Lung Transplantation in Chronic HCV Infection With Post Transplant EPCLUSA Treatment: A Pilot Feasibility and Efficacy Study
Phase: PHASE4
Conditions: Hepatitis C, Chronic, Lung Transplant
Sponsor: Duke University

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 Protocol Title 
Lung Transplantation in Chronic Hepatitis C Infection with Post Transplant EPCLUSA 
Treatment: A Pilot Feasibility and Efficacy Study 
 
Purpose of the Study 
Primary objectives 
 Assess feasibility, safety and efficacy of Epclusa treatment after lung transplant in those 
with chronic Hepatitis C Virus infection.   
 Establish Sustained Virologic Response (SVR)12 rates in HCV-infected lung transplant 
recipients treated with EPCLUSA.  SVR 12 is the absence of detectable hepatitis C virus 
in the blood after 12 weeks of antiviral therapy.  This is the standard outcome in studies 
evaluating therapies to treat hepatitis C virus. 
 
Secondary Objective 
o Evaluate impact of considering donors who are hepatitis C nucleic acid 
amplification test (NAT) positive in recipients with pre-existing hepatitis C 
viremia on wait times and post transplant survival. 
 Are wait times shortened by considering HCV NAT positive donors? 
Do HCV NAT positive donors otherwise meet criteria for lung donation? 
 
Primary endpoints 
 Sustained Virologic Response 12 weeks (SVR 12) in those treated with EPCLUSA 
 Adverse events resulting in discontinuation of EPCLUSA 
 Eligibility for EPCLUSA treatment within 12 months of lung transplant.   
o If subjects do not have adequate renal function or require medications with 
significant drug interactions with epclusa, they will not be eligible for treatment.  
Eligibility is an outcome because it is not known if these factors will limit utility 
of epclusa in this setting due to common complications associated with lung 
transplantation. 
 
Secondary endpoints 
 Serum HCV RNA levels at 12-, 24-, and 48-weeks after initiation of EPCLUSA 
 Adverse events requiring temporary interruption in Epclusa therapy 
 90-day and 1-year post transplant patient survival 
 90-day and 1-year post transplant patient survival in recipients of HCV NAT positive 
donor organ 
 
Exploratory outcomes   
 Change in transient elastography score at 48-weeks post Epclusa treatment 

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 Acute rejection rates   
 Primary graft dysfunction scores 
 Infections requiring treatment 
 Wait times associated with donor HCV status 
 
Background & Significance 
Nearly 150,000 deaths are attributed to end stage lung disease annually in the United States.i  
Lung transplantation remains the only effective therapy for end stage lung disease, yet just over 
2000 were performed in the US in 2015 and hundreds of patients continue to die each year while 
awaiting a suitable organ.ii  This is related to a limited donor pool as well as strict inclusion 
criteria.  Active chronic hepatitis C infection in the recipient has been considered a 
contraindication to lung transplantation at most programs, however new highly effective direct-
acting antiviral (DAA) treatment regimens have changed the landscape of hepatitis C and prompt 
reconsideration of this practice.  More importantly, HCV is now a curable condition and these 
medications offer the promise of expanding the organ donor pool and increasing access to lung 
transplantation by utilizing HCV positive donors in HCV positive candidates. 
 
A single center, retrospective review out of Canada comparing lung transplant recipients with 
detectable HCV RNA at time of transplant (n=14) with those who were HCV antibody positive 
(n=13) and those who were HCV antibody negative (n=443), demonstrated no difference in 1-, 
3- and 5-year survival, in the absence of hepatitis-C directed treatment.iii  A review of the U.S. 
national experience comparing outcomes between lung transplant recipients who were HCV 
antibody positive and those who were HCV antibody negative between 2000-2011 similarly did 
not reveal a difference in median survival (4.4 vs 5.4 years, P=0.10), although HCV RNA status 
was not captured in this highly selected cohort, so extrapolation of this data is limited.iv    
 
In spite of this encouraging data, there is likely a negative long term impact from untreated HCV 
infection as demonstrated by 15% worse 10-year survival in kidney transplant recipients with 
chronic HCV infection compared with those who are HCV negativev as well as the overall 
mortality rates associated with HCV in the general population.  Additionally, liver function is a 
legitimate concern given reports of acute worsening hepatic fibrosis in lung transplant recipients 
with HCV.vi vii  DAA regimens to cure HCV result in improved liver function and survival in 
non-transplant populations and a retrospective study has demonstrated efficacy and safety of 
DAA regimens to treat HCV infection after renal transplantation.viii  Presumably, viral clearance 
will optimize outcomes for these individuals post-transplant.    
 
Given the promising initial reports, many renal transplant centers are now using HCV positive 
donors in order to minimize wait times for their HCV positive recipients, and then treating them 
with DAA regimens post-transplant to clear the HCV infection and preserve liver function.  This 
strategy appears to be both safe and effective based on a single center retrospective review of 43 

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renal transplant recipients, 19 of whom received organs from HCV antibody positive donors who 
were treated with 4 different DAA regimens.  100% of the patients in this cohort achieved SVR 
12, regardless of DAA regimen used, immunosuppressive induction agent or HCV status of 
donor.  While wait times were significantly shorter in the HCV-positive donor cohort (median 
485 days vs 969 days), there was no difference in allograft function or patient survival post-
transplant.ix   
 
Lung transplant recipients require the highest levels of maintenance immunosuppression for 
solid organ transplant; therefore, establishing efficacy in this population is critical for the solid 
organ transplant community as a whole.  It is also an important and necessary step in working 
towards more widespread use of HCV positive donors.   Again, this is particularly relevant in 
lung transplantation as lungs remain the least likely of the commonly transplanted organs to be 
utilized with only 17% of multi-organ donors providing lungs.  HCV positive donors are 
routinely turned down due to published reports describing notably worse survival and major liver 
complications in HCV negative recipients receiving lungs from HCV positive donors,x however 
the potential to treat and make these lungs useful could revolutionize solid organ transplant and 
save thousands of lives.   
 
Epclusa is a fixed-dose combination product containing sofosbuvir, an HCV NS5B polymerase 
inhibitor, and velpatasvir, an HCV NS5A inhibitor.  It was approved by the FDA in June 2016 
for the treatment of chronic HCV genotypes 1, 2, 3, 4, 5 and 6.  The first antiviral approved to 
treat all major forms of HCV, it can be used in patients with compensated and uncompensated 
cirrhosis, as well as those without cirrhosis.  Response rates, defined as a RCV RNA pcr less 
than the lower limit of quantification (<LLOQ) 12 weeks after completion of therapy (SVR12), 
in those without decompensated cirrhosis who were treated for 12 weeks range from 94-99%.  It 
is recommended as first line therapy by the American Association for the Study of Liver 
Diseases (AASLD) and the Infectious Diseases Society of America (ISDA) for treatment of 
chronic HCV infection with genotypes 1, 2, 3, 4, 5 and 6. 
 
The goal of this study is to assess whether a strategy of performing lung transplant in individuals 
with end stage lung disease and chronic HCV infection, and then treating them post-transplant 
with Epclusa is feasible, safe and effective at curing HCV. 
 
The reason to wait until after lung transplant to treat the hepatitis C virus is two-fold.  First, it 
opens up the donor pool to include those with chronic hepatitis C.  This can potentially shorten 
wait times and increase the number of lungs used for transplantation, which could increase 
access to a life-saving transplant and for those suffering with end stage lung disease and decrease 
deaths on the waiting list.  The second reason to adopt this strategy is that it allows those with 
rapidly progressive lung disease to be transplanted prior to completing 12 weeks of antiviral 

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therapy, during which time their lung disease might progress to the point where they are too sick 
to survive a lung transplant. 
 
As a first step, this study includes only lung transplant candidates with chronic HCV infection.  
For these candidates with chronic HCV infection, consideration would be given to organ offers 
from both HCV NAT positive and HCV NAT negative donors.  Donors would be accepted based 
on quality and suitability, independent of HCV status.  There would be no intentional utilization 
of an HCV positive donor into an HCV negative recipient. 
 
Design & Procedures 
Prospective, open-label study evaluating feasibility, safety and efficacy of Epclusa treatment in 
lung transplant recipients.  Lung transplant recipients who are chronically infected with hepatitis 
C virus will be treated with Epclusa for 12 weeks and evaluated for evidence of hepatitis C virus 
in their blood at 12, 24 and 48 weeks after therapy initiation.   
 
Individuals with chronic hepatitis C infection will be enrolled prior to transplant.  Participation in 
this study will allow individuals with active chronic hepatitis C infection to be considered for 
candidacy for lung transplant, as chronic HCV infection has, until this study, been considered a 
contraindication for lung transplant at Duke.   
 
Once the subject has undergone lung transplant, been discharged from the hospital and clinically 
stabilized (a process that can take weeks to months, depending on complications associated with 
this lung transplant), the subject will be referred for treatment screening.  A regaining of 
functional status, increasing independence in activities of daily living, and a lack of significant or 
poorly controlled acute infections or need for hospitalization are markers of clinical stability 
which will be determined by the treating transplant pulmonologist. 
 
If eligible, the subject will then be given study drug which will be taken for 12 weeks.  Subject 
will be monitored throughout treatment course for adverse events.  Upon completion of therapy, 
repeat testing will be performed to assess for clearance of the virus from the blood.  Subjects will 
be followed for 48 weeks after initiation of study drug to monitor for recurrence and to evaluate 
change in degree of liver stiffness, as assessed by transient elastography. 
 
Regimen (drug/dose/frequency) 
Epclusa (sofosbuvir 400mg/velpatasvir 100mg) 1 tablet PO or VT daily x 12 weeks, taken with 
or without food. 
 
Projected duration of treatment 
12 weeks 
 

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Projected duration of enrollment 
2 years 
 
Study Details 
 Treating pulmonologist will refer for treatment screening visit when clinically 
appropriate.  Repeat HCV PCR and genotyping will be done prior to start of Epclusa 
treatment.as part of the treatment screen.  
 Drug-drug interaction considerations: Many lung transplant recipients develop atrial 
fibrillation after lung transplant and may require treatment with amiodarone.  Due to risk 
of bradycardia associated with concomitant use of epclusa and amiodarone, subjects must 
be off amiodarone for at least 60 days in order to be eligible for epclusa treatment.   
 After 5 subjects complete 12 weeks of epclusa treatment, a preplanned analysis will be 
performed to assess safety and efficacy. 
 HCV positive donors will have blood collected at time of procurement to be sent for 
genotyping and quantitative PCR. 
 Because Epclusa is FDA-approved for all HCV genotypes, there is no anticipated safety 
risk associated with the organ donor having a different genotype than recipient. 
 
Early discontinuation 
If a subject decides to withdraw from the study prior to completion, the subject will be asked to 
return for a final visit for data collection.   
 
Selection of Subjects 
Inclusion criteria: 
1. HCV RNA >= 10^3 IU/ml at screening 
2. Chronic HCV infection, defined as positive HCV antibody and/or HCV RNA more than 
6 months prior to screening 
3. HCV Genotype 1, 2, 3, 4, 5 or 6 
4. Otherwise eligible for lung transplant at study site 
 
Exclusion criteria: 
1. Age <18  
2. Treatment with any of the following agents: 
o Amiodarone.  Subjects previously treated with amiodarone must have stopped the 
amiodarone at least 60 days prior to day 1 SOF/VEL 
o Carbamazepine, phenytoin, phenobarbital, oxcarbazepine 
o Rifabutin, rifampin or rifapentine 
o HIV regimens containing tenofovir, tipranavir/ritonavir, or efavirenz 
o St John’s wort 
o Modafinil 

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3. Have any serious or active medical or psychiatric illness which, in the opinion of the 
investigator, would interfere with subject treatment, assessment or compliance 
4. Hepatitis B surface antigen positive (This is checked at the time of transplant evaluation.) 
. ( 
5. History of hepatic encephalopathy or variceal hemorrhage 
6. Abnormal hematological and biochemical parameters, including: 
o Hemoglobin <8g/dL 
o Platelets <= 50,000/mm^3 
o ALT (alanine aminotransferase), AST (aspartase aminotransferase) or alkaline 
phosphatase >=10 times ULN 
o Total bilirubin >3mg/dL 
o Severe renal impairment, ie creatinine clearance (CrCl) <30mL/min 
7. Pregnant women or women planning to become pregnant 
8. Women who are breastfeeding 
9. Active or recent history (<=1 year) of drug or alcohol abuse 
 
Subject Recruitment and Compensation 
10 subjects will be enrolled. Subjects will be identified during the transplant evaluation phase by 
the clinical team.  The clinical team will assess subject’s willingness to participate in the study 
prior to being approached by the research team.  Due to active chronic HCV infection currently 
being considered a contraindication to transplant at Duke, declining to enroll in the study may 
impact the subject’s candidacy for transplant.   The suitability for transplant is ultimately made 
by the Lung Transplant Team, and dependent on multiple factors.  Agreeing to participate in this 
study is not a guarantee for transplant.  Subjects will not be compensated for participating in this 
study; however, subjects will receive study drug free of charge.   
 
Consent Process – see Section 14 of the e-IRB submission form.  
 
Risk/Benefit Assessment 
The most common adverse reactions observed with treatment with EPCLUSA for 12 weeks are 
headache and fatigue.  Bradycardia can occur when taken with amiodarone.   
 
Hepatitis B virus reactivation: There have been case reports of hepatitis B reactivation with 
Epclusa treatment.  All subjects will be screened for hepatitis B prior to enrollment. 
 
Costs to the Subject 
There will no additional costs to the subjects as a result of participating in this study.  Every 
attempt will be made to coordinate study visits with routine clinical care.   
 
Data Analysis & Statistical Considerations 

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This study is a small, pilot feasibility study and therefore not powered for comparative statistics.  
Descriptive and non-parametric statistics will be performed.  A matched, case-control cohort will 
based on age and underlying lung disease from same center over same time period will be used 
to evaluate survival outcomes.  An unadjusted Kaplan-Meier survival analysis for cumulative 
survival will be performed. 
 
Data & Safety Monitoring 
In accordance with federal regulations the PI will monitor for, review, and promptly report to the 
IRB, appropriate institutional officials, sponsor, coordinating center and the appropriate 
regulatory agency head all unanticipated problems involving risks to subjects or others that occur 
in the course of a subject’s participation in a research, all AE reports will be reported per the 
DUHS IRB policies. 
 
Data collection, storage and confidentiality 
 All data collected in the case report forms (CRF) will be by review of the subject’s Duke 
medical record documentation or through patient interview.  All subjects will be given a 
study ID in order to protect PHI. This will be stored on a secure study drive. 
 The CRF will be built into a password protected REDCap database behind the Duke 
firewall. 
 All paper forms will be stored in a locked cabinet in the research team’s locked office. 
Schedule of Assessments: 
 
Screening Visit 
Informed consent will be reviewed with the subject. After informed consent is signed, subjects 
will be assessed for eligibility for inclusion into the trial. 
The following data will be collected from the subject’s medical chart: 
 Medical and medication history  
 Liver biopsy results 
 FibroScan results 
 Laboratory results 
 EKG results 
 
Treatment Screening Visit 
After the lung transplant subjects will have a treatment screening visit.  
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam   
 Vital Signs 
 Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR).  
 Medical history will be reviewed. 
 

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The following tests and procedures will be done at this visit for research purposes: 
 Female subjects of  child-bearing potential will have serum beta HCG test 
Female subjects are considered “of child-bearing potential” if they (a) are anatomically and 
physiologically capable of becoming pregnant and (b) they will be, or could possibly be, 
engaging in sexual activity with males while study interventions that pose the possibility of harm 
to a fetus are occurring. Sterilization (tubal ligation/cauterization or vasectomy of the male 
partner), while highly effective, does not perfectly prevent pregnancy. Women using these 
contraceptive methods are considered “of child-bearing potential.” 
 
Women are considered past the age of “child-bearing potential” if 
 they are greater than 55 years of age, OR 
o they are at least 50 years of age AND 
o have not menstruated for at least 12 months, OR 
o have a documented Follicule Stimulating Hormone (FSH) level of greater than 40 
mIU/mL. 
 they are at least 45 years of age AND 
o have not menstruated for at least 18 months, OR 
o have a documented Follicule Stimulating Hormone (FSH) level of greater than 40 
mIU/mL. 
 A blood sample will be collected for HCV status. 
 EKG  
 If the subject is eligible to start Epclusa treatment a 6 week supply will be dispensed. A 
drug log will be provided to the subject for accountability purposes. 
 Concomitant medications will be review 
 Clinical data related to transplant and donor will be collected from subject’s medical 
chart. 
 
 
 

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Treatment Initiation  
Subjects will be started on EPCLUSA treatment. Treatment consists of 1 pill taken by mouth 
once a day, either with or without food.  Treatment will last 12 weeks. This visit can be 
combined with the treatment screening visit if subjects are eligible at that time. 
 
Week 4 
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam  
 Vital Signs 
Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR).The following will be done at 
this visit for research purposes: 
 Dispense 6 weeks supply of Epclusa. 
 Drug accountability review 
 Adverse Events (AE) assessment 
 Concomitant medications review 
 
Week 8 
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam  
 Vital Signs 
 Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR). 
 
The following will be done at this visit for research purposes: 
 AE assessment 
 Concomitant medications review 
 
Week 12 
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam  
 Vital Signs 
 Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR). 
 
The following test and procedures will be done at this visit for research purposes: 
 A blood sample will be collected for HCV status.  
 Drug accountability review 
 AE assessment 
 Concomitant medications review 
 
 
 

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Week 24 
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam  
 Vital Signs 
 Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR). 
 
The following test and procedures will be done at this visit for research purposes: 
 A blood sample will be collected for HCV status.  
 AE assessment 
 Concomitant medications review 
 
Week 48 
The following tests and procedures will be done at this visit as part of standard of care: 
 Physical exam  
 Vital Signs 
 Routine blood tests will be collected (CBC, CMP, Mg, and PT/INR). 
 
The following test and procedures will be done at this visit for research purposes: 
 A blood sample will be collected for HCV status.  
 AE assessment 
 Concomitant medications review 
 Transient Elastography 
 
 
 

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Schedule of Assessments  
 
Study Week 
+/- 21 days 
Lung 
transplant 
evaluation 
Study 
Screening 
Transplant 
Treatment 
Screening Visit 
Treatment initiation 
(can be combined with 
treatment screening) 
Week 4 
 
Week 8 
 
Week 12 
 
Week 24 
 
Week 48 
 
Study Informed 
consent 
 
X 
 
 
 
 
 
 
 
 
Inclusion/Exlusio
n 
 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
Medical history 
 
 
 
X 
 
 
 
 
 
 
Physical exam 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Vital Signs 
Height/Weight 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Confirm 
treatment 
eligibility 
 
 
 
X 
 
 
 
 
 
 
Serum HCG 
 
 
 
X 
 
 
 
 
 
 
Liver biopsy 
X 
 
 
 
 
 
 
 
 
 
Transient 
elastography 
X 
 
 
 
 
 
 
 
 
X 
HCV PCR 
X 
 
 
X 
 
 
 
X 
X 
X 
HCV genotype 
X 
 
 
X 
 
 
 
 
 
 
Routine labs 
(CBC, CMP, Mg, 
PT/INR) 
X 
 
 
X 
 
X 
X 
X 
X 
X 
Drug and alcohol 
Screen 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B 
Screen 
X 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
X 
 
 
 
 
 
 
Dispense Drug 
 
 
 
 
X (6 week supply) 
X (6 week 
supply) 
 
 
 
 
Review Con 
Meds 
 
 
 
X 
 
X 
X 
X 
X 
X 
Review for AEs 
 
 
 
 
 
X 
X 
X 
X 
X 
Donor HCV 
PCR/genotype (if 
donor HCV NAT 
positive) 
 
 
X (At time of 
procurement) 
 
 
 
 
 
 
 
*All follow-up visits may occur inpatient or outpatient.  
*Boxes marked in red are part of standard of care for lung tx candidates/recipients. 

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Note: To ensure compliance with CMS guidelines, all studies involving patient care at Duke are 
required to have study protocol-specific EMR build for ordering, resulting and billing of 
protocol-related activities.  This ensures SOC activities are billed to insurance and protocol-
related activities are billed to the study.  This is referred to as EPIC initiation.  The EPIC build is 
specific to each protocol and will not be used for any future studies. 
 
 
 
References 
i http://www.cdc.gov/nchs/fastats/copd.htm 
ii https://www.unos.org/about/annual-report/ 
iii Doucette KE1, Halloran K2, Kapasi A2, Lien D2, Weinkauf JG2. Outcomes of Lung Transplantation in Recipients with Hepatitis C 
Virus Infection. Am J Transplant. 2016 Mar 21 [Epub ahead of print]. 
 
iv Englum BR1, Ganapathi AM2, Speicher PJ2, Gulack BC2, Snyder LD3, Duane Davis R2, Hartwig MG2. Impact of donor and recipient 
hepatitis C status in lung transplantation. J Heart Lung Transplant. 2016 Feb;35(2):228-35 
v J. Levitsky, K. Doucette. AST Infectious Diseases Community of Practice. Viral hepatitis in solid organ transplantation. Am 
J Transplant, 13 (Suppl 4) (2013) 147-68. 
vi Doucette K1, Sumner S2, Weinkauf J3. Treatment of hepatitis C in a lung transplant recipient with sofosbuvir and 
daclatasvir. J Heart Lung Transplant. 2016 Feb 8. pii: S1053-2498(16). [Epub ahead of print]. 
vii Hartwig MG, Patel V, Palmer SM, Cantu E, Appel JZ, Messier RH, Davis RD.  Transplantation. Hepatitis B core antibody positive 
donors as a safe and effective therapeutic option to increase available organs for lung transplantation. 2005 Aug 15;80(3):320-5. 
viii Kamar N, Marion O, et al.  Efficacy and Safety of Sofosbuvir-Based Antiviral Therapy to Treat Hepatitis C Virus Infection After 
Kidney Transplantation. Am J Transplant. 2016 May;16(5):1474-9.. Epub 2015 Nov 20. 
 
ix Sawinski D1, Patel N1, Appolo B2, Bloom RD1. Use of HCV+ donors does not affect HCV clearance with directly acting antiviral 
therapy but shortens the wait time to kidney transplantation. Transplantation. 2016 Aug 4. [Epub ahead of print] 
 
x Englum BR1, Ganapathi AM2, Speicher PJ2, Gulack BC2, Snyder LD3, Duane Davis R2, Hartwig MG2. Impact of donor and recipient 
hepatitis C status in lung transplantation. J Heart Lung Transplant. 2016 Feb;35(2):228-35