For subjects in the Virologic Failure 
Substdy, SOF/VEL/VOX (sofosbuvir 400 mg/ 
velpatasvir 100 mg/ voxilaprevir 100 mg). 
 
Dose and Mode of Administration: 
One tablet SOF/VEL daily with or without 
food for 12 weeks. For subjects in the 
Virologic Failure Substudy, one tablet 
SOF/VEL/VOX daily with food for 12 weeks. 

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Criteria for Evaluation: 
 
Efficacy: 
The primary efficacy endpoint is the 
proportion of subjects who achieve a 
sustained 
virologic 
response 
(SVR12). 
Secondary endpoints include proportion of 
subjects who achieve SVR24, the proportion 
of subjects with viral relapse or viral 
breakthrough and patient and graft survival 
at Week 36 (24 weeks after starting study 
drug).  
 
Safety: 
Safety will be assessed through the reporting 
of adverse events and clinical laboratory 
tests 
 
 
When the first 10 subjects reach treatment 
week 4, the lead investigators and the 
independent data and safety monitor will 
conduct a Safety Review. When these same 
subjects reach follow up week 12 (24 weeks 
after starting study drug), the lead 
investigators and the independent data and 
safety monitor will conduct another Safety 
Review.  
 
Statistical Methods: 
Sample size was selected to provide safety 
and efficacy data. The small size of the pilot 
study does not permit hypothesis testing. 
Descriptive statistics on the number and 
types of AEs 
will be recorded and 
presented. 
 
Safety Analysis: 
 
 
 
Safety analysis will include summaries of  
 
 
 
 
 
 
AEs and laboratory evaluations 
 
 
 

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BACKGROUND AND SCIENTIFIC RATIONALE 
 
In the Unites States, the number of patients listed for solid organ transplant 
dramatically exceeds the numbers of organs available and utilized for donation. 
For kidney transplant, mean waiting times are measured in years. There is a 4 % 
mortality on the kidney wait list, with much higher rates for diabetic and 
elderly candidates. On the liver wait list, the mortality rate is considerably 
higher, averaging about 20% at most centers. Numerous strategies are utilized to 
expand the standard donor pool for kidney or liver transplant, including using 
organs from deceased donors exposed to chronic viral infections (e.g. 
cytomegalovirus and hepatitis B virus), Public Health Services increased risk 
donors, older donors, donation after cardiac death, and livers with increased 
steatosis. 
 
Deceased solid organ donors with hepatitis C virus (HCV) infection represent 
another potential source of expanding the organ donor pool. HCV affects about 
1.6% of the general population in the United States.  The prevalence of HCV was more 
than triple this number for American organ donors from 2004 - 2008 (Armstrong). 
Among high-risk donors, who represent up to 30% of all donors,  the prevalence 
was as high as 18.2% (Ellingson, (Kucirka Am J Transplant 2009 PMID 20353475). 
Perhaps reflecting the ongoing opioid crises in the United States, in some organ 
procurement organization areas, nearly 15% of even the current general organ donor 
pool is HCV positive (personal communication, Alex Glazier, CEO, New England Organ 
Bank). As these donors are typically young, the organs may be higher quality than 
would be otherwise available from HCV negative donors. 
 
Historically, organs from HCV-positive donors have been underutilized. Reese, et al. 
identified 3273 HCV-antibody positive deceased kidney donors from 2005-2014 for 
whom organ donation was authorized (Reese). Only 2402/6546 (37%) of the donated 
kidneys were transplanted; 91% of the recipients had documented HCV infection. The 
other kidneys were discarded. In addition, as many as one third of solid organs may 
not be procured from potential donors who were HCV-antibody positive (Seem), 
presumably due to concerns they would not be utilized by any transplant center. 
 
In the past, this hesitancy to use HCV-positive organs reflected concerns about the 
negative liver and extrahepatic outcomes of refractory HCV infection in the setting of 
immunosuppression. Still, many centers in the United States have utilized hepatitis C-
positive solid organs for hepatitis C-positive recipients. For liver transplant, most 
studies have shown equivalent survival for those HCV-positive recipients who receive 
carefully selected HCV-positive livers, particularly if older donors (>55 years) and 
donor livers with fibrosis are avoided (Vargas, Marroquin, Berenguer). For kidney 
transplant, in one study the median waiting time for patients who accepted HCV-
positive kidneys was 469 days versus 856 days for patients who received HCV-negative 
organs (Kucirka 20353475). In the era before direct acting antiviral agents (DAAs), the 
reduced mortality on the kidney wait list may have been offset by some increase in 
adverse post-transplant outcomes (Morales, Kucirka Am J Kid, Gasink, Fabrizi).  

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The advent of safe and highly effective DAAs has revolutionized the treatment of 
HCV. In non-cirrhotic, immunocompetent patients, 12 weeks of treatment with the 
pan-genotypic regimen of sofosbuvir/velpatasvir (SOF/VEL) has demonstrated 
sustained virological response (SVR) rates above 94% for all HCV genotypes 
(Foster, Feld). In kidney transplant recipients with HCV, there are numerous 
publications showing excellent safety and near universal SVR using DAAs. In liver 
transplant recipients, including those with compensated cirrhosis, the SVR rates for all 
genotypes were 96-98% with sofosbuvir/ledipasvir with or without ribavirin. (Saab, 
Charlton, Manns) and at least 91% with sofosbuvir, daclatasvir and ribavirin 
(Poordad).  In a recent study of 79 liver transplant recipients with chronic genotype 1-
4 HCV infection treated with SOF/VEL,   SVR rates were greater than 93% for all 
genotypes, including genotype 1 subtypes (Agarwal). 
 
While there is ample precedent for using HCV-positive organs for HCV-positive 
recipients, utilizing an HCV-positive organ for an HCV-negative recipient has 
been done rarely and only in highly selected situations (Northup, Gasink, 
Gudmundsson). In an open-label pilot study, 10 HCV-negative kidney recipients 
received an HCV genotype-1 infected kidney (Goldberg). On day 3 after transplantation, 
all recipients had detectable HCV RNA. All 10 were cured with 12 weeks of the 
genotype-specific regimen of grazoprevir and elbasvir.   
 
The need to study using HCV positive organs for HCV negative recipients was identified 
in a recent position paper from the American Society of Transplantation (Levitsky). In 
this current pilot study, we will utilize kidneys and livers from HCV NAT positive donors 
for HCV-negative recipients. Pan-genotypic HCV therapy with sofosbuvir and 
velpatasvir (SOF/VEL) will be started usually within the first week (but up to 4 weeks 
per investigator discretion) after transplant and continued for 12 weeks. Unlike the 
pilot study in kidney transplant recipients described above, we will not restrict 
donation to donors with genotype 1 or 4 HCV. The justification for using a pan-
genotypic regimen is the imperative to start treating the HCV infection as soon as 
possible after transplant, potentially before commercial testing for HCV genotype 
would be available.  
 
In summary, this study has the potential to demonstrate that organs from HCV NAT 
positive donors can be used safely and effectively in HCV negative patients. Given the 
established safety and efficacy of pan-genotypic regimens such as SOF/VEL, we 
hypothesize that the post-transplant de novo HCV infections will be successfully cured 
with a favorable safety profile. The importance of this study is that it may demonstrate 
an effective way to increase the organ donor pool and to shorten the waiting time for 
patients being transplanted who might otherwise not receive an organ. 
 
Pharmacologic considerations. Velpatasvir is a substrate for Cytochrome p450 3A4 
(CYP3A4), CYP2C8 and CYP2B6 and a weak (P-glycoprotein, organic anion-
transporting polypeptide) to moderate (breast cancer resistance protein) transport 
inhibitor. It is moderately affected by potent inhibitors and to a greater extent, potent 

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inducers of enzyme/drug transporter systems (Mogalian). Based on this profile, which 
is similar to ledipasvir, clinically significant drug-drug interactions would not be 
expected for co-administration of SOF/VEL with tacrolimus, cyclosporine, 
corticosteroids and/or mycophenolate mofetil.  
 
One potential concern for using SOF/VEL in the early post-transplant setting may be 
the development of post-transplant acute kidney insufficiency. The labelling 
information states that the safety and efficacy of SOF/VEL have not been established in 
patients with severe renal impairment (estimated glomerular filtration rate < 30 
mL/min/1.73 m2) or ESRD requiring hemodialysis. However, post marketing data have 
characterized the safety of sofosbuvir-based therapy in patients with severe renal 
failure or on hemodialysis (Desnoyer, Dumortier) and specifically in the post-kidney 
(Beinhardt) and post-liver transplantation setting (Saab J Clin Gastro). Moreover, the 
principal investigators in this trial will use their discretion as to the exact timing of the 
initiation of DAA therapy and the subjects will be intensely monitored during the 
treatment and follow-up periods.  
 
Risk/Benefit Assessment. This study will provide information regarding the safety of 
efficacy of SOF/VEL in HCV negative liver and/or kidney transplant recipients with 
HCV NAT positive donors. The potential benefits of utilizing HCV NAT-positive organs 
are reduced morbidity and mortality compared to what would be expected from 
remaining on the transplant waiting lists until a suitable HCV negative organ would 
become available. Potential risks of this study include those related to unsuccessfully 
treated HCV infection. To mitigate these potential risks, antiviral therapy will be started 
usually within the first week (but up to 4 weeks per investigator discretion) after 
transplant and there will be close monitoring of laboratory values as well as AEs. In 
addition, in the event of virologic failure following treatment with SOF/VEL, subjects 
will be eligible for re-treatment with 12 weeks of sofosbuvir/velpatasvir/voxilaprevir 
(SOF/VEL/VOX) VOSEVI therapy in the Virologic Failure Substudy There will also be 
two Safety Reviews conducted by the independent data and safety monitor in 
conjunction with the lead investigators. While the potential benefits and risks must be 
confirmed in this pilot study, the data from the THINKER trial, the endorsement of such 
a study from the American Society of Transplantation, and the favorable safety profile 
of SOF/VEL provide strong rationale for a positive benefit/risk ratio in support of this 
study. 
 
Compliance. This study will be conducted in compliance with this protocol, Good Clinical 
Practice (GCP), and all applicable regulatory requirements. 
 
 
 
 
 
 

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OBJECTIVES 
 
Objective #1: To determine the efficacy of sofosbuvir/velpatasvir (SOF/VEL) 
therapy among HCV negative liver and/or kidney transplant recipients with HCV NAT 
positive donors.   
Hypothesis: SOF/VEL therapy initiated in the early post-transplant period provides a 
high rate of sustained virological response in HCV negative liver and/or kidney 
transplant recipients transplanted with HCV NAT positive donors. 
 
 
Objective #2: To determine the safety and tolerability of SOF/VEL therapy among HCV 
negative liver and/or kidney transplant recipients with HCV NAT positive donors.   
Hypothesis: SOF/VEL therapy initiated in the early post-transplant period is safe and 
well tolerated in HCV negative liver and/or kidney transplant recipients 
transplanted with HCV NAT positive donors. 
 
 
Objective #3: To compare the observed waiting time for transplant for HCV negative 
liver and/or kidney transplant recipients with HCV nucleic acid test (NAT) 
positive donors to the expected waiting time for transplant with HCV negative donors 
in participating regions. 
Hypothesis: Receiving a NAT positive liver and/or kidney substantially shortens the 
wait time for liver and/or kidney transplant. 
 
 
 
 
 
 

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STUDY DESIGN 
 
Description 
 
This is a prospective multicenter, open-label, proof of concept study being conducted 
at up to 6 American sites (See Appendix 2). The study aims to enroll up to 30 study 
subjects undergoing liver and/or kidney transplantation, at least 10 of them 
undergoing liver transplant and at least 10 undergoing kidney transplant.  
 
Potential study candidates will be identified through the active wait-list for liver of 
kidney transplant at each participating institution. The informed consent process for 
this trial is comprised of three steps: 
 
1) Pre-screening: As part of pre-transplant evaluation, treating nephrologists and 
hepatologists will have a detailed discussion with their patients regarding high-risk 
donors, including those who are HCV NAT-positive. For HCV negative patients who 
express interest in receiving an HCV NAT-positive donor, their treating hepatologist or 
nephrologist will refer them to the principal investigator or co-investigator for this 
study.  
 
2. Informed consent: the principal investigator, or co-investigator, will review the 
potential risks and benefits of participating in this trial, including a discussion regarding  
HCV treatment and complications of unsuccessfully treated post-transplantation HCV, 
including graft loss, fibrosing cholestatic hepatitis, cirrhosis and death. The discussion 
will also describe that organ donors in the trial might be classified as Public Health 
Service elevated risk for window infection with HIV. This step of the informed consent 
process will include documentation that each of these elements has been reviewed with 
the patient who understands and has ample opportunity to have all of their questions 
and concerns addressed. Participants who are deemed eligible and sign consent will be 
rendered eligible for HCV-viremic kidney or liver offers through an opt-in mechanism 
in the allocation system administered by the Organ Procurement and Transplantation 
Network/United Network for Organ Sharing (OPTN/UNOS). 
 
3. Confirmation of Informed Consent: eligibility and subject’s willingness to proceed 
with an HCV-positive donor will be re-confirmed by the subject signing the 
confirmation of consent block on the original consent form.  This will be documented 
by study staff within 24 hours before the planned liver or kidney transplant (the “Pre-
Transplant day”) with a review of the potential risks and benefits of participating in this 
trial, including a discussion regarding HCV treatment and complications of 
unsuccessfully treated post-transplantation HCV, complications including graft loss, 
fibrosing cholestatic hepatitis, cirrhosis and death. This step of the informed consent 
process will include documentation that each of these elements has been reviewed with 
the patient who understands and has ample opportunity to have all of their questions 
and concerns addressed.  
 
On the Pre-Transplant Day, after it has been confirmed that both the recipient and the 

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donor meet the eligibility criteria, the recipient will proceed with transplant surgery. 
 
Treatment Regimen. Study medication will be initiated usually within the first week 
post-transplant (but up to 4 weeks post-transplant per investigator discretion). HCV 
viremia will be confirmed before study treatment is started. Day 1 is defined as the day 
that the study drug commences. Subjects will be administered SOF/VEL (Sofosbuvir 
400 mg/Velpatasir 100 mg fixed-dose combination) once daily with or without food for 
12 weeks. 
 
             Administration of study medication may be permanently discontinued at any time 
during the treatment period due to a clinical or laboratory event at the discretion of 
the investigator. There is no option for SOF/VEL dose reduction. If subjects miss a 
dose (or doses) of study drug, they will still complete the full 84 days of study drug.  
 
 
Subjects who meet any of the following criteria must stop all study medications: 
x Any medical condition, in the opinion of the investigator, where the risks of 
continuing the study medications outweighs the benefits; 
x Any Grade 4 adverse event assessed as related to SOF/VEL. 
 
Immunosuppressant therapy will be per the individual center’s usual treatment 
protocol. Immunosuppressant levels will be done and immunosuppressant dosages 
will be recorded on treatment days 3 and 7; weekly during the treatment period; at 
the end of treatment; and 4, 12 and 24 weeks after discontinuation of therapy. 
Unscheduled therapeutic drug levels may be obtained more frequently at the 
discretion of the investigator. Modifications in immunosuppression regimen will be at 
the discretion of the investigator. 
 
Efficacy. Serial quantitative HCV RNA testing will be performed by day 7 after 
transplant if study medication has not been started, Day 1, on treatment weeks 
1 and 4; end of treatment; and weeks 4, 12 and 24 after discontinuation of therapy.  
 
Safety. Adverse events (AEs) will be recorded for all patients who receive a NAT-
positive HCV organ through 4 weeks after the last dose of study drug.  Serious 
adverse events (SAEs) will be reported to the lead investigators and the independent 
data and safety monitor within 24 hours of recognition by study staff. SAEs will be 
collected for the entire duration of the study. After the 10th study subject has 
reached treatment week 4, the lead investigators and the independent data and 
safety monitor will conduct a safety and efficacy review of all safety and efficacy data 
to date. When these same subjects reach follow up week 12 (corresponding to 24 
weeks after starting study drug), the lead investigators and the independent data 
and safety monitor will conduct another safety and efficacy review. 
 
Virologic Failure Substudy. In the event of virologic failure following treatment with 
SOF/VEL, subjects will be eligible for re-treatment with 12 weeks of 
sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) VOSEVI therapy in the Virologic 

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Failure Substudy.  These subjects must complete their Day 1 visit within 30 days of 
documentation of virologic failure. Day 1 is defined as the day that the SOF/VEL/VOX 
commences. Subjects will be administered SOF/VEL/VOX (Sofosbuvir 400 
mg/Velpatasvir 100 mg/Voxilaprevir 100 mg fixed-dose combination) once daily with 
food for 12 weeks. SOF/VEL/VOX is not to be co-administered with cyclosporine. On-
treatment visits will occur on Weeks 1, 4, 8 and 12. Post-treatment visits will occur at 
Weeks 4, 12 and 24 after last dose of SOF/VEL/VOX. There is no option for 
SOF/VEL/VOX dose reduction. If subjects miss a dose (or doses) of study drug, they 
will still complete the full 84 days of study drug. 

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SUBJECT POPULATION 
 
This study will enroll approximately 30 HCV negative subjects  
 
Inclusion criteria: 
1.    Adult (≥ 18 year-old), wait-listed for primary kidney or liver transplant  
       without a potential suitable living donor or for simultaneous liver kidney 
       transplant; 
2.    HCV non-infected at the time of transplant. Subjects who were previously 
       HCV infected but who have had documented SVR12 are eligible to  
       participate; 
3.   Able to provide informed consent; 
4.   Agree to use two methods of birth control during the study;  
5.   Donor characteristics: serum HCV NAT-positive and negative for hepatitis  
       B surface antigen. Subjects who receive an organ from hepatitis B core 
       antibody positive donors may be included, but will need to remain on 
       nucleos(t)ide analogues for at least the study treatment period and follow- 
       up period; 
•     For liver transplant: pre-donation liver biopsy with no fibrosis (F0) 
        or minimal fibrosis (F1); 
•     For kidney transplant: kidney donor profile index < 85%. 
 
Exclusion criteria: 
1. Donor and/or recipient HIV infection 
2. Subject pregnant or nursing 
3. Donor and/or recipient Hepatitis B surface antigen positive 
4. Kidney-pancreas transplant 
5. Single organ liver recipients who received hemodialysis for more than 7 
days prior to liver transplantation 
6. Kidney recipients:  
• on dialysis for > 5 years at time of Screening 
• subjects sensitized with panel reactive antibody > 80% 
• for single organ kidney transplant, subjects with advanced liver 
fibrosis (Knodell stage 3) or cirrhosis  
7. Individuals b e i n g  t r e a t e d  w i t h  a n d  n e e d i n g  t o  c o n t i n u e  
rifabutin, 
rifampin, 
carbamazepine, 
phenytoin, 
phenobarbital, 
oxcarbazepine, St. John’s wort (Hypericum perforatum), medium- or high-
dose rosuvastatin or atorvastatin, or high-dose proton pump inhibitors (See 
Concomitant Medications).  
8. Individuals treated with amiodarone within 42 days of organ transplant. 
 
 

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INESTIGATIONAL MEDICINAL PRODUCTS 
 
Study drugs to be distributed to centers will be labeled to meet applicable requirements 
of the United States Food and Drug Administration. Study drug should be stored at 
controlled room temperature of 25°C (77°F); excursions are permitted between 15°C and 
30°C (59°F and 86°F). Until dispensed to study subjects, all bottles of study drugs should 
be stored in a securely locked area, accessible only to authorized site personnel. To 
ensure the stability and proper identification, study drugs should not be stored in a 
container other than the container in which they were supplied.  
 
SOF/VEL will be provided by Gilead Sciences (Foster City, California). Subjects will take 
one tablet once daily at approximately the same time each day with or without food. If 
needed for virologic failure following treatment with SOF/VEL, re-treatment with, 
SOF/VEL/VOX  (VOSEVI) will be provided by Gilead Sciences (Foster City, California) and 
administered at the discretion of the principal investigator in the Virologic Failure 
Substudy. VOSEVI is not to be co-administered with cyclosporine. 
 
Prior and Concomitant Medications  
Concomitant medications of interest will be recorded throughout the treatment period 
and will include immunosuppressants, proton pump inhibitors, H2 antagonists, and 
beta-blockers. Immunosuppressant doses will be recorded until follow up week 24. 
Concomitant medications, which are not recommended to be taken with the study 
drug, include, but are not limited to: rifabutin, rifampin, carbamazepine, phenytoin, 
phenobarbital, oxcarbazepine and St. John’s wort (Hypericum perforatum). 
Amiodarone must be discontinued at least 6 weeks before study drug commences and 
is prohibited during the study treatment period. For subjects who must be treated with 
statins during the treatment period, low dose statins (such as pravastatin) may be used 
per package insert. H2-receptor antagonists (in doses not to exceed famotidine 40 mg 
bid) may be administered simultaneous with or 12 hours apart from SOF/VEL. If it is 
medically necessary to co-administer with proton pump inhibitors, SOF/VEL should 
be administered with food and taken 4 hours before the dose equivalent to 20 mg 
omeprazole daily.  
 
For subjects in the Virologic Failure Substudy, concomitant medications of interest will 
be recorded throughout the treatment period and will include immunosuppressants, 
proton pump inhibitors, H2 antagonists, and beta-blockers. Immunosuppressant doses 
will be recorded until follow up week 24. Concomitant medications, which are not 
recommended to be taken with SOF/VEL/VOX, include, but are not limited to: 
rifabutin, carbamazepine, phenobarbital, oxcarbazepine, rosuvastatin, and St. John’s 
wort (Hypericum perforatum). SOF/VEL/VOX is not to be co-administered with 
cyclosporine. Co-administration with rifampin is contraindicated. Amiodarone must 
be discontinued at least 6 weeks before SOF/VEL/VOX commences and is prohibited 
during the study treatment period. For subjects who must be treated with statins 
during the treatment period, low dose statins (such as pravastatin) may be used per 
package insert. H2-receptor antagonists (in doses not to exceed famotidine 40 mg bid) 
may be administered simultaneous with or 12 hours apart from SOF/VEL/VOX. If it is 

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medically necessary to co-administer with proton pump inhibitors, SOF/VEL/VOX can 
be administered simultaneous with 20 mg omeprazole daily. 
 
Investigational Medicinal Product Accountability 
The investigator or designee (e.g. pharmacist) is responsible for ensuring adequate 
accountability of all used and unused study drug. This includes acknowledgement of 
receipt of each shipment of study drug, dispensing records and returned or destroyed 
study drug. Dispensing records will document quantities received from Gilead Sciences 
and quantities dispensed to subjects, including the lot/kit number, date dispensed, 
subject identification number, and the initials of the person dispensing the medication. 
All unused study drug dispensed to subjects must be returned to the site. 
 
Investigational Medicinal Product Return or Disposal 
If a site has a standard operating procedure (SOP) for drug destruction, the site may 
destroy unused study drug in accordance with the site’s SOP. 

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STUDY PROCEDURES 
 
The study procedures to be conducted for each subject enrolled in the study are 
presented in tabular form in Appendix 3 and described in the text that follows. 
 
Subject Enrollment 
It is the responsibility of the site investigator to ensure that subjects are eligible to 
participate in the study prior to enrollment and throughout the study.  Documentation 
of the personally signed and dated the informed consent (ICF), using the study-specific 
ICF, is required before initiating the Screening process. After written informed consent  
is obtained and eligibility to participate established, investigative site personnel will 
obtain the subject’s identification number.  
 
Documentation of the personally signed and dated confirmation of consent section, 
using the subject’s original signed consent, required before proceeding with HCV NAT-
positive organ transplant. After confirmation of consent has been obtained and eligibility 
to participate confirmed, investigative site personnel will obtain the subject’s study 
identification number (ST-ID). 
 
Clinical Evaluations 
Clinical data from the pre- and post-transplant assessment will be reviewed from the 
electronic medical record. 
 
Recipient data Pre-Transplant Day: 
x Age, sex, ethnicity, race, weight and body mass index; 
x Type of transplant: liver, kidney, or simultaneous liver/kidney; 
x Primary indication for transplant; 
x Serum blood urea nitrogen, creatinine, estimated glomerular filtration rate, INR, 
sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, 
albumin, hemoglobin, serum or urine hCG for females of childbearing potential, 
HCV quantitative RNA, hepatitis B surface antigen and hepatitis B core antibody 
total; 
x For liver transplant, presence or absence of hepatocellular carcinoma; 
x For liver transplant, presence and severity of hepatic encephalopathy and ascites;  
x For liver transplant, Lab MELD-Na, MELD exception score (if any) and Child-Pugh 
score (Appendix 4) at the time of transplant; 
x For kidney transplant, panel reactive antibody. 
 
Donor data Pre-Transplant Day: 
x Age, sex, cause of death (brain or cardiac); 
x UNOS region; 
x For kidney transplant, kidney donor profile index; 
x HCV RNA NAT testing, HCV genotype, hepatitis B core antibody;  
x Sample for possible baseline resistance associated substitutions; 
x Sample for serum banking; 
x Liver biopsy: stage of fibrosis and estimated percentage of fat. 

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Transplant surgery data: 
x For liver transplant, surgical technique: piggyback vs other; 
x Cold and warm ischemia times (in hours); 
x Time and date of transplant (time of reperfusion for liver transplant). 
 
Recipient data in the post-transplant period: 
x Time and date of first administration of study drug; 
x Interval (in days) between time of transplant and time and date of first 
administration of study drug;  
x HCV RNA on day 3 after transplant, If result is “HCV RNA not detected”, 
HCV RNA to be repeated on day 7 after transplant and then weekly until 
HCV RNA is detected; 
x Serum blood urea nitrogen, creatinine, estimated glomerular filtration rate, INR, 
sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, 
albumin, hemoglobin, and immunosuppressant level and dosage on treatment 
days 1, 3, and 7; weekly throughout the treatment period; at the end of 
treatment; and 4, 12, and 24 weeks after discontinuation of therapy; 
x serum or urine serum hCG for females of childbearing potential at weeks 4 and 
8 and at end of treatment; 
x Serial quantitative HCV RNA testing will be done on Day 1, treatment weeks 
1 and 4; end of treatment; and weeks 4, 12 and 24 after discontinuation of 
therapy; 
x Testing for resistance associated substitutions if virologic failure; 
x Length of index hospital stay (in days);  
x Number, length and reason for subsequent post-transplant admissions (if 
any); 
x Concomitant medications of interest; 
x Interruptions of antiviral therapy > 72 hours. 
 
Resistance Monitoring 
Plasma samples will be collected for viral sequence analysis and possible phenotypic 
testing from the donor at baseline and from the recipient at treatment failure (if it 
occurs).  
 
Subject identification number assignment 
Subject Identification (ID) numbers will be assigned sequentially at each site to each 
subject who has signed informed consent (Part 1). A new subject ID number (indicated 
by the prefix “ST-” followed by the ID number previously assigned at the time of signing 
informed consent Part 1) will be assigned when eligibility has been confirmed, the 
subject has signed informed consent Part 2 and the subject undergoes transplant 
surgery. If a patient discontinues from the study, the Subject ID Number will not be 
reused.  
 
 

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Study Visits 
 
1st visit: Screening Visit 
 
This visit is anticipated to require 1 hour of the subject’s time. During this visit, the 
following will take place: 
x Review of eligibility criteria; 
x Informed consent; 
x Assignment of subject ID number. 
 
2nd visit: Pre-Transplant Day 
 
Screening/baseline visit is anticipated to require 1 hour of the subject’s time. During 
this visit, the following will take place: 
x Confirmation of consent signed and documentation of subject’s willingness to 
proceed with HCV positive donor;  
x Review of eligibility criteria; 
x Laboratory tests including Quantitative HCV RNA, hepatitis B surface antigen, 
Serum blood urea nitrogen, creatinine, estimated glomerular filtration rate, INR, 
sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, 
albumin, hemoglobin, serum or urine hCG for females of childbearing potential; 
x Assessment of presence and severity of ascites and hepatic encephalopathy; 
x Assignment of subject ST-ID number. 
 
3rd visit: Day 3 after transplant  
 
x Quantitative HCV RNA. (if “HCV RNA not detected”, repeat day 7 after transplant. 
If result is “HCV RNA not detected”, HCV RNA to be repeated weekly after 
transplant until detected) 
 
Day 1 (The day study drug commences) 
 
x Confirm recipient still meets eligibility criteria; 
x First administration of study drug; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline phosphatase, total bilirubin, albumin, hemoglobin, immunosuppressant 
level, and quantitative HCV RNA.; 
x Concomitant medications of interest including immunosuppressant; 
 
 
 
 

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On HCV treatment visits 
 
These 7 visits will occur in the hospital or at the outpatient clinic per the schedule of 
assessments on Day 3, Week 1, Week 2, Week 3, Week 4, Week 6 and Week 8.  It is 
anticipated that each of these visits will require 30 minutes of the subject’s time. The 
following events will take place: 
x Clinical examination; 
x Laboratory tests including s erum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, sodium, potassium, bicarbonate, ALT, AST, alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
INR, 
and 
immunosuppressant level; 
x Serum or urine hCG for females of childbearing potential at weeks 4 and 8; 
x Quantitative HCV RNA on weeks 1 and 4; 
x Hepatitis B surface antigen on week 4; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
Laboratory only visits 
 
These 5 visits will occur at either the transplant center laboratory or a local laboratory per 
the schedule of assessments on Weeks 5, 7, 9, 10, and 11. These visits may also include a 
telephone call to confirm the dose of the immunosuppressant medication. It is 
anticipated that each of these visits will require 15 minutes of the subject’s time.  
 
End of HCV treatment visit 
 
This visit will occur at the end of antiviral treatment at the outpatient clinic. It is 
anticipated to require 30 minutes of the subject’s time. The following events will take 
place: 
x Clinical examination; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
and 
immunosuppressant level; 
x Serum or urine hCG for females of childbearing potential;  
x Quantitative HCV RNA; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
Post-HCV treatment Follow Up visits 
 
These three visits will occur at 4, 12, and 24 weeks after discontinuation of antiviral 
treatment. Follow Up visits 4 and 12 will take place in the outpatient clinic while Follow 
Up Week 24 will occur either in the transplant clinic or local laboratory and may also 
include a telephone call to confirm the dose of the immunosuppressant medications.  
Each visit is anticipated to require 15-30 minutes of the subject’s time. The following 

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events will take place: 
x Clinical examination (Follow Up visits 4 and 12 only;) 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, sodium, potassium, bicarbonate, ALT, AST, alkaline 
phosphatase, total bilirubin, albumin, hemoglobin, INR, and 
immunosuppressant level; 
x Serum or urine hCG for females of childbearing potential at Follow Up Week 4; 
x Hepatitis B surface antigen at Follow Up Week 4; 
x Quantitative HCV RNA; 
x Concomitant medications of interest including immunosuppressant on follow 
up week 4; 
x Immunosuppressant dose; 
x Assessment for AEs on Follow Up Week 4. 
 
Early End of Treatment or Treatment Failure visit 
 
This unscheduled visit will occur if the subject discontinues study drug prior to 
planned end of treatment for any reason OR the subject has been determined to have 
viral breakthrough or relapse. This visit must occur within 2 weeks of stopping 
treatment or recognition of viral breakthrough or relapse.  Each visit is anticipated to 
require 30 minutes of the subject’s time. The following events will take place: 
x Clinical examination; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
and 
immunosuppressant level; 
x Quantitative HCV RNA and HCV genotype; 
x Testing for HCV resistance associated substitutions; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
Visit Windows 
The study visit windows are +/- 2 days for the day 3 visit, +/- 4 days for the weekly on 
treatment visits and end of treatment visit, and +/- 10 days for the follow up visits 
 
End of Study Definition 
End of study is considered to be completion of the Follow Up Week 24 Visit. Subjects 
who enter the Virologic Failure Substudy will also follow an additional  
 
 
 
Schedule of Assessments for the Virologic Failure Substudy (See Appendix 3a). 
 
Sample Storage 
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human genetic testing will be performed without express consent of the study subjects. 
At the conclusion of this study, these samples may be retained in storage per individual 
institution policy. 
 
Study Visits for Virologic Failure Substudy 
Study visits for the Virologic Failure Substudy may coincide with visits for the main 
study. When this occurs, laboratory assessments for the main study may also be used for 
the Virologic Failure Substudy. 
 
Day 1 (The day SOF/VEL/VOX commences) 
 
x First administration of study drug; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline phosphatase, total bilirubin, albumin, hemoglobin, immunosuppressant 
level, and quantitative HCV RNA.  
x Concomitant medications of interest including immunosuppressant; 
 
 
On HCV treatment visits 
 
These 3 visits will occur in the outpatient clinic per the schedule of assessments on 
Week 1, Week 4, and Week 8.  It is anticipated that each of these visits will require 30 
minutes of the subject’s time. The following events will take place: 
x Clinical examination; 
x Laboratory tests including s erum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, sodium, potassium, bicarbonate, ALT, AST, alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
INR, 
and 
immunosuppressant level; 
x Serum or urine hCG for females of childbearing potential at weeks 4 and 8; 
x Quantitative HCV RNA on weeks 1 and 4; 
x Hepatitis B surface antigen on week 4; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
End of HCV treatment visit 
 
This visit will occur at the end of antiviral treatment at the outpatient clinic. It is 
anticipated to require 30 minutes of the subject’s time. The following events will take 
place: 
x Clinical examination; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
and 
immunosuppressant level; 
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x Quantitative HCV RNA; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
Post-HCV treatment Follow Up visits 
 
These three visits will occur at 4, 12, and 24 weeks after discontinuation of antiviral 
treatment. Follow Up visits 4 and 12 will take place in the outpatient clinic while Follow 
Up Week 24 will occur either in the transplant clinic or local laboratory and may also 
include a telephone call to confirm the dose of the immunosuppressant medications.  
Each visit is anticipated to require 15-30 minutes of the subject’s time. The following 
events will take place: 
x Clinical examination (Follow Up visits 4 and 12 only;) 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, sodium, potassium, bicarbonate, ALT, AST, alkaline 
phosphatase, total bilirubin, albumin, hemoglobin, INR, and 
immunosuppressant level; 
x Serum or urine hCG for females of childbearing potential at Follow Up Week 4; 
x Hepatitis B surface antigen at Follow Up Week 4; 
x Quantitative HCV RNA; 
x Concomitant medications of interest including immunosuppressant on follow 
up week 4; 
x Immunosuppressant dose; 
x Assessment for AEs on Follow Up Week 4. 
 
Early End of Treatment or Treatment Failure visit 
 
This unscheduled visit will occur if the subject discontinues study drug prior to 
planned end of treatment for any reason OR the subject has been determined to have 
viral breakthrough or relapse. This visit must occur within 2 weeks of stopping 
treatment or recognition of viral breakthrough or relapse.  Each visit is anticipated to 
require 30 minutes of the subject’s time. The following events will take place: 
x Clinical examination; 
x Laboratory tests including serum blood urea nitrogen, creatinine, estimated 
glomerular filtration rate, INR, sodium, potassium, bicarbonate, ALT, AST, 
alkaline 
phosphatase, 
total 
bilirubin, 
albumin, 
hemoglobin, 
and 
immunosuppressant level; 
x Quantitative HCV RNA and HCV genotype; 
x Testing for HCV resistance associated substitutions; 
x Concomitant medications of interest including immunosuppressant; 
x Assessment for AEs. 
 
Visit Windows 
The study visit windows are +/- 2 days for the day 3 visit, +/- 4 days for the weekly on 
treatment visits and end of treatment visit, and +/- 10 days for the follow up visits 

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End of Study Definition 
End of the Virologic Failure Substudy study is considered to be completion of the Follow 
Up Week 24 Visit. 
 
Sample Storage 
Residual biological samples will be frozen and stored at the individual study sites. No 
human genetic testing will be performed without express consent of the study subjects. 
At the conclusion of this study, these samples may be retained in storage per individual 
institution policy. 
 

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ADVERSE EVENTS AND TOXICICTY MANAGEMENT 
 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a study subject 
administered a medicinal product. It does not necessarily have a causal relationship with 
the treatment. Preexisting events that increase in severity or change in nature during 
participation in a clinical study are considered AEs.  
 
A serious adverse event (SAE) is defined as an event that results in the following: 
x Death; 
x Life threatening event in which the subject was at risk of death at the time of the 
event; 
x Inpatient hospitalization or prolongation of existing hospitalization; 
x Persistent or significant disability/incapacity; 
x A congenital anomaly/birth defect; 
x A medically important event or reaction that may jeopardize the subject or may 
require intervention to prevent one of the other outcomes constituting SAEs. 
 
Safety monitoring 
Safety data will be collected for all subjects who sign their confirmation of consent at 
the end of the consent form and undergo a NAT-positive transplant through 4 weeks 
after the last dose of study drug. The Principal Investigators will continuously monitor 
the study for safety. An independent data and safety monitor will act in an advisory 
capacity to monitor participant safety and data quality, as well as to evaluate the 
progress of the study. 
 
The lead investigators will be responsible for holding periodic meetings to update the 
study group regarding enrollment, study conduct, and potential safety issues that may 
affect subjects’ decisions about enrolling or continuing study drug throughout the 
study, including, but not limited to: AEs, SAEs, and new treatments that come available. 
 
Clinical Laboratory Abnormalities. Laboratory abnormalities without clinical 
significance are not recorded as AEs or SAEs. However, laboratory abnormalities that 
require medical or surgical intervention or lead to investigational medicinal product 
interruption or discontinuation must be recorded as an AE, as well an SAE, if applicable. 
In addition, laboratory assessments that are associated with signs and/or symptoms 
must be recorded as an AE, or SAE, if applicable. If the laboratory abnormality is part of 
a syndrome, record the diagnosis (i.e. anemia), not the laboratory abnormality (i.e. 
decreased hemoglobin). 
 
Adverse Events. The investigator, or sub-investigator, is responsible for assessing AEs 
and SAEs for causality and severity. AEs will be graded using the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 4.03. This grading scale can be found at 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf. 
 

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For AEs associated with laboratory abnormalities, the event should be graded on the 
clinical severity in the context of the underlying conditions. All AEs, regardless of cause 
or relationship, must be collected and reported in the eCRF database as instructed. 
 
SAEs will be collected for the duration of the study. SAEs related to study drug, graft 
loss, or death will be reported to the lead investigators and the independent data 
and safety monitor within 24 hours of recognition by study staff. Stable chronic 
conditions that are present prior to the Pre-Transplant Day and do not worsen during 
the treatment period and safety follow up period are not considered adverse events. 
 
Safety Review. When the first 10 study subjects reach treatment week 4, the lead 
investigators and the independent data and safety monitor will conduct a safety and 
efficacy review. When these subjects reach follow up week 12 (24 weeks after 
starting study drug), the lead investigators and the independent data and safety 
monitor will conduct another safety and efficacy review. 
 
Early termination: Participants may withdraw their consent to participate in this 
study at any time after they sign informed consent. Principal investigators can 
terminate participant(s) from the study for safety concerns. Subjects who take at least 
one dose of study drug and do not complete the planned 12 weeks of treatment will 
come for an early end of treatment visit.

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STATISTICAL CONSIDERATIONS 
 
Analysis Objectives 
The primary objective of this study is to determine the efficacy of SOF/VEL in viral 
eradication among HCV negative liver and/or kidney transplant recipients with HCV 
NAT positive donors. 
 
The secondary objective of this study is to determine the safety and tolerability of all 
SOF/VEL among HCV negative liver and/or kidney transplant recipients with HCV NAT 
positive donors.   
 
The exploratory objective of this study is to compare the observed waiting time for 
transplant for HCV negative liver and/or kidney transplant recipients with HCV NAT 
positive donors to the expected waiting time for transplant with HCV negative donors 
at the participating centers. 
 
Primary Efficacy Endpoint 
The proportion of participants with SVR 12 defined as HCV RNA < lower limit of 
quantification 12 weeks after last dose of antiviral therapy.  
 
Secondary Endpoints: 
x Proportion of subjects with SVR24 defined as HCV RNA < lower limit of 
quantification 24 weeks after last dose of antiviral therapy; 
x Proportion of subjects with viral relapse defined as HCV RNA <LLOQ at end of 
treatment with subsequent quantifiable HCV RNA; 
x Proportion of participants with on-treatment virologic breakthrough defined as 
> 1 log increase in viral RNA after treatment week 1;  
x Proportion of subjects who prematurely discontinue antiviral therapy before 
the planned end of treatment; 
x Patient and graft survival at 6 months post-transplant. 
 
Exploratory Endpoint 
Change in wait time for kidney and/or liver transplant based on UNOS data for the 
participating regions.   
 
Analysis Sets 
The primary analysis set for safety and efficacy analyses includes all subjects who 
undergo liver and/or kidney transplant after signing Part 2 of the Informed Consent. 
Treatment-emergent data will be analyzed and defined as data collected from the first 
dose of study drug through the date of the last dose of study drug plus 30 days. 
 
Data Handling Conventions 
Missing data will not be imputed other than for quantitative HCV PCR. If a quantitative 
PCR is missing, the value will be imputed as LLOQ if the viral load before and after are 
both LLOQ.  
 

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Efficacy Analysis 
 
Primary and Secondary Endpoints 
No formal hypothesis testing will be performed, as this is an exploratory study. No 
inferential statistics or statistical comparisons are planned for efficacy endpoints. All 
subjects who undergo liver and/or kidney transplant with a nucleic acid test positive 
organ will be included in the analysis. We assume that none of the subjects will 
achieve SVR 12 without any antiviral therapy. The existing data for SOF/VEL have 
demonstrated a SVR rate above 94% in non-cirrhotic patients. We anticipate a 
similar SVR rate for our study. Along with the percentage of patients with SVR12, a 
two-sided 95% confidence interval (CI) is constructed by using the Clopper-Pearson 
method. With a sample size of 30 patients, if the SVR12 rate is 90%, the lower bound 
of the 95% CI would be 79% and the upper bound of the 95% CI would be 100%. 
 
Exploratory Endpoint 
Shorter wait time from listing to transplant is a potential benefit of accepting a HCV 
positive organ. To characterize wait time among HCV positive organ recipients, mean 
wait time in log10 days will be calculated separately for liver and kidney transplant 
recipients. With a sample size of 10, 15, or 20 patients per HCV positive organ type and 
a standard deviation of 1 log10 days of wait time, we have 80% power to obtain a two-
sided 95% CI half-width of 8, 5, and 4 days, respectively (CI half-width of 0.9, 0.7, and 
0.6 log10 days).  
 
To explore wait time by acceptance of HCV positive versus negative organs, wait time 
would be collected for the HCV positive organ recipient and the next HCV negative organ 
recipient at the transplant center, matched on blood type, gender, and transplant MELD 
(+/-5) for liver recipients and KDPI (+/- 0.25) for kidney recipients. Mean wait time in 
log10 days for a HCV positive versus negative organ would be compared separately 
among liver and kidney recipients. We anticipate obtaining wait time on 60 transplant 
recipients (at least 20 liver and 20 kidney recipients). For a two-sided paired t-test 
assuming an alpha level of 0.05, we estimate having 80% power to detect a mean 
difference in wait time of 20, 10, and 8 days for sample sizes of 20, 30, and 40 patients, 
respectively. 
 
Safety Analysis 
Safety will be assessed during the study through the reporting of AEs and by clinical 
laboratory tests at various time points during the study. Concomitant medication usage 
will also be assessed throughout the study. Descriptive statistics on the number and 
types of AEs will be recorded and presented in a tabular format. Treatment-emergent 
AEs (TEAEs) will also be summarized by relationship to study drug and severity. In 
addition, TEAEs leading to premature discontinuation of the study drug will be 
summarized and listed. Liver or kidney grade 3 or 4 laboratory abnormalities will be 
described in the narrative. 
 
Independent Data and Safety Monitor (IDSM) 
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or other conflict of interest with the trial. The IDSM will review the progress of the study, 
perform interim review of safety data, and provide recommendations whether the 
nature, frequency, and severity of AEs associated with the study warrant the early 
termination of the study in the best interests of the participants, whether the study 
should continue as planned, or the study should continue with modifications. The IDSM 
will also consider factors external to the study when relevant information becomes 
available, such as scientific or therapeutic developments that may have an impact on the 
safety of the participants or the ethics of the trial. When the first 10 study subjects reach 
treatment week 4, the lead investigators and the IDSM will conduct an open safety 
and efficacy review. When these same subjects reach follow up week 12 (24 weeks 
after starting study drug), the lead investigators and the IDSM will conduct another 
open safety and efficacy review. The IDSM will make recommendations to the lead 
investigators, and, if required, to the Food and Drug Administration concerning 
continuation, termination, or other modifications of the trials based on the observed 
beneficial or adverse effects of the treatment under study.  
 

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RESPONSIBILITIES 
 
Investigator Responsibilities 
 
The Principal Investigators will be responsible for recruiting study personnel, 
obtaining REB/IRB approval, ensuring clinic staffs are informed about the study, 
and supervising study activities. The study personnel will be responsible for: 
identifying 
participants, 
obtaining 
informed 
consent, confirming eligibility, 
monitoring compliance, conducting study visits, ensuring subjects have regular 
follow-up, encouraging attendance at visits, and collecting subject data. 
 
Study-wide coordination 
 
The Lead Investigators will be responsible for: 
1. Holding periodic meetings to update the study group regarding enrollment, 
study conduct, and potential safety issues that may affects the patient’s decisions 
about enrolling or continuing study drug throughout the study; 
2. Conducting safety reviews with the IDSM after the first 10 subjects reach 
treatment week 4, and after the first 10 subjects reach Follow Up week 12; 
3. Distributing the recommendations from the safety reviews to all co-
investigators and IRBs associated with the study; 
4. Supervising data management and analysis. 
 
Quality Control and Assurance 
 
It is the responsibility of the Principal Investigators to ensure the quality of 
computerized data for this study. Information documents will be specifically developed 
and the data will be collected securely.  For each subject consented, an electronic case 
report form (eCRF) will be completed by an authorized study staff member. eCRFs 
should be completed on the day of the subject visit. The eligibility criteria eCRF should 
be completed only after all data related to eligibility have been received. Investigators 
will ensure that entries accurately reflect the information in the source documents. The 
site coordinator is responsible for responding to queries in a timely manner and 
providing reasons for updates, as needed.  All records will be kept in a secure location 
and will only be available only to the study investigators and assigned research staff. 
Center specific research ethics approval will be obtained before initiating the study at 
that center. 
 
Ethical Considerations 
 
ICH Guidance E6: Good Clinical Practice: Consolidating Guideline/ Declaration of 
Helsinki 
 
The conduct of this study will conform to the International Conference for 
Harmonization and Good Clinical Practice (ICH-GCP) regulations and guidelines and 
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all the study centers’ institutional review boards. 
 
Research Ethics Board/ Institutional Review Board 
 
A copy of the protocol (including protocol amendments), all versions of the informed 
consents, other information to be completed by subjects such as questionnaires, and 
any proposed advertising/ recruitment materials will be reviewed and approved by 
the center’s REB/IRB prior to implementation of the study. The investigator will 
notify the REB/IRB of violations from the protocol and serious adverse events. 
 
Informed Consent Process 
 
The informed consent process for this trial is comprised of three steps:  
 
1) Pre-screening: As part of pre-transplant evaluation, treating n e p h r o l o g i s t s  
a n d  hepatologists will have a detailed discussion with their H C V  n e g a t i v e  
patients regarding high-risk donors, including those who are HCV NAT-positive. 
For patients who express interest in receiving an HCV NAT-positive donor, their 
treating hepatologist or nephrologist will refer them to the principal investigator 
or co-principal investigator for this study. 
 
2) Informed Consent: The principal investigator or co-principal investigator will review 
the potential risks and benefits of participating in this trial, including a discussion 
regarding HCV treatment and complications of unsuccessfully treated post-
transplantation HCV, including graft loss, fibrosing cholestatic hepatitis, cirrhosis and 
death. The discussion will also describe that organ donors in the trial might be classified 
as Public Health Service elevated risk for window infection with HIV. This step of the 
informed consent process will include documentation that each of these elements has 
been reviewed with the patient who understands and has ample opportunity to have 
all of their questions and concerns addressed. Part 1 of the informed consent, 
describing in detail the study procedures, anticipated benefits and potential risks, 
will be given to each participant and written documentation of informed consent is 
required prior to starting the study. Subjects must voluntarily sign and date Part 1 of 
the informed consent document that has been approved by a participating center’s 
REB/IRB prior to any procedures being done specifically for the trial. Each subject 
should have sufficient opportunity to discuss the study and consider the information 
in the consent process prior to agreeing to participate. Subjects may withdraw 
consent at any time during the course of the trial. The informed consent will be 
signed and dated by the subject, the person who conducted the informed consent 
discussion and the investigator. The original signed informed consent form will be 
retained in the subject’s study files and a copy will be provided to the subject. 
Participants who are deemed eligible and sign consent will be rendered eligible for 
HCV-viremic kidney or liver offers through an opt-in mechanism in the allocation 
system administered by the Organ Procurement and Transplantation Network/United 
Network for Organ Sharing (OPTN/UNOS).  
 

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3. Confirmation of Consent: Eligibility and subject’s willingness to proceed with an 
HCV-positive donor will be re-confirmed and documented by study staff within 24 
hours of the planned liver or kidney transplant (the “Pre-Transplant day”) with a 
review of the potential risks and benefits of participating in this trial, including a 
discussion regarding HCV treatment and complications of unsuccessfully treated post-
transplantation HCV, including graft loss, fibrosing cholestatic hepatitis, cirrhosis and 
death. This step of the informed consent process will include documentation that each 
of these elements has been reviewed with the patient who understands and has ample 
opportunity to have all of their questions and concerns addressed. Part 2 The consent 
the patient originally signed will be presented to the patient to review and sign the 
Confirmation of Consent section at the bottom of the informed consent and written 
documentation of informed consent is required prior to proceeding with the study. 
Subjects must voluntarily sign and date the Confirmation of Consent section of the 
informed consent document that has been approved by a participating center’s 
REB/IRB prior to proceeding with the trial. Each subject should have sufficient 
opportunity to discuss the study and consider the information in the consent process 
prior to agreeing to participate. Subjects may withdraw consent at any time during 
the course of the trial. The informed consent will be signed and dated by the subject, 
the person who conducted the informed consent discussion and the investigator. The 
original signed informed consent form will be retained in the subject’s study files and 
a copy will be provided to the subject. 
 
Virologic Failure Substudy. In the event of virologic failure following treatment with 
SOF/VEL, subjects will be eligible for re-treatment with 12 weeks of 
sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) VOSEVI therapy in the Virologic 
Failure Substudy. The principal investigator or co-principal investigator will review the 
potential risks and benefits of participating in this Substudy, Subjects will sign a 
separate consent form for the Virologic Failure Substudy. These subjects must 
complete their Day 1 visit in the Virologic Failure Substudy within 30 days of 
documentation of virologic failure in the main study.  
 
Participant Confidentiality 
 
All subject related information including the consent, laboratory samples, evaluation 
forms, reports, etc. will be kept strictly confidential. All records will be kept in a 
secure, locked location and only research staff will have access to the records. Subjects 
will be identified only by means of a coded number specific to each subject, and a 
subject letter code.    All computerized databases will identify subjects by numeric 
codes only, and will be password protected. Upon request, clinical information may 
be reviewed by or released to auditors or regulatory agencies. 
 
Record Retention 
 
Data and study documents at all sites will be stored securely for at least 2 years after 
completion of the study per FDA requirements (with the specific length of time according 
to the site’s specific requirements), after which they will be destroyed in keeping with 

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the privacy and confidentiality regulations and guidelines. Samples collected will be 
retained for at least 2 years after completion of the study (with the specific length of time 
according to the site’s specific requirements), after which they will be destroyed. 
 
Protocol violations and deviations 
 
Protocol violations or deviations will be reported to the Principal Investigator and 
Lead Investigators. Protocol exemptions, violations, and deviations will be logged. 
 

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Radosavljevic M, Mullhaupt B, Agarwal K, Angus P, Yoshida EM, Colombo M, Rizzetto M, 
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Van Vlieberghe H, van Hoek B, Forns X, SOLAR-2 Investigators. Ledipasvir and 
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A. Use of multiple probes to assess transporter-and cytochrome p450-mediated drug-
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APPENDIX 1 
Investigator Signature Page 
 
 
S T U D Y  A C K N O W L E D G E M E N T  
 
P R O - A C T :  Prevention of De Novo HCV with Antiviral HCV Therapy Post-Liver 
and Post-Kidney Transplant  
 
I have read the protocol, including all appendices, and I agree that it contains all necessary details 
for me and my staff to conduct this study as described. I will conduct this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated. 
 
I will provide all study personnel under my supervision copies of the protocol. I will discuss this 
material with them to ensure they are fully informed about the drugs and the study. 
 
 
_____________________________________________________  
 
 
_____________________________ 
Principal Investigator Name (Printed)  
 
 
 
Signature 
 
 
 
 
_____________________________________________________  
 
 
_____________________________ 
Date 
 
 
 
 
 
 
 
 
Site Number 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX 2 
Investigators (Principal Investigators for each site in bold) 
 
Investigator 
Specialty* 
Site 
Norah Terrault, MD, MPH 
Claus Niemann, MD 
Chris Freise, MD 
Shiang-Cheng Kung, MD 
H 
A 
S 
N 
01-University of California, 
San Francisco 
Raymond A. Rubin, MD 
Harrison Pollinger, DO 
Christina Klein, MD 
H 
S 
N 
02-Piedmont Transplant 
Institute (Atlanta) 
James Trotter, MD 
Johanna Bayer, MD 
Bernard Fischbach, MD 
H 
S 
N 
03-Baylor Health Care 
(Dallas) 
David Victor, MD 
R. Mark Ghobrial, MD, PhD 
Hassan Ibrahim, MD 
H 
S 
N 
04-Methodist Houston 
James R. Burton, MD 
James Pompeselli MD 
Alexander Wiseman MD 
H 
S 
N 
05-University of Colorado 
Elizabeth Verna, MD 
Lloyd Ratner MD, MPH: Jean Emond, MD 
Sumit Rohan MD, MPH 
H 
S 
N 
06-Columbia University 
 
*H=Hepatology, A=Anesthesiology, S=Surgery, N=Nephrology

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APPENDIX 3 
Schedule of Assessments 
 
 
 
 
TREATMENT PERIOD 
FOLLOW UP 
PERIOD 
 
 
Screen 
Pre-
Transplant 
Day 
Day 
1* 
Day 3 
Wk 
1 
Wk 
2 
Wk 
3 
Wk 
4 
Wk 
5 
Wk 
6 
Wk 
7 
Wk 
8 
Wk 
9 
Wk 
10 
Wk 
11 
End 
of Rx 
FU 4 
FU 12 
FU 
24 
Early end 
of Rx or Rx 
fail 
Visit 
Window (d) 
 
1 
N.A. 
2 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
10 
10 
10 
14 
Informed 
consent 
● #1 
●# 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
recipient 
clinical data a 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Donor 
assessment b 
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
 
 
● 
● 
●  
●  
●  
● 
● 
● 
● 
● 
● 
● 
● 
 
 
 
 
 
Study visit c 
 
 
● 
●  
●  
●  
● 
● d 
 
● 
 
●  
 
 
 
●  
● d 
●  
 
●e 
Lab visit only 
c 
 
 
 
 
 
 
 
 
●  
  
●  
 
●  
●  
●  
 
 
 
●  
 
hCG 
if 
childbearing 
potential 
 
● 
 
 
 
 
 
● 
 
 
 
● 
 
 
 
● 
● 
 
 
 
HCV RNA* 
 
 
●f 
 
● 
 
 
● 
 
 
 
 
 
 
 
● 
● 
● 
● 
● 
AE 
assessment 
 
 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
 
 
● 
● 
 
 
 
Concomitant 
medications 
of interest g 
 
 
● 
● 
● 
● 
● 
● 
 
● 
 
● 
 
 
 
● 
 
 
 
 
 
*HCV RNA will be checked day 3 after transplant. If HCV RNA is positive, may proceed with Day 1. If , If result is “HCV RNA not detected”, HCV RNA to be repeated on day 7 after transplant 
and then weekly until HCV RNA is detected. HCV RNA must be positive before starting study drug. 
a Age, sex, ethnicity, race, weight, BMI, type of transplant (liver or kidney), indication for transplant, BUN, creatinine, GFR, INR, sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total 
bilirubin, albumin, hemoglobin, presence of HCC (liver), CP score (liver), lab MELD (liver), exception MELD (liver), panel reactive antibody (kidney), quantitative HCV RNA,HBV surface antigen, HBV 
core antibody 
b Age, sex, cause of death, UNOS region, kidney donor profile index (kidney), HCV nucleic acid test, HCV genotype, HBV core antibody, sample for baseline resistance associated substitution (RAS), 
sample for serum banking, liver biopsy fibrosis stage and fat percentage 
c BUN, creatinine, GFR, INR, sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, albumin, hemoglobin, and immunosuppressant level and dosage.  
d hepatitis B surface antigen added to other evaluations 
e BUN, creatinine, GFR, INR, sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, albumin, hemoglobin, HCV genotype, sample for RAS, and immunosuppressant level and 
dosage.  
f if subject has not started study drug within 7 days after transplant, a quantitative HCV RNA will also be obtained day 7 after transplant 

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g proton pump inhibitors, H2 antagonists, and beta blockersAPPENDIX 3a 
Schedule of Assessments for Virologic Failure Substudy 
 
 
 
Day 1a 
Wk 
1 
Wk 
4 
Wk 
8 
End of 
Rx 
FU 4 
FU 12 
FU 
24 
Early end of 
Rx or Rx fail 
Visit Window 
(d) 
N.A. 
4 
4 
4 
4 
10 
10 
10 
14 
Informed 
consent 
● 
 
 
 
 
 
 
 
 
Study drug 
● 
●  
● 
● 
 
 
 
 
 
Study visit b 
● 
●  
● c 
●  
●  
● c 
●  
 
●d 
Lab visit only a 
 
 
 
 
 
 
 
●  
 
hCG 
if 
childbearing 
potential 
 
 
● 
● 
● 
● 
 
 
 
HCV RNA 
● 
● 
● 
 
● 
● 
● 
● 
● 
AE 
assessment 
● 
● 
● 
● 
● 
● 
 
 
 
Concomitant 
medications 
of interest e 
● 
● 
● 
● 
● 
 
 
 
 
 
a Day 1 must occur within 30 days of documentation of virologic failure 
bBUN, creatinine, GFR, INR, sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, albumin, hemoglobin, and immunosuppressant level and dosage.  
c hepatitis B surface antigen added to other evaluations 
dBUN, creatinine, GFR, INR, sodium, potassium, bicarbonate, ALT, AST, alkaline phosphatase, total bilirubin, albumin, hemoglobin, HCV genotype, sample for RAS, and immunosuppressant level and 
dosage.  
e proton pump inhibitors, H2 antagonists, and beta blockers 
 
 
 

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APPENDIX 4- CHILD-PUGH CLASSIFICATION OF THE SEVERITY OF CIRRHOSIS 
 
 
Child-Pugh class: 
A= 5-6 points 
B= 7-9 points 
C= 10-15 points