Clinical trial NCT02631772
Conditions: Hepatitis C
Sponsor: Medical University of South Carolina
Start date: 2016-06-01; Completion date: 2018-06-30
Enrollment: 32 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The predominant remaining questions for post-transplant treatment of Hepatitis C virus (HCV) in the DAA (direct acting anti-virals) era are whether a ribavirin-free regimen is possible and whether pre-emptive treatment is now a potential option to prevent long-term damage to the allograft.

Our aim is to provide answers to these primary questions with our multicenter, prospective, randomized, open-label intent-to-treat phase IV study

Detailed description:
This is a multicenter, prospective, randomized, open-label phase IV study.

Compare ledipasvir/sofosbuvir + ribavirin for 12 weeks vs ledipasvir/sofosbuvir alone for 12 weeks in patients over 90 days post-liver transplant

Arms: arm 1: Ledispasvir (LDV) and Sofosbuvir (SOF) monotherapy x 12 weeks arm 2: Ledispasvir (LDV) and Sofosbuvir (SOF) +ribavirin x 12 weeks
Interventions: intervention 1: Sofosbuvir/Ledipasvir x 12 weeks intervention 2: Sofosbuvir/Ledipasvir + Ribavirin x 12 weeks
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
LIVE-C-FREE (LIVEr transplant for hepatitis C: recurrence FREE) 
Early and late treatment of Hepatitis C with Sofosbuvir/Ledipasvir in Liver Transplant Recipi-
ents 
 
Study Chair: 
 
Derek A. DuBay, MD 
Associate Professor of Surgery 
Chief, Division of Transplant Surgery 
Medical University of South Carolina 
 
 
Supported by: 
 
Gilead Sciences 
IN-US-337-1830 
 
 
Study Intervention Provided by: 
Gilead Sciences 
 
 
Sponsor of Study: 
Derek DuBay/MUSC 
 
ClinicalTrials.gov 
NCT02631772 
 
Protocol Version 6 
Protocol Version Date: March 7, 2017 
 
(Any modification to the protocol should be annotated on the coversheet or in an appendix.  The 
annotation should note the exact words that are changed, the location in the protocol, the date 
the modification was approved by the Executive Committee, and the date it became effective.) 


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TABLE OF CONTENTS 
 
1. STUDY OBJECTIVES ............................................................................................................. 4 
1.1 PRIMARY OBJECTIVE .............................................................................................................. 4 
1.2 SECONDARY OBJECTIVES ....................................................................................................... 4 
2. BACKGROUND ....................................................................................................................... 4 
2.1 RATIONALE ............................................................................................................................ 4 
2.2 SUPPORTING DATA ................................................................................................................. 5 
3. STUDY DESIGN ....................................................................................................................... 6 
4. SELECTION AND ENROLLMENT OF SUBJECTS .......................................................... 7 
4.1 INCLUSION CRITERIA ............................................................................................................. 7 
4.2 EXCLUSION CRITERIA ............................................................................................................ 7 
4.3 STUDY ENROLLMENT PROCEDURES ....................................................................................... 8 
5. STUDY INTERVENTIONS .................................................................................................. 10 
5.1 INTERVENTIONS, ADMINISTRATION, AND DURATION ........................................................... 10 
5.2 PROHIBITED INTERVENTIONS ............................................................................................... 12 
5.3 ADHERENCE ASSESSMENT ................................................................................................... 13 
6. CLINICAL AND LABORATORY EVALUATIONS ......................................................... 14 
6.1 SCHEDULE OF EVALUATIONS ............................................................................................... 14 
6.2 TIMING OF EVALUATIONS .................................................................................................... 14 
7. MANAGEMENT OF COMMON OR EXPECTED ADVERSE EXPERIENCES .......... 16 
8. CRITERIA FOR INTERVENTION DISCONTINUATION ............................................. 23 
9. STATISTICAL CONSIDERATIONS .................................................................................. 24 
9.1 GENERAL DESIGN ISSUES ..................................................................................................... 24 
9.2 OUTCOMES ........................................................................................................................... 25 


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9.3 SAMPLE SIZE ESTIMATION FOR THE PRIMARY OUTCOME ..................................................... 25 
9.4 STATISTICAL EVALUATION OF PRIMARY ENDPOINT ............................................................. 25 
9.5 MISSING DATA AND IMPUTATION METHODS.................. ERROR! BOOKMARK NOT DEFINED. 
9.6 SECONDARY ENDPOINTS ................................................ ERROR! BOOKMARK NOT DEFINED. 
9.7 SAFETY ANALYSIS ............................................................................................................... 26 
10. DATA COLLECTION, SITE MONITORING, ADVERSE EVENT REPORTING .... 27 
10.1 DATA PROCESSING ............................................................................................................. 27 
10.2 DATA SECURITY AND CONFIDENTIALITY ........................................................................... 28 
10.3 DATA QUALITY ASSURANCE .............................................................................................. 28 
10.4 ADVERSE EXPERIENCE REPORTING .................................................................................... 29 
11. HUMAN SUBJECTS ............................................................................................................ 30 
11.1  INSTITUTIONAL REVIEW BOARD (IRB) REVIEW AND INFORMED CONSENT ...................... 30 
11.2 STUDY MODIFICATION/DISCONTINUATION ........................................................................ 30 
12. PUBLICATION OF RESEARCH FINDINGS .................................................................. 30 
13. REFERENCES ...................................................................................................................... 31 
APPENDIX I ............................................................................................................................... 32 
APPENDIX II .............................................................................................................................. 33 
 


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1. STUDY OBJECTIVES 
1.1 Primary Objective 
 
 
 
LDV/SOF for 12 weeks will have an equivalent SVR12 compared to LDV/SOF+ribavirin 
for 12 weeks, both initiated after liver transplant. 
1.2 Secondary Objectives 
Secondary objectives include the emergence and effect of NS5A and NS5B viral substitu-
tions at baseline and in the event of relapse. 
2. BACKGROUND 
2.1 Rationale 
Therapeutic response rates for the treatment of recurrent hepatitis C virus (HCV) after 
liver transplant have historically lagged behind non-transplant patients (1).  While the lat-
est studies in HCV therapy with new direct-acting antivirals (DAA) have drastically im-
proved sustained virologic response rates (SVR) in non-transplant patients, HCV is still 
the most common cause of end stage liver disease (ESLD) leading to liver transplant 
(2,3,4,5).  Although the DAAs have shown efficacy in recurrent HCV post-transplant, 
this is with late treatment, since preemptive therapy has not shown benefit with previous 
agents (6,7).  An attempt at preventing recurrence by clearing the virus with SOF and 
RBV prior to transplant has shown encouraging preliminary results in patients who had 
HCV RNA undetectability for ≥ 30 days, however this was in well-compensated cirrhot-
ics (CTP ≤ 7) with concomitant HCC (8).  Due to the poor tolerability of RBV in patients 
with more advanced cirrhosis, it is unknown if this regimen would have external validity 
to the overall HCV population awaiting liver transplant.  Also complicating the reproduc-
ibility of this data is the unpredictable timing of liver transplant surgery. 
Preliminary results of the ongoing SOLAR-1 study have shown excellent sustained viro-
logic response (SVR) rates with 12 weeks of therapy both pre and post-transplant, when 
utilizing a regimen of LDV/SOF and RBV (9).  However, this is with a regimen that in-
cludes an antiviral with poor tolerability post-transplant, ribavirin.   
The predominant remaining questions for post-transplant treatment of HCV in the DAA 
era are whether a ribavirin-free regimen is possible and whether pre-emptive treatment is 
now a potential option to prevent long-term damage to the allograft. 


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These questions require formal testing in a clinical trial conducted in transplant centers. 
2.2 Supporting Data 
 
SOLAR-1 – Phase III randomized, open-label study including post-transplant (Cohort B) (ongo-
ing) 
 
 
 
a. Results 
Post-transplant F0-F3, CPT A/B/C (cohort B) 
i. 
N=223, 12 vs 24 wks of LDV/SOF+riba (weight-based in F0-F3 and CPT 
A, 600mg titrated up in CPT B and C) 
ii. Median time since transplant 2.9-8.1 yrs depending on arm 
iii. SVR rate 
1. F0-F3  96-98% (N=111) 
2. CPT A  96-96% (N=51) 
3. CPT B  85-83% (N=44) 
4. CPT C (N=8) (only 9 pts in this arm, 1 has not reached SVR end-
point timeframe) 60-67% 


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Risks of therapy 
 
HARVONI 8 weeks 
HARVONI 12 weeks  
HARVONI 24 weeks  
N=215 
N=539  
N=326  
Fatigue  
16%  
13%  
18%  
Headache  
11%  
14%  
17%  
Nausea  
6%  
7%  
9%  
Diarrhea  
4%  
3%  
7%  
Insomnia  
3%  
5%  
6%  
Bilirubin elevations 
1.5x ULN 
3% 
<1% 
2% 
Lipase elevations 
3x ULN 
<1% 
2% 
3% 
 
3. STUDY DESIGN 
Multi-center, prospective, randomized, open-label, pilot study  
 
ARM 1: LDV/SOF x 12 weeks 
ARM 2: LDV/SOF + RBV x 12 weeks 
 
Number subjects: 
Multi-center  
50 subjects, with 25 subjects in each arm 
 
 
 


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4. SELECTION AND ENROLLMENT OF SUBJECTS 
4.1 Inclusion Criteria 
 
a. At least 18 years of age  
b. Signed informed consent 
c. History of HCV genotype 1 or 4 
d. No clinically significant abnormalities or changes on EKG 
e. Randomization post orthotopic liver transplant 
f. Detectable HCV RNA at baseline 
g. Creatinine Clearance of at least 40ml/min using the Cockcroft Gault equation 
h. Negative pregnancy test for female subjects of child bearing potential within 
48 hours of randomization 
Subjects of reproductive potential agree to use (or have their partner use) two 
effective contraception methods through 6 weeks following completion of in-
tervention.  Subjects who are not of reproductive potential, not sexually ac-
tive, whose current partner(s) is not of reproductive potential, or whose sexual 
activity is exclusively homosexual are eligible without requiring the use of 
contraception. 
 
4.2 Exclusion Criteria 
 
a. Pregnant or nursing female, or male with a pregnant female partner 
b. A condition or disorder that, in the opinion of the investigator, may adversely 
affect the outcome of the study or the safety of the subject 
c. Stomach disorder that could interfere with the absorption of study drug 
d. Co-infected with HBV or HIV 
e. Allergic to sofosbuvir or ledipasvir 
f. History of completed treatment with a Nonstructural Protein 5A (NS5a) inhib-
itor 


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g. Participation in a clinical study with an investigational drug or biologic within 
30 days of randomization 
h. Fibrosing cholestatic hepatitis 
i. Amiodarone use within 6 months of randomization 
j. Unwilling/unable to stop taking any of the prohibited medications (Section 
5.2) 
k. Total bilirubin >10mg/dL 
l. Alanine transaminase (ALT), aspartate transaminase (AST), or alkaline phos-
phatase (ALP) ≥ 10x ULN 
m. Serum sodium < 125mmol/L 
n. Platelet count of ≤ 30 k/mm3 
o. Hemoglobin < 10g/dL 
p. Allergic to or intolerant of ribavirin 
q. Within 1 year of transplant AND history of Hepatocellular Carcinoma (HCC) 
with tumor burden outside of the Milan Criteria (See Appendix II) prior to 
transplant 
r. History of significant or unstable cardiac disease 
s. Recipients of an allograft from a donor that was infected with HCV with an 
unknown genotype or non-genotype 1 or 4 unless the recipient is demonstrat-
ed to have only genotype 1 or 4 HCV replication post-transplant 
t. Childs Turcotte Pugh (CTP) B or C 
 
4.3 Study Enrollment Procedures 
4.3.1 Subject Identification/Recruitment: Members of the research team will identify po-
tentially eligible patients who are undergoing liver transplantation or have previous-
ly undergone liver transplantation that are infected with Hepatitis C. An initial eval-
uation of existing patient information may be performed to determine potential eli-
gibility.  This initial review may be performed prior to consent; however no proto-
col driven tests or procedures may be performed until signed informed consent has 
been obtained. 
4.3.2 Informed Consent: Authorized personnel will approach patients to explain the study 
and offer the opportunity to participate in the study. The personnel who will obtain 


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consent will have completed Human Subjects Protection Training. This research 
study will be explained in lay terms to each potential research participant. In com-
pliance with the informed consent process outlined in CFR Title 21 Part 50, the au-
thorized personnel will conduct a face-to-face meeting with the study candidate to 
review all of the required elements of informed consent. The potential study partici-
pant will sign an informed consent form before undergoing any screening study 
procedures. The original consent form will be kept with the subject’s file in the of-
fice. A copy of the consent will be given to the patient and another copy will be put 
in his/her chart. At the time of consent, patients will be assured that their care will 
not be affected in any way if they choose not to participate in the study. Patients 
will also be reminded that it is their right to withdraw their participation in the study 
at any time.   
4.3.3 Enrollment: Patients who give informed consent to study participation will go on to 
complete baseline procedures necessary to determine eligibility for randomization. 
Once deemed eligible for the study according to the inclusion/exclusion criteria, the 
patient will be enrolled as study subject in the WebDCUTM clinical trial manage-
ment system (CTMS).  Information to be entered upon enrollment includes demo-
graphic information and date of transplant surgery. Enrolled subjects will be ran-
domized to one of the treatment arms. The study team will receive the randomiza-
tion assignment from WebDCUTM.  
 


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5. STUDY INTERVENTIONS 
5.1 Interventions, Administration, and Duration 
i. 
SOF/LDV administration 
At the time of randomization, all subjects will be initiated on SOF/LDV 
400mg/90mg enterally daily either with food or on an empty stomach.  This med-
ication will be administered predominantly outpatient, although it may be started 
or continued on both general hospital floors as well as the ICU.  The medication 
will be continued for 12 weeks in both arms.  
ii. 
Ribavirin administration 
At the time of randomization, subjects in Arm 2 will be initiated on the appropri-
ate weight-based dose to be taken with food.  Subjects < 75kg will be initiated on 
RBV 400mg enterally in the morning (QAM) and 600mg enterally at night 
(QPM).  Subjects ≥ 75kg will be initiated on RBV 600mg enterally in the morn-
ing and night (BID).  
This medication will be administered predominantly outpatient, although it may 
be started or continued on both general hospital floors as well as the ICU.   
Ribavirin dosing may be adjusted as medically required for toxicity (see section 
iii). 


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iii. 
Dosage adjustment of ribavirin 
 
 
 
 
 
 
 
 
 
 
Laboratory Abnormality 
Reduction in current ribavirin dose 
Hgb 8.5 to <10 g/dL and/or decrease 
by > 2 g/dL within 4 weeks 
1.  Decrease dose to 600mg daily 
(200mg QAM, 400mg QPM) 
2.  If Hgb < 12 g/dL despite 4 weeks of 
dose reduction in subjects with a history 
of stable cardiac disease, discontinue 
ribavirin 
Hgb <8.5 g/dL 
Discontinue ribavirin 
WBC <1000 mm3 and/or ANC <500 
mm3 
Discontinue ribavirin 
Platelets < 25 k/mm3 
Discontinue ribavirin 
eGFR 30-50 ml/min 
Alternating doses, 200mg and 400mg 
every other day 


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5.2 Prohibited Interventions 
Medications listed below will be prohibited during treatment period. 
 
Concomitant Drug Class: 
Drug Name  
Effect on Concentration 
Clinical Comment  
Antiarrhythmics:  
amiodarone  
Effect on amiodarone, ledipasvir, and 
sofosbuvir concentrations unknown  
Coadministration of amiodarone 
with HARVONI may result in seri-
ous symptomatic bradycardia. The 
mechanism of this effect is un-
known. Coadministration of amio-
darone with HARVONI is not rec-
ommended;  
Anticonvulsants:  
carbamazepine  
phenytoin  
phenobarbital 
oxcarbazepine  
Decreases ledipasvir  
Decreases sofosbuvir  
Decreases GS-331007  
Coadministration of HARVONI 
with carbamazepine, phenytoin, 
phenobarbital, or oxcarbazepine is 
expected to decrease the concentra-
tion of ledipasvir and sofosbuvir, 
leading to reduced therapeutic effect 
of HARVONI. Coadministration is 
not recommended.  
Antimycobacterials: 
Rifabutin 
Rifampin 
Rifapentine 
Decreases sofosbuvir 
Decreases GS-331007 
Coadministration of HARVONI 
with rifabutin or rifapentine is ex-
pected to decrease the concentration 
of sofosbuvir, leading to reduced 
therapeutic effect of HARVONI.  
Coadministration is not recom-
mended 
Coadministration of HARVONI 
with rifampin, an intestinal P-gp 
inducer, is not recommended 
Herbal supplements: 
St. John’s wort (Hypericum 
perforatum) 
Decreases sofosbuvir 
Decreases GS-331007 
Coadministration of HARVONI 
with ST. Joh’s wort, an intestinal P-
gp inducer, is not recommended 
HMG-CoA Reductase In-
hibitors: 
Rosuvastatin 
Increases rosuvastatin 
Coadministration of HARVONI 
with rosuvastatin may significantly 
increase the concentration of rosu-
vastatin which is associated with 
increased risk of myopathy, includ-
ing rhabdomyolysis.  Coadministra-
tion of HARVONI with rosuvastat 
in not recommended 
 
 


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5.3 Adherence Assessment 
Adherence to study intervention will be assessed at all study visits noted on the Schedule of 
Evaluations (Section 6.1).   
Subjects will have adherence assessed based on medication counts.  This will be utilized in a 
subanalysis to determine if measured adherence rates of < 80% impact clinical outcomes in each 
Arm. 


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6. CLINICAL AND LABORATORY EVALUATIONS 
6.1 Schedule of Evaluations 
 
 
  
  
Baseline / 
Randomi-
zation 
Days 
Week 1 
Week 2 
Week 4 
Week 8 
Week 12 
Week 16 
Week 20 
Week 24 
Week 32 
Week 36 
End of 
Study 
Day Post-Randomization 
0 
1 
2 
4 
7 
14 
28 (+/-5 days) 
56 (+/-5 days) 
84 (+/-5 days) 
112 (+/-5 days) 
  
168 (+/-5 days) 
  
252 (+/-5 days) 
  
Informed Consent Obtained 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Randomization  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of Inclusion and Exclu-
sion Criteria  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical History 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Liver Transplant Recipient 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Liver Transplant Donor 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Vital Signs 
X 
  
  
  
  
  
O 
O 
O 
O 
  
O 
  
O 
  
Laboratory Assessments  
X 
  
  
  
  
  
X 
X 
X 
O 
  
O 
  
O 
  
Hepatitis C Viral Load Test (HCV 
PCR RNA) 
X 
  
  
  
  
  
X 
X 
X 
X 
  
X 
  
X 
  
EKG 
X 
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Review of Immunosuppressants 
X 
  
  
  
  
  
X 
X 
X 
X 
  
X 
  
X 
  
Viral Substitutions 
X 
  
  
  
  
  
O 
O 
O 
O 
  
O 
  
O 
  
Pregnancy Test (within 48 hrs of 
randomization) 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Review of Prohibited Medications 
X 
  
  
  
  
  
X 
X 
X 
 
 
 
 
 
  
Study Drug Compliance 
  
  
  
  
  
  
X 
X 
X 
  
  
  
  
  
  
Virologic Failure 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 X 
Liver Allograft Biopsy 
  
  
  
  
  
  
O 
O 
O 
O 
  
O 
  
O 
  
Fibro Scan 
O 
 
 
 
 
 
O 
O 
O 
 
 
 
 
 
 
Adverse Events 
X 
  
  
  
  
  
X 
X 
X 
X 
  
X 
  
X 
  
End of Study 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
X=required; O=optional 
6.2 Timing of Evaluations 
 


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6.2.1 Pre-Randomization Evaluations 
These evaluations occur prior to the subject receiving any study interventions.  
Baseline  
The evaluations listed under the Baseline visit may be performed up to 14 days prior to 
randomization, with the exception of the pregnancy test, which must be performed within 
48 hours of randomization. Additionally, HCV PCRs may be performed up to 30 days 
prior to randomization, provided that it was performed after the liver transplant. 
Once the subject has been successfully screened and accepted for randomization, ran-
domization must be complete within 48 hours. All subjects randomized will be included 
in the intent-to-treat analysis. 
 
6.2.2 Intervention and Evaluations 
Once the subject has been successfully randomized, the intervention should be initiated 
upon that day, but must be initiated within 5 days in case of extenuating circumstances.   
Study evaluations must take place within the time window indicated on the Schedule of 
Evaluations (Section 6.1). 
 
6.2.3 Intervention Discontinuation Evaluations 
At the scheduled time of intervention discontinuation (EOT, last date of study medica-
tion), the following evaluations must be completed:  HCV PCR and HCV viral substitu-
tions (in the event of virologic failure) 
If a subject prematurely terminates study intervention, a visit will be scheduled with the 
Principal-Investigator (PI) or designee within 72 hours to evaluate the reason for early 
termination.  The PI or designee will attempt to resolve any issues leading to early termi-
nation and encourage the subject to resume study intervention as soon as possible.  It will 
be clarified whether they are terminating from all components of the trial or only from 
the primary intervention component of the trial.  If possible, the subjects will be encour-
aged to continue to be followed and evaluated according to the Schedule of Evaluations 
(Section 6.1) even if they no longer wish to receive study treatment.  
Subjects that discontinue intervention due to virologic failure will be withdrawn from the 
study and deemed a treatment failure.  These subjects may receive alternative treatment at 


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the investigator’s discretion.  SOF/LDV will be supplied upon request and RBV will be 
reimbursed by Gilead Sciences, Inc for up to 24 weeks if requested. 
   
7. MANAGEMENT OF COMMON OR EXPECTED ADVERSE EXPERIENCES 
The severity of adverse events will be determined using the grading system outlined in the NCI 
Common Terminology Criteria for Adverse Events Version 4.03 (CTCAE), as it best fits the diagnos-
tic terminology used in naming the event at the site clinical level.  
  
SOFOSBUVIR/LEDIPASVIR OR RIBAVIRIN (ADVERSE EVENTS IN COMMON) 
CTCAE SOC 
Adverse Event 
Grade Description 
Criteria for 
Modification of 
Intervention 
Procedure for Modification 
General disor-
ders and ad-
ministration 
site conditions 
Fatigue 
1 – Relieved by rest 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Not relieved by 
rest; limiting instru-
mental ADL 
3 – Not relieved by 
rest; limiting self-
care ADL 
Nervous system 
disorders 
Headache 
1 – Mild pain 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Moderate pain; 
limiting instrumental 
ADL 
3 – Severe pain; lim-
iting self-care ADL 
Gastrointestinal 
disorders 
Nausea 
1 – Loss of appetite 
without alteration in 
eating habits 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Oral intake de-
creased without 
significant weight 
loss, dehydration or 
malnutrition 
3 – Inadequate oral 
caloric or fluid in-
take; tube feeding, 
TPN, or hospitaliza-
tion indicated 
Gastrointesti-
nal disorders 
Vomiting 
1 – 1-2 episodes 
(separated by 5 
minutes) in 24 hours 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – 3-5 episodes 
(separated by 5 min) 
in 24 hours 


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3 - ≥ 6 episodes (sep-
arated by 5 min); 
tube feeding, TPN or 
hospitalization indi-
cated 
Gastrointestinal 
disorders 
Diarrhea 
1 – Increase of < 4 
stools per day over 
baseline; mild in-
crease in ostomy 
output compared to 
baseline 
Grade 3 if re-
quested by study 
participant, 
treatment-
resistant or re-
current;  Grade 4 
or 5 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
Grade 5:  Intervention will be 
permanently discontinued 
2 – Increase of 4-6 
stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline 
3 – Increase of  ≥ 7 
stools per day over 
baseline; inconti-
nence; hospitaliza-
tion indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self 
care ADL 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 - Death 
Psychiatric 
disorders 
Insomnia 
1 – Mild difficulty 
falling asleep, staying 
asleep or waking up 
early 
If requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Moderate difficul-
ty falling asleep, 
staying asleep or 
waking up early 
3 – Severe difficulty 
in falling asleep, 
staying asleep or 
waking up early 
Musculoskele-
tal and connec-
tive tissue dis-
orders 
Arthralgia 
1 – Mild pain 
Grade 3 or if 
requested 
by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Moderate pain; 
limiting instrumental 
ADL 
3 – Severe pain; lim-
iting self care ADL 


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Renal and uri-
nary disorders 
Chronic kidney 
disease 
1 – CrCl < LLN-
60ml/min/1.73m2; 
proteinuria 2+ pre-
sent; 
urine 
pro-
tein/creatinine > 0.5 
Grade 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Grade 3-5 
 
 
 
Sofosbuvir/Ledipasvir to be 
held 
if 
CrCl 
<40ml/min/1.73m2.  Interven-
tion can be withheld for up to 5 
days.  If there is no resolution, 
the case will be discussed with 
the medical monitor and the 
intervention may be discontin-
ued.   
 
Ribavirin dose should be re-
duced to alternating doses of 
200mg and 400mg every other 
day 
if 
CrCl 
30-
50ml/min/1.73m2 
 
 
Interventions can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
Grade 5:  Intervention will be 
permanently discontinued 
 
2 
– 
CrCl 
59-
30m/min/1.73m2 
3 
– 
CrCl 
29-
15ml/min/1.73m2 
4 
- 
< 
15ml/min/1.73m2; 
dialysis indicated 
5 - Death 
Investigations 
Blood bilirubin 
increased 
1 - >ULN – 1.5x ULN 
Grade 3-4 
 
 
 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 - >1.5-3x ULN 
3 - >3-10x ULN 
4 - >10x ULN 
Investigations 
Lipase increased 1 - > ULN-1.5x ULN 
Grade 3-4 
 
 
 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 - >1.5-2x ULN 
3 - >2-5x ULN 
4 - >5x ULN 
 
 
Ribavirin  
CTCAE SOC 
Adverse Event 
Grade Description 
Criteria for 
Modification of 
Intervention 
Procedure for Modification 
Blood and lym-
phatic system 
disorders 
Anemia 
1 – Hgb <LLN-
10g/dL 
Grade 2, modifi-
cations to dosage 
 
Grade 3-5: per-
manently discon-
tinue ribavirin 
Grade 2:  see dosage adjust-
ment procedure in section 
5.1.iii 
 
Grade 3-5:  ribavirin will be 
permanently discontinued.  
Subject experiencing Grade 3 
or 4 will continue the study 
intervention and follow study 
2 – Hgb <10-8g/dL 
3 - < 8g/dL 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 


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5 – Death 
evaluations as detailed in sec-
tion 6.1 
 
Blood and lym-
phatic system 
disorders 
Hemolysis 
1 – Laboratory evi-
dence of hemolysis 
only (e.g. DAT, 
Coombs’, schisto-
cytes, decreased 
haptoglobin) 
Grade 2: modifi-
cations to dosage 
 
Grade 3-5: per-
manently discon-
tinue 
Grade 2:  see dosage adjust-
ment procedure in section 
5.1.iii 
 
Grade 3-5:  intervention will be 
permanently discontinued.   
 
2 – Evidence of he-
molysis and ≥ 2g/dL 
decrease in Hgb 
3 – Transfusion or 
medical intervention 
indicated 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Hepatobiliary 
disorders 
Hepatic failure 
3 – Asterixis; mild 
encephalopathy; 
limiting self care ADL 
Grade 3-5 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Moderate to se-
vere encephalopathy; 
coma; life-
threatening conse-
quences 
5 – Death 
Immune system 
disorders 
Allergic reaction 
1 – Transient flush-
ing or rash, drug 
fever < 38 degrees C; 
intervention not 
indicated 
Grade 3-5 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
2 – Intervention 
indicated; responds 
promptly to symp-
tomatic treatment;  
prophylactic medica-
tions indicated for ≤ 
24 hours 
3 – Prolonged (not 
rapidly responsive to 
symptomatic medica-
tion); recurrence of 
symptoms following 
initial improvement; 
hospitalization indi-
cated for clinical 
sequelae 


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4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 - Death 
Immune system 
disorders 
Anaphylaxis 
3 – Symptomatic 
bronchospasm, with 
or without urticarial; 
parenteral interven-
tion indicated; aller-
gy-related ede-
ma/angioedema; 
hypotension 
Grade 3-5 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Gastrointestinal 
disorders 
Pancreatitis 
2 – Enzyme elevation 
or radiologic findings 
only 
Grade 3-5 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
3 – Severe pain; vom-
iting; medical inter-
vention indicated 
(e.g. analgesia, nutri-
tional support) 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
General disor-
ders and ad-
ministration 
site conditions 
 
Irritability 
1 – Mild; easily con-
solable 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Moderate; limit-
ing instrumental 
ADL; increased atten-
tion indicated 
3 – Severe abnormal 
or excessive re-
sponse; limiting self 
care ADL; inconsola-
ble 
Skin and subcu-
taneous tissue 
disorders 
Pruritis 
1 – Mild or localized; 
topical intervention 
indicated 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 


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2 – Intense or wide-
spread; intermittent; 
skin changes from 
scratching (e.g. ede-
ma, papulation, exco-
riations, lichenifica-
tion, oozing/crusts); 
oral intervention 
indicated; limiting 
instrumental ADL 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
3 – Intense or wide-
spread; constant; 
limiting self care ADL 
or sleep; oral cortico-
steroid or immuno-
suppressive therapy 
indicated 
Respiratory, 
thoracic and 
mediastinal 
disorders 
Dyspnea 
1 – Shortness of 
breath with moder-
ate exertion 
Grade 3-5 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
2 – Shortness of 
breath with minimal 
exertion; limiting 
instrumental ADL 
3 – Shortness of 
breath at rest; limit-
ing self care ADL 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Musculoskele-
tal and connec-
tive tissue dis-
orders 
Myalgia 
1 – Mild pain 
Grade 3 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 – Moderate pain; 
limiting instrumental 
ADL 
3 – Severe pain; lim-
iting self care ADL 
Investigations 
Neutrophil 
count decreased 
1 - <LLN-1500/mm3 
Grade 3-4 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
may be discontinued.   
2 - <1500-
1000/mm3 
3 - <1000-500/mm3 
4 - <500/mm3 
Psychiatric 
disorders 
Depression 
1 – Mild depressive 
symptoms 
Grade 3-5 or if 
requested by 
study participant 
Intervention can be withheld 
for up to 5 days.  If there is no 
resolution, the case will be 
discussed with the medical 
monitor and the intervention 
2 – Moderate depres-
sive symptoms; limit-
ing instrumental ADL 


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3 – Severe depressive 
symptoms; limiting 
self care ADL; hospi-
talization not indi-
cated 
may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Life-threatening 
consequences; 
threats of harm to 
self or others; hospi-
talization indicated 
5 – Death 
 
 
Transplant and Immunosuppression-related 
CTCAE SOC 
Adverse Event 
Grade Description 
Criteria for 
Modification of 
Intervention 
Procedure for Modification 
Infections and 
infestations 
Abdominal in-
fection 
3 – IV antibiotic, 
antifungal, or antivi-
ral intervention indi-
cate; radiologic or 
operative interven-
tion indicated 
Grade 4-5  
Grade 4: Intervention can be 
withheld for up to 5 days.  If 
there is no resolution, the case 
will be discussed with the 
medical monitor and the inter-
vention may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Infections and 
infestations 
Biliary tract 
infection 
3 – IV antibiotic, 
antifungal, or antivi-
ral intervention indi-
cate; radiologic or 
operative interven-
tion indicated 
Grade 4-5 
Grade 4: Intervention can be 
withheld for up to 5 days.  If 
there is no resolution, the case 
will be discussed with the 
medical monitor and the inter-
vention may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Infections and 
infestations 
Hepatic infec-
tion 
3 – IV antibiotic, 
antifungal, or antivi-
ral intervention indi-
cate; radiologic or 
operative interven-
tion indicated 
Grade 4-5 
Grade 4: Intervention can be 
withheld for up to 5 days.  If 
there is no resolution, the case 
will be discussed with the 
medical monitor and the inter-
vention may be discontinued.  
 
Grade 5:  Intervention will be 
permanently discontinued 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 


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Infections and 
infestations 
CMV  
1 – Isolation of CMV 
from blood or sterile 
site or positive CMV 
PCR without clinical 
symptoms 
Grade 4-5 
Grade 4: Intervention can be 
withheld for up to 5 days.  If 
there is no resolution, the case 
will be discussed with the 
medical monitor and the inter-
vention may be discontinued.   
 
Grade 5:  Intervention will be 
permanently discontinued 
2 – Isolation of CMV 
from blood or sterile 
site or positive CMV 
PCR with clinical 
symptoms (fever, 
malaise, leukopenia, 
thrombocytopenia) 
3 - Isolation of CMV 
from blood or sterile 
site or positive CMV 
PCR with clinical 
symptoms (fever, 
malaise, leukopenia, 
thrombocytopenia) 
and histological evi-
dence of viral cyto-
pathic effect or posi-
tive CMV culture 
from a deep tissue 
specimen 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
5 – Death 
Infections and 
infestations 
Wound infection 2 – localized; local 
intervention indicat-
ed (e.g. topical anti-
biotic, antifungal, 
antiviral) 
Grade 4-5 
Grade 4: Intervention can be 
withheld for up to 5 days.  If 
there is no resolution, the case 
will be discussed with the 
medical monitor and the inter-
vention may be discontinued.  
 
Grade 5:  Intervention will be 
permanently discontinued 
3 – IV antibiotic, 
antifungal, or antivi-
ral intervention indi-
cated; radiologic or 
operative interven-
tion indicated 
4 – Life-threatening 
consequences; ur-
gent intervention 
indicated 
6 
– Death 
8. CRITERIA FOR INTERVENTION DISCONTINUATION 
The intervention will be withheld/discontinued for specific grades of adverse effects as detailed 
in section 7. Additionally, the intervention will be discontinued if the subject meets criteria for 
the following reasons: 


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Virologic failure, defined as: 
Breakthrough: HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ, 
while on treatment, confirmed with 2 consecutive values (note: second confirmation 
value can be posttreatment), or last available on-treatment measurement with no sub-
sequent follow up values, OR 
Rebound: > 1 log10IU/mL increase in HCV RNA from nadir while on treatment, 
confirmed with 2 consecutive values (note: second confirmation value can be post-
treatment), or last available on-treatment measurement with no subsequent follow up 
values, OR 
Nonresponse: HCV RNA persistently ≥ LLOQ through 8 weeks of treatment, OR 
Relapse: HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV 
RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last avail-
able posttreatment measurement 
 
Pregnancy:  If a woman becomes pregnant or a male’s female partner becomes pregnant while 
on-study, the subject will be required to instruct investigators immediately.  If he/she is in Arm 
1, he/she may remain on therapy but will be ineligible for treatment with ribavirin in the event of 
virologic failure.  If he/she is in Arm 2, therapy must be discontinued immediately and the sub-
ject will be counseled on the potential risks of exposure by the PI or designee.  A discussion will 
occur with the medical monitor to decide whether the subject is eligible to be continued on 
sofosbuvir/ledipasvir alone.   
 
Loss of graft:  Defined as death or need for retransplant.  Patients will be deemed a treatment 
failure and the intervention will be discontinued. 
 
9. STATISTICAL CONSIDERATIONS 
9.1 General Design Issues 
This is a multi-center, prospective, randomized, open-label, intent-to-treat pilot study.   
 
The primary objective is to estimate the effect that LDV/SOF for 12 weeks will have on 
SVR12 compared to LDV/SOF plus ribavirin for 12 weeks. 
 


25 
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  Version 6 
 
 
9.2 Outcomes 
9.2.1     Primary outcome - Treatment efficacy, defined as the proportion of subjects 
achieving sustained virologic response 12 (SVR12) weeks after completing the antiviral 
regimen  
9.2.2     Secondary outcomes - Secondary endpoints include the proportion of subjects 
achieving clearance of viremia during therapy, at the end of therapy, week 4 and 24 SVR 
(week 4, week 8, EOT, SVR4, SVR24). 
9.2.3     Safety outcomes - Overall safety and tolerability of each regimen will be estimat-
ed by measuring the incidence of adverse drug reactions and the development of medica-
tion intolerance requiring dose reduction, temporary withdrawal, or removal of the study 
drug(s), incidence of the need for supportive medications (erythropoietins, colony-
stimulating factors), incidence of intolerance requiring dose reduction, temporary with-
drawal, or removal of immunosuppressants, overall and opportunistic infections, biopsy-
proven rejection rates, death, and graft loss.  Other safety outcomes include virologic mu-
tations based on NS5A and NS5B viral substitutions at baseline and in the event of viro-
logic failure. 
 
9.3 Sample Size Estimation for the Primary Outcome 
For a definitive trial, if we assume an efficacy rate of 95% with an acceptable noninferi-
ority margin of 10%, 75 subjects would be needed in each arm to provide an alpha level 
of 0.05 with 80% power to demonstrate noninferiority.  Assuming a 10% dropout rate 
(indicating randomization, but failure to receive a dose of study medication), 85 subjects 
would need to be randomized in each arm.  In this pilot study of 50 subjects, we will be 
able to obtain estimates of these rates for  the two groups for use in the future definitive 
trial. 
 
9.4 Statistical Evaluation of Primary Endpoint 
9.4.1   Statistical Hypotheses: 
The specific null and alternative hypotheses for comparing these two treatments in a non-
inferiority design are: H0: πLDV/SOF+ribavirin – π LDV/SOF = δo and HA: πLDV/SOF+ribavirin – π 
LDV/SOF  < δo (non-inferior) where δo =0.10. where π LDV/SOF+ribavirin  (assumed to be 95%) 
represents the proportion with a successful outcome due to treatment with LDV/SOF plus 
ribavirin for 12 weeks and πLDV/SOF  represents the proportion of a successful outcome 
due to treatment with LDV/SOF for 12 weeks.   


26 
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9.4.2   Efficacy Analysis: 
Although there is insufficient power to conduct any formal statistical analyses, prelimi-
nary estimates of effects for treatment comprisons will be intent-to-treat, where all ran-
domized subjects will be included in the analysis and each subject will be included in the 
treatment to which they were randomized.   
Baseline demographics and clinical outcomes will be presented by treatment. Estimates 
of the differences between these, along with 95% confidence intervals, will be generated. 
The primary outcome of proportion of subjects with success (defined as the proportion of 
subjects achieving sustained virologic response 12 (SVR12) weeks after completing the 
antiviral regimen) as well as estimates of all secondary outcomes for each treatment will 
be reported along with 95% confidence intervals.  
9.7 Safety Analysis 
9.7.1   Safety Outcomes 
Safety outcomes include the proportion of subjects who experience any treatment-related 
serious adverse events (SAEs) during the treatment phase and up to 30 days following 
completion of the treatment.  
Overall safety and tolerability of each regimen will be estimated by measuring the inci-
dence of: 
• Development of medication intolerance requiring dose reduction, temporary with-
drawal, or removal of the study drug(s) 
• Incidence of the need for supportive medications (erythropoietins, colony-
stimulating factors) 
• Incidence of intolerance requiring dose reduction, temporary withdrawal, or removal 
of immunosuppressants 
• Overall and opportunistic infections 
• Biopsy-proven rejection rates 
• Mortality 
• Graft loss 
 
Other specific SAEs to be monitored may be added in consultation with the DSMB.  The 
cumulative incidences of each outcome will be estimated along with 95% confidence in-
tervals.  
 


27 
LIVE-C-Free                                                         
  Version 6 
 
 
9.7.2   Interim Safety Monitoring 
The Data Safety Monitoring Board (DSMB) will review study safety event rates, center 
performance, adverse events (AEs), and serious adverse events (SAEs) periodically.  This 
review will identify any clinical, operational, or other data issues that might require 
changes or adjustments in the way in which the trial is conducted as well as any safety is-
sues that may need to be addressed.  In order to accommodate this, the Data Coordination 
Unit (DCU) will generate safety monitoring reports as well as a comprehensive statistical 
report periodically for the DSMB.  These reports will contain compiled data on enroll-
ment, demographic and baseline characteristics, eligibility and protocol violations, safety 
data, concomitant medications and procedures, and data quality (e.g., timeliness of data 
entry, and number of data clarification requests generated and resolved).  All AEs and 
SAEs will be coded using MedDRA and summarized in terms of frequency of the event, 
number of subjects having the event, timing relative to randomization, and severity and 
relatedness to treatment. For each review, the DCU will generate two statistical reports – 
an open, blinded report to be distributed to the Executive Committee and the DSMB, and 
a closed report to be distributed only to the DSMB.  For the closed report only, the statis-
tics will also be provided by partially blinded treatment group (A vs B).  If the DSMB 
wishes to be completely unblinded for closed reports, a sealed treatment identification 
envelope will be provided to the DSMB; this envelope can be opened at the discretion of 
the DSMB.  The closed report will also contain data listings identifying subjects with 
specific safety outcomes such as mortality. 
9.7.3   Stopping the Trial Based on Interim Safety Data 
In case of concern for safety issue arises from DSMB, the trial may be stopped temporari-
ly or permanently if the serious adverse event rate (SAEs related to the study treatment) 
exceeds a clinically acceptable rate of 10% in either arm.  Data for events will not be 
evaluated until the first 30 subjects have completed 30 day post treatment follow-up for 
each arm. 
 
10. DATA COLLECTION, SITE MONITORING, ADVERSE EVENT REPORTING 
10.1 
Data Processing 
Data management will be handled by DCU.   All study activities will be conducted in 
coordination with the study PI, and will use an electronic data acquisition method where 
all clinical data on enrolled subjects will be entered by the site personnel in real time. 
The latest version of each CRF will be available as a PDF file on the study website for 


28 
LIVE-C-Free                                                         
  Version 6 
 
 
use as worksheets and source documents by study personnel. The study data will be 
managed (including data queries) by DCU using the WebDCU™ system. This user-
friendly web-based database system, developed by DCU, will be used for regulatory 
document management, subject randomization, data entry, data validation, project pro-
gress monitoring, subject tracking, user customizable report generation and secure data 
transfer. 
10.2 Data Security and Confidentiality 
During the course of the trial, user access to the files with subject identifiers, treatment 
assignment and files with study outcomes will be restricted to core staff. In addition to 
use of passwords and other security measures, all documents containing identifying in-
formation on individuals or physicians are considered confidential materials and will be 
safeguarded to the greatest possible extent. No information, which identifies a specific 
person, hospital, or physician, will be released to, or discussed with anyone other than 
study team members. 
Because the DCU uses a web-based system, source documents and CRFs will remain at 
the participating sites. The study database only identifies study subjects by unique study 
identification codes. All data will be stored in a manner that is HIPAA compliant, with-
out the ability to track the information back to a specific subject except through a pass-
word protected system. All collected information about a subject will be stored by a 
unique identification code. All DCU personnel have current Human Subjects Protection 
Training Certification. Clinical information will not be released without written permis-
sion of the subject, except as necessary for monitoring by IRB, the FDA, OHRP, the 
sponsor, or the sponsor’s designee. 
10.3 Data Quality Assurance 
The study data will be managed (including data queries) by DCU using the WebDCU™ 
system. This user-friendly web-based database system, developed and validated by the 
DCU, will be used for regulatory document management, subject randomization, data en-
try, data validation, project progress monitoring, subject tracking, user customizable re-
port generation and secure data transfer. In addition to the study database, the DCU will 
provide the clinical site staff access (via password) to a standard set of web-enabled tools, 
including subject visit calendar, subject accrual status, case report form completion sta-
tus, and outstanding data clarification request status pertaining to their respective clinical 
sites. Furthermore, all approved study materials, such as the protocol, informed consent 
template and manual of procedures, will be housed on the website to ensure that the clini-
cal sites always have access to the most current trial documents.  
 


29 
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  Version 6 
 
 
Data should be independently entered by the designated personnel at each clinical site in-
to WebDCU™ within the time intervals specified in the schedule of assessments. En-
rollment data, however, must be entered into the WebDCU™ database before the subject 
can be randomized. Serious adverse events must be entered into the WebDCU™ within 
24 hours of the site staff’s first awareness of the event.  It is critically important to the ef-
fective and efficient conduct of the study that data be entered in a timely manner. An 
electronic copy of the CRFs will be made available to the clinical sites prior to initiation 
of the study to be used as worksheets to capture the required data for the study. The DCU 
staff will perform range verification, consistency checks, and quality assurance on the da-
ta. The staff at the DCU will contact the sites regarding missing data or queries on CRF 
data. They will maintain direct contact with the staff at the participating sites to ensure 
the study is conducted according to the Good Clinical Practice Guidelines and all appli-
cable regulations. 
Experienced clinical research monitors will be contracted through the DCU to perform on 
site source data verification (SDV) of key outcome and safety data variables during the 
study.   In addition to data verification, the monitor will evaluate drug accountability and 
site facilities. The CRFs and corresponding source documents should be made available 
to the study monitor at each site visit.  It is also expected that the PI, or a designated 
member of the research staff, will be available during the monitoring visit to review the 
data and resolve any queries.   
10.4 Adverse Experience Reporting 
In order to ensure prompt reporting of adverse events, all adverse events (as well as all 
related study data) must be entered into the WebDCUTM within five days of collection 
date. All serious adverse events (SAEs) must be reported on the WebDCUTM within 24 
hours of the study site staff first being made aware of its occurrence. The site investiga-
tors are required to provide relevant information, including description of the adverse 
event, date/time of onset and resolution, severity and seriousness, action taken, and sus-
pected relationship to the study treatment.  
Reporting of any serious adverse event will trigger notification of the event to the DCU 
Project Manager (PM) and the independent Medical Safety Monitor (MSM).  The MSM 
will conduct an independent review of each of these events to determine if it is serious, 
unexpected, and study treatment related.    
Periodically throughout the study, the MSM will review reports on the incidence rates of 
all reported adverse events, whether serious or not.  Should such monitoring uncover is-
sues that may threaten subject safety (e.g. unexpectedly high rate of adverse events), the 
study statistician and principal investigator will prepare a report to be submitted to the 
DSMB for their review and further actions to be taken, if any.  


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11. HUMAN SUBJECTS 
11.1   Institutional Review Board (IRB) Review and Informed Consent 
This protocol, the ICF, and any subsequent modifications must be reviewed and approved by 
the local IRB at each of the participating institutions. A signed and dated ICF must be ob-
tained from the subject as defined in 21CFR50.3.  The ICF must also be signed and dated by 
a member of the study staff qualified to be delegated the authority to obtain informed con-
sent, and a witness (if required by the local IRB).  A copy of the ICF must be given to the 
subject and the consent process must be documented in the subject’s medical record.  The PI 
or delegated sub-Investigator is responsible for ensuring that informed consent is obtained 
from each patient prior to conducting any study-related activities.  
 
No deviations from or changes to the study protocol should be initiated except when neces-
sary to eliminate immediate hazard to the subject.  However, the IRB, DCU, and Study 
Sponsor must be informed of this as soon as possible thereafter.  It is the study site PI’s re-
sponsibility to report SAEs occurring during the study to their IRB, as required and as soon 
as possible.   
 
11.2    Study Modification/Discontinuation 
The study may be modified or discontinued at any time by the IRB, the sponsor, the OHRP, 
the FDA, or other government agencies as part of their duties to ensure that research subjects 
are protected. 
 
12. PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be reviewed and approved by all coinvestigators.  
Final results will be submitted to ClinicalTrials.gov.  Any presentation, abstract, or manu-
script will be made available for review by the sponsor prior to submission. 


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13. REFERENCES 
1.  Gordon FD, Kwo P, Ghalib R. Peginterferon alfa-2b and ribavirin for hepatitis C recur-
rence post orthotopic liver transplantation.  J Clin Gastroenterol. 2012; 46: 700-708. 
2.  Gane EJ, Stedman CA, Hyland RH, et.al.  Nucleotide polymerase inhibitor sofosbuvir 
plus ribavirin for hepatitis C.  N Engl J Med.  2013; 368(1): 34-44. 
3.  Lawitz E, Mangia A, Wyles D, et.al.  Sofosbuvir for previously untreated hepatitis C in-
fection.  N Engl J Med.  2013; 368(20): 1878-87. 
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LIVE-C-Free                                                         
  Version 6 
 
 
APPENDIX I 
US Public Health Service (PHS)Guideline for Reducing Human Immunodeficiency Virus, Hepa-
titis B Virus, and Hepatitis C Virus Transmission Through Organ Transplantation, 2013 ed. 
Donor at Increased Risk for recent HIV, HBV, and HCV infection 
1. People who have had sex with a person known or suspected to have HIV, HBV, or HCV 
infection in the preceding 12 months 
2. Men who have had sex with men (MSM) in the preceding 12 months 
3. Women who have had sex with a man with a history of MSM behavior in the preceding 
12 months 
4. People who have had sex in exchange for money or drugs in the preceding 12 months 
5. People who have had sex with a person who had sex in exchange for money or drugs in 
the preceding 12 months 
6. A child who is ≤ 18 months of age and born to a mother known to be infected with, or at 
increased risk for, HIV, HBV, or HCV infection 
7. A child who has been breastfed within the preceding 12 months and the mother is known 
to be infected with, or at increased risk for, HIV infection 
8. People who have injected drugs by intravenous, intramuscular, or subcutaneous route for 
non-medical reasons in the preceding 12 months 
9. People who have been in lockup, jail, prison, or a juvenile correctional facility for more 
than 72 consecutive hours in the preceding 12 months 
10. People who have been newly diagnosed with, or have been treated for, syphilis, gonor-
rhea, Chlamydia, or genital ulcers in the preceding 12 months 
11. Donor who is at increased risk for recent HCV infection only: 
a. People who have been on hemodialysis in the preceding 12 months 
 


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LIVE-C-Free                                                         
  Version 6 
 
 
APPENDIX II 
Milan Criteria 
 
1.   A single HCC nodule with a maximum size of 5 cm 
OR 
2.   Up to 3 HCC nodules with the largest not exceeding 3 cm 
AND 
       No macrovascular invasion