Clinical trial NCT03208127
Conditions: End Stage Liver Disease Hepatitis C
Keywords: HCV Epclusa ESLD
Sponsor: Massachusetts General Hospital
Start date: 2017-11-21; Completion date: 2021-06-04
Enrollment: 33 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a single center study for the donation of Hepatitis C Virus (HCV)-positive livers to HCV negative recipient patients, with preemptive, interventional treatment to prevent HCV transmission upon transplantation.

Detailed description:
Patients will be selected based on diminished likelihood of receiving a liver from the waitlist within a period during which they would be likely to succumb to severe comorbidities. This will be determined in part through use of a patient's Model of End Stage Liver Disease (MELD) score, listing status, and clinical judgment. To ensure maximal benefit for the recipient, only high quality donor livers will be accepted.

Arms: arm 1: 12 weeks of HCV treatment with medically appropriate direct acting antiviral
Interventions: intervention 1: Treatment with Direct Acting Antiviral tablet
Intervention descriptions: intervention 1: HCV Treatment for 12 Weeks

Protocol documents:
Prot_SAP_000.pdf: 
Version Date: 28 September 2020 
NCT03208127 
1 
 
Partners Human Research Committee Detailed Protocol 
 
Title: Pan-genotypic direct acting antiviral therapy in donor HCV-positive to recipient HCV-negative 
liver or simultaneous liver-kidney transplant 
PI: Raymond Chung, MD 
 
I. 
Background and Significance 
 
In the United States the prevalence of patients with end stage liver disease (ESLD) in need of 
transplantation has continued to rise, while the number of annual transplants performed has remained 
unchanged over the last decade. Donor liver availability continues to be the limiting factor. As this 
definite shortage of transplant viable organs in the U.S. continues, it is of paramount importance that 
available resources are handled efficiently; namely, that all transplantable organs are recognized for their 
enormous value as scarce resources and utilized to their maximum potential for the maximum benefit (the 
principle of Utility). 
 
Hepatitis C virus (HCV)-positive organs have been used successfully for liver transplantation into HCV-
positive recipients for years.  In HCV-positive recipients, the outcome of HCV-positive liver 
transplantation is identical to transplantation using non-infected organs.  An advantage of using HCV-
positive organs is a potential decrease in wait time and waitlist mortality.  In addition, as a result of the 
opioid epidemic currently plaguing the young demographic, the quality of HCV-positive donor organs is 
often better than other extended criteria organs, as many derive from youthful donors, age 18 to 35, 
following drug overdoses.   
 
The use of HCV-positive organs is increasing in the era of safe, well tolerated, oral antiviral therapy with 
high cure rates.  Previously, recurrent infection in the allograft, including fibrosing cholestatic HCV, with 
high viral loads and accelerated allograft damage were significant concerns. In addition, in the setting of 
immunosuppression, the potential for transplant recipients with HCV infection to experience an increase 
in opportunistic infections, new onset diabetes mellitus, post-transplant extra-hepatic neoplasia, and 
adverse effects of HCV on patient and graft survival also limited the number of HCV-donor organ 
transplants performed. However, these risks were determined prior to the current era of HCV treatment 
and were associated with untreated infection or interferon therapy.  Now that HCV is largely curable 
following transplantation, we anticipate that many of these complications can be avoided with timely 
treatment.  
 
Direct acting antiviral agents (DAAs) have dramatically improved treatment options and outcomes for 
patients with HCV in both the pre- and post-transplant setting.  SOLAR-1 was a large, multicenter, 
randomized controlled trial of sofosbuvir/ledipasvir (SOF/LED) with weight-based ribavirin in 223 liver-
transplant recipients infected with HCV genotypes 1 and 4, with a wide range of liver disease severity.  
The cure rate for 12 weeks of combination therapy was 96%.  In patients with HCV without cirrhosis in 
the allograft, cure rates of many DAA regimens have been reported in the range of 95% or higher. The 
discontinuation rate for these medications is low and side effects rare.  Importantly, the sofosbuvir-based 
regimens do not have major interactions with the commonly used post-transplant immunosuppressive 
regimens. 
 
The daily, fixed-dose, of co-formulated sofosbuvir/velapatasvir (SOF/VEL) is similarly effective to its 
predecessor SOF/LED but has pan-genotypic activity. It is currently recommended as a first-line therapy 
for treatment-naïve, noncirrhotic HCV infection for genotypes 1-5.  Reported cure rates in the non-
transplant setting have been high in the 98-100% range. In the ASTRAL-1, ASTRAL-2 and ASTRAL-3 


Version Date: 28 September 2020 
NCT03208127 
2 
 
studies, more than 1,000 patients have been treated with SOF/VEL with an overall cure rate of 98%, 
without safety or tolerability concerns in the post-transplant setting.  
 
In light of these recent advances in HCV therapy, we believe that DAAs have the potential to play an 
important role in curtailing the current discard rates for HCV-positive donor livers. In this study we plan 
to administer DAA therapy in donor HCV-positive to recipient HCV-negative liver transplantation. We 
plan for use of SOF/VEL in this study. The advantage of SOF/VEL as compared to other DAAs is that is 
has pan-genotypic activity.  This avoids the need for rush donor genotyping, and prevents losing potential 
good-quality organs that are infected by a genotype not covered by the other antiviral drugs that lack pan-
genotypic activity.  
 
In the fall of 2017 an additional pan-genotypic regimen, glecaprevir/pibrentasvir (GLE/PIB), trade name 
Mavyret, was FDA approved. The Magellan-2 study demonstrated the safety and efficacy of GLE/PIB in 
liver transplant adults with chronic HCV infection. We updated our initial protocol to allow for inclusion 
of this additional pan-genotypic agent. SOF/VEL and GLE/PIB are both pan-genotypic regimens planned 
for use in this study.  
 
A subset of patients awaiting liver transplant also require kidney transplant. The efficacy of DAAs in the 
treatment of donor derived HCV infection in kidney transplant has been documented in recent trials at the 
University of Pennsylvania and John’s Hopkins Hospitals (THINKER and EXPANDER trials 
respectively). Given this recent data, patients requiring simultaneous liver-kidney transplant (SLKT) are 
also being considered for enrollment in this study.  
 
 
II. 
Specific Aims 
 
Primary Objective -  
Aim 1a 
Determine if preemptive administration of pan-genotypic direct-active antiviral (DAA) therapy in liver 
transplantation prevents the development of chronic hepatitis C virus (HCV) infection from a viremic 
HCV-positive donor liver to an HCV-negative recipient patient.  
Aim 1b 
Determine the rate of HCV transmission in patients receiving an HCV-antibody positive RNA-negative 
(non-viremic) donor liver, and evaluate the efficacy of DAA therapy when administered through a 
reactive approach, following viremia development.  
Secondary Objectives - Aim 2-3 
Aim 2 
Evaluate the safety and tolerability of pan-genotypic DAA therapy in patients undergoing liver 
transplantation.  
Aim 3 
Determine the proportion of subjects with undetectable serum HCV RNA at study day 0, 1, 3, 7, 14, 28, 
42, 56, 84, 112, 168, 252, and 365 in liver transplant recipients receiving pan-genotypic DAA therapy 
following transplant from an HCV infected donor.  
 
Clinical hypotheses 
Hypothesis 1. 


Version Date: 28 September 2020 
NCT03208127 
3 
 
We hypothesize that administration of pan-genotypic DAA therapy following liver transplantation will be 
well-tolerated and halt the development of chronic HCV infection in a transplant recipient as evidenced 
by a negative HCV viral RNA at 12 weeks post treatment.   
Hypothesis 2. 
We hypothesize that administration of pan-genotypic DAA therapy after HCV-positive donor liver 
transplantation will produce non-inferior survival results in recipient patients as compared to historical 
Scientific Registry of Transplant Recipients (SRTR), Organ Procurement and Transplantation (OPTN), 
and United Network for Organ Share (UNOS) data.  
 
III. 
Subject Selection 
 
 Cohort study (N=300) 
 
This is a single center study for the donation of HCV-positive livers to HCV negative recipient patients, 
with interventional treatment to prevent the development of chronic HCV infection following 
transplantation. Up to 300 patients will be enrolled study wide, with 50 total patients receiving transplant 
and treatment with study drug. We plan to enroll all 300 subjects and perform all 50 transplants at MGH. 
Patients will be selected based on the severity of their disease, overall prognosis, and diminished 
likelihood of receiving a liver from the waitlist. This will be determined in part through use of a patient’s 
MELD score, listing status, and clinical judgment. Patients who are already being consented for extended 
criteria donor organs as part of their transplant evaluation will be considered for enrollment in this study; 
this will include patients with MELD scores greater than 20 or patients with significant morbidity 
associated with their end stage liver disease. To ensure maximal benefit for the recipient, only high 
quality donor livers will be accepted.  Both in-person and remote written informed consent will be 
conducted in accordance with current Partners policy.  Additionally, for this study, we (study staff) will 
implement the Mass General Brigham REDCap (Research Electronic Data Capture) eConsent as an 
option for obtaining and documenting remote written consent. 
 
1. Donor Inclusion/Exclusion Criteria 
1a. Donor Inclusion Criteria: 
Donor is HCV antibody positive or has active HCV infection 
Organ is otherwise acceptable for transplantation per usual evaluation 
 
1b. Donor Exclusion Criteria: 
Donor is known to have previously received HCV treatment (interferon, ribavirin or DAA) 
Liver disease or signs of liver decompensation noted during recovery (splenomegaly, ascites, advanced 
fibrosis or cirrhosis)  
Any standard contra-indication to donation noted in donor (significant malignancy, infection with human 
immunodeficiency virus (HIV), unusual infection, etc).   
 
2. Recipient Inclusion/Exclusion Criteria 
2a. Recipient Inclusion Criteria: 
Recipient is Age ≥ 18 years and ≤ 70 years at time of enrollment 
Met MGH transplant center criteria, listed for liver transplant 
 
2b. Recipient Exclusion Criteria: 
Any contra-indication to liver transplantation per center protocol 
Pregnant or nursing (lactating) women 


Version Date: 28 September 2020 
NCT03208127 
4 
 
HIV positivity 
For study patients in whom MavyretTM therapy is being considered, exclusion criteria includes patients on 
the following medications who cannot stop therapy: carbamazepine, rifampin, St. John’s wort, and ethinyl 
estradiol-containing oral contraceptives.  
 
For any patient receiving pan-genotypic DAA therapy, the corresponding drug administration instructions 
will be followed as listed in the MavyretTM package insert. This includes review of potentially significant 
drug interactions and discontinuation or alteration in dosages and monitoring as recommended. The 
Tables that will be followed can be found on the MavyretTM package insert pg. 8 Table 5.  
 
A subset of patients awaiting liver transplant also require kidney transplant. The efficacy of DAAs in the 
treatment of donor derived HCV infection in kidney transplant has been documented in recent trials at the 
University of Pennsylvania and John’s Hopkins Hospitals. Given this recent data, patients requiring 
simultaneous liver-kidney transplant (SLKT) are being considered for enrollment in this study. If patients 
screened for enrollment meet inclusion criteria for liver transplant, they will not be excluded based on the 
need for SLKT. Their case will be discussed with the study’s transplant nephrologist, and enrolled 
accordingly with plans to update UNET listing status for SLKT transplant. As far as DAA therapy is 
concerned, if a patient is already undergoing treatment based on receipt of an HCV-positive liver, there 
are no changes in MavyretTM therapy duration that would be required if a kidney transplant is also 
performed. In patients receiving SLKT, a patient’s renal function and potential for delayed graft function 
(DGF) will come into play when initiating DAA treatment.. 
 
Standard of care at Partners includes confirming that female patients are not pregnant at the time of organ 
transplantation. For women of childbearing potential, a urine pregnancy test will be performed as needed 
per standard of care prior to enrollment. A negative result will be required at the time of transplant and 
prior to continuing study treatment. 
 
As part of standard transplant protocol, potential transplant recipients will be screened for Hepatitis B 
virus (HBV) infection and managed per guidelines. As part of standard protocol, donor livers will also be 
screened for hepatitis B virus (HBV) infection through HBV surface antigen, surface antibody, and core 
antibody testing. In patients who test positive for core antibody (anti-HBc), further close monitoring 
and/or treatment with HBV therapy will be initiated as per protocol algorithm. See protocol attachment 
algorithm ‘HBV Monitoring’. In addition, for all patients who are core antibody positive, scheduled HBV 
viral load testing will occur alongside HCV viral load testing while on DAA therapy; additional draws 
will occur on an as needed basis.  
 
IV. Subject Enrollment 
 
This is a proof of concept, single center study for the donation of HCV-positive livers to HCV-negative 
recipients, with interventional treatment to prevent the development of chronic recipient HCV infection 
following transplantation.  
 
A study clinician investigator (physician and/or nurse practitioner and/or physicians assistant) will obtain 
informed consent. The consent form and protocol will be reviewed with the potential subject and any 
questions will be answered. During in person informed consent, the subject may be seen in a private area 
located in the Hepatology or Transplant Clinic. Patients will have as much time as they feel necessary to 
review study consent. Subjects will have the option to take the consent form home with them to decide 
whether or not they wish to participate. 
 


Version Date: 28 September 2020 
NCT03208127 
5 
 
Ability to provide informed consent will be determined by the study investigator in discussion with the 
subjects treating physician. Encephalopathy occurs in patients with end stage liver disease and can limit a 
patient’s ability to provide thorough informed consent. In cases where it is felt a patient cannot provide 
informed consent, surrogate consent for enrollment in this study will be obtained.  
 
The PHRC preferred order of surrogates will be followed as outlined below, and the Investigator will 
document the relationship of the surrogate to the subject in the research records. 
 
The following categories of surrogates (listed in general order of preference) may provide consent 
in writing on behalf of individuals incapable of providing informed consent: 
i. 
court appointed guardian with specific authority to consent to participation in research or 
authority to make healthcare decisions for a class of diagnostic and therapeutic decisions 
inclusive of the proposed research 
ii. 
health care proxy/person with durable power of attorney with specific authority for making health 
care decisions inclusive of the proposed research 
iii. 
spouse, adult child, or other close family member who knows the subject well and has been 
involved in their care 
 
Assent of subjects will be a requirement for participation in the research unless the subject is incapable of 
giving assent due to his/her medical condition. If the individual objects to participation, s/he should not be 
enrolled. When surrogate consent is relied upon, the Investigator must ensure that the surrogate 
understands that his or her decisions should be based on "substituted judgment." This means that the 
decision reflects a potential subject's own views when s/he had the capacity to express them. If a potential 
subject did not previously express a view on the matter, the surrogate should make the decision based on 
the potential subject's best interests.  
 
V. Study Procedures 
 
Prior to enrollment in the study, research staff will be working with patient insurance to confirm that the 
patient insurer will be covering the cost of HCV treatment. In the event that insurance does not agree to 
cover the cost of HCV DAA therapy, the cost of medication will be covered by pre-established hospital 
funds.  
 
Day 0 is the day of transplantation. Detailed outline of information, studies, and labs obtained throughout 
enrollment is outlined in Appendix 1 (Schedule of Events) .  
 
Full biochemical profiles of the patient will be performed at various stages throughout the study. On-
treatment safety monitoring review of labs obtained as post-transplant standard of care, including baseline 
LFTs, BMP, and CBC.   
 
Targeted physical assessment, vital sign measurements, emergence of treatment related adverse events 
and concomitant medication usage will be assessed throughout the study period and as needed at the time 
of any unscheduled contact during the 84 day study period and/or the 365 day post-dosing safety follow-
up.  
 
The screening visit will take place within an estimated 1-week to 6 months prior to liver transplantation. 
For all patients enrolled in the protocol, their transplant case will be reviewed on a weekly, bi-weekly, or 
monthly basis based on MELD and position on the waitlist as per usual active transplant waitlist patient 
management.  


Version Date: 28 September 2020 
NCT03208127 
6 
 
Day 0 represents the day of liver transplantation; study DAA treatment will be initiated within 7 days of 
liver transplant. After initiation of therapy, each subject will receive their study drug daily through 12-
week course completion. 
Patients will initially provide in person or remote written informed consent to be “waitlisted” for HCV-
positive donor livers under this protocol.  At the time a liver transplant becomes available, the 
“waitlisted” patients will be contacted and again sign informed consent for transplantation (standard of 
care surgical consent). 
 
Upon receiving notification that an HCV-antibody (Ab) positive donor organ is available, we will review 
if the organ is nucleic acid testing (NAT) positive or negative. A pre-emptive treatment approach will be 
used in patients receiving NAT-positive donor organs, and a reactive treatment approach will be 
performed in patients receiving NAT-negative donor organs, as outlined below: 
 
A study patient who receives an HCV NAT-negative donor liver (or liver and kidney) will be 
followed with HCV viral load (VL) testing per study protocol on study days 0, 1, 3, 7, 14, 28, 42, 56, 84, 
112, 168, 252, and 365. Additional monitoring will be obtained if needed based on new LFT 
abnormalities.  
• 
If the study patient does not develop a positive VL during this 365 day duration they will not 
undergo treatment with DAA therapy.  
• 
If the study patient does demonstrate seroconversion with a newly positive HCV VL then we will 
initiate pan-genotypic therapy per study protocol.  
 
Upon receiving notification that an HCV-positive donor organ is available with plans for transplantation, 
a patient’s case will be reviewed and the appropriate DAA selected based on individual patient factorsthe 
study subject will be scheduled to receive treatment with the below  pan-genotypic DAA: 
• 
co-formulated glecaprevir (300mg)/pibrentasvir (120mg) (MavyretTM) given orally for a duration 
of 12 weeks post-transplantation.  
 
Serum pregnancy tests (for all females of childbearing potential) will be conducted at screening and 
performed immediately prior to transplantation for all women of reproductive age as per transplant 
standard of care. Because the effect, if any, of MavyretTM on an embryo or fetus (developing baby still in 
the womb) is not known, patients may not participate in this study if they are pregnant, breastfeeding, or 
planning to become pregnant. Females who are able to become pregnant must agree to use adequate birth 
control  throughout the duration of the study. For the purposes of this study, adequate birth control means 
one of the following: 
 
1. Intrauterine device (IUD) 
2. Condom with spermicide 
3. Diaphragm with spermicide 
4. Complete abstinence (not having sex at all) 
 
Hormonal forms of birth control including birth control pills, vaginal rings (like NuvaRung), implants 
(like Implanon), or injections (like Depo-Provera) may not work during treatment with MavyretTM and are 
not on the acceptable forms of birth control list. After patients have been off MavyretTM for at least two 
weeks, they can again begin to use a hormonal form of birth control.  
 
Men enrolled in the protocol must also agree to use adequate contraception while participating in this 
study. Adequate contraception is:  
1. Condom with spermicide, and  
2. Female partners must use an approved method of birth control as listed above 
Men must also agree that they will not donate sperm during the entire study period. 


Version Date: 28 September 2020 
NCT03208127 
7 
 
Donor genotyping – HCV genotyping will be performed by MAYO sendout and/or by New England 
Donor Services. Because the treatment in this study is pan-genotypic, we do not need genotype results to 
return prior to medication administration; delays in HCV genotyping will not influence initiation of the 
study drug. 
Drug to be used. As the DAA therapy used in this study may be given preemptively before donor 
genotype is known, the ideal medication would provide universal coverage of all potential genotypes. The 
two currently available, FDA approved pan-genotypic regimens are co-formulated sofosbuvir (400 
mg)/velapatasvir (100 mg) (Epclusa®) and co-formulated glecaprevir (300mg)/pibrentasvir (120mg) 
(MavyretTM).  For the purposes of this study, Mavyret will be utilized as the DAA of choice and once 
initiated, will be given orally for a duration of 12 weeks post-transplantation. 
 
 
Achievement of Sustained Virologic Response (SVR). Patients who received an HCV-positive donor 
liver who have an undetectable viral load 12 weeks after completing therapy (SVR 12) are liver recipient 
patients in whom the use of DAA treatment has successfully prevented the development of chronic HCV 
infection. If during monitoring while on DAA therapy a positive viral load is detected, a plan may be 
made to extend the patient’s course of MavyretTM beyond 12 weeks. We may also add additional Hep C 
medications to increase the chance of curing HCV infection. If this happens, we will plan to review all of 
these details in person with the patient and determine, based on recent updates and clinical practice, the 
best regimen with which to treat the patient and achieve HCV cure.  
 
The detailed protocol version of this study dated 3/13/2017 was reviewed by the food and drug 
administration (FDA). It was found that preemptive treatment with DAA therapy for donor HCV positive 
to recipient HCV negative liver transplant was determined to be IND exempt; this exemption letter has 
been uploaded to insight. 
VI. Biostatistical Analysis 
 
Variables/Time Points of Interest 
The primary variable of interest will be HCV RNA at the multiple time-points assessed during and after 
treatment. 
 
The primary efficacy outcome “prevention of HCV infection in liver recipient” will be determined by a 
negative HCV RNA test at 12 weeks following therapy completion (SVR 12). 
 
The safety outcomes include summation of treatment related adverse events and transplant rejection or 
patient mortality. On treatment eGFR, proteinuria, hemoglobin, and liver function tests will be 
summarized to assess safety. 
 
Statistical Methods 
Patient characteristics for this cohort (N=50) will be presented with summary statistics for baseline 
demographics and clinical variables. The SVR12 rate will be presented and 95% CI constructed with the 
exact test. Mean and standard deviation for on-treatment laboratory values will be presented to analyze 
safety. 
 
Power/Sample Size: 
This is a pilot study. Up to 300 patients will be enrolled (consented for the possible receipt of an HCV-
positive organ), the total number of patients eligible to receive transplant and study drug = 50. 
 
 


Version Date: 28 September 2020 
NCT03208127 
8 
 
VII. Risks and Discomforts 
 
Psychological risk 
Participation in research may result in undesired changes in thought process or emotion (episodes of 
depression, stress, guilt). Patients may experience discomfort when being asked questions about their 
medical history that they deem to be private. 
 
Risks related to transplantation with an HCV-positive liver 
Liver problems 
While unlikely, it is possible that DAAs will not result in the same efficacy following liver transplant. If 
HCV is transmitted and not eradicated it is possible that HCV infection post-transplant could cause health 
problems, including liver injury. In the short term, infection with HCV can cause a flu-like illness that 
includes fatigue, nausea, fever, abdominal pain, vomiting, joint pain, and yellowing of the skin (jaundice). 
Although it is very rare, infection with HCV can cause severe inflammation of the liver or even liver 
failure, including a condition called fibrosing cholestatic hepatitis. The risk of this complication in 
patients without HCV who receive a transplant from a donor with HCV is unknown. This complication 
can be treated and cured in the majority of cases with the HCV medications. 
 
Cirrhosis of the liver can cause someone to experience leg swelling, yellow skin, skin itching, abdominal 
bleeding, shortness of breath, and the abdomen to fill with fluid (ascites). Liver failure can also cause 
death. Based on the limited data available, it would be extremely rare for someone in the study to 
experience liver failure in the first few months after transplantation because the study will be giving HCV 
treatment right away.  
 
In the unlikely event that the patient develops HCV infection despite DAA therapy, we will be prepared 
to offer 2nd line treatment and continue to reassess potential treatment options in the rapidly evolving field 
of HCV therapy. In the unlikely event that treatment fails, there may be continued inflammation and 
scarring of the liver that over many years lead to cirrhosis. If HCV causes cirrhosis, the patient is at 
increased risk of developing liver cancer, liver failure requiring a subsequent liver transplant, or death. Of 
note, we anticipate that with study drug treatment, or if necessary additional HCV therapies, we will be 
able to successfully eradicate HCV in our study population.  
 
Additional risks of HCV: 
HCV can cause other types of inflammation in the body, such as arthritis, rash, anemia, nerve pain and 
inflammation damage to your kidney. These problems are rare, and affect less than 2% of people who 
have HCV. These problems should respond to effective HCV treatment. 
 
 
Risks Related to Study Medications 
 
 
Risks of glecaprevir/pibrentasvir (MavyretTM) 
Glecaprevir/pibrentasvir (MavyretTM) is an FDA approved pan-genotypic regimen for treating HCV 
infection. Thousands of patients have received this medication for HCV treatment.  
 
The adverse reactions data for MavyretTM in subjects without cirrhosis were derived from nine Phase 
2 and 3 trials which evaluated approximately 2,300 subjects infected with HCV genotype 1, 2, 3, 4, 
5, or 6 who received MavyretTM for 8, 12 or 16 weeks. In patients receiving MavyretTM the most 
common side effects were headache (13%), fatigue (11%), and nausea (8%). The overall proportion of 


Version Date: 28 September 2020 
NCT03208127 
9 
 
subjects who permanently discontinued treatment due to adverse reactions was 0.1% for subjects 
who received MavyretTM for 8, 12 or 16 weeks.  
 
The safety and tolerability of MavyretTM after liver transplantation has not yet been extensively studied. It 
is possible that taking immunosuppressant medications needed after liver transplant may change the 
effectiveness or side effects of MavyretTM. 
 
Risk of allergic reaction 
As with any drug, an allergic reaction can occur. Allergic reactions can be mild or serious, and can even 
result in death in some cases. Common symptoms of an allergic reaction are rash, itching, skin problems, 
swelling of the face and throat, or trouble breathing. If a patient develops an allergic response to study 
drug the medication will be discontinued and an alternative treatment initiated 
 
Risks Related to Study Procedures 
 
Risks of Blood Draws 
The patient may have a bruise (a black-and-blue mark) or pain where researchers take the blood samples. 
There is also a small risk of feeling lightheaded, fainting, or infection. 
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
Because the effect, if any, of Mavyret on an embryo or fetus is not known, the patient may not participate 
in this study if they are pregnant, breastfeeding, or planning to become pregnant. This is not a new 
requirement necessitated by this protocol, as patients on the liver transplant list must also agree to not 
become pregnant while awaiting and for a period of time post-transplantation.  
 
 
VIII. Potential Benefits 
 
Receipt of an organ 
Participants may receive a high quality liver transplant because they are enrolled in this study. For some 
patients, they may have not received an organ at all if the severity of their disease would have otherwise 
led to death while awaiting organ transplant. 
 
Shortened wait time 
Participants may spend a significantly shorter duration on the transplant waitlist than they otherwise 
would have if they had not been a part of the research study.  
 
Improved patient quality of life  
A liver that would have otherwise gone to waste can potentially be used to prolong the life and 
significantly improve morbidity for an individual.  
 
Cost Reduction 
This procedure could also eliminate costs associated with the management of end stage liver disease and 
hospitalization.  
 
Increase organ donor pool 
This study could increase the number of viable livers for transplant and reduce the HCV-positive liver 
discard rate. 
 
 
IX. Monitoring and Quality Assurance 


Version Date: 28 September 2020 
NCT03208127 
10 
 
An independent data safety monitoring board (DSMB) will not be used in this study as it is an open label 
study, will have low enrollment, and will only take place at 1 site. 
 
Once a patient is enrolled (transplanted with an HCV Ab+ organ), Dr. Chung, Dr. Markmann, and Dr. 
Bethea will meet in person every three months to review any safety concerns. More frequent meetings 
will occur if needed. 
 
Dr. Chung and Dr. Bethea will be regularly monitoring documents for accuracy and meeting with staff to 
review the status of the study. This protocol will be incorporated into the hepatology standard of care 
post-transplant protocol. A pool of hepatology and transplant attendings will be caring for the patients 
enrolled in this study. Dr. Chung will ultimately be responsible for protecting the rights, safety and 
welfare of all subjects enrolled in this study. In the case of Dr. Chung’s absence, monitoring 
responsibilities will be delegated to one of the subinvestigators listed on the IRB protocol application. 
 
Adverse events will be thoroughly assessed at each treatment visit. Adverse events will be reported to the 
HRC as per current guidelines. We plan to comply with the reporting of any IND safety reports or any 
other federal regulations. The research team will work with the physician investigators to process the 
report of these events as they happen.  
 
Adverse events and unanticipated problems involving risks to subjects or others will be reported to the 
PHRC in accordance with PHRC adverse event and unanticipated problems reporting guidelines. 
 
The study staff will ensure that all adverse events are reported according to the PHRC guidelines. The 
study staff will meet monthly to review the accuracy and completeness of case report form entries, source 
documents, informed consent, and all regulatory documents. 
 
X. References 
1. OPTN Data accessed 12/30/16: https://optn.transplant.hrsa.gov/data/view-data-reports/national-data/  
2. Division of Transplantation, Bureau of Health Resources Development. 2005 Annual Report of the 
US Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation 
Network — Transplant Data:1995-2004. Health Resources and Services Administration; US 
Department of Health and Human Services, Rockville, MD 2005. 
3. OPTN Liver Data accessed 1/6/17: https://optn.transplant.hrsa.gov/data/view-data-reports/national-
data/# 
4. OPTN Final Rule §121.8 Allocation of organs, 64 FR 56659, Oct. 20, 1999, as amended at 64 FR 
71626, Dec. 21, 1999. 
5. Data from New England Organ Bank (NEOB): http://neob.org/  
6. Division of Transplantation, Bureau of Health Resources Development. 2005 Annual Report of the 
US Scientific Registry for Transplant Recipients and the Organ Procurement and Transplantation 
Network — Transplant Data:1995-2004. Health Resources and Services Administration; US 
Department of Health and Human Services, Rockville, MD 2005. 
7. Successful treatment of donor-derived hepatitis C viral infection in three transplant recipients from a 
donor at increased risk for bloodborne pathogens. Shah AP, Cameron A, Singh P, Frank AM, Fenkel 
JM. Transpl Infect Dis. 2017 Jan 6. doi: 10.1111/tid.12660. [Epub ahead of print] PMID:28060446 
8. Favorable short-term outcome of HCV-positive liver graft with bridging fibrosis: A plea for very 
early viral eradication. Martini S, Salizzoni M, David E, Tandoi F, Fonio P, Delsedime L, Strona S, 
Dell Olio D, Saracco GM, Romagnoli R. Hepatology. 2016 Dec 16. doi: 10.1002/hep.28978. [Epub 
ahead of print] PMID: 27981614 
9. Long-term outcomes of liver transplantation in patients with hepatitis C infection are not affected 
by HCV positivity of a donor. Stepanova M, Sayiner M, de Avila L, Younoszai Z, Racila A, 
Younossi ZM. BMC Gastroenterol. 2016 Nov 15;16(1):137. PMID: 27846801 


Version Date: 28 September 2020 
NCT03208127 
11 
 
10. Liver transplantation from HCV RNA-positive donors in the era of interferon-free HCV therapeutics: 
a re-examination of the situation. Willuweit K, Canbay A, Gerken G, Timm J, Paul A, Treckmann J, 
Herzer K. Minerva Gastroenterol Dietol. 2017 Mar;63(1):55-61. doi: 10.23736/S1121-
421X.16.02347-3. PMID: 27824245  
11. Gilead Announces SVR12 Rates from Four Phase 3 Studies Evaluating a Once-Daily, Fixed-Dose 
Combination of Sofosbuvir (SOF) and Velpatasvir (VEL) (GS-5816) for the Treatment of All Six 
Hepatitis C Genotypes. www.gilead.com/news/press-releases/2015/9/gilead-announces-svr12-rates-
from-four-phase-3-studies-evaluating-a-oncedaily-fixeddose-combination-of-sofosbuvir-sof-and-
velpatasvir-vel-gs5816-for-the-treatment-of-all-six-hepatitis-c-genotypes 
12. Hepatitis C fact sheet no. 164. Geneva: World Health Organization, 2015 (http:// 
www.who.int/mediacentre/factsheets/ fs164/en).  
13. Everson GT, Towner WJ, Davis MN, et al. Sofosbuvir with velpatasvir in treatment-naïve non-
cirrhotic patients with genotype 1-6 hepatitis C virus infection: a randomized trial. Ann Intern Med 
2015 
14. Jordan J. Feld, M.D., M.P.H., Ira M. Jacobson, M.D., Christophe Hézode, M.D., Tarik Asselah, M.D., 
et al. for the ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 
6 Infection. N Engl J Med 2015; 373:2599-2607  
15. Ampuero J, Romero-Gómez M, Reddy KR. Review article: HCV genotype 3 — the new treatment 
challenge. Aliment Pharmacol Ther 2014;39:686-98.  
16. Goossens N, Negro F. Is genotype 3 of the hepatitis C virus the new villain? Hepatology 
2014;59:2403-12.  
17. American Association for the Study of Liver Diseases and the Infectious Diseases Society of 
America. Recommendations for testing, managing, and treating hepatitis C 
(http://www.hcvguidelines.org).  
18. European Association for Study of Liver. EASL recommendations on treatment of hepatitis C 2015. J 
Hepatol 2015; 63:199-236.  
19. Rebetol (ribavirin) prescribing information. Whitehouse Station, NJ: Merck, 2013 (package insert) 
(http://www.merck .com/product/usa/pi_circulars/r/rebetol/ rebetol_pi.pdf).  
20. Sovaldi (sofosbuvir) prescribing information. Foster City, CA: Gilead Sciences, 2014 (package insert) 
(http://www.gilead .com/~/media/Files/pdfs/medicines/liver -disease/sovaldi/sovaldi_pi.pdf).  
21. Cheng G, Yu M, Peng B, et al. GS-5816 A second generation HCV NS5A inhibitor with potent 
antiviral activity, board genotypic coverage and a high resistance bar. n engl j med 373;27 
22. Doehle B, Dvory-Sobol H, Hebner C, et al. Deep sequencing of HCV NS5A from a 3-day study of 
GS-5816 monotherapy confirms the potency of GS-5816 against pre-existing genotype 1–3 NS5A 
resistance-associated variants. Presented at the 64th Annual Meeting of the American Association for 
the Study of Liver Diseases, Washington DC, November 1–5, 2013. abstract.  
23. Lawitz E, Freilich B, Link J, et al. A phase 1, randomized, dose-ranging study of GS-5816, a once-
daily NS5A inhibitor, in patients with genotype 1-4 hepatitis C virus. J Viral Hepat 2015 July 16 
(Epub ahead of print).  
24. Everson GT, Towner WJ, Davis MN, et al. Sofosbuvir with velpatasvir in treatment-naïve non-
cirrhotic patients with genotype 1-6 hepatitis C virus infection: a randomized trial. Ann Intern Med 
2015 November 10 (Epub ahead of print).  
25. Pianko S, Flamm SL, Shiffman ML, et al. Sofosbuvir-velpatasvir combination therapy for treatment-
experienced patients with genotype 1 and 3 hepatitis C virus infection: a randomized trial. Ann Intern 
Med 2015 November 10 (Epub ahead of print).  
26. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and velpatasvir for HCV genotype 1, 2, 4, 5, and 6 
infection. N Engl J Med 2015;373:2599-607.  
27. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and ribavirin in HCV genotypes 2 and 3. N 
Engl J Med 2014; 370:1993-2001.  


Version Date: 28 September 2020 
NCT03208127 
12 
 
28. Nelson DR, Cooper JN, Lalezari JP, et al. All-oral 12-week treatment with daclatasvir plus sofosbuvir 
in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 
61:1127-35.  
29. Foster GR, Pianko S, Brown A, et al. Efficacy of sofosbuvir plus ribavirin with or without 
peginterferon-alfa in patients with HCV genotype 3 infection and treatmentexperienced patients with 
cirrhosis and HCV genotype 2 infection. Gastroenterology 2015 August 4 (Epub ahead of print). 
30. Curry MP, O’Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with 
decompensated cirrhosis. N Engl J Med 2015;373:2618-28 
31. Reau N, Kwo PY, Rhee S, et al. MAGELLAN-2: safety and efficacy of glecaprevir/pibrentasvir in 
liver or renal transplant adults with chronic hepatitis C genotype 1-6 infection. Journal of Hepatology 
2017; accessible at: http://www.journal-of-hepatology.eu/article/S0168-8278(17)30444-0/abstract and 
http://www.natap.org/2017/EASL/EASL_32.htm