Clinical trial NCT03781726
Conditions: Renal Failure Chronic Hepatitis C
Keywords: hemodialysis renal failure kidney transplant
Sponsor: Raymond Chung
Start date: 2019-04-10; Completion date: 2021-12-31
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Open label multi center study for the donation of HCV positive kidneys to HCV negative recipients with interventional treatment to prevent HCV transmission upon transplantation.

Detailed description:
The study objective is to determine if the administration of the direct acting antiviral glecaprevir/pibrentasvir for 8 weeks after kidney transplantation is both safe and effective at preventing the spread of HCV infection from donor kidney with known HCV infection (all genotypes) to an HCV negative recipient as evidenced by a negative HCV viral RNA at 12 weeks post treatment.

Arms: arm 1: 8 weeks of HCV treatment with combination tablet of glecaprevir and pibrentasvir
Interventions: intervention 1: glecaprevir/pibrentasvir treatment
Intervention descriptions: intervention 1: combination treatment with glecaprevir and pibrentasvir fixed dose tablet.

Protocol documents:
Prot_000.pdf: 
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1.0 Title Page  
Clinical Study Protocol  
A Multi-Center, Open-Label Study of Glecaprevir/Pibrentasvir to Treat Recipients of 
Transplanted Kidneys from Deceased Donors with Hepatitis C Virus 
(MYTHIC: Multi-center studY to Transplant Hepatitis-C InfeCted kidneys) 
 
AbbVie 
Investigational  
Product: 
 
Glecaprevir, Pibrentasvir 
Date: 
Feb 13, 2019 
Development 
Phase: 
4 
Study Design: 
This is an open-label, multi-center study. 
Investigators: 
Investigator information is on file with Massachusetts General Hospital, 
Harvard University 
Sponsor: 
Massachusetts General Hospital 
Sponsor/Emergenc
y  
Contact: 
Raymond Chung, MD 
Address: Gastrointestinal Unit, 
Massachusetts General Hospital 
55 Fruit Street 
Boston, MA 02114 
E-mail: chung.raymond@mgh.harvard.edu 
 
Phone: 617-643-2257 
Mobile: 617-529-3942  
 
 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable 
regulatory requirements, including the archiving of essential documents. 
Confidential Information 
No use or disclosure outside the Sponsor and AbbVie is permitted without prior written 
authorization from the Sponsor and Abbvie


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1.1 Synopsis 
 
Sponsor: Massachusetts General Hospital 
Protocol Number:  B17-166 
Name of Study Drug: Glecaprevir (ABT-
493), Pibrentasvir (ABT-530)  
Phase of Development: 4 
Name of Active Ingredient: ABT-493, 
ABT-530 
Date of Protocol Synopsis: October 09, 
2018 
Protocol Title: A Multi-Center, Open-Label Study of glecaprevir/pibrentasvir to Treat 
Recipients of Transplanted Kidneys from Deceased Donors with Hepatitis C Virus 
 (MYTHIC: Multi-center studY to Transplant Hepatitis-C InfeCted kidneys ) 
Objectives:   
The primary objective of this study is to demonstrate the safety and efficacy (sustained 
viral response 12 weeks post treatment [SVR12]) of an 8-week treatment with 
glecaprevir/pibrentasvir (G/P) in Hepatitis C Virus (HCV)-negative recipients who 
received study eligible HCV RNA-positive kidneys in Arm 1. 
The secondary objectives are: 
1) Among all subjects enrolled in the study, to describe time to kidney transplant 
and cumulative incidence of each type of transplant: a study-eligible HCV RNA-
positive kidney (Arm 1), a study-eligible HCV RNA-negative/HCV antibody-
positive kidney (Arm 2A), or a kidney transplant performed as part of standard of 
care treatment (Arm 2B).  
 
2) To describe clinical outcomes while on the waitlist after consent (Serious Adverse 
Event [SAEs], delisting from waitlist, death) between those who receive a study-
eligible HCV RNA-positive kidney (Arm 1) and in subjects consented for this 
study who do not receive a study-eligible kidney transplant from an HCV RNA-
positive donor (all Arm 2 subjects) overall and with breakdown by the 3 
categories of Arm 2 as below: 
A: subjects who receive a kidney from a study-eligible HCV RNA-


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negative/HCV Ab-positive donor 
B: subjects who receive a standard of care kidney transplant 
C: subjects who were not transplanted within 1 year of consent 
Hereafter, these categories will be referred to as Arms 2A, 2B and 2C.  
 
A “standard of care” transplant will be defined as any of the following kidney 
transplants: a deceased donor HCV RNA-positive kidney transplant that did not 
meet donor criteria for Arm 1 or HCV RNA-positive kidney transplant that place 
after last transplant allowed for Arm 1 but met criteria for Arm 1 inclusion (2B1); 
a deceased donor  HCV RNA-negative/HCV Ab-positive kidney transplant that 
either did not meet donor criteria or took place > 6 months after the last Arm 1 
transplant (2B2); a deceased donor HCV RNA-negative/HCV Ab-negative 
transplant at a MYTHIC clinical site (2B3); any living donor kidney transplant at 
a MYTHIC clinical site (2B4); or any kidney transplant at a different center than 
the 7 clinical sites (2B5). 
In addition, to compare the total number of inpatient hospital days while on the 
waitlist and after study consent in those who did receive a study-eligible  HCV 
RNA-positive kidney (Arm 1) vs total inpatient hospital days in those who did not 
(Arm 2) overall and with breakdown by the 3 categories of Arm 2 (2A, 2B and 
2C).  
3) To describe clinical outcomes and data post-transplant (death, graft failure, acute 
allograft rejection, delayed graft function, estimated glomerular filtration rate 
[eGFR], proteinuria, ALT elevation > 5 times the upper limit of normal (ULN), 
SAEs) between those who receive an HCV RNA-positive kidney (Arm1) and in 
subjects who receive an HCV RNA-negative/HCV Ab-positive kidney allograft 
(Arm 2A) or a standard of care kidney transplant  (from Arm 2B1 – 2B4) 
combined and separately. For subjects of Arm 1 and Arm 2A who become HCV 
infected, we will collect additional clinical outcomes of sclerosing cholestatic 
hepatitis and extrahepatic manifestations of HCV. In addition, the clinical 


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outcomes and data post-transplant will be compared between Arm 1 and Arm 2 
where a) any study drug (G/P) related severe treatment emergent adverse events 
are included as a clinical outcome for Arm 1 and b) all events of treatment 
emergent Grade≥ 3 laboratory values and severe G/P-related treatment emergent 
adverse events are included as clinical outcomes for Arm 1. 
4) To compare time to deceased donor kidney transplantation among all patients 
who enrolled in this MYTHIC trial to transplant candidates from the Organ 
Procurement and Transplantation Network (OPTN) database; MYTHIC 
participants will be matched 1:3 to OPTN patients on demographics and 
characteristics known to influence waiting time including waiting list priority, 
blood group, geographic region, and sensitization. 
 Investigators: Multi-center, names on file with sponsor 
Study Sites: Up to 7 sites 
Study Population: HCV-negative subjects wait-listed for a kidney transplant 
Number of Subjects to be Enrolled: Up to 90, including a target number of 30 kidney 
transplantation events from study eligible HCV RNA-positive kidney donors. 
Methodology: 
This is an open-label, multi-center, two-arm study to evaluate the efficacy and safety of 
fixed-dose combination tablets of glecaprevir/pibrentasvir (G/P) in HCV-negative 
subjects who consent to receive a kidney transplant from an HCV RNA-positive 
deceased kidney donor. 90 subjects will be consented for trial participation, out of whom 
30 subjects at up to 7 sites are planned to receive an HCV RNA-positive kidney meeting 
study criteria and will be enrolled into a post-transplant treatment arm (Arm 1) receiving 
open-label G/P for 8 weeks post-transplant. The remaining enrolled subjects including 
those who do not receive a kidney meeting study criteria from an HCV RNA-positive 
donor will be followed in Arm 2 for the minimum duration of 1 year post-enrollment. 
Arm 2 includes subjects who do not receive a kidney at one of the study sites or who 
receive a  standard of care kidney transplant (Arm 2B5 patients will be censored at the 
time of transplant at a non-study site).  For subjects enrolled in Arm 1 of the study, the 


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first dose of G/P will be given as early as 3 days post-transplant. Patients must be out of 
the ICU, able to eat and drink, and take oral medications, so that G/P treatment can be 
safely initiated orally as judged by the site investigator. 
 
Subjects who are transplanted with kidneys from HCV RNA-positive donors in Arm 1 
will be followed for 1 year after the date of transplantation to evaluate safety, graft 
survival, mortality, allograft rejection, and potential hepatic and extrahepatic 
manifestations of HCV infection. All recipients of Arm 1 HCV RNA-positive kidneys 
will be assessed for SVR-12 after G/P treatment. Scheduled visits for subjects who 
accept an organ from HCV RNA-positive donors in Arm 1 and receive G/P treatment 
will consist of screening, day of transplant, day 1 of G/P treatment, week 1, week 2, week 
4, week 6 and week 8 of treatment (planned end of treatment visit) after starting G/P. 
Additional scheduled visits will take place at weeks 4, 12 and 24 following completion of 
the G/P treatment and week 52 (1 year) after transplant. Subjects treated with G/P who 
experience virological failure will be evaluated for the emergence/persistence of direct-
acting antiviral agent (DAA)-resistant viral variants, and suitable retreatment will be 
offered to study participants.  
 
All subjects in study arm 2 will be followed for a minimum of 1 year from enrollment. In 
addition, subjects in study arm 2A who received a kidney from an HCV RNA-
negative/HCV Ab-positive donor will be followed for a minimum of 24 weeks after the 
date of transplantation or 1-year post enrollment, whichever is longer, to evaluate safety, 
graft survival, mortality, and allograft rejection, and potential development of HCV 
viremia. Study visits for patients receiving a HCV RNA-negative/HCV Ab-positive 
kidney transplant in Arm 2A will take place at weeks 1, 4, 8, 12, and 24 weeks after 
transplantation. If a recipient of an HCV RNA-negative/HCV antibody-positive kidney in 
Arm 2A develops HCV infection within the first 24 weeks of follow-up after 
transplantation, that recipient will be offered treatment with G/P for 8 weeks. G/P 
treatment will be administered and subject will be followed as per local transplant center 


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standard-of-care and study-objective pertinent data from the G/P treatment period and 
post treatment period will be collected. This includes SAEs, treatment-emergent Grade 3 
or greater laboratory abnormalities, and HCV RNA 12 weeks post G/P treatment 
completion. 
 
Other subjects in Arm 2 who remain on the transplant waiting list, receive a standard of 
care kidney transplant at a study site (Arms 2B1 - 2B4) will be followed as per transplant 
center standard of care for at least 12 months post-enrollment with study-objective 
pertinent collection of data during waitlist period and/or related to transplant events 
which may include transplant-related complications and graft function, SAEs, delisting 
from the transplant wait list and death. 
 
Efficacy and safety data will be monitored throughout the study for all participants. 
However, the approach to surveillance for adverse events will be customized for patients 
on the waiting list and after transplantation. 
Inclusion Criteria for Kidney Transplant Candidates at Enrollment 
1. Age >21 and <65 years at the time of consent 
2. Estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2 (calculated 
using the 4-variable Modification of Diet in Renal Disease [MDRD] equation) at 
the time of consent 
3. Listed for an isolated kidney transplantation 
4. Subjects must be able to understand and adhere to the study visit schedule and all 
other protocol requirements, and must voluntarily sign and date an informed 
consent 
5. No available medically acceptable, compatible living kidney donor 
6. Subject must agree to use an effective method of birth control as outlined in 
Appendix D, and must have implemented the method by the day of transplant  
7. Assent from the patient’s primary transplant nephrologist that participation would 
be reasonable for the patient 


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8. Attended an educational session on use of HCV seropositive allografts 
Exclusion Criteria for Kidney Transplant Candidates at Enrollment 
1. History of severe, life-threatening or other significant sensitivity to 
immunosuppressants utilized in kidney transplant. 
2. Female who is pregnant, breastfeeding, or is planning to become pregnant during 
the study 
3.   Human immunodeficiency virus (HIV) RNA-positive or HIV antibody-positive 
4.   HCV RNA-positive 
5.   Hepatitis B Virus (HBV) surface Ag-positive or detectable HBV DNA 
6. Primary focal segmental glomerulosclerosis (FSGS) or disease process with 
increased risk of causing early graft failure as assessed by the transplant 
nephrologist and/or investigator team 
7.   Presence of clinically significant liver disease evident after review of history, labs 
and fibroscan imaging 
a) Persistently elevated liver enzymes (Alanine aminotransferase [ALT] >2 times 
upper limit of normal) of unknown cause  
b) Liver fibroscan result >8kPA, or >F2 on liver biopsy 
8.   Transplant candidate requiring antibody desensitization protocol for 
transplantation 
9.   Most recent calculated panel reactive antibody (cPRA) >80%. For this purpose, 
the cPRA assessed will be the cPRA most-recently reported to United Network of 
Organ Sharing (UNOS) at the time of wait listing. 
10. Prior recipient of a non-renal solid organ transplant     
11. Subject has any other medical condition that, in the opinion of the Investigator, 
would adversely affect the participant's participation in the study. Additionally, 
the investigator may exclude any patient with a pre-existing cancer that does not 
have a high probability of cure or control and as per local transplant center 
guidance. 
12.  Requirement for and inability to safely discontinue the medications or 


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supplements listed in Table 7 of the protocol at least 2 weeks or 10 half-lives 
       (whichever is longer) prior to the first dose of any study drug  
13. Participation in another interventional study of any investigational agent or   
approved medication, or participation in another interventional study that the 
responsible investigator deemed to be an exclusion, from 6 months prior to 
screening to the last study visit.  
Inclusion criteria for kidney donor and allograft* 
1. Deceased donor organ with kidney donor profile index (KDPI) ≤0.85 
2. HCV RNA-positive 
 
Exclusion criteria for HCV RNA-positive kidney donor and allograft 
1. Known prior HCV treatment with direct acting antiviral medication  
2. HIV RNA-positive  
3. HBV Surface antigen-positive or HBV DNA-positive 
 
*Standard of care deceased or living donor kidney transplants are allowed to be 
accepted by enrolled subjects. For HCV RNA-negative/HCV antibody-positive donor 
offers in Arm 2A, all other donor inclusion and exclusion criteria above apply, except 
the donor is not HCV RNA-positive. For subjects who accept a standard of care 
transplant (Arm 2B), no study allograft criteria apply. 
Investigational Product: 
Glecaprevir/pibrentasvir 100 mg/40 mg Film-coated Tablet 
Doses: 
Glecaprevir Dose:  300 mg QD 
Pibrentasvir Dose:  120 mg QD 
Glecaprevir/pibrentasvir tablets:  300 mg/120 mg QD (3 
tablets) 
Mode of Administration: 
Oral once daily with food  
Reference Therapy: 
 N/A 


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Duration of Treatment: 
Treatment duration is 8 weeks  
Criteria for Evaluation: 
Efficacy:   
Efficacy will be assessed by plasma HCV RNA levels after start of G/P treatment 
DAA Resistance: 
The following resistance information will be analyzed for Arms 1 or 2A kidney 
transplant recipients receiving G/P who experienced virologic failure and who have a 
sample from time of failure with HCV RNA ≥1000 IU/mL after failure. The HCV NS3 
and NS5A amino acid sequences from the sample closest in time after virologic failure or 
treatment discontinuation will be determined by population sequencing or next 
generation sequencing, and a listing by subject of all substitutions at GLE and PIB 
signature amino acid positions relative to the appropriate prototypic reference sequence 
of NS3 and NS5A will be provided. 
Safety:  
Separate safety data will be collected for patients while on the waiting list and after 
transplantation. Because subjects are unlikely to suffer adverse events related to study 
participation while on the waiting list, adverse event ascertainment will take place every 
two months by phone as well as during an in-person evaluation every 6 months while on 
the waiting list. The following clinical outcomes will be collected from all subjects while 
on the waiting list: SAEs, hospital days, delisting from waitlist, death. 
 
For all transplanted subjects in Arm 1 or Arm 2, the following data will be collected and 
analyzed descriptively post-transplant: death, graft failure, acute allograft rejection, 
delayed graft function, eGFR, proteinuria, ALT elevations greater 5 times upper limit of 
normal, and SAEs. For transplanted subjects of Arm 1 and Arm 2A of the study who 
develop HCV viremia, the additional data of potential sclerosing cholestatic hepatitis and 
extrahepatic manifestations of HCV will be collected.  
 


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The analysis of adverse events after kidney transplantation will include categorization of 
the event as to whether the event was caused by transplantation or its treatment generally 
, or caused by HCV infection and/or HCV therapy as applicable.  
  
All subjects who receive at least one dose of G/P in Arm 1 will have additional safety 
data collected including treatment-emergent adverse events of all grades, physical 
examinations, clinical laboratory tests, and vital signs. 
Statistical Methods 
Efficacy: 
The primary efficacy endpoint is sustained virologic response 12 weeks post dosing 
(SVR12), defined as HCV RNA < LLOQ 12 weeks after the last actual dose of G/P. The 
SVR12 rate will be determined from all enrolled subjects who received an HCV RNA-
positive kidney in Arm 1 and received at least one dose of G/P study drug along with a two-
sided 95% confidence interval. The confidence interval for the SVR 12 rate will be 
calculated using Wilson’s score method. 
The secondary efficacy endpoints for recipients of kidney transplants from HCV RNA-
positive donors in Arm 1 are: 
1. The percentage of subjects with on-treatment virologic failure; 
2. The percentage of subjects with post-treatment virologic relapse. 
Additional efficacy analyses will be performed. 
Clinical endpoints:   
Secondary endpoints for the secondary objectives are: 
 
1. Among all subjects enrolled in the study who receive a kidney transplant, the time 
to kidney transplant and cumulative incidence of each type of transplant will be 
determined for: study-eligible HCV RNA-positive kidneys (Arm 1), study-
eligible HCV RNA-negative/HCV Ab-positive kidneys (Arm 2A), and standard 
of care kidney transplants (Arm 2B). 
2. The number and percentage of subjects with clinical outcomes while on the 


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waitlist (SAEs,  delisting from waitlist, death) among subjects who receive an 
HCV RNA-positive kidney in Arm 1 and among those subjects who do not 
receive a study eligiblee HCV RNA-positive kidney (all Arm 2 subjects) overall 
and with breakdown by the category in Arm 2 (2A, 2B and 2C). In addition, the 
total number of inpatient hospital days while on waitlist in those who did receive 
a study eligible HCV RNA-positive kidney (Arm 1) and total inpatient hospital 
days in those who did not (Arm 2) overall and with breakdown by categories of 
Arm 2 will be summarized descriptively.  
3. The number and percentage of subjects with the following clinical outcomes and 
data post-transplant as applicable: death, graft failure, acute allograft rejection, 
delayed graft function, ALT elevations > 5x ULN, and SAEs. The difference in 
the overall percentage of subjects with clinical outcomes and data post-transplant 
between Arm 1 and Arms (2A + 2B1 – 2B4) will be assessed by logistic 
regression with Arm as a factor and appropriate covariates to adjust for possible 
differences between Arms including waiting list priority, blood group, geographic 
region and sensitization as appropriate. 
 
For subjects of Arm 1 and Arm 2A who become HCV infected, we will collect 
additional clinical outcomes of sclerosing cholestatic hepatitis and extrahepatic 
manifestations of HCV. 
 
In additional analyses, G/P treatment-related severe adverse events, and G/P 
treatment-emergent Grade ≥ 3 laboratory values will be counted as clinical 
outcomes for subjects in Arm 1.  
4. Additional allograft function outcomes for subjects post-transplant: mean eGFR 
over time and proteinuria.  
5. Time to deceased donor kidney transplantation will be compared between all 
patients who enrolled in this MYTHIC trial and transplant candidates from the 
Organ Procurement and Transplantation Network (OPTN) database using a Cox 


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proportional hazards model; MYTHIC participants will be matched 1:3 to OPTN 
patients on demographics and characteristics known to influence waiting time 
including waiting list priority, blood group, geographic region, and sensitization. 
6. In addition, for subjects in study Arm 2A receiving HCV RNA-negative/HCV 
Ab-positive kidneys, the rate of HCV transmission will be summarized.  
  
 


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1.2 List of Abbreviations, Definitions and Terms 
Abbreviations 
AASLD 
American Association for the Study of Liver Diseases 
Ab 
Antibody 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ANC 
Absolute neutrophil count 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
APRI 
Aminotransferase/platelet ratio index 
aPTT 
Activated partial thromboplastin time  
AST 
Aspartate aminotransferase 
BMI 
Body Mass Index 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
CCC 
Clinical Coordinating Center 
CKD 
Chronic kidney disease 
CLIA 
Clinical Laboratory Improvement  Amendment 
CMP 
Comprehensive metabolic panel 
CPK 
Creatine phosphokinase 
cPRA 
Calculated panel reactive antibody 
CR/CL 
Creatinine clearance 
CRF 
Case report form 
CT 
Computed Tomography 
DAA 
Direct-acting antiviral agent 
D/C 
Discontinuation 
DCC 
Data Coordinating Center 
DMS 
Data management system 
DNA 
Deoxyribonucleic acid 


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DSMC 
Data safety monitoring committee  
EC 
Ethics Committee 
EDC 
Electronic data capture 
EDTA 
Edetic acid (ethylenediaminetetraacetic acid) 
EHR 
Electronic health record 
EMR 
Electronic medical record 
EOT 
End of treatment 
ESRD 
End stage renal disease 
EU 
European Union 
FSGS 
Focal Segmental Glomerulosclerosis 
FSH 
Follicle stimulating hormone 
GAM 
Generalized additive method 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GLE 
Glecaprevir 
G/P 
Glecaprevir/Pibrentasvir fixed dose combination 
GT 
Genotype 
HBsAg 
Hepatitis B surface antigen 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
hCG 
Human Chorionic Gonadotropin 
HCV 
Hepatitis C virus 
HCV Ab 
Hepatitis C virus antibody 
Hemoglobin A1c 
Glycated hemoglobin 
HIV 
Human immunodeficiency virus 
HIV Ab 
Human immunodeficiency virus antibody 
ICH 
International Conference on Harmonization 
ICU 
Intensive Care Unit 
IEC 
Independent ethics committee 


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IFN 
Interferon 
IL28B 
Interleukin 28B 
IMP 
Investigational Medical Product 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IU 
International units 
IUD 
Intrauterine device 
KDPI 
Kidney Donor Profile Index 
KT 
Kidney transplant 
LLN 
Lower limit of normal 
LLOD 
Lower limit of detection 
LLOQ 
Lower limit of quantification 
MGH 
Massachusetts General Hospital 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
NGS 
Next generation sequencing 
NONMEM 
Non-linear mixed-effect modelling 
NS3 
Nonstructural viral protein 3 
NS5A 
Nonstructural viral protein 5A 
OPTN 
Organ Procurement and Transplantation Network 
PBMC 
Peripheral blood mononuclear cells 
PCR 
Polymerase Chain Reaction 
PE 
Physical exam 
PegIFN 
Pegylated-interferon alfa-2a or alfa-2b 
PegIFN/RBV 
Combination of pegylated-interferon alfa-2a or alfa-2b and ribavirin 
PI 
Protease Inhibitor 
PIB 
Pibrentasvir 


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PK 
Pharmacokinetic 
POR 
Proof of Receipt 
PRA 
Panel reactive antibody 
PRS 
IFN, pegIFN, RBV and/or sofosbuvir 
PT 
Post-Treatment 
QD 
Once daily 
RBC 
Red blood cells 
RBV 
Ribavirin 
RNA 
Ribonucleic acid 
RT-PCR 
Reverse transcriptase PCR 
SAE 
Serious adverse event 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
System Organ Class/Standard of Care 
SOF 
Sofosbuvir 
SVR 
Sustained virologic response 
SVR4 
Sustained virologic response 4 weeks post dosing 
SVR12 
Sustained virologic response 12 weeks post dosing 
SVR24 
Sustained virologic response 24 weeks post dosing 
TE 
Treatment experienced 
TN 
Treatment naive 
ULN 
Upper limit of normal 
UNOS 
United Network of Organ Sharing 
USPI 
United States Prescribing Information 
VS 
Vital signs 
WBC 
White blood cells 
 


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Definition of Terms 
Study Drug 
Glecaprevir (GLE, ABT-493), pibrentasvir (PIB,ABT-530) 
fixed dose combination tablets (G/P)  
G/P Day 1 
First day of study drug  (G/P) dosing  
G/P Treatment 
Period 
From G/P Day 1 through last dose of G/P (week 8) treatment  
 Post-Treatment 
Period 
From Day after the last dose of G/P up to 1 year post transplant  
 
 
 


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2.0 Table of Contents 
1.0 Title Page ................................................................................................... 1 
1.1 Synopsis 
2 
1.2 List of Abbreviations, Definitions and Terms .............................................................. 13 
2.0 Table of Contents ................................................................................... 18 
3.0 Introduction ............................................................................................ 22 
3.1 Glecaprevir/Pibrentasvir (G/P) ..................................................................................... 26 
3.1.1 Efficacy ........................................................................................... 27 
3.1.2 Impact of Baseline Polymorphisms on Treatment Outcome .......... 29 
3.1.3 Amino Acid Substitutions in Subject Experiencing Virologic 
Failure ...................................................................................................... 29 
3.1.4 Integrated Safety Results ................................................................ 30 
3.2 Study Rationale ............................................................................................................ 33 
3.3 Benefits and Risks ........................................................................................................ 33 
4.0 Study Objectives ..................................................................................... 34 
4.1 Primary Objective ......................................................................................................... 34 
4.2 Secondary Objectives ................................................................................................... 34 
5.0 Investigational Plan ................................................................................ 36 
5.1 Overall Study Design, Rationale and Plan: Description ............................................... 36 
5.1.1 Standard of Care Assessments – (patient managed clinically and 
billed per standard medical practice) ....................................................... 42 
5.1.2 Protocol Required Assessments ...................................................... 42 
5.1.3 Screening ........................................................................................ 43 
5.1.4 Waiting List and Transplantation Phases ........................................ 47 
5.1.5 Treatment Period with G/P ............................................................. 49 
5.1.6 Post-Treatment Period ..................................................................... 56 
5.1.8   “Reactive G/P Treatment Phase” -- only for subjects who 
experience HCV infection after transplantation of a kidney from a HCV 
RNA-negative/HCV antibody-positive donor ......................................... 66 
5.1.9 Additional Visits ............................................................................. 67 
5.1.11 Future Research ............................................................................ 68 
5.2 Selection of Study Population ...................................................................................... 68 
5.2.1 Inclusion/Exclusion Criteria for kidney transplant candidates ....... 69 
5.2.2 Main Inclusion Criteria for kidney donors and allografts ............... 73 
5.2.3 Prior and Concomitant Therapy ...................................................... 74 
5.3 Efficacy, Pharmacogenetic and Safety Assessments/Variables ................................... 76 
5.3.1 Efficacy and Safety Measurements Assessed and Flow Chart ....... 76 
5.3.2 Efficacy Variables ........................................................................... 81 
5.3.3 Resistance Variables ....................................................................... 81 


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5.3.4 Safety Variables .............................................................................. 82 
5.4 Removal of Subjects from Therapy or Treatment Duration Assessment ..................... 83 
5.4.1 Discontinuation of Individual Subjects ........................................... 83 
5.4.2 Discontinuation of Entire Study ...................................................... 84 
5.5 Treatments 85 
5.5.1 Treatments Administered ................................................................ 85 
5.5.2 Identity of Investigational Products ................................................ 86 
5.5.3 Packaging and Labelling ................................................................. 86 
5.5.4 Method of Assigning Subjects to Treatment Groups ....................... 86 
5.5.5 Selection and Timing of Dose for Each Subject.............................. 87 
5.5.6 Blinding .......................................................................................... 88 
5.5.7 Treatment Compliance .................................................................... 88 
5.5.8 Drug Accountability & Destruction ................................................ 88 
6.0 
 Complaints ............................................................................ 90 
6.1 Medical Complaints ..................................................................................................... 91 
6.1.1 Definitions ...................................................................................... 91 
6.1.2 Adverse Event Severity .................................................................. 94 
6.1.3 Relationship to Study Drug ............................................................. 95 
6.1.4 Adverse Event Reporting ................................................................ 95 
6.1.5 Serious Adverse Event Reporting ................................................... 97 
6.1.6 Pregnancy ........................................................................................ 98 
6.1.7 Toxicity Management ..................................................................... 99 
6.1.8. Management of ALT elevations while on study drug G/P........ 100 
6.1.9. Management of suspected kidney rejection while on study drug 
G/P 
100 
6.2. Product Complaint ..................................................................................................... 101 
6.2.1 Definition ...................................................................................... 101 
6.2.2 Reporting ...................................................................................... 102 
7.0 
Major Protocol Deviations .................................................. 102 
8.0 
Statistical Methods and Determination of Sample Size ... 103 
8.1 Statistical and Analytical Plans .................................................................................. 103 
8.1.1 Demographics ............................................................................... 104 
8.1.2 Efficacy ......................................................................................... 105 
8.1.3 Resistance Analyses ...................................................................... 107 
8.1.4 Secondary Clinical Outcomes ....................................................... 107 
8.1.5 Additional Adverse Event Analyses for Arm 1 ......................... 110 
8.1.6 Additional Clinical Laboratory Data ............................................ 111 
8.2 Determination of Sample Size .................................................................................... 111 
8.3 Assignment of Participants to Study Arms: Methods ................................................ 112 
9.0 
Ethics ..................................................................................... 112 
9.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) ............. 112 


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9.2 Ethical Conduct of the Study ..................................................................................... 113 
9.2.1 Ethics Analysis ............................................................................. 113 
9.3 Subject Information and Consent ............................................................................... 113 
9.4 Potential Risks and Benefits ....................................................................................... 114 
9.4.1 Risks of Study Procedures ............................................................ 114 
9.4.2 Risk of Study Drugs and Mycophenolate Mofetil ........................ 116 
9.4.3 Risk of Developing HCV Infection .............................................. 116 
9.4.4 Potential benefits ........................................................................... 117 
9.4.5 Alternatives ................................................................................... 117 
10.0 Study Administration, Data Handling, and Record Keeping ........ 118 
10.1 Confidentiality .......................................................................................................... 118 
10.2 Source Documents .................................................................................................... 118 
10.3 Case Report Forms ................................................................................................... 119 
10.4 Data Collection and Management ............................................................................ 119 
10.5 Medical record review/verification .......................................................................... 125 
10.6 HIPAA Privacy Rule for Elements of PHI and Uploaded Records ......................... 126 
11.0 Monitoring .......................................................................................... 127 
12.0 Records Retention .............................................................................. 128 
13.0  
Study Drug Records ............................................................ 128 
14.0 Data Quality Assurance ..................................................................... 129 
15.0 Data Safety Monitoring Committee ................................................. 129 
16.0 Completion of the Study .................................................................... 129 
17.0 Investigator's Agreement ................................................................... 131 
18.0 Reference List ..................................................................................... 132 
Appendix A: Educational material to be distributed at MYTHIC trial 
education session ........................................................................................ 134 
Appendix B: Responsibilities of the Clinical Investigator ...................... 139 
Appendix C: Medicare National Coverage Decision for Clinical Trials
 ...................................................................................................................... 141 
Appendix D: Methods of Contraceptives ................................................. 147 
D1 Contraception requirement for all subjects who will not receive mycophenolate 
mofetil following transplantation. .......................................................... 147 
D2 Contraception requirements for all subjects who will receive mycophenolate mofetil 
post kidney transplant ............................................................................ 149 
Appendix E: Extrahepatic Manifestations of HCV infection ................ 150 


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List of Tables 
Table 1. Overview of Registrational and Supportive Phase 2  Clinical Studies by Subject 
Population……………………………………………………………………………………………………………………..27 
Table 2. SVR12 Rates by Treatment Experience and HCV Genotype – GT1 – 6                 (ITT 
Population, Phase 2 and 3 Analysis Set) ............................................................................... 28 
Table 3. Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 Analysis Set) ................... 31 
Table 4: Screening visit procedures ................................................................................................... 46 
Table 5: Transplantation, G/P treatment and post treatment Phase Study Procedures for 
Recipients of Kidneys from HCV-RNA-Positive Donors ..................................................................... 59 
Table 6: Transplantation Phase Study Procedures for Recipients of Kidneys from HCV-RNA-
Negative, HCV-Antibody-Positive Donors ......................................................................................... 65 
Table 7: Prohibited Medications and Supplements .......................................................................... 75 
Table 8: Clinical Laboratory Tests Performed at Baseline or as Part of Wait-listing Evaluation as 
Standard of Care                                                                                                                                               76 
Table 9: Identity of Investigational Products ..................................................................................... 86 
Table 10: Estimated Lower Bound for 95% Confidence Interval for Cure Rate Based on Observed 
Number of Cures ............................................................................................................................. 111 
  
List of Figures 
Figure 1a: Overall Study Schematic ................................................................................................... 40 
Figure 1b: Schematic for patients undergoing transplantation with HCV RNA-negative/HCV-
antibody-positive kidney……………………………………………………………………………………………………………..39 
Figure 2: Subject flow, data collection and data transfer activities during the trial ....................... 119 
 
 
 


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3.0 Introduction 
Approximately 71 million people are chronically infected with HCV worldwide, including 
up to 4 million in the United States.1,2 Without treatment, the majority of infected 
individuals will develop chronic hepatitis, which can lead to cirrhosis, liver failure, and 
hepatocellular carcinoma (HCC).3 HCV is the leading cause of liver transplantation and 
HCC in most countries.3 Recently, the development of oral, interferon-free, direct-acting 
antiviral therapy has been a major advance for the treatment of HCV with available 
combinations curing the majority of infected patients and leading to few adverse effects.4,5  
 
Currently in the United States, approximately 95,000 patients are waiting for kidney 
transplantation and these numbers continue to rise.6 There is a definite shortage of viable 
donated organs, and it is of paramount importance that available resources are handled 
efficiently. All transplantable organs must be recognized for their enormous value as scarce 
resources and utilized to their maximum potential for the maximum benefit (the principle of 
utility), while also promoting equity.7 Transplantation of HCV-infected donor kidneys to 
HCV-infected recipients has been performed for over twenty years with increasing 
evidence of long-term safety and decreased mortality compared to remaining on the 
waitlist.8 However, in a survey of kidney donations between 1995 and 2009, of the 93,825 
HCV-positive deceased donors (potentially 187,650 kidneys), over 50% were discarded. 
An advantage of using HCV-infected organs is a 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-infected donor organ may often be better, as compared to 
other extended criteria organs, as many derive from a young population, age 18 to 35 years, 
following drug overdoses.9 
 
With pre-emptive HCV treatment shortly after transplantation, we hope to prevent 
significant viremia from ever occurring in the recipient and abrogate establishment of HCV 
infection in the liver. Glecaprevir/Pibrentasvir (G/P) is the first pan-genotypic regimen that 
is safe and effective in patients with renal impairment. G/P has potent in vitro antiviral 


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activity against genotypes 1 through 6 and a high genetic barrier to resistance, with no or 
little loss of potency against common resistant-associated substitutions. G/P is co-
formulated Glecaprevir 100 mg and Pibrentasvir 40 mg as a fixed-dose combination tablet, 
which provides patients with a convenient treatment regimen of three tablets once daily to 
be taken with food.10  
 
Expedition 4 was an international, open-label Phase 3 study of 12 weeks of G/P in 104 
patients with eGFR < 30mL/min/1.73m2 including 85 patients on dialysis and 19 with pre-
dialysis chronic kidney disease (CKD). By intention to treat analysis 102/104 patients were 
cured and there were no virologic failures (1 treatment discontinuation due to diarrhea and 
1 died of unrelated causes). Also, there were no treatment-related serious adverse events.11  
 
G/P has multiple advantages in the solid organ transplantation context. G/P is the only 
DAA regimen that is appropriate to administer among dialysis patients or in the immediate 
post-kidney transplant period (where a substantial proportion of deceased donor transplant 
recipients have delayed graft function)12 that is effective against all genotypes of HCV.13 
Furthermore, G/P 300mg/120mg once daily given for 12 weeks has also been studied in 
100 patients with chronic HCV infection post liver (n=80) or kidney transplantation (n=20). 
The overall SVR12 rate was 98% (98/100) with 1 post liver transplant patient experiencing 
virologic relapse and one patient was lost to follow-up. The most common adverse events 
in >10% of patients included headache, fatigue, nausea, pruritus, and diarrhea. There were 
two serious AEs deemed related to G/P including sinusitis and abnormal hepatic function at 
post-treatment week 4. There was one AE, a cerebrovascular accident that led to study drug 
discontinuation at week 6 of treatment and the patient achieved SVR12. Subjects were on 
the following immunosuppressant medications Tacrolimus (n=68), Mycophenolate mofetil 
(n=30), Cyclosporine (n=13), Prednisone (n=13), Everolimus (n=8), Azathioprine (n=6), 
and Sirolimus (n=7)14. 
The results of the THINKER trial provided preliminary evidence that HCV-infected organs 
could be safely transplanted into recipients who do not have HCV infection, and the virus 


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could be eradicated shortly after kidney transplant. This open-label, single-arm trial 
performed by Goldberg and colleagues, transplanted ten patients without HCV with 
kidneys from HCV-infected deceased donors with active viremia. When the recipient 
developed viremia, which occurred in all patients within three days post kidney transplant, 
they immediately began treatment with elbasvir-grazoprevir for twelve weeks. Patients 
received kidneys only from deceased donors with genotype 1 infection, because elbasvir-
grazoprevir is not effective at treating genotypes 2 or 3. All patients were cured of HCV, 
and elbasvir-grazoprevir was well tolerated in the immediate post-transplant period. 
Notably, one patient with biopsy-proven IgA nephropathy pre-transplant received an HCV-
infected kidney and developed proteinuria subsequent to completing 12 weeks of elbasvir-
grazoprevir. The patient underwent kidney biopsy which demonstrated focal segmental 
glomerulosclerosis. This event was considered possibly related to HCV or its therapy.15 
 
 
To allow for more widespread use of this protocol, an ideal regimen to treat HCV infection 
in the post-kidney transplant (KT) recipient would need to be safe in patients with low 
eGFR so it could be used in patients with delayed graft function, should have few to no 
interactions with immunosuppressant medications, and ideally treat all genotypes of HCV 
infection, thus obviating the need for rapid genotyping of donors prior to transplantation. 
The American Society of Transplantation Consensus Conference on the Use of Hepatitis C 
Viremic Donors in Solid Organ Transplantation has highlighted the urgent need for 
prospective research protocols that study the risk versus benefit of using organs from 
hepatitis C-infected donors.16 
 
 
In light of these recent advances in DAA therapy, we hypothesize that G/P could prevent 
transmission of HCV or establishment of HCV infection in the liver that could occur after 
transplantation of an HCV RNA-positive kidney into an HCV uninfected recipient. Because 
it is a pan-genotypic regimen, it would eliminate the need to rapidly genotype deceased 
donors prior to transplantation. Other regimens that could be used in the post-transplant 
period require genotyping to be sure the agents are active against the particular genotype 
that the donor has or are not safe in patients with eGFR < 30 mL/min/1.73m2. Genotyping 


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is a multi-step process that would require extra logistics during the time pressured process 
of organ allocation. Using a pan-genotypic regimen streamlines this process and ensures all 
HCV-infected organs are effectively utilized. If this approach proves successful, it could 
curtail the current high discard rates for HCV-infected kidneys and other organs. This new 
approach of using a pan-genotypic HCV regimen and avoiding donor genotyping has the 
potential to result in a large increase in the number of organs available in the kidney donor 
pool. Demonstration that pre-emptive treatment of HCV can prevent HCV transmission or 
establishment of HCV infection in the liver would greatly expand the viable kidney donor 
pool and could result in a substantial reduction in long-term healthcare costs for patients 
with end-stage renal disease. 
 
While there are no data for G/P in acute HCV infection, we hypothesize that an 8-week 
duration of G/P will be highly effective when given shortly after transplant of an HCV 
RNA-positive kidney into an HCV RNA-negative recipients who is non-cirrhotic and 
before a chronic HCV infection is established.  On the basis of the clinical studies 
referenced17,18, an 8-week duration of G/P has been approved for the treatment of an 
established, chronic HCV infection with genotype 1-6 in treatment naive non-cirrhotic 
subjects.10 
 
Because the focus of this study is about transplantation of kidneys from HCV-seropositive 
donors, we will also allow kidneys from patients who have a positive HCV antibody test 
(HCV Ab-positive) but have no detectable plasma HCV RNA. Prior to offering an organ, 
the Regional Organ Bank is aware of both the status of the HCV antibody and HCV RNA 
testing. In most parts of the country, the current organ allocation schema, categorizes organ 
donors who are HCV RNA-negative/HCV Ab-positive as similar to HCV RNA-positive 
despite the important difference of absence of HCV viremia in donors who are only HCV 
Ab- positive. Kidneys from HCV-positive donors (including HCV RNA-negative/HCV Ab-
positive and HCV RNA-positive) are still being discarded despite the fact that kidneys from 
HCV RNA-negative/HCV Ab-positive donors  are unlikely to transmit HCV. If HCV 


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transmission occurs from a study-eligible HCV RNA-negative/HCV Ab-positive kidney in 
Arm 2A of this study, which is anticipated to be a rare event, we would provide “reactive” 
G/P treatment. Patients would be treated with G/P as per transplant center standard of care. 
Limited data from the “reactive” G/P treatment and HCV outcome will be collected from 
these subjects. The following data will be obtained from these subjects: Plasma HCV RNA 
prior to HCV treatment initiation with G/P, SAEs that occurred during the G/P treatment 
period, HCV RNA results at post treatment week 12, early discontinuation of G/P 
treatment, and reasons for not achieving SVR12, as applicable.  
 
3.1 Glecaprevir/Pibrentasvir (G/P) 
Overview of G/P Registration Program and Supportive Studies 
The G/P registration program included a broad subject population including subjects with 
compensated liver disease and subjects with severe renal insufficiency across all 6 major 
genotypes using a single dose of 300 mg/120 mg QD.  Supportive Phase 2 studies used the 
Phase 2 formulation of separate GLE and PIB tablets, with each tablet containing 100 mg 
and 40 mg, respectively.  Treatment arms from these supportive Phase 2 studies using the 
regimen selected for registration studies (GLE 300 mg plus PIB 120 mg) were pooled with 
arms from the registration studies for analyses of efficacy and safety.  Treatment-naïve 
(TN) and treatment experienced (TE) subjects to any combination of pegylated IFN 
(pegIFN), RBV, sofosbuvir (SOF), NS5A inhibitors, or PIs were allowed in the program.  
In addition, the program included subjects with human immunodeficiency virus (HIV) 
coinfection (Study M13-590), subjects with chronic kidney disease [CKD] Stages 4 – 5, 
including those on hemodialysis (Study M15-462), subjects with compensated cirrhosis 
(Studies M14-172, M15-462, and M14-868), and subjects with or without cirrhosis who 
failed a previous regimen containing an NS5A inhibitor and/or an NS3/4A PI (Study M15-
410). 
A total of 2,376 subjects were randomized or enrolled in the registration studies or 
supportive Phase 2 studies to receive G/P 300 mg QD/120 mg QD.  Of these, 2,369 
subjects received at least 1 dose of G/P 300 mg QD/120 mg QD (Table 1). 


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Table 1. 
Overview of Registrational and Supportive Phase 2 Clinical Studies 
by Subject Population 
Genotype 
Clinical Study  Summary of Study Design  
TN and TE Subjects Without Cirrhosis 
GT1 
M13-590 
G/P 300 mg/120 mg QD for 8 (n = 351) or 12 weeks (n = 352) 
M14-867 
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 34) 
GT2 
M15-464 
G/P 300 mg/120 mg QD (n = 202) or placebo (n = 100) for 
12 weeks 
M14-868 
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 199) or 12 weeks 
(n = 25) 
GT3 
M13-594 
G/P 300 mg/120 mg QD for 8 (n = 157) or 12 weeks (n = 233) or 
SOF 400 mg + DCV 60 mg QD for 12 weeks (n = 115) (all subjects 
in study were TN) 
M14-868 
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 29; TN only), 
12 weeks (n = 76), or 16 weeks (n = 22; TE only) 
GT4, 5, 6 
M13-583 
G/P 300 mg/120 mg QD for 12 weeks (n = 121) 
M14-867 
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 32) 
 
M14-868 
GLE/PIB 300 mg/120 mg QD for 8 weeks (n = 58) 
TN and TE Subjects with compensated Cirrhosis 
GT1, 2, 4, 5, 6 
M14-172 
G/P 300 mg/120 mg QD for 12 weeks (n = 146) 
GT3 
M14-868 
GLE/PIB 300 mg/120 mg QD for 12 weeks (n = 64; TN only) or 
16 weeks (n = 51; TE only) 
Subjects with CKD Stages 4 – 5 With or Without compensated Cirrhosis 
GT1 – 6 
M15-462 
G/P 300 mg/120 mg QD for 12 weeks (n = 104) 
NS5A Inhibitor and/or PI-Experienced Subjects With or Without compensated Cirrhosis 
GT1, 4 
M15-410 
G/P 300 mg/120 mg QD for 12 (n = 66) or 16 weeks (n = 47) 
CKD = chronic kidney disease; DCV = daclatasvir; GLE = glecaprevir; GT = genotype; NS5A = nonstructural viral 
protein 5A; PI = protease inhibitor; PIB = pibrentasvir; QD = once daily; SOF = sofosbuvir; TE = treatment-experienced; 
TN = treatment-naïve 
3.1.1 Efficacy 
 
In TN or IFN, pegIFN, RBV, and/or SOF treatment-experienced (TE-PRS) subjects, the 
pooled overall SVR12 rates with G/P were > 97% across GT1, 2, 4, 5 and 6 regardless of 
treatment experience, treatment duration, including any degree of renal impairment, 
presence of cirrhosis, or HIV-1 coinfection (Table 2).   
Among subjects with GT3 infection, the pooled SVR12 rates across durations were 95.2% 
among all subjects, 96.6% among cirrhotic subjects, and 100% among subjects with CKD 


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Stages 4 – 5.  The SVR12 rates among subjects previously treated with a PI and/or NS5A 
inhibitor were ≥ 89.0% for GT1 and GT4. 
 
Table 2. 
SVR12 Rates by Treatment Experience and HCV Genotype – GT1 – 6 
(ITT Population, Phase 2 and 3 Analysis Set) 
Genotype 
TN 
n/N (%) 
95% CIa 
TE-PRS 
n/N (%) 
95% CIa 
TN + TE-PRS 
TE-NS5A 
and/or PIs 
n/N (%) 
95% CIa 
Overall 
n/N (%) 
95% CIa 
Alla 
Cirrhotic 
n/N (%) 
95% CIb 
CKD 4 – 5 
n/N (%) 
95% CIb 
Phase 2 
and 3 
Analysis 
Set 
1604/1640 
(97.8) 
97.1, 98.5 
602/616 
(97.7) 
96.6, 98.9 
2206/2256 
(97.8) 
97.2, 98.4 
274/281 
(97.5) 
95.7, 99.3 
102/104  
(98.1) 
95.4, 100.0 
101/113 
(89.4) 
83.7, 95.1 
2307/2369 
(97.4) 
96.7, 98.0 
GT1 
555/561 
(98.9) 
98.1, 99.8 
326/328 
(99.4) 
98.5, 100.0 
881/889 
(99.1) 
98.5, 99.7 
98/101 
(97.0) 
93.7, 100.0 
53/55 
(96.4) 
91.4, 100.0 
97/109 
(89.0) 
83.1, 94.9 
978/998c 
(98.0) 
97.1, 98.8 
GT2 
365/369 
(98.9) 
97.9, 100.0 
95/97  
(97.9) 
95.1, 100.0 
460/466 
(98.7) 
97.7, 99.7 
35/35  
(100) 
100.0, 
100.0 
16/16  
(100) 
100.0, 100.0 
N/A 
460/466 
(98.7) 
97.7, 99.7 
GT3 
499/521 
(95.8) 
94.0, 97.5 
113/122 
(92.6) 
88.0, 97.3 
612/643 
(95.2) 
93.5, 96.8 
112/116 
(96.6) 
93.2, 99.9 
11/11  
(100) 
100.0, 100.0 
N/A 
612/643 
(95.2) 
93.5, 96.8 
GT4 
119/122 
(97.5) 
94.8, 100.0 
55/56  
(98.2) 
94.7, 100.0 
174/178 
(97.8) 
95.6, 99.9 
20/20  
(100)  
100.0, 
100.0 
20/20  
(100)  
100.0, 100.0 
4/4  
(100)  
100.0, 
100.0 
178/182 
(97.8) 
95.7, 99.9 
GT5 
26/26  
(100) 
100.0, 
100.0 
6/6  
(100) 
100.0, 
100.0 
32/32  
(100) 
100.0, 
100.0 
2/2  
(100)  
100.0, 
100.0 
1/1  
(100)  
100.0, 100.0 
N/A 
32/32  
(100)  
100.0, 100.0 
GT6 
40/41  
(97.6) 
92.8, 100.0 
7/7  
(100) 
100.0, 
100.0 
47/48  
(97.9) 
93.8, 100.0 
7/7  
(100) 
100.0, 
100.0 
1/1  
(100) 
100.0, 100.0 
N/A 
47/48  
(97.9) 
93.8, 100.0 
CI = confidence interval; CKD = chronic kidney disease; GT = genotype; HCV = hepatitis C virus; ITT = intention-to-
treat; N/A = not applicable; NS5A = nonstructural viral protein 5A; PI = protease inhibitor; PRS = regimens containing 
interferon, pegylated interferon, ribavirin, and/or sofosbuvir; SVR12 = sustained virologic response 12 weeks post dosing; 
TE = treatment-experienced; TN = treatment-naïve; TE-NS5A and/or PI = TE with NS5A inhibitor and/or PI 
1. 
CI was calculated using a stratum-weighted proportion and variance. 
2. 
CI was calculated using the normal approximation to the binomial distribution. 
3. 
Eleven subjects were classified by the central laboratory and treated as GT2 but included here as GT1 due to  
being identified as such by phylogenetic analysis; all 11 subjects achieved SVR12 
4. 
Cross reference:  AbbVie, data on file. 
 


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3.1.2 Impact of Baseline Polymorphisms on Treatment Outcome 
The association between baseline polymorphisms and treatment outcome in TN and TE-
PRS subjects who received G/P 300 mg/120 mg QD in the registration or supportive 
Phase 2 studies was evaluated by conducting an integrated analysis of baseline sequence 
data.  Next-generation sequencing (NGS) was conducted on all baseline samples at 15% 
detection threshold at key amino acid positions 155, 156, and 168 in NS3, and 24, 28, 30, 
31, 58, 92, and 93 in NS5A.  
 
In subjects who were TN or TE-PRS, baseline polymorphisms in NS3 were detected in 
1.1% (9/845), 0.8% (3/398), 1.6% (10/613), 1.2% (2/164), 41.9% (13/31), and 2.9% (1/34) 
of subjects with HCV genotype 1, 2, 3, 4, 5 and 6 infection, respectively.  Baseline 
polymorphisms in NS5A were detected in 26.8% (225/841), 79.8% (331/415), 22.1% 
(136/615), 49.7% (80/161), 12.9% (4/31), and 54.1% (20/37) of subjects with HCV 
genotype 1, 2, 3, 4, 5, and 6 infection, respectively. 
 
The presence of baseline polymorphisms in NS3 and/or NS5A did not have an impact on 
SVR12 rates for GT1-, 2-, 4-, 5-, or 6-infected subjects. 
Within GT3-infected subjects, baseline polymorphisms in NS3 and the NS5A 
polymorphisms at positions 24, 28, 31, 58, 92, or 93 did not have an impact on treatment 
outcome.  
3.1.3 Amino Acid Substitutions in Subject Experiencing Virologic Failure 
Among TN and TE-PRS subjects with or without cirrhosis treated for 8, 12, or 16 weeks, 
23 subjects experienced virologic failure (2 with GT1, 2 with GT2, and 19 with GT3). One 
GT3-infected subject experiencing virologic failure was determined to have been re-
infected with GT3a virus distinct from the one present at baseline.  Therefore, baseline 
polymorphisms and treatment-emergent substitutions were analyzed for 22 subjects 
experiencing virologic failure.  
 


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Among the 2 GT1-infected subjects, 1 had treatment-emergent substitutions A156V in NS3 
and Q30R/L31M/H58D in NS5A, and 1 had treatment-emergent Q30R/H58D (while Y93N 
was present at baseline and post-treatment) in NS5A. 
Among the 2 GT2-infected subjects, no treatment-emergent substitutions were observed in 
NS3 or NS5A; the prevalent M31 polymorphism in NS5A was present at baseline and post-
treatment in both subjects. 
 
Among the 18 GT3-infected subjects, the majority of subjects had treatment-emergent 
variants at the time of failure in NS3 (61.1%, 11/18) and NS5A (88.9%, 16/18).  
Treatment-emergent NS3 substitutions Y56H/N, Q80K/R, A156G, and Q168L/R were 
observed in 11 subjects, and A166S or Q168R was present at both baseline and 
post-treatment in 5 subjects.  Treatment-emergent NS5A substitutions M28G, A30G/K, 
L31F, P58T, or Y93H were observed in 16 subjects, and 13 subjects had A30K (n = 9) or 
Y93H (n = 5) at both baseline and post-treatment. 
3.1.4 Integrated Safety Results 
A summary of treatment-emergent adverse events (AEs) from pooled analyses of the 
registration studies and supportive Phase 2 studies are presented in Table 3. The severity of 
the underlying renal disease and its associated comorbidities in patients with CKD Stages 4 
and 5, the frequency and severity of the AEs in subjects enrolled Study M15-462 were 
expected to be higher than in subjects enrolled in the other registration studies.  Therefore, 
the summary of adverse events reported in Table 3 does not include the results of Study 
M15-462. 
 
As shown in Table 3, the AEs occurring with a frequency ≥ 5% are headache, fatigue, 
nausea and diarrhea.  The majority of subjects experienced an AE, which were mostly 
considered to be mild in severity by the investigator (Grade 1).  Rates of AEs that were 
serious, led to premature study drug discontinuation or had a severity Grade ≥ 3 were low.  
Including data from Study M15-462, there were 7 deaths, none of which were related to 
study drug, and the majority occurred several months after the last dose of study drug.  


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Table 3. 
Adverse Events Reported for ≥ 5.0% of Subjects (Phase 2 and 3 
Analysis Set) 
 
Phase 2 and 3 Analysis Seta 
(N = 2,265) 
n (%) 
 
All Adverse Events 
DAA-Related Adverse 
Eventsb 
Any AE 
1,529 (67.5) 
929 (41.0) 
An AE Grade ≥ 3 
65 (2.9) 
4 (0.2) 
Any SAE 
48 (2.1) 
1 (< 0.1) 
Discontinuation of study drug due to any AE 
8 (0.4) 
3 (0.1) 
All deathsc 
6 (0.3) 
0 
Preferred Termd 
 
 
Headache 
410 (18.1) 
298 (13.2) 
Fatigue 
330 (14.6) 
259 (11.4) 
Nausea 
208 (9.2) 
172 (7.6) 
Diarrhea 
146 (6.4) 
86 (3.8) 
AE = adverse event; DAA = direct-acting antiviral agent; GLE = glecaprevir; PIB = pibrentasvir; SAE = serious adverse 
event 
a. 
Excludes Study M15-462. 
b. 
DAAs = GLE, PIB, or GLE/PIB. 
c. 
Includes non-treatment-emergent deaths.  One additional death occurred in Study M15-462. 
d. 
DAA-related AEs reported for ≥ 5.0% of subjects in the Phase 2 and 3 Analysis Set.  
Cross reference:  AbbVie, data on file.  
 
Adverse events in subjects without cirrhosis (n = 1,977) were similar in type, frequency, 
and severity compared with subjects with cirrhosis (n = 288).  The safety profile in subjects 
with HCV/HIV-1 co-infection (n = 33) was similar to that in HCV mono-infected subjects.  
Overall, the safety profile of G/P in the elderly population (≥ 65 years old, n = 328) was 
comparable to the safety profile in the non-elderly population (n = 2,041). 
The frequency and severity of hepatic-related AEs as well as liver chemistry abnormalities 
evaluating potential hepatotoxicity were low across the Phase 2 and 3 studies.  Liver-related 
safety results indicated that: 
• Four subjects had post-nadir Grade 3 ALT abnormalities or Grade 2 ALT with 
total bilirubin ≥ 2 × ULN.  None of these subjects prematurely discontinued study 
drug due to an ALT or bilirubin increase. 


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• ALT abnormalities in 3 of these 4 subjects were not clinically significant  
• One subject experienced concurrent ALT > 3 × ULN (increased from nadir grade) 
and total bilirubin ≥ 2 × ULN in the context of multiple gallstones and was not 
considered to have drug-induced liver injury 
• Based on exposure-response analyses, no exposure-dependent ALT increases were 
observed in subjects with ALT abnormalities  
• Grade 3 increases in bilirubin were infrequent (0.4%) and without bilirubin-related 
AEs; none were associated with liver disease progression 
• No subjects experienced drug-related hepatic decompensation.  One subject with 
cirrhosis (Study M14-172) who had known esophageal varices experienced an 
episode of esophageal varices hemorrhage that was considered not related to study 
drug.  Treatment was continued without clinical or laboratory signs of liver 
disease progression.   
• A total of 6 (0.3%) subjects experienced a de novo event of HCC.  In all 
6 subjects, the events were considered related to subject's medical history of 
underlying liver disease and not to G/P.   
 
In summary, G/P demonstrated a favorable safety profile similar across durations of 8, 12, 
and 16 weeks.  The regimen was well tolerated across a broad and diverse population of 
subjects, including subjects with cirrhosis, HIV co-infection, and CKD Stage 4 or 5. 
Based on the combined Phase 2 and 3 Analysis Set common study drug-related AEs 
occurring in ≥ 5% of subjects were headache, fatigue, nausea (Table 3) and were mostly 
Grade 1 (mild) in severity. Serious AEs and AEs leading to premature study drug 
discontinuation were rare. There were no hematological or blood chemistry findings of 
concern or considered likely related to treatment. Unlike other protease inhibitors, no liver-
related toxicities and no cases consistent with drug-induced liver injury were identified. 
 
 


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3.2 Study Rationale  
DAA therapy has made is possible to effectively and safely treat HCV before or after 
kidney transplant. However, most waitlisted end-stage renal disease patients are predicted 
to live longer with transplant than on dialysis;19-21 this benefit extends to HCV-infected 
patients. Approximately 500 kidneys from HCV-infected donors are discarded annually in 
the United States. Strategies to increase utilization of HCV-infected kidneys to shorten wait 
time for patients on dialysis are desperately needed. 22 The purpose of this study is to 
determine if G/P treatment when initiated early after kidney transplant (e.g., as early as 3 
days post-transplant) can prevent significant HCV viremia and prevent establishment of 
HCV infection in the liver and associated complications. G/P’s registration program has 
demonstrated high efficacy with an overall SVR12 rate of 98% for the label-recommended 
regimen/duration, good safety and tolerability. These data suggest that G/P may achieve 
similar high SVR12 rates and safety results in HCV negative recipients of HCV viremic 
kidneys when G/P treatment is started early post-transplant. 
3.3 Benefits and Risks 
Potential benefits of early post-transplant treatment with G/P in the setting of high unmet 
need subjects on the kidney transplant wait list include:  
1. 
Potential for high SVR rate in a population with long and/or additional waiting 
times on the kidney transplant list and substantial risk for health complications 
before a good-quality HCV-negative kidney becomes available for transplantation. 
2. 
The approved dose of G/P e.g., 300mg/120mg (=3 tablets) once daily can be used in 
subjects with or without any level of renal impairment and for all HCV genotypes 1-
6.  
3. 
The safety profile and high efficacy (98% SVR12 with no virologic failure) of G/P 
in subjects with end-stage renal disease has been established. 
4. 
G/P demonstrated good tolerability, safety and high efficacy in patients treated for 
chronic HCV infection post kidney transplantation.  
5. 
The benefit of a short 8 week therapy and no Ribavarin (RBV) needed as part of the 
treatment regimen 


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6. 
The benefit of early treatment initiation of G/P after transplant of an HCV RNA-
positive allograft greatly reduces the risks of sequelae of acute HCV infection. 
 
The safety of G/P has been established in a diverse population of patients with and without 
compensated cirrhosis in Phase II and III clinical trials (Section 3.1.4). The most common 
AEs in greater than 10% of subjects include headache, and fatigue. Additional Safety data 
for G/P are detailed in the Mavyret USPI.10 In addition, subjects may experience 
inconvenience or discomfort related to the study visits or study procedures.  
 
Risks associated with acute HCV infection,15,23 the treatment with G/P, including the risks of 
medication toxicity, virologic failure, and development of resistance-associated substitutions 
(Section 3.1.3), appear to be limited and manageable based upon the available data. A 
subject experiencing G/P treatment failure in this study will be offered retreatment with a 
regimen deemed suitable. Given the potential for high rates of SVR in this population with 
limited current treatment options, the risk-benefit assessment is favourable. 
 
4.0 Study Objectives 
4.1 Primary Objective 
The primary objective of this study is to demonstrate the safety and efficacy (SVR12) of an 
8-week treatment with G/P in HCV-negative recipients who received a study eligible HCV 
RNA-positive kidneys in Arm 1 
4.2 Secondary Objectives 
The secondary objectives are: 
1) Among all subjects enrolled in the study, to describe time to kidney transplant and 
cumulative incidence of each type of transplant: a study-eligible HCV RNA-positive 
kidney (Arm 1), a study-eligible HCV RNA-negative/HCV antibody-positive kidney 
(Arm 2A), or a kidney transplant performed as part of standard of care treatment (Arm 
2B).  


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2) To describe clinical outcomes while on the waitlist after consent (Serious Adverse 
events [SAEs], delisting from waitlist, death) between those who receive a study-
eligible HCV RNA-positive kidney (Arm 1) and in subjects consented for this study 
who do not receive a study-eligible kidney transplant from an HCV RNA-positive 
donor (all Arm 2 subjects) overall and with breakdown by the 3 categories of Arm 2 
as below: 
A: subjects who receive a kidney from a study-eligible HCV RNA-negative/HCV Ab-
positive donor 
B: subjects who receive a standard of care kidney transplant 
C: subjects who were not transplanted within 1 year of consent 
Hereafter, these categories will be referred to as Arms 2A, 2B and 2C.  
 
A “standard of care” transplant will be defined as any of the following kidney transplants: 
a deceased donor HCV RNA-positive kidney transplant that did not meet donor 
criteria for Arm 1 or HCV RNA-positive kidney transplant that place after last 
transplant allowed for Arm 1 but met criteria for Arm 1 inclusion (2B1); a deceased 
donor  HCV RNA-negative/HCV Ab-positive kidney transplant that either did not 
meet donor criteria or took place > 6 months after the last Arm 1 transplant (2B2); a 
deceased donor HCV RNA-negative/HCV Ab-negative transplant at a MYTHIC 
clinical site (2B3); any living donor kidney transplant at a MYTHIC clinical site 
(2B4); or any kidney transplant at a different center than the 7 clinical sites (2B5). 
In addition, to compare the total number of inpatient hospital days while on the waitlist 
and after study consent in those who did receive a study eligible HCV RNA-positive 
kidney (Arm 1) vs total inpatient hospital days in those who did not (Arm 2) overall 
and with breakdown by the 3 categories of Arm 2 (2A, 2B and 2C).  
3)  To describe clinical outcomes and data post-transplant (death, graft failure, acute 
allograft rejection, delayed graft function, estimated glomerular filtration rate [eGFR], 
proteinuria, ALT elevation > 5 times the upper limit of normal (ULN), SAEs) 


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between those who receive an HCV RNA-positive kidney (Arm1) and in subjects 
who receive an HCV RNA-negative/HCV Ab-positive kidney allograft (Arm 2A) or a 
standard of care kidney transplant  (from Arm 2B1 – 2B4) combined and separately. 
For subjects of Arm 1 and Arm 2A who become HCV infected, we will collect 
additional clinical outcomes of sclerosing cholestatic hepatitis and extrahepatic mani-
festations of HCV. In addition, the clinical outcomes and data post-transplant will be 
compared between Arm 1 and Arm 2 where a) any study drug (G/P) related severe 
treatment emergent adverse events are included as a clinical outcome for Arm 1 and 
b) all events of treatment emergent Grade≥ 3 laboratory values and severe G/P-related 
treatment emergent adverse events are included as clinical outcomes for Arm 1. 
4) To compare time to deceased donor kidney transplantation among all patients who 
enrolled in this MYTHIC trial to transplant candidates from the Organ Procurement 
and Transplantation Network (OPTN) database; MYTHIC participants will be 
matched 1:3 to OPTN patients on demographics and characteristics known to 
influence waiting time including waiting list priority, blood group, geographic 
region, and sensitization. 
5.0 Investigational Plan 
5.1 Overall Study Design, Rationale and Plan: Description 
This is a Phase 4, open-label, multi-center, 2-arm study with the primary objective of 
evaluating the efficacy (SVR12) and safety of the fixed-dose combination tablets of 
glecaprevir/pibrentasvir (G/P) in HCV-negative subjects who receive a kidney transplant 
from an HCV RNA-positive deceased kidney donor. Among 90 subjects consented for trial 
participation, 30 subjects at up to 7 sites are planned to receive an HCV RNA-positive 
kidney and will be enrolled into a post-transplant treatment arm (Arm 1) receiving open-
label G/P for 8 weeks post-transplant. The remaining consented patients who do not receive 
a study eligible kidney from an HCV RNA-positive donor will be followed in Arm 2 for the 
minimum duration of 1 year post-enrollment (Arm 2B and 2C), or 24 weeks post-
transplant, whichever is longer (Arm 2A). These Arm 2 subjects include patients who do 


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not receive a kidney transplant (Arm 2C) or who receive a study eligible kidney from an 
HCV RNA-negative/HCV Ab-positive donor (Arm2A), or from a standard of care donor 
(Arm 2B). Follow-up for study participants who receive a kidney transplant at a non-study 
site (Arm 2B5) will be censored at transplantation. 
For subjects of Arm 1 of the study, the first dose of G/P will be given as early as 3 days 
post-transplant. Patients must be out of the ICU, able to eat and drink, take oral 
medications, and G/P treatment can be safely initiated orally as judged by the site 
investigator. 
 
Enrolled subjects will be activated in the United Network for Organ Sharing (UNOS) 
allocation system as eligible for kidney allograft offers from deceased donors that are HCV 
RNA-positive,  HCV Ab-positive, or both. 
 
Subjects who are transplanted with kidneys from HCV RNA-positive donors in Arm 1 will 
be followed for 1 year after the date of transplantation to evaluate SVR12, SVR24, safety, 
death, graft failure, acute allograft rejection, delayed graft function, ALT elevation >5 times 
the upper limit of normal, eGFR and proteinuria. Specifically, scheduled in-person visits 
for subjects who received organs from HCV RNA-positive donors in Arm 1 and receive 
G/P treatment will consist of day of transplant, Day 1 of G/P treatment, weeks 1, 2, 4, and 8 
(planned end of treatment visit) after starting G/P. Additional scheduled visits will take 
place at Post Treatment Week 4, Post Treatment Week 12, Post Treatment Week 24  (e.g., 
post G/P treatment visits) to evaluate SVR4, SVR12 and SVR24 and 1 year post transplant. 
The post-transplant study visit schedule for MYTHIC has been designed such that these 
visits should take place on the same days as standard of care clinical visits. For subjects in 
Arm 1 study-objective pertinent data will be collected while awaiting a transplant (ie, 
SAEs, hospitalizations, delisting from waitlist, death), and post-transplant (ie, death, graft 
failure, acute allograft rejection, delayed graft function, eGFR, proteinuria,  ALT elevation 
>5 times the upper limit of normal, and SAEs). Subjects who experience virologic failure in 


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Arm 1 will be evaluated for the emergence/persistence of DAA-resistant viral variants, and 
suitable retreatment will be offered.  
 
Study visits in Arm 2A will take place at weeks 1, 4, 8, 12, and 24 weeks after 
transplantation. Safety, graft survival, mortality, allograft rejection, and results of HCV 
RNA testing will be captured for a period of 24 weeks post-transplant. Study-objective 
pertinent data will be collected while awaiting a transplant (i.e., SAEs, delisting from 
waitlist, death), and post-transplant (i.e., death, graft failure, acute allograft rejection, 
delayed graft function, eGFR, proteinuria, ALT elevation >5 times the upper limit of 
normal, and SAEs. For subjects of Arm 1 and Arm 2A who become HCV infected, we will 
collect additional clinical outcomes of sclerosing cholestatic hepatitis and extrahepatic 
manifestations of HCV. 
 
If any recipients of a study-eligible HCV RNA-negative/HCV antibody-positive kidney 
develops HCV infection within 24 weeks after transplantation, that recipient will be offered 
treatment with G/P for 8 weeks. G/P treatment will be administered and subject will be 
followed as per local transplant center standard of care not reimbursed by the study but G/P 
will be supplied by the study. Limited data of this “reactive” G/P treatment and HCV 
outcome will be collected from these subjects. The following data will be obtained: plasma 
HCV RNA prior to HCV treatment initiation with G/P, SAEs that occurred during the G/P 
treatment period, any early discontinuation of G/P treatment, HCV RNA results at post 
treatment week 12, , and reasons for not achieving SVR12, as applicable. In the case of 
active HCV viremia, a sample of plasma and PBMCs will be sent to MGH as early as 
possible after viremia is detected. 
 
Other subjects in Arm 2 who remain on the transplant waiting list, or receive a standard of 
care kidney transplant will be followed as per transplant center standard of care for at least 
12 months post enrollment with study-objective pertinent collection of data while awaiting 
a transplant (e.g., SAEs, delisting from waitlist, death), and post-transplant events as 


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applicable (death, graft failure, acute allograft rejection, delayed graft function, eGFR, 
proteinuria, ALT elevation >5 times the upper limit of normal, and SAEs). However, for 
Arm 2B5 recipients, no further data will be collected after transplantation. 
 
During the first 6 months after the trial commences, each study site will be assured of the 
ability to perform at least one kidney transplantation from an HCV RNA-positive donor 
and G/P therapy provided through the trial. The period of “the first 6 months after the trial 
commences” will start on the date that the first clinical site has institutional review board 
approval to start enrolling patients into the trial until 183 days later. The other kidney 
transplants from HCV RNA-positive donors will take place competitively, such that any 
site may perform kidney transplants up to a maximum of 10 transplants from HCV-RNA-
positive donors with recipients receiving study drug and being analyzed in Arm 1. 
 
Treatment Period for recipients of HCV RNA-positive kidneys in Arm 1:  
Eligible subjects will initiate G/P 300 mg/120 mg QD for 8 weeks early after kidney 
transplantation. Day 3 post-transplant is targeted for the start of G/P treatment for HCV 
RNA-positive kidney recipients, with the conditions met that the subject should be out of 
the ICU, able to eat and drink and take medications orally, and in the judgement of the 
investigator, starting oral G/P treatment is safe for the subject.  
 
A delay in commencing G/P after day 3 should only take place because the responsible site 
investigator and/or responsible clinicians believe that G/P cannot be safely administered or 
because of a high probability that G/P will subsequently need to be discontinued or held for 
prolonged period because the patient is likely to experience clinical deterioration. In the 
case of any patient who has not started G/P by day 3 after transplantation, the site 
investigator will discuss that case with the Principal Investigator  Ray Chung, MD, or 
delegate, and develop and document a plan to start G/P at a later time. 
 
Post Treatment (PT) Period for recipients of HCV RNA-positive kidneys in Arm 1 :  


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Subjects who complete or prematurely discontinue G/P treatment will be followed for 24 
weeks after their last dose of study drug to evaluate efficacy and to monitor HCV RNA and 
the emergence and persistence of viral substitutions in the NS3 and NS5A, and subjects will 
be followed up at 1 year post the date of kidney transplant to assess graft function and 
survival and anti-HCV antibody serology. 
 
Figure 1A: Overall Study Schematic 
 
Treatment and PT Period for Study Arm 2A  recipients of HCV RNA-negative/HCV 
antibody-positive kidneys:  
Eligible subjects will be followed for 24 weeks after transplantation or 12 months after 
enrollment, whichever is longer, with surveillance for HCV infection using HCV RNA testing on 
week 1, week 4 (usual care), and week 24 (Figure 1B) after transplantation. A maximum number 
of up to n=20 subjects who are enrolled into the study can accept a study-eligible kidney from an 
HCV RNA-negative/HCV antibody-positive donor and be assigned to Arm 2A and will be 
followed in the study for 24 weeks post-transplant. The last study-eligible kidney transplant from 
an HCV RNA-negative/HCV antibody-positive donor in Arm 2A must occur no later than 24 
weeks after the date of the 30th kidney transplant from and HCV RNA-positive donor in Arm 1 
(see also section 5.1.5).  
Any subject in Arm 2A who develops HCV infection by 24 weeks after transplantation will be 
offered open-label G/P 300 mg/120 mg QD for 8 weeks. G/P will be provided by AbbVie, 
and while all patients will receive an 8-week course, the patient treatment visit schedule 


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and follow-up will be guided by the transplant center standard of care and AASLD/IDSA 
Guidelines for HCV treatment26, and as described in section 5.1.1, 5.1.2 and Table 6. 
Outcome data, including SAEs, treatment emergent Grade 3 or greater laboratory 
abnormalities, sclerosing cholestatic hepatitis and extra-hepatic manifestations, and post-
treatment week-12 HCV RNA will be collected from the subject medical record and 
entered into the study eCRFs. For kidneys from HCV RNA-negative/HCV Ab-positive 
donors in Arm 2A, the inclusion/exclusion criteria for donors are identical to donor 
inclusion/exclusion criteria as outlined in section 5.2.1 and 5.2.2, except that donor must be 
HCV RNA-negative. 
 
Figure 1B: Schematic for patients undergoing transplantation with HCV 
RNA-negative/HCV antibody-positive kidney in Arm 2A 
 
Observation period for other Study Arm 2 subjects  
Enrolled Arm 2 subjects who were not transplanted will be followed for 1 year post 
enrollment and Arm 2 subjects who received an standard of care kidney (Arm 2B) will be 


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followed for a minimum of 1 year post-enrollment, or 24 weeks post transplantation 
whichever is longer, unless they are transplanted at a non-study site (Arm 2B5), in which 
case no further data will be collected after transplant. 
 
5.1.1 Standard of Care Assessments for all patients – (patient managed clinically 
and billed per standard medical practice) 
 
1. Subject assessment for kidney transplant candidacy, kidney transplantation, and 
follow-up care after transplant; prior HCV treatment history; medical history; co-
morbid conditions; for-cause kidney biopsy or for cause liver biopsy, due to new 
or worsening symptoms of pre-transplant kidney or liver disease; or post-
transplant delayed or decreasing kidney graft function with suspicion for FSGS, 
graft rejection, or suspicion for post-transplant fibrosing cholestatic hepatitis, or 
other new liver disease. 
2. Donor kidney assessment and organ procurement, and including HCV RNA  
3. Assessment of recipient and donor-organ match  
4. G/P treatment regimen monitoring that takes place as part of SOC visits 
5. Clinical factors (physical examinations, vital signs) 
6. Adverse events and related safety management 
7. Concomitant medications 
8. Assessments during waitlist period 
9. Clinical Chemistry and Hematology labs 
10. Pregnancy tests post-transplant, except as noted below for research purposes 
11. Drug level monitoring of tacrolimus or other immunosuppressants post-transplant 
5.1.2 Protocol Required Assessments  
1. All outside standard of care, study-required safety and efficacy labs, G/P 
treatment monitoring during study visits, including baseline liver fibrosis 
assessment by Fibroscan as specified in Tables 4, 5, and 6. 


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2. NS3- and NS5A sequencing at evidence of failure of HCV treatment with 
G/P in Arm 1 or 2A 
3. Determination of HCV genotype from blood sample of HCV RNA-positive 
donor 
4. Archive plasma samples 
5.1.2.1 Protocol Optional Assessments  
1. Archive peripheral blood mononuclear cell (PBMC) samples 
 
5.1.3 Screening 
Potential subjects will first be contacted by the investigator, research coordinator and/or 
research staff to determine interest and provide basic information about the study. Potential 
subjects will be invited to attend an educational session on HCV infection and 
transplantation. There should be at least 3 days between the initial contact and the 
educational session. During this educational session, study investigators and research staff 
will teach participants about HCV, how it is spread, and the human disease it causes. They 
will explain the study and its risks and benefits. The potential subject will be encouraged to 
attend the educational session with at least one other family member or friend. The 
educational session may be attended by one or multiple potential subjects (and people the 
subjects invite) at a time. After completion of the educational session, the subject will be 
eligible for a screening visit. The Appendix A contains an educational handout for 
participants that will be reviewed in the educational session. 
 
If the patient is interested in participating in the study, the patient will undergo a screening 
visit. There should be at least 24 hours between the educational session and the screening 
visit. However, in specific cases, the site PI can allow the education session and screening 
visit at which the subject consent is obtained to happen on the same day: The subject 
wishes to proceed with the screening visit on the same day, and there are extenuating 
circumstances that make it very beneficial to the subject. One such circumstance may be 
that a subject is travelling a long distance to the study site for a one-day evaluation and it 


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would pose a financial or logistical burden to the subject to come back another day. After 
patient education and signed written and dated informed consent to participate in the study 
is obtained, subject eligibility will be verified based the protocol inclusion and exclusion 
criteria. Each subject will receive a unique subject number assigned sequentially by the 
study site. Enrolled subjects will keep their screening number as their subject number 
throughout the study. 
 
The investigator/clinician designee will evaluate whether the subject meets all of the 
eligibility criteria for the organ recipient specified in Section 5.2.1 and Section 5.2.2 and 
will record the results of this assessment and the details of the informed consent process in the 
subject's medical records and enter required subject data into the electronic case report form 
(eCRF) for this study. Enrolled patients will then enter the “waiting list phase.” Transplants 
will occur as deceased donor kidneys become available for consented patients and the study 
aims for accrual of 30 study-eligible kidney transplants from HCV-RNA positive donors. 
However, subjects who received a study-eligible HCV RNA-positive kidney offer and 
scheduled to be transplanted within 24 hours after the 30th HCV-RNA-positive kidney 
transplant will be allowed into Arm 1 of the study. Subjects who provided consent but do 
not receive an HCV RNA-positive organ offer will be actively followed in study Arm 2 for 
at least 1year post enrollment, or 24 weeks post-transplantation, whichever is longer , 
unless they are transplanted at a non-study site (Arm 2B5), in which case no further data 
will be collected after transplant. 
 
Medical records to support the medical history will be entered into the study electronic case 
report forms (eCRFs) developed by the Data Coordinating Center (DCC). Pre-specified 
information entered will include data from clinic visits, telephone contacts, relevant local 
laboratory testing and diagnostic/disease screening results (e.g. laboratory studies) collected 
as part of the standard medical care of the subject and relevant to their kidney transplant 
candidacy. The up-to-date data should also include sufficient medical history medications 


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to determine study candidacy. Older records (greater than 24 months) to document key 
medical history such as kidney disease and HCV treatment history may also be submitted. 
 
Laboratory testing to determine eligibility for the study is part of standard of care 
assessments supplemented by protocol required laboratory testing outside standard of care 
and will include the testing specified in Table 4. Additional, protocol-required laboratory 
tests will be performed by the central laboratory at MGH. All clinical laboratory tests 
which are standard of care will be performed by the local study site lab. For screening lab 
results without specific entry criteria that are abnormal and noted as clinically significant 
by the study investigator, the study investigator or designee will consult with the study 
Medical Monitor from Massachusetts General Hospital (MGH) for approval to enroll the 
patient in the study. 
 
This phase will also include identification of any medications used by the subject that are 
contraindicated or not recommended with the concomitant use of G/P (listed in Table 7, 
and see recipient exclusion criteria 5.2.2).  Patients who cannot switch to alternative 
allowed co-medications or cannot stop contraindicated or not recommended medications at 
least 14 days or 10 half-lives (whichever is longer) prior to the first dose of G/P treatment 
are not eligible to participate in the trial. Contraindicated or not recommended medications 
include: atorvastatin, lovastatin, simvastatin, carbamazepine, phenytoin, pentobarbital, 
phenobarbital, primidone, rifabutin, rifampin, astemizole, cisapride, terfenadine, ethinyl 
estradiol, St John’s Wort, and Red yeast rice (monacolin K). 
  
• Subject eligibility for study participation has to be verified by the CCC at MGH, Boston, 
MA. In addition to study eligibility criteria, the subject’s UNOS status as being 
changed to receive offers from HCV RNA-positive and/or HCV Ab-positive donors 
should be documented. Once a subject is identified as an eligible study subject by 
the local clinical site, the local clinical site will submit the subject’s 


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screening/historical medical record information according to the CCC to be verified 
for meeting enrollment eligibility criteria for organ recipient.   
 
During this phase prior to transplantation, the study staff will contact the study subjects by 
phone every two months and in-person every six months. The two goals of these 
interactions will be to a) ascertain adverse events and b) ensure that the subject still meets 
study eligibility criteria for organ recipient. 
 
Table 4: Screening visit procedures 
1 Acceptable screening data: HBV serologies/reflex HBV DNA if HBV core antibody positive, 
HIV antibody, HCV antibody, liver fibroscan or liver biopsy all obtained <18 months before or at 
date of screening date.  Vital Signs & Physical Exam, HCV RNA, Clinical Chemistry, Hematology, 
serum pregnancy test (only for women of childbearing potential) obtained ≤60 days before or at 
date of screening. Research Labs are obtained at screening. 
2 If no fibroscan was obtained <18 month before screening visit, a fibroscan will be obtained. 
3 PBMC sample is optional and restricted to sites with collection capability. 
 
5.1.3.1 Rescreening 
Subjects may be retested or rescreened only once. These subjects must be rescreened for all 
laboratory and eligibility criteria, not just those that were exclusionary. Subjects may be 
rescreened only in the event that they failed initial screening for the following reasons: 
1) Exclusionary laboratory parameter in which the primary investigator believes initial 
results were not accurate or indeterminate or in the case of cPRA, the investigator 
Screening visit 
Research Visit 
Activities 
Standard of care data to review, and data 
obtained at screening visit1 
Research 
labs 
Informed Consent 
Current Medications 
Liver fibrosis assessment2 
Review cause of ESRD 
HBV: Surface antigen, 
core antibody, HBV DNA 
HCV Antibody 
HCV RNA 
HIV antibody 
Hematology labs 
Clinical Chemistry labs 
Vitals and Physical Exam 
pregnancy test 
Archive plasma sample, 
PBMC3sample 
 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ ✓ 
✓ 
✓ 
✓ 
✓ 
✓ 


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confirms that the cPRA is now <80%. The cPRA of record shall be the cPRA 
reported to UNOS for organ allocation. 
2) Subject had a potential living kidney donor initially, but no longer has a potential 
living donor 
3) ALT > 2x the upper limit of normal 
4) Investigator initially deemed participant not an acceptable candidate for the trial 
 
For subjects who rescreen or subjects that do not meet the study eligibility criteria upon 
retest/rescreen, the site personnel must contact the sponsor and identify the subject as a 
screen failure. 
5.1.4 Waiting List and Transplantation Phases 
5.1.4.1 Waiting List Phase 
The waiting list phase will commence when the CCC at MGH authorizes the clinical site to 
render the participant eligible for kidney allograft offers that are seropositive for HCV 
using the United Network for Organ Sharing allocation system.  
 
Subsequently, during the waiting list phase, the study staff will contact the study subjects 
by phone every two months and in-person every six months. The two goals of these 
interactions will be to a) ascertain adverse events and b) ensure that the subject still meets 
study eligibility criteria. 
 
5.1.4.2  
Maintenance of Enrollment status 
For enrolled subjects who did not receive a kidney transplant at 6 months post-enrollment, 
the following data are acceptable to verify continued study eligibility at 6 months post 
enrollment: vital signs and physical exam, liver function test panel (see footnote C, Table 
8), serum or urine pregnancy test as appropriate (obtained <60 days or at date of 6 month 
post enrollment visit), review of co-medications, medical history, AEs and hospitalizations, 
and transplant waitlist status. 


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5.1.4.3 Transplantation Phase 
At the end of any organ offer from a deceased donor, per usual transplant center practice, 
the investigator will discuss with the subject characteristics of the allograft and risks and 
benefits presented by transplantation using that allograft, and the subject can accept or 
reject that allograft. 
A kidney transplantation event will prompt a shift to the “transplantation phase.” The 
elements of the transplantation phase will depend on the type of kidney transplant. Subjects 
who undergo transplantation with a study-eligible HCV RNA-negative/HCV Ab-positive in 
Arm 2A will be followed as per standard of care, and with surveillance of HCV RNA as per 
Figure 1b, and outcomes of G/P treatment collected up to 1 year post transplant if 
applicable and according to Table 6 and Section 5.1.5.2. 
 
5.1.4.4 Peri-Transplant and Post-Kidney Transplant Visits and Laboratory 
Evaluations for Recipients of Kidneys from HCV RNA-positive donors in Arm 1 
Starting around the time of organ offer and transplantation, patients are followed closely by 
both the surgical and nephrology team. As a part of standard of care visits, the following 
procedures activities will be performed: 
• Phlebotomy 
• Vital signs 
• Physical exam 
The study staff will follow procedures and activities closely along with transplant team and 
this information (vital signs, physical exam, and phlebotomy results) will be collected as a 
part of data collection. In addition to these standard of care procedures and activities, the 
study team will also perform specific research related activities at specific time points.  
5.1.4.5 Post-Kidney Transplant Research Phlebotomy in Arms 1  
Research laboratory blood draws will take place along with standard of care blood draws. 
The study staff will call the research subject to coordinate research blood draws 
appropriately. In addition, study staff will assess for adverse events/side effects and obtain 


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current medication data. Additional laboratory testing will be performed if the PIs feel it is 
necessary for patient safety. 
 
5.1.5 Treatment Period with G/P for patients treated for HCV infection in 
Arm 1 and Arm 2A 
 
Subjects who undergo transplantation with a study-eligible HCV RNA-positive kidney in 
Arm 1 will initiate G/P 300 mg/120 mg QD for 8 weeks early after kidney transplantation. 
Day 3 post-transplant is targeted for the start of G/P treatment. The subject should be out of 
the ICU, able to eat and drink and take medications orally, and by judgement of the 
investigator it is safe to start G/P treatment orally. These subjects will be followed 
according to Table 5 schedule.  Subjects who undergo transplantation with a study-eligible 
HCV RNA-negative/HCV-Ab-positive kidney in Arm 2A will undergo surveillance for 
HCV RNA for 24 weeks post-transplant and be treated with G/P if necessary and according 
to transplant center standard of care in the event of HCV infection (Figure 1B). 
 
Efficacy and safety outcomes assessments recorded in the medical record as part of the 
subject’s standard clinical management and follow up will be submitted using 
electronic CRFs where available in the medical record, except for protocol defined 
central laboratory assessment collection, drug dispensation and accountability, and 
required monthly medical record source record verification/submission. The central 
laboratory will be at MGH. 
 
The schedule of procedures for the study regarding the treatment of HCV infection for 
recipients of HCV RNA-positive kidneys in Arm 1 (Table 5) is more intense but 
principally based on the AASLD guidelines26 for the treatment of HCV, which 
recommends:  
1) Baseline: hepatic fibrosis assessment, drug-drug interaction assessment, hepatitis B 
serologies (HBs Ag, anti-HBc, anti-HBs, reflex HBV DNA if anti-HBc-positive), 


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CBC/platelets, hepatic function panel, and estimated glomerular filtration rate (eGFR, 
done in this study using the MDRD equation);  
2) On treatment monitoring: HCV RNA and routine CBC/platelets, hepatic panel and 
eGFR) are recommended at week 4 and as clinically indicated;  
3) Post-treatment monitoring: HCV RNA and routine labs are recommended at 4 and 12 
weeks post-treatment.  
 
In Arm 1, G/P dosing in Arm 1, treatment/side effect management, and duration will be 
recorded in the study CRFs by the site PI and or clinical provider designee and managed 
according to the AASLD guidelines, center standard of care, with additional assessments 
required by the protocol according to the Study Activities table (Table 5).  
The schedule of procedures regarding kidney transplantation activities is based on the 
local center’s practice for kidney transplant care. 
 
Relevant medical records include clinic visits and telephone contact as clinically indicated to 
ensure medication adherence and to monitor for adverse events. Original clinic notes, 
telephone notes, locally available safety labs/evaluations and/or diagnostic tests or health 
screenings collected during HCV treatment period will be abstracted on-site to identify 
adverse events and to record vital signs, physical examinations, concomitant medications, 
HCV RNA, HCV resistance, and clinical laboratory tests that were collected as part of 
standard of care practice. Sites will follow their standard of care practice as far as 
collection of vital sign data and clinical laboratory tests. Specifically, for example, it will 
not be considered a protocol violation if a site does not collect respiratory rate or 
temperature at every outpatient visit if such measurements are not always performed as 
standard of care practice. 
 
During the post-transplantation period, study staff will also perform periodic verification 
for new clinical interactions that may have occurred. This involves reviewing records 
from the prior 4 weeks when the subject visits the site laboratory assessment collection 


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and drug dispensing/accountability.  
 
Study visits and procedures during the post-transplantation period for Arm 1 and ARM 2A 
are detailed in Tables 5, and 6, respectively. Safety and tolerability will be assessed 
throughout the study per AASLD and center guidelines with additional assessments 
required by the protocol according to the Study Activities (Tables 5, 6). Central laboratory 
testing at MGH will include DAA resistance testing.  All other laboratory testing will be 
performed by local laboratories, which must be CLIA certified and using laboratory test which 
are approved by FDA. 
 
All Arm 1 and Arm 2A subjects will continue to return to the site on an inpatient/outpatient 
basis as outlined in Tables 5 and 6. Sites should ensure that subjects adhere to all the study 
visits for laboratory sample collection and drug dispensing/reconciliation. Subjects who 
cannot complete their study visit per the visit schedule should ensure that they do not run 
out of study drug prior to their next study visit. Compliance is critical to ensure adequate 
drug exposure. 
 
Virologic stopping criteria will be evaluated and applied by the investigator as detailed in 
Section 5.4.1.1. 
 
Subjects who prematurely discontinue treatment during the transplantation phase should return 
for a Treatment Discontinuation Visit and undergo the study procedures as outlined in 
Tables 5 and 6.  
 
In Arm 1, 30 candidates will undergo kidney transplantation with kidneys from HCV RNA-
positive donors. After n=30 kidney transplantation events from HCV RNA-positive donors 
have occurred, no further subjects will be enrolled into the study. Already enrolled subjects 
who receive an HCV RNA-positive donor kidney offer that meets study criteria and are 
scheduled to be transplanted within 24 hours after the 30th kidney transplant from an HCV 
RNA-positive donor will also be allowed into treatment arm A of the study.  


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Patients enrolled in the trial will be notified by phone that the HCV RNA-positive arm of 
the trial has completed enrollment and remaining subjects (now in Arm 2) will have the 
ability to accept (i) a study-eligible kidney from an HCV RNA-negative/HCV Ab-positive 
donor up until 24 weeks after the last kidney transplant event from a study-eligible HCV 
RNA-positive donor, (ii) a standard of care kidney transplant, or remain on the waiting list 
for the duration of the study. G/P treatment, if needed, will be provided free of charge to a 
subject in Arm 2A who developed HCV viremia after up to 24 weeks post-transplant of a 
kidney from an HCV RNA-negative/HCV Ab-positive donor.  
 
5.1.5.1 G/P treatment phase/Visits and laboratory evaluations after 
transplantation for subjects who receive a study eligible HCV RNA-positive 
kidney in Arm 1 
 
Visit 1: Peri-transplant visit  
The treating physician will evaluate the patient’s overall condition and make a judgment on 
whether transplantation is safe. The following recipient-donor-kidney match results exclude 
transplantation in this protocol: a) Blood group incompatibility between donor and 
recipient; b) Cross match reactivity, or clinically meaningful donor specific antibody, or 
other immunological reactivity related to an allograft offer deemed a substantial risk for 
rejection by the responsible investigator. 
The following research procedures and activities will be performed: 
• Obtain medication data 
• Donor blood sample (if available) 
• Assessment of recipient and donor-kidney match for exclusion from transplantation in 
this protocol  
Visit 2: Post-kidney transplant (Day 3  1 day) 
The study staff will meet the subject in their hospital room, three days after their kidney 
transplant.  


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The following research procedures and activities will be performed: 
• Assess for Adverse Events 
• Obtain medication data 
• Research Phlebotomy 
This visit will be the target date to start G/P, as per judgement by the investigator.   
 
Visit 3: (Day 1 of G/P treatment) 
Visit 3 may be combined with visit 2, 3 days post-transplant, if G/P treatment can be safely 
initiated as per judgement by the investigator.  The following research procedures and 
activities will be performed: 
• 
Assess for Transplant-related, HCV-related and study drug related Adverse Events, 
including clinical outcomes and data (death, graft failure, acute allograft rejection, eGFR, 
delayed graft function ALT elevation > 5x ULN, SAEs, sclerosing cholestatic hepatitis, and 
extrahepatic manifestations of HCV)  
• 
Obtain medication data 
• 
Research Phlebotomy 
• 
Pregnancy test, as indicated  
• 
Start G/P treatment with food, and dispense 1 month supply of G/P 
• 
Schedule appointments for follow-up visits 
 
The study staff will reinforce instructions on bringing the subject’s routine and study 
medications to each visit, and reinforce adherence with the study medication and protocol.  
Visit 4: (1 week after start of G/P) 
Visit 4 should occur one week ( 3 days) after starting G/P and should immediately follow 
the subject’s regularly scheduled post-transplant follow-up visit. The subject will arrive at 
the study site outpatient clinic (or the hospital, if needed). The following research 
procedures and activities will be performed: 


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• 
Assess for Transplant-related, HCV-related and study drug related Adverse Events, 
including clinical outcomes (same as described in Visit 3) 
• 
Obtain medication data 
• 
Research Phlebotomy  
• 
Pill count of G/P tablets 
• 
Confirm follow-up visits 
• 
Replenish study drug if necessary 
 
Visit 5:  Telephone encounter or in-person visit (2 weeks after start of G/P treatment) 
Visit 5 should occur 2 weeks ± 3 days after starting G/P and should follow the subject’s 
regularly scheduled post-transplant follow-up visit. The subject will arrive at the study site 
outpatient clinic (or the hospital, if needed). Alternatively, this can be a telephone 
encounter. The following research procedures and activities will be performed: 
• 
Assess for Transplant-related, HCV related and study drug related Adverse Events, 
including clinical outcomes (same as described in Visit 3) 
• 
Obtain medication data 
• 
Pill count of G/P tablets 
• 
Confirm follow-up visits 
 
Visit 6: (4 weeks after start of G/P treatment)  
Visit 6 should occur 4 weeks ± 3 days) after start of G/P. If possible, this visit should 
follow the subject’s regularly scheduled post-transplant follow-up visit (or the hospital, if 
needed).  
The following procedures and activities will be performed: 
• 
Assess for Transplant-related, HCV-related, and study drug related Adverse Events, 
including clinical outcomes (same as described in Visit 3 plus eGFR and proteinuria) 
• 
Obtain medication data 
• 
Research Phlebotomy 


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• 
Pregnancy test, as indicated  
• 
 Pill count of G/P tablets 
• 
Dispense G/P 4 week supply 
• 
Confirm follow-up visits 
 
 
Visit 7: Telephone encounter (6 weeks after start of G/P treatment) 
This visit should occur at 6 weeks ±3 days after start of G/P treatment as a telephone 
encounter. Note that this visit can be performed as an in person visit to the study site, if 
there is a standard of care post-transplant visit on the same date.  
The subject is called by authorized study staff who perform the following activities: 
• Assess for Transplant-related, HCV-related, and study drug related Adverse 
Events, including clinical outcomes (same as described in Visit 3) 
• 
Obtain medication data 
• check on adherence with taking G/P 
• confirm follow up visits 
 
Visit 8: End of G/P treatment visit (8 weeks after start of G/P treatment) 
Visit 8 should occur approximately 8 weeks ±7 days after start of G/P treatment. If 
possible, this visit should follow the subject’s regularly scheduled post-transplant follow-up 
visit (or the hospital, if needed).  
The following procedures and activities will be performed: 
• 
Assess for Transplant-related, HCV-related, and study drug related Adverse Events, 
including clinical outcomes (same as described in Visit 3 plus eGFR and proteinuria) 
• 
Obtain medication data 
• 
Research Phlebotomy (including optional PBMC collection for sites with 
capability) 
• 
Pregnancy test, as indicated  
• 
 Pill count of G/P tablets 


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• 
Confirm follow up visits 
 
5.1.6 Post-Treatment Period for Arm 1 
All subjects who received at least one dose of study drug will be monitored during the post-
transplantation period for safety, HCV RNA, and the emergence and persistence of 
resistance-associated viral substitutions for an additional 12 and 24 weeks following the last 
dose of G/P. For recipients of HCV RNA-positive transplants in Arm 1, a 1-year post 
kidney transplant visit is included to assess for graft function and survival, eGFR and 
proteinuria, and donor specific antibody (abstracted from the center’s medical records), as 
applicable per the center’s standard of care. 
 
Appropriate information from original clinic notes, telephone notes, locally available 
safety labs/evaluations and/or diagnostic tests, or health screenings collected during the 
post-HCV treatment period will be abstracted at the clinical sites to identify and report 
adverse events, vital signs, physical examinations, concomitant medications, HCV RNA, 
HCV resistance, and clinical laboratory tests that were collected as part of standard of care 
practice.  
 
The Post-Treatment Period will begin the day following the last dose of study drug 
treatment.  
 
Subjects who prematurely discontinue treatment should return to the site for a Post-
Treatment Discontinuation Visit as outlined in Tables 5 and 7 and will be followed for all 
post-treatment safety, HCV RNA, and resistance-associated substitutions according to the 
post treatment period schedule. 
 
5.1.6.1 Post-treatment visits for subjects who receive an HCV RNA-positive 
kidney in Arm 1 
Visit 9: Telephone encounter or in person visit (4 week after end of G/P treatment) 


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Visit 9 should occur 4 weeks after end of G/P treatment ±7 days. Note that this visit can be 
performed as an in-person visit to the study site, if there is a standard of care post-transplant 
visit on the same date.  
   The following research procedures and activities will be performed 
• Assess for Transplant-related, HCV-related, and study drug related Adverse Events, 
including clinical outcomes (same as described in Visit 3) 
• Obtain medication data 
• Confirm follow-up visits 
 
Visit 10: (12 weeks after end of G/P treatment)    
Visit 10 should occur 12 weeks after end of G/P treatment ± 14 days. If possible, it 
should immediately follow the subject’s regularly scheduled post-transplant follow-up 
visit at the study site and will provide an opportunity to assess SVR12.  
The following research procedures and activities will be performed: 
• 
Assess for Transplant-related- and HCV-related Adverse Events, including clinical 
outcomes (same as described in Visit 3 plus eGFR and proteinuria) 
• Obtain medication data 
• Research Phlebotomy (including optional PBMC collection for sites with 
capability) 
• Confirm follow up visits  
 
Visit 11: (24 weeks after end of G/P treatment)  
Visit 11 should occur 24 weeks ± 28 days after end of G/P treatment.  If possible, the visit 
should follow the subject’s regularly scheduled post-transplant follow-up visit and will 
provide an opportunity to assess SVR-24.  
The following research procedures and activities will be performed: 
• 
Assess for Transplant-related and HCV-related Adverse Events, including clinical 
outcomes (same as described in Visit 3 plus eGFR and proteinuria) 


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• Obtain medication data 
• Research Phlebotomy 
• Confirm follow up visit  
 
Visit 12: (1 year post-transplant, end of study visit) 
Visit 12 should occur 1 year ±28 days after the kidney transplant and is the end of study 
visit. If possible, the visit should immediately follow the subject’s regularly scheduled post-
transplant follow-up visit and provides an opportunity to perform an end of study 
assessment  
The following research procedures and activities must be performed: 
• 
Assess for Transplant-related and HCV-related Adverse Events, including clinical 
outcomes (same as described in Visit 3 plus eGFR and proteinuria) 
• Obtain medication data 
• Research Phlebotomy (including optional PBMC collection for sites with 
capability) 
•  Obtain information on donor specific antibodies as applicable per center’s 
standard of care 
 The Research Staff should fill out the Study Closeout Form. This form must be signed by 
the site investigator.


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Table 5: Transplantation, G/P treatment and post-treatment Phase Study Procedures 
for Recipients of Kidneys from HCV RNA-Positive Donors in Arm 1 
 
1 Visit types: V - in person visit to site; L - Lab visit; T - Telephone encounter 
2 Includes evaluation of blood type and HLA compatibility 
3  HCV RNA testing at V2, V4, V8, and V10 and V11 are study paid labs.  HCV RNA testing at 
visit 6 is billed as SOC. All HCV RNA testing is done at local laboratory by a CLIA certified 
laboratory and with an FDA approved test.  
4 Archived plasma samples (required) and PBMC (optional at Visits 8, 10, and 12) samples are 
shipped to the clinical coordinating center at Massachusetts General Hospital, see section 5.3.1.1 
5 Lack of availability of donor blood sample will not preclude donor eligibility or transplant. HCV 
genotype is determined from the donor blood sample at local laboratory; Another portion of the 
donor sample is frozen for storage and potential testing for DAA resistance as needed. See section 
 
Visit 
Research Visit 
Activities 
Research labs 
G/P 
 
Standard of Care 
Transplant, 
 G/P treatment, & 
post treatment 
 follow-up 
Visit1 
Assess Adverse Events12 
Current Medications 
Confirm donor-recipient 
 pair meet trial criteria2 
        
G/P adherence  
HCV Antibody 
Urine Prot./Creat. Ratio 
HCV RNA3 
Archive blood samples4  
DAA resistance 
Donor  blood sample5  
Pregnancy test6 
Study drugs  dispensed 
Vitals & PE7 
Clinical Chemistry8 
Hematology 
HCV RNA3 
Pregnancy test6 
Tacrolimus level9 
Peri-transplant visit 
V1  ✓ ✓ ✓ 
 
 
 
 
 
 
✓ 
 
 
 
✓ ✓ ✓  
 
 
Day 37 
Post KT 
V2  ✓ ✓  
 
✓  
✓ ✓  
 
✓  
✓ ✓ ✓  
As per transplant  center standard of care 
As per transplant center standard of care 
Day 1 of 
G/P treatment 
V3  ✓ ✓ 
 
 
 
 
 
 
 
 
 
✓ ✓ 
✓ ✓ ✓ 
 
Treatment week 1±3 days 
V4  ✓ ✓  
✓  
 
✓  
 
 
 
 
✓ ✓ ✓  
Treatment week 2 ±3 days 
V5 
T5  ✓ ✓  
✓  
 
 
 
 
 
 
 
 
 
 
 
Treatment week 4 ±3 days 
 V6  ✓ ✓  
✓ ✓ ✓  
✓  
 
✓ ✓ 
✓ ✓ ✓ ✓ 
Treatment week 6 ±3 days10 
T7  ✓ ✓  
✓  
 
 
 
 
 
 
 
 
 
 
 
Treatment week 8 ±7 days (EOT) 
V8  ✓ ✓  
✓  
✓ ✓ ✓  
 
✓  
✓ ✓ ✓  
Post treatment week 4 ±7 days 
V9 
T9  ✓ ✓  
 
 
 
 
 
 
 
 
 
 
 
 
 
Post treatment week 12 ±14 days 
V10  ✓ ✓  
 
 
✓ ✓ ✓  
 
 
 
 
 
 
 
Post treatment week 24 ±28 days 
V11  ✓ ✓  
 
 
✓ ✓ ✓  
 
 
 
✓ ✓ ✓  
1 year Post transplant ±28 days; End of study11 V12  
✓ ✓  
 
✓ ✓  
✓  
 
 
 
✓ ✓ ✓  
G/P treatment failure 
 
 ✓  
 
 
 
 
✓ ✓ ✓  
 
 
 
 
 
 
Premature discontinuation 
 
 ✓  
 
 
 
✓ ✓ ✓  
 
 
 
✓ ✓ ✓  
 
 


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5.3.1.1 
6 If visit 2 and visit 3 are on the same day or within 14 days of each other only 1 serum pregnancy 
test need to be obtained. Visit 6 and Visit 8 pregnancy tests can be urine tests. Additional pregnancy 
tests not billed to the study are obtained as per transplant center standard of care.  
7 Vitals and physical exam will be conducted and documented as per standard of care at transplant  
    center 
8 Liver function tests (ALT, AST, Alk Phos., total bilirubin) will be ordered as a study lab if not 
standard of care as part of clinical chemistry labs at the local transplant center. See table 8 for 
clinical chemistry labs and hematology labs. 
9 Includes Tacrolimus level and/or other utilized immunosuppressant that requires therapeutic drug 
   monitoring as per transplant center standard of care; 
10 Telephone call will be performed between clinic visits at treatment week 6 to assess subject 
adherence to G/P treatment. 
11 Obtain information on donor specific antibodies as applicable per center’s standard of care from 
subject medical record. 
12. Assess for clinical outcomes, including fibrosing cholestatic hepatitis, and extrahepatic 
manifestations of HCV at Visits 4-11. 
 
5.1.7. Peri-Transplant and Post-Kidney Transplant Visits and Laboratory 
Evaluations for Recipients of Kidneys from HCV RNA-negative/HCV Antibody-
Positive donors in Arm 2A 
Starting around the time of organ offer and transplantation, patients are followed closely by 
both the surgical and nephrology team. As a part of standard of care visits, the following 
procedures activities will be performed: 
• Phlebotomy 
• Vital signs 
• Physical exam 
The study staff will follow procedures and activities closely along with transplant team and 
this information (vital signs, physical exam, and phlebotomy results) will be collected as a 
part of data collection. In addition to these standard of care procedures and activities, the 
study team will also perform specific research related activities at specific time points. 
 
Research laboratory blood draws will take place along with standard of care blood draws. 
The study staff will call the research subject to coordinate research blood draws 
appropriately. In addition, study staff will assess for adverse events/side effects and obtain 


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current medication data. Additional laboratory testing will be performed if the PIs feel it is 
necessary for patient safety. 
 
Visit 1: Peri-transplant visit  
The treating physician will evaluate the patient’s overall condition and make a judgment on 
whether transplantation is safe. The following recipient-donor-kidney match results exclude 
transplantation in this protocol: a) Blood group incompatibility between donor and 
recipient; b) Cross match reactivity, or clinically meaningful donor specific antibody, or 
other immunological reactivity related to an allograft offer deemed a substantial risk for 
rejection by the responsible investigator. Given the requirement for rapid evaluations and 
decision-making around the time of kidney transplantation, the treating physician will 
likely be the transplant surgeon (and/or transplant nephrologist) and will contact study staff 
in the pre-transplant period about the suitability of the candidate, donor and allograft for the 
MYTHIC study. 
 
The following research procedures and activities will be performed: 
• Obtain medication data 
• Assessment of recipient and donor-kidney match for exclusion from transplantation in 
this protocol  
 
 
Visit 2: (day 7  2 days) 
Visit 2 should occur 7  2 days after the subject’s kidney transplant and will immediately 
follow the subject’s regularly scheduled post-transplant follow-up visit. The subject will 
arrive at the study site outpatient clinic if discharged from hospital or in hospital if not yet 
discharged. The following procedures and activities will be performed: 
• 
Assess for Adverse Events, and clinical outcomes, including: death, graft failure, 
acute allograft rejection, delayed graft function ALT elevation > 5x ULN, SAEs, sclerosing 
cholestatic hepatitis, and extrahepatic manifestations of HCV. Obtain HCV plasma RNA. 


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• 
Obtain medication data 
• 
Research Phlebotomy  
• 
Schedule appointments for follow-up visits 
The study staff will inform the patient of the results of their HCV RNA within 1 week after 
their visit. If at any time the patient’s HCV RNA becomes detectable, then the patient will 
move immediately into the “Reactive G/P Treatment Phase”. 
 
Visit 3: (week 4  7 days) 
Visit 3 should occur 4 weeks  7 days after the subject’s kidney transplant and will 
immediately follow the subject’s regularly scheduled post-transplant follow-up visit. The 
subject will arrive at the study site outpatient clinic. The following procedures and activities 
will be performed: 
• 
Assess for Adverse Events, and clinical outcomes as described in Visit 2 and eGFR 
and proteinuria 
• 
Obtain medication data 
• 
Standard of care Phlebotomy including plasma HCV RNA test 
• 
Research Phlebotomy  
• 
Schedule appointments for follow-up visits 
The study staff will inform the patient of the results of their HCV RNA within 1 week after 
their visit. If at any time the patient’s HCV RNA becomes detectable then the patient will 
move immediately into the “Reactive G/P Treatment Phase”. 
 
Visit 4: (week 8  7 days) 
Visit 4 should occur 8 weeks  7 days after the subject’s kidney transplant and will 
immediately follow the subject’s regularly scheduled post-transplant follow-up visit. The 
subject will arrive at the study site outpatient clinic. The following procedures and activities 
will be performed: 


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• 
Assess for Adverse Events, and clinical outcomes as described in Visit 2, except 
that assessments for HCV-related complications will take place only if HCV infection has 
been detected. 
• 
Obtain medication data 
• 
Schedule appointments for follow-up visits 
• 
Research Phlebotomy, including required plasma and optional PBMCs at sites with 
capability 
 
Visit 5: (week 24  14 days post kidney transplant) 
Visit 5 should occur 24 weeks  7 days after the subject’s kidney transplant and will 
immediately follow the subject’s regularly scheduled post-transplant follow-up visit. The 
subject will arrive at the study site outpatient clinic. The following procedures and activities 
will be performed: 
• 
Assess for Adverse Events, and clinical outcomes as described in Visit 2, except 
that assessments for HCV-related complications will take place only if HCV infection has 
been detected, and assess for eGFR and proteinuria.  
• 
Obtain medication data 
• 
Research Phlebotomy, including plasma HCV RNA and other labs as per Table 6, 
and required stored plasma and optional stored PBMCs at sites with capability 
• 
 
• 
Schedule end of study visit if needed 
The study staff will inform the patient of the results of their HCV RNA within 1 week after 
their visit. If at any time the patient’s HCV RNA becomes detectable then the patient will 
be scheduled for a “Reactive G/P Treatment Visit.” If the patient remains HCV RNA 
negative at visit 5 they will be considered to have not have had HCV transmitted by 
transplant and will only have passive data collected related to usual care encounters with 
the health care system. 


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If study visit 6 ±28 days is equal to or exceeding 365 days after date of enrollment then this 
will be also the end of study visit (see additional research procedure for end of study visit 
below in visit 6).  
 
Visit 6: (1 year ±28 days post enrollment and end of study visit) 
Visit 6 should occur 1 year  28 days after the subject enrolled into the study and is the end 
of study visit. If possible the visit should follow immediately the subject’s regularly 
scheduled post-transplant follow-up visit. This visit is only necessary if visit 5 occurred 
before 337 days after date of enrollment.   
 The following procedures and activities will be performed: 
• Assess for Adverse Events, and clinical outcomes as described in Visit 2, except 
that assessments for HCV-related complications will take place only if HCV 
infection has been detected. Assess for eGFR and proteinuria. 
• Obtain medication data 
• 
Research Phlebotomy, including required stored plasma and optional stored PBMCs 
at sites with capability 
• 
 
The Research Staff should fill out the Study Closeout Form. This form must be signed by 
the site investigator. 
 
 
 


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Table 6: Transplantation Phase Study Procedures for Recipients of 
Kidneys from HCV RNA-Negative/HCV Antibody-Positive Donors in 
Arm 2A 
 
 1 Includes evaluation of blood type and HLA compatibility 
2 First quantifiable HCV RNA should trigger the reactive G/P treatment; First “detectable” 
but not quantifiable HCV RNA requires a follow-up HCV RNA blood draw and test for  
confirmation within 1 week of results of 1st “detectable” but not quantifiable  RNA result; 
the second (confirmatory) positive e.g., “detectable or quantifiable” HCV RNA should 
trigger the reactive G/P treatment 
3 If available. Lack of availability of donor blood sample will not preclude donor  
   eligibility. Donor blood sample will be frozen and will be shipped to clinical coordinating 
center laboratory at MGH as needed for DAA resistance testing. See section 3.5.1.1 
4  Includes Tacrolimus level and/or other utilized immunosuppressant that requires 
therapeutic drug monitoring  
5 If subject visit 6 ±28 days would be equal to or exceeds 365 days from date of 
 
 
Study 
Visit 
Research Visit 
Activities 
Research labs 
G/
P 
 
Standard of Care 
Week of 
 or after 
 Kidney 
Transpl
ant 
Day of 
or after 
 Kidney 
Trans-
plant* 
Visit 
Assess Adverse Events6 
Current Medications 
Confirm donor-recipient 
pair meet trial criteria1 
HCV Antibody 
Urine Prot./Creat. Ratio 
HCV RNA2 
Archive blood7sample 
DAA resistance sample  
Donor blood sample3  
Study drugs dispensed 
HCV RNA 
Vitals & PE 
Clinical Chemistry 
Hematology 
Tacrolimus Level4 
Pregnancy Test 
0 
Peri-
transpla
nt visit 
V1 
✓ 
✓ 
✓ 
 
 
 
 
 
✓ 
 
 
 
Per standard of care 
Per standard of care 
Per standard of care 
Per standard of care 
Per standard of care 
1 
7 ±  
2 day 
V2 
✓ 
✓ 
 
 
 
✓ 
 
 
 
 
 
4 
28 ±  
7 days 
V3 
✓ 
✓ 
 
 
✓ 
 
✓ 
 
 
 
✓ 
8  
 
56 ±  
7 days 
V4 
✓ 
✓ 
 
 
 
 
✓ 
 
 
 
 
245 
 
168 ± 
14 days 
V5 
✓ 
✓ 
 
✓ ✓ ✓ ✓ 
 
 
 
 
End of 
study 
 Visit 
1 year ± 
28 days   
V6 
✓ ✓ 
 
✓ ✓  
✓  
 
 
 
 
 
 
 
 
HCV 
RNA 
Detected 
 
 
✓ 
✓ 
 
 
✓ ✓ ✓ 
 
 
✓ 
 
 
✓ ✓ 
 
 


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Protocol  
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enrollment, then visit 5 will be also the end of study visit. 
6 Assess for clinical outcomes, including sclerosing cholestatic hepatitis, and extrahepatic 
manifestations of HCV at Visits 2-6 if treated with G/P. 
7 4 Archived plasma samples (required) and PBMC (optional and restricted to sites with collection 
capability at weeks 8, 24, and end of study) samples are shipped to the clinical coordinating center 
at Massachusetts General Hospital, see section 5.3.1.1 
 
5.1.8  
 “Reactive G/P Treatment Phase” -- only for subjects who 
experience HCV infection after transplantation of a kidney from a HCV RNA-
negative/HCV antibody-positive donor in Arm 2A 
 
Reactive Visit 1 (within 2 weeks of positive HCV RNA) 
Reactive Visit 1 should occur approximately within 2 weeks after the subject’s first positive 
HCV RNA. The first quantifiable HCV RNA should trigger the reactive G/P treatment. If 
the first positive HCV RNA is “detectable” but not quantifiable, then, to confirm the result, 
a follow-up HCV RNA blood draw is required as soon as possible. A second 
(confirmatory) positive, e.g., “detectable or quantifiable”, HCV RNA should trigger the 
reactive G/P treatment. The subject will arrive at the study site outpatient clinic. The 
following standard of care procedures and activities will be performed: 
• 
Assess for Adverse Events, and clinical outcomes, including: death, graft failure, 
acute allograft rejection, delayed graft function ALT elevation > 5x ULN, SAEs, sclerosing 
cholestatic hepatitis, and extrahepatic manifestations of HCV. 
• 
Obtain medication data 
• 
Physical examination, vital signs 
• 
Phlebotomy  
• 
Where applicable, pregnancy testing must be performed prior to starting G/P, and 
G/P should not be started when pregnancy test is positive 
• 
Schedule appointments for follow-up visits 
• 
Dispense G/P 


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The following information of  standard-of care follow up visits after reactive Visit 1 will be 
collected retrospectively, abstracted from subject records and recorded in study eCRFs: 
Any SAE and relatedness of SAE to G/P during G/P treatment from the 1st dose of G/P to 
30 days post last dose of  G/P treatment; any G/P treatment emergent laboratory 
abnormality ≥ Grade 3 until 2 days post last day of G/P treatment; any  early 
discontinuation of G/P,; HCV plasma RNA before start of G/P treatment and post G/P 
treatment week 12; reason for not achieving SVR12 if applicable.  
5.1.9 Additional Visits  
Additional visits will only be necessary in the case of G/P treatment failure of subjects who 
received an HCV RNA-positive kidney. After treatment failure has been confirmed, a 
suitable retreatment regimen will be provided by the MYTHIC study. The retreatment 
regimen will be chosen at the discretion of the overall PI, Ray Chung, MD with input from 
the site investigator. The retreatment of study subjects, however, will be followed by the 
site investigator and as per local center standard of care. The following information of  
standard-of care visits for retreatment of a subject who failed G/P in this study will be 
obtained: Any SAE and relatedness of SAE to retreatment regimen from the 1st dose of  
retreatment regimen to 30 days post last dose of  retreatment regimen; Any  retreatment 
regimen emergent laboratory abnormality ≥ Grade 3 until 2 days post last dose of 
retreatment regimen; any  early discontinuation of  retreatment regimen, reason for not 
achieving SVR12; HCV plasma RNA before start of re-treatment regimen and  12 weeks 
after end of re-treatment.  
 
5.1.10 Schedule of events for patients who receive no transplant or standard of 
care kidney transplant 
Enrolled subjects who undergo a standard of care kidney transplant or who remain on the 
transplant waiting list will have limited study visits and procedures. These subjects will be 
followed for a minimum of 1 year post enrollment if they did not receive a transplant 
during that time. Subjects who received a standard of care kidney transplant will be 


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followed for 24 weeks post transplant or a minimum of 1 year post enrollment, whichever 
is longer.  
 
After enrollment and while on the waiting list, there will be telephone contacts with study 
subjects every two months to ascertain interim events of importance to protocol-data 
collection, including non-SAE hospitalizations, SAEs, change in wait list status. For those 
who have a standard of care kidney transplant, death, graft failure, acute allograft rejection, 
delayed graft function ALT elevation > 5x ULN, eGFR, proteinuria (as available) and 
SAEs will be obtained from the subject’s medical record. eGFR will be measured at each 
standard of care clinic visit, with particular focus on the 6-month visit. These data will be 
entered into study eCRFs.  
 5.1.11 Future Research 
De-identified plasma samples, and/or PBMC samples collected for research purposes from 
subjects may be sent only to study investigators for their research. These samples may 
include information such as sex, age, health history, or ethnicity. These samples will not be 
sold. Some future studies may need health information (such as smoking history or present 
health status) that may require contacting the subject to obtain further information.  If 
future contact with study subjects is contemplated after when this study has ended, the 
patient must consent to allow contact after the study has ended. 
 
5.2 Selection of Study Population 
The study population consists of HCV RNA-negative patients on the kidney transplant 
waiting list.  
 
Subjects who meet all the transplant candidate inclusion criteria and none of the transplant 
candidate exclusion criteria will be eligible for enrollment into the study. As noted 
elsewhere in the protocol, the study will be divided into the screening phase, the waiting list 
phase, and the post-transplantation phase. 
 


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5.2.1 Inclusion/Exclusion Criteria for kidney transplant candidates 
5.2.1.1 Inclusion Criteria for kidney transplant candidates 
1. Age ≥21 and ≤65 years at consent 
2. Estimated glomerular filtration rate < 15 ml/min/1.73m2 (calculated using the 4-variable 
MDRD equation) at the time of consent  
3. Listed for an isolated kidney transplantation 
4. Subjects must be able to understand and adhere to the study visit schedule and all other 
protocol requirements, and must voluntarily sign and date an informed consent 
5. No available medically acceptable, compatible living kidney donor 
6. Subject must agree to use an effective method of birth control as outlined in Appendix 
D, and starting on the day of transplant 
7. Assent from the patient’s primary transplant nephrologist that participation would be 
reasonable for the patient 
8. Attended an educational session on use of HCV positive allografts 
 
5.2.1.2 Rationale for Main Inclusion Criteria 
 
The rationale for each criterion is listed in the order of inclusion criteria. 
1.  The rationale for the age inclusion criteria is that participants > 65 years may have more 
severe responses to acute HCV infection  
2. While listing for kidney transplantation is allowed when eGFR<20 ml/min/1.73m2, some 
patients with an eGFR in the 15 – 20 ml/min/1.73m2 range continue to have good 
quality of life. Participants with eGFR <15 ml/min1.73m2 are more likely to be at risk 
of renal disease-related complications than participant with eGFR>=15 ml/min/1.73m2. 
As a result, it is consistent with the ethical principle of beneficence to require eGFR<15 
ml/min/1.73m2 for study entry. 
3. Multi-organ transplant recipients often have poor post-transplant life expectancy and 
elevated risk for peri-transplant contraindications. 
4.  Respect for autonomy necessitates that all participants have a full understanding of the 
risk of participation. 


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5.  Living kidney donor transplantation often offers substantial advantages over deceased 
donor kidney transplantation. Patients with the option of a living donor transplant need 
not accept the risk of acute HCV infection and treatment. 
 
6.    Acute HCV infection or the use of study drug and/or mycophenolate mofetil might 
carry risks to a pregnancy that must be avoided. 
7.  The primary transplant nephrologist’s assent for participation should help the study sites 
leadership to identify suitable participants for the trial because the transplant 
nephrologists and their staff can weigh study participation in light of  
a. the subject’s other options for renal replacement therapy,  
b. risk of developing FSGS or recurrent GN post-transplantation, and  
c. ability to adhere to the study regimen 
8.  This education requirement provides an additional tool for candidate subjects to learn 
about and comprehend about HCV infection that would be transmitted from the donor 
organ and is aimed to further their understanding of risks and benefits associated with 
the study. 
 
5.2.1.3 Exclusion Criteria for kidney transplant candidates 
1.    History of severe, life-threatening or other significant sensitivity to 
immunosuppressants utilized in kidney transplant. 
2.    Female who is pregnant, planning to become pregnant during the study, or breast 
feeding 
3.   HIV RNA-positive or HIV antibody positive 
4.   HCV RNA-positive 
5.     HBV surface Ag-positive or detectable HBV DNA 
6.   Primary focal segmental glomerulosclerosis (FSGS) or disease process with increased 
risk of causing early graft failure as assessed by the transplant nephrologist and/or 
investigator team.  
7.   Absence of clinically significant liver disease evident after review of history, labs and 
fibroscan imaging 


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a) Persistently elevated liver enzymes (ALT >2 times upper limit of normal) of 
unknown cause  
b) Liver fibroscan result >8kPA, or >F2 on liver biopsy 
8.    Transplant candidate requires antibody desensitization protocol for transplantation 
9.    Most recent calculated panel reactive antibody (cPRA) >80%. For this purpose, the 
cPRA assessed will be the cPRA most-recently reported to UNOS at the time of 
waitlisting. 
10.   Prior recipient of a non-renal solid organ transplant     
11.   Subject has any other medical condition that, in the opinion of the Investigator, would 
adversely affect the participant's participation in the study. Specifically, the 
investigator may exclude any patient with a pre-existing cancer that does not have a 
high probability of cure or control and increase the risk or decrease the benefit for the 
transplant as per local transplant center guidance 
12.    Requirement for and inability to safely discontinue the medications or supplements 
listed in Table 7 of the protocol at least 2 weeks or 10 half-lives (whichever is longer) 
prior to the first dose of any study drug.   
13. Participation in another interventional study of any investigational agent or approved 
medication, or participation in another kind interventional study that the responsible 
investigator deems to be an exclusion from period 6 months prior to screening to last 
study visit 
5.2.1.4 Rationale for Exclusion Criteria  
The rationale for each criterion is listed in the order of exclusion criteria. 
1.  To minimize participant risks, we will exclude participants with a history of adverse 
drug reactions to commonly used transplant drugs. 
2.  To reduce risks to pregnancies and nursing children from HCV or study medications.  
3.  Participants with HIV are at elevated risk of rejection after transplant and may need 
medications with complex drug-drug interactions. 
4.  Patients with HCV should not participate because they already commonly accept HCV 
RNA-positive kidneys; the study does not offer them a new option. 


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5.    We will exclude participants with these serologies in order to limit the risks of acute 
HCV infection on the liver. 
6.  Case series and other preliminary data suggest the possibility that donor-derived HCV 
infection or its treatment could increase the risk of post-transplant FSGS; therefore, we 
will not accept patients who plausibly have an elevated pre-existing risk of GN. 
Primary FSGS can recur in a transplant kidney requiring intensification of 
immunosuppression or early graft failure. 
7.  We will exclude participants with evidence of liver disease in order to limit the risks of 
acute HCV infection on the liver.  
  8. Desensitization treatment is associated with elevated risk of rejection and the need for 
additional immunosuppression treatment 
9.  Elevated PRA is associated with elevated risk of rejection and the need for additional 
immunosuppression treatment. Additionally, patients with high PRA are often able to 
get enhanced access to deceased donor organs under the US organ allocation system. 
10.  Prior non-renal solid organ transplant recipients commonly have substantial 
comorbidities and elevated risk of post-transplant complications, including death. 
11.  Investigators may identify reasons (not otherwise identified in the criteria) why 
candidates are not suitable for participation, but which cannot be comprehensively 
enumerated prior to the start of the trial. For example, the investigator team will 
confirm that prior malignancies have been appropriately considered by the primary 
treating clinical team as unlikely to recur and be uncontrolled after transplantation. 
12. The medications listed in Table 7 interact with G/P and could increase the risk of 
adverse events, and/or reduce antiviral activity of G/P. 
13.  The effects of other interventions could confound interpretation of the study results and 
add risks to the participant. 
• Investigator evaluation of candidacy shall also include assessment of the 
candidate’s ability and willingness to receive high quality post-transplant 
care without using any of the contraindicated medications or supplements 
listed in Table 7. 


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5.2.2 Main Inclusion Criteria for kidney donors and allografts 
 
1.  Deceased donor organ with kidney donor profile index (KDPI) ≤ 0.85 
2. HCV RNA positive* 
 
5.2.2.1 Rationale for Main Inclusion Criteria for HCV RNA-positive kidney 
donors and allografts 
1. To offset the risks associated with HCV infection and treatment, participants should 
derive the plausible benefit of a good quality allograft. 
 
5.2.2.2 Main exclusion criteria for HCV RNA-positive kidney donor and 
allograft 
1. Known prior HCV treatment with direct acting antiviral medications 
2. HIV RNA-positive 
3. HBV Surface antigen positive or HBV-DNA positive 
 
* Kidney offers from HCV RNA-negative/HCV antibody-positive donors or HCV 
RNA-negative/HCV antibody-negative donors are allowed to be accepted by enrolled 
subjects; for study-eligible HCV RNA-negative/HCV antibody-positive donor offers, 
all other donor inclusion and exclusion criteria above apply, except the donor is not 
HCV RNA-positive. No study allograft criteria apply to standard of care allografts 
and their donors. 
5.2.2.3.4 Rationale for Main Exclusion Criteria for HCV RNA-positive 
kidney donors and allografts 
Rationales are listed in the same order as exclusion criteria. 
1. Prior failed HCV treatment with DAAs of the donor virus increases the risk of   HCV 
treatment failure with DAA retreatment due to potential viral resistance to the DAAs. 
2. Donor-derived HIV could substantially elevate the risk of transplantation. 
3. Donor-derived HBV could elevate the risk of transplantation. 


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5.2.3 Prior and Concomitant Therapy 
During screening, the investigator/clinician designee should review all concomitant 
medications for any potential interactions with G/P via the Sponsor-provided drug-drug 
interaction tool. With the permission of the treating physicians, the patients should be 
changed from any prohibited medications or supplements listed in Table 7. The subject 
must be able to safely discontinue any prohibited medications or supplements listed in Table 
7 at least 2 weeks or 10 half-lives (whichever is longer) prior to the first dose of G/P. 
 
During the period after HCV treatment ends, all medications taken will be recorded in the 
medical record at subsequent clinic visit until the 12 month post-transplant endpoint.  
During the transplantation phase, any medication or vaccine (including over-the-counter or 
prescription medicines, vitamins and/or herbal supplements) that the subject is receiving 
from the time of transplantation study drugs are stopped, must be recorded in the medical 
record along with the reason for use according to standard medical care. Where the reason 
for use of a concomitant medication is missing from the submitted medical records, the site 
will be queried.   
 
The medical monitor should be contacted if there are any questions regarding concomitant 
or prior therapies. 
5.2.3.1 Prior HCV Therapy 
Enrolled subjects can be HCV treatment-experienced but must have been cured from prior 
HCV infection.  
5.2.3.2 Concomitant Therapy 
The investigator should confirm that a concomitant medication/supplement can be safely 
administered with study drugs. Some concomitant medications may require dose 
adjustments due to the potential for drug-drug interactions. 
 
During the Post-Treatment Period, investigators should reassess concomitant 
medications/supplements, and subjects may resume previously prohibited 


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medications/supplements or revert to pre-study doses 2 weeks following discontinuation of 
study drugs as applicable. 
5.2.3.3 Prohibited Therapy 
Subjects must be able to safely discontinue any prohibited medications or supplements 
listed in Table 7 at least 2 weeks or 10 half-lives (whichever is longer) prior to the first dose 
of study drug G/P and not use these during the entire Treatment Period and for 2 weeks 
following discontinuation of study drugs. 
 
Table 7: Prohibited Medications and Supplements 
Medication or Supplement Name 
red yeast rice (monacolin K), St. John's Wort 
Ethinyl estradiol 
Atorvastatin, lovastatin, simvastatin* 
Carbamazepine, phenytoin, pentobarbital, phenobarbital, primidone, rifabutin, 
rifampin 
Astemizole, cisapride, terfenadine 
 
 
*  The HMG-CoA reductase inhibitors  atorvastatin, lovastatin, or simvastatin should not be taken with the 
study drugs. Subjects receiving these statins should either switch to pravastatin or rosuvastatin prior to the 
first dose of study drugs. If switching to or continuing pravastatin or rosuvastatin, it is recommended to 
reduce the pravastatin dose by 50% or limit the rosuvastatin dose to 10 mg QD when taking with the study 
drugs. 
 
 
Use of high dose (0.035mg) ethinyl estradiol containing oral contraceptives with G/P 
combination was associated with asymptomatic ALT increases (one Grade 3, and one Grade 2) 
without concurrent bilirubin increases in 2 healthy female subjects. Therefore hormonal 
contraceptives (including oral, topical [including vaginal rings], injectable or implantable 
varieties) containing any ethinyl estradiol may not be used from 2 weeks prior to the first 
dose of study drug until 2 weeks after the end of study drug dosing. Progestin-only 
contraceptives, such as those containing norethindrone, desogestrel, or levonorgestrel, 
without ethinyl estradiol, may be used with G/P. Post-menopausal hormone replacement 
therapy, such as with esterified or conjugated estrogens, i.e., not containing ethinyl estradiol, 
may be used with G/P at the discretion of the Investigator. 


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G/P may be initiated in subjects receiving cyclosporine ≤ 100 mg per day. Concomitant 
administration of G/P with cyclosporine doses of greater than 100mg per day is not 
recommended. 
5.3 Efficacy, Pharmacogenetic and Safety Assessments/Variables 
5.3.1 Efficacy and Safety Measurements Assessed and Flow Chart 
Study procedures described in this protocol for the screening phase are summarized in 
section 5.1.3. and Table 4, for the waiting list phase in section 5.1.4.1., and for the 
transplantation phase in sections 5.1.4.2 and Tables 5, 6. 
5.3.1.1 Study Procedures 
Informed Consent 
Signed study-specific informed consent will be obtained from the subject before any study 
procedures are performed. 
Subjects will be required to first attend an educational session about HCV and the study. 
After completion, the subjects will be eligible for a screening visit. The following 
procedures and activities will be performed during the screening process (and outlined in 
Table 4), after the informed consent is signed: 
• 
Review medical history 
• 
Vital signs 
• 
Physical exam 
• 
Review current medications 
• 
Review labs/phlebotomy: hepatic function panel, HCV RNA, HBV DNA, HBV 
Core Antibody will be checked in patients during screening, if not checked 
previously; HIV serologies 
• 
Serum pregnancy test (for women of childbearing potential) 
• 
Fibroscan 
• 
Provide instructions on recording of new medications and dose changes 
 


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Medical History, Physical Examinations, Vital Signs and Weight, Clinical Assessment 
in the Post-Transplant phase 
Study sites will enter data into electronic CRFs obtained from study visits, AEs related to 
post-transplant events, and testing results, as appropriate. 
 
Clinical Laboratory Tests 
Clinical tests that will be performed during the screening period as a part of routine care are 
shown in Table 8.  
 
Table 8: Clinical Laboratory Tests Performed at Baseline or as Part of Wait-listing 
Evaluation as Standard of Care 
Hematology 
Clinical Chemistry 
Hematocrit 
Hemoglobin 
Red Blood Cell (RBC) count 
White Blood Cell (WBC) count 
Neutrophils 
Bands, if detected 
Lymphocytes 
Monocytes 
Basophils 
Eosinophils 
Platelet count (estimate not 
acceptable) 
 
Blood Urea Nitrogen (BUN) 
Creatinine 
Total bilirubinc 
Alanine aminotransferasec 
(ALT)  
Aspartate aminotransferasec 
(AST)  
Alkaline phosphatasec 
Sodium 
Potassium 
Calcium 
Total protein 
Glucose  
Albumin 
Chloride 
Bicarbonate  
 eGFR by MDRD equation 
Other Tests 
Urine and Serum Human 
Chorionic Gonadotropin 
(hCG) for femalesb 
(pregnancy) 
HCV RNA 
HCV genotype  
HBsAg, anti-HBc, anti-HBs, 
HBV DNAa 
HCV Ab 
HIV Ab 
 
      
a If HBsAg neg, antiHBc positive at Screening 
bIn women of childbearing potential serum hCG test will be performed at screening, and after enrollment if urine testing is 
not feasible    
cLiver function test panel 


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Protocol  
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During the post-transplant period, the blood tests obtained during follow-up visits are 
shown in Tables 5 –6.  
 
For any laboratory test value outside the reference range that the investigator considers to be 
clinically significant: 
o The investigator will request that the transplant center repeat the test to 
verify the out-of-range value. 
o The investigator will follow the out-of-range value to a satisfactory clinical 
resolution. 
o A laboratory test value that requires a subject to be discontinued from the 
study, or requires a subject to receive treatment will be recorded as an 
adverse event. 
 
The management of laboratory abnormalities that may occur during the study is described in 
Section 6.1.7. 
 
Contraception Recommendations and Pregnancy Testing  
A serum pregnancy test will be performed for all female subjects of childbearing potential at 
Screening as per transplant center protocol. Additional urine pregnancy tests will be 
performed if feasible, or if not serum pregnancy tests will be performed as indicated by center 
protocol and at any time that HCV treatment is started. Pregnancy testing is not required 
for females of non-childbearing potential. Determination of postmenopausal status will be 
made during the Screening period, based on the subject's history. 
 
Concomitant Medication Assessment 
Excluding the medications and substances listed in Table 7, use of medications (prescription 
or over-the-counter, including vitamins, herbal supplements, and vaccines) from the time of 
signing the consent, through the post-transplantation phase and 30 days after study drugs are 
stopped must be recorded in the medical record according to the local standard of care.    


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The concomitant medication listing will be updated in the standard of care medical record 
at the time of informed consent. All original clinic notes and telephone notes collected prior 
to, during, and post HCV treatment period will be abstracted to identify concomitant 
medication(s) that were prescribed as part of standard of care practice.   
 
Enrollment and Assignment of Subject Numbers 
Screening numbers will be unique numbers and will be assigned sequentially at the site 
beginning with the first digits representing the investigative site, and the last digits 
representing the subjects at that site. Enrolled subjects will keep their screening number as 
their subject number throughout the study. 
 
All screening activities of transplant candidate subjects must be completed and reviewed prior 
to enrollment and advancement of the subjects into the waiting list phase of the study. Prior 
to enrollment in the waiting list phase, subject eligibility will be verified by the lead CCC at 
MGH. The site will submit sufficient data to be verified for meeting enrollment eligibility 
criteria.  
 
Study Drug Compliance for Kits 
G/P will be provided for subject dosing to the site. Each subject will have compliance 
documented by the site in the subject's source records for G/P. At each study drug 
accountability visit in Table 5, the overall number of tablets of G/P remaining will be 
recorded if the patient brought their G/P to the visit. 
 
HCV Genotype and Subtype 
Study sites will make reasonable efforts to collect donor plasma samples for HCV genotype 
and subtype determination from the kidney donor. Donor HCV genotype and subtype will 
subsequently be assessed using the Versant® HCV Genotype Inno LiPA Assay, Version 2.0 
or higher (LiPA; Siemens Healthcare Diagnostics, Tarrytown, NY). If the LiPA assay is 


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Protocol  
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unable to assign a genotype, genotyping will be determined by a Sanger sequencing assay of 
the HCV NS5B region at MGH. 
 
HCV RNA Levels 
Plasma samples for HCV RNA levels will be collected as indicated in Tables 4-6. The 
central laboratory at MGH will be using the Roche COBAS® AmpliPrep/COBAS® 
TaqMan® HCV Quantitative Test, v2.0. The lower limit of detection (LLOD) and lower 
limit of quantification (LLOQ) for this assay (regardless of genotype) are both 15 IU/mL. 
 
HCV Resistance Testing Sample 
Where available, a plasma sample for HCV resistance testing will be collected from the 
kidney donor at day 0 and for study subjects with confirmed virological failure at the required 
lab collection visits indicated in Tables 5, and 6. Specific instructions for preparation and 
storage of HCV RNA and HCV resistance samples will be provided by the central 
laboratory at MGH. 
 
Archived Plasma Sample and PBMC Samples 
Archived plasma samples will be collected at the study visits, indicated in Tables 4, 5, 6 
from all subjects and stored frozen. At sites with collection capability, optional PBMC 
collection and archiving will also be performed at selected time points as indicated in 
Tables 5 and 6. These samples are being collected for possible additional analyses, 
including but not limited to, study drug or metabolite measurements, HCV RNA levels, 
safety/efficacy assessments, HCV gene sequencing, HCV resistance testing, immune 
response to HCV infection, and other possible predictors of response, as determined by 
AbbVie and the sponsor. Specific instructions for preparation and storage of archive samples 
will be provided by the central laboratory at MGH. Archived plasma and PBMC samples 
which have not been utilized for additional analyses as described above or in future research 
as described in section 5.1.11 by 3 years after the last subject visit of the study will be 
destroyed.  


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5.3.1.2 Meals and Dietary Requirements 
Tablets of G/P should be taken with food. 
 
5.3.1.3 Handling/Processing of Samples 
Specific instructions for collection, preparation, and shipment of those blood  samples, 
plasma samples, PBMC samples, and tissue samples which will be analyzed, and /or stored 
at the central laboratory at MGH will be provided by the sponsor to all participating sites.. 
 
5.3.2 Efficacy Variables 
Virologic response will be assessed by plasma HCV RNA levels in IU/mL at various time 
points from Day 3 of treatment through 24 weeks post treatment for all recipients of HCV-
RNA-positive kidneys. 
5.3.2.1 Primary Efficacy Variable 
The primary efficacy variable is SVR12 (HCV RNA < LLOQ) 12 weeks after the last actual 
dose of study drug) among subjects receiving study-eligible HCV-RNA positive kidneys 
treated with G/P (Arm 1). 
 
5.3.2.2 Secondary Efficacy Variables 
The secondary efficacy endpoints will be calculated among subjects receiving study 
eligible HCV-RNA-positive kidneys treated with G/P (Arm 1). 
• The percentage of subjects with on-treatment virologic failure; 
• The percentage of subjects with post-treatment relapse. 
 
5.3.3 Resistance Variables 
 
The following resistance information will be analyzed for subjects receiving G/P who do not 
achieve SVR12 and who have a post-baseline sample with HCV RNA ≥ 1000 IU/mL in 


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Arms 1 and 2A. The HCV NS3 and NS5A amino acid sequences from the sample closest in 
time after virologic failure or treatment discontinuation with an HCV RNA level of ≥ 1000 
IU/mL will be determined by population sequencing or NGS, and a listing by subject of all 
substitutions at GLE and PIB signature amino acid positions relative to the appropriate 
prototypic reference sequence of NS3 and NS5A will be provided. 
 
5.3.4 Safety Variables 
Separate safety data will be collected for patients while on the waiting list versus after 
transplantation. Because subjects are unlikely to suffer adverse events related to study 
participation while on the waiting list, adverse event ascertainment will take place every 
two months by phone as well as during an in-person evaluation every 6 months while on 
the waiting list. The following clinical outcomes will be collected from subjects while on 
the waiting list: SAEs, non SAE hospitalizations, delisting from waitlist, death. (see section 
6.1.4). 
 
For all transplanted subjects in Arm 1 or Arm 2, the following data will be collected: death, 
graft failure, acute allograft rejection, delayed graft function, ALT elevations ≥5 times 
upper limit of normal, eGFR, proteinuria, and SAEs. Events of fibrosing cholestatic 
hepatitis and extrahepatic manifestations of HCV infection will also be collected for 
subjects who received an HCV RNA-positive kidney in Arm 1, and from subjects who 
became HCV viremic after transplant of a kidney from an HCV RNA-negative/HCV 
antibody-positive donor in Arm 2A.  
 
Adverse events after kidney transplantation will be categorized as to whether the event was 
caused by transplantation generally, or caused by HCV infection and/or HCV therapy as 
applicable.  
 
All subjects who receive at least one dose of G/P in Arm 1 will have additional safety 
collected as specified in section 8.1.5, and 8.1.6.  


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5.4 Removal of Subjects from Therapy or Treatment Duration Assessment 
5.4.1 Discontinuation of Individual Subjects 
Each subject has the right to withdraw from the study at any time. In addition, the 
investigator may discontinue a subject from the study at any time if the investigator 
considers it necessary for any reason, including the occurrence of an adverse event or 
noncompliance with the protocol. 
 
If, during the course of study drug administration, the subject prematurely discontinues, the 
procedures outlined for the applicable Premature D/C Visit should be completed as defined 
in Table 5 and Table 6. Ideally this should occur on the day of study drug discontinuation, 
but no later than 2 days after their final dose of study drug and prior to the initiation of any 
other anti-HCV therapy. However, these procedures should not interfere with the initiation 
of any new treatments or therapeutic modalities that the investigator feels are necessary to 
treat the subject's condition. Following discontinuation of study drug, the subject will be 
treated in accordance with the site investigator's best clinical judgment, and input from the 
study’s principal investigator. The last dose of any study drug and reason for 
discontinuation will be recorded in the medical record and submitted for centralized 
abstraction.  
 
The subject should then begin a period of post-transplant monitoring for 24 weeks for HCV 
RNA, the emergence and persistence of resistant viral variants. The subject will be assessed 
at 1-year post transplant for kidney graft function and anti-HCV antibody (only if HCV Ab 
negative at screening).  
 
If a subject is discontinued from study drugs or the Post-Treatment Period with an ongoing 
adverse event or an unresolved laboratory result that is significantly outside of the reference 
range, the investigator will attempt to provide follow-up until a satisfactory clinical 
resolution of the laboratory result or adverse event is achieved. 
In the event that a positive result is obtained on a pregnancy test for a subject or a subject 
reports becoming pregnant during the Treatment Period, the administration of DAAs to that 


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subject may be continued at site investigators discretion and in consultation with the study’s 
principal investigator  after discussion with the subject, if the benefit of continuing DAAs is 
felt to outweigh the potential risk. Specific instructions regarding subject pregnancy can be 
found in Section 6.1.5. If a subject is discontinued, the subject will be monitored for SVR in 
the Post-Treatment Period as described in Section 6.1.5. 
 
5.4.1.1 Virologic Stopping Criteria 
Individual patient  
Virologic stopping criteria are defined as one of the following: 
 
1. 
Confirmed HCV RNA ≥ 100 IU/mL (defined as 2 consecutive HCV RNA 
measurements ≥ 100 IU/mL) after HCV RNA < LLOQ during treatment. 
 
2. 
Confirmed increase from nadir in HCV RNA (defined as 2 consecutive HCV 
RNA measurements of > 1 log10 IU/mL above nadir) at any time point during 
treatment. 
 
When confirmatory testing is required, it should be completed as soon as possible and the 
subject should remain on study treatment until the virologic stopping criteria has been 
confirmed. Subjects meeting virologic stopping criteria will be discontinued from study 
drug and will continue to be followed in the Post-Treatment Period for the emergence and 
persistence of resistant viral variants until 12 weeks post-treatment. 
 
5.4.2 Discontinuation of Entire Study 
 
The sponsor, in agreement with AbbVie, may terminate this study prematurely, either in its 
entirety or the sponsor may terminate this study at any study site, for reasonable cause 
provided that written notice is submitted in advance of the intended termination. The 
investigator may also terminate the study at his/her site for reasonable cause, after providing 
written notice to the sponsor in advance of the intended termination. 


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Advance notice is not required by either party if the study is stopped due to safety concerns. 
If the sponsor terminates the study for safety reasons, the sponsor will immediately notify 
the investigator by telephone and subsequently provide written instructions for study 
termination. If 3 virologic treatment failures are observed among the first 10 recipients of 
kidneys from HCV RNA-positive donors, or 5 virologic treatment failures are observed 
among the first 20 recipients of kidneys from HCV RNA-positive donors, then no further 
offers of HCV RNA-positive kidneys will be accepted as part of the study. 
5.5 Treatments 
5.5.1 Treatments Administered 
Each dose of study drug (G/P) will be dispensed in the form of co-formulated G/P tablets at 
the visits listed in Tables 5 and 6 (and as needed). Subjects will be instructed to take study 
drugs at the same time every day with food.  
 
G/P will be provided to the investigator as G/P 100 mg/40 mg tablets. G/P will be taken 
orally as three tablets once daily with food, which corresponds to G/P 300 mg/120 mg QD. 
The maximal dose of G/P is 300mg/120mg for 8 weeks (56 doses, given once daily). There 
is no dose adjustment for G/P for any reason in this study. 
 
All subjects who receive at least one dose of study drug and meet the virologic stopping 
criteria defined in Section 5.4.1.1 will be discontinued from treatment. 
 
5.5.1.1 G/P Initial Treatment Failures 
Study subjects with treatment failure, defined as meeting virologic stopping criteria 
(Section 5.4.1.1) or virologic relapse (unquantifiable viral load after completion of 
treatment that during the post-treatment follow-up period becomes quantifiable) will be 
provided with either 1) Open-label Sofosbuvir + G/P ± Ribavirin or 2) Open-label 
sofosbuvir/velpatasvir/voxilaprevir +/- Ribavirin. The regimen will be chosen at the 
discretion of study’s Principal Investigator (Ray Chung, MD), with input from the site 
investigator where the patient is located. The retreatment of study subject will be followed 


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by the site investigator and as per local center standard of care. Outcomes of HCV re-
treatment will also be collected. AbbVie will provide G/P, and funds for purchasing 
sofosbuvir, ribavirin, or funds for purchasing Vosevi (sofosbuvir/velpatasvir/voxilaprevir) 
for retreatment. 
 
5.5.2 Identity of Investigational Products 
Information about the study drugs to be used in this study is presented in Table 9. 
 
Table 9: Identity of Investigational Products 
Investigational 
    Mode of 
Product 
Manufacturer 
Administration 
Dosage Form 
Strength 
Tablets/bottle 
Glecaprevir/ 
Pibrentasvir 
     AbbVie 
     Oral 
      Tablet 
100 mg/40 mg 
           30 
 
5.5.3 Packaging and Labelling 
All study drug will be supplied in bottles. Each bottle will be labelled as required per FDA. 
The labels must remain affixed to the bottles. All blank spaces should be completed by site 
staff prior to dispensing to subject. 
5.5.3.1 Storage and Disposition of Study Drugs 
The study drug (G/P 100 mg/40 mg) is for investigational use only and is to be used only 
within the context of this study. The storage conditions are 15° to 25°C (59° to 77°F). The 
study drug supplied for this study must be maintained under adequate security and stored 
under the conditions specified on the label until dispensed for subject use, destroyed on-site, 
or returned to AbbVie (or designee). 
 
5.5.4 Method of Assigning Subjects to Treatment Groups  
At the Screening Visit, all subjects will be assigned a unique subject number assigned 
sequentially by the study site. Enrolled subjects will keep their screening number as their 
subject number throughout the study. 


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For subjects who do not meet the study selection criteria, the site personnel will identify the 
subject as a screen failure by submitting adequate records about the reason for screen 
failure to the DCC using electronic CRFs.   
 
For enrollment of eligible wait-listed subjects into the study, subject eligibility will be 
verified centrally by the CCC. At a minimum of 5 business days prior to activating the 
patient for offers of organs from donors who are seropositive for HCV, the site will submit 
the subject’s medical record to be verified for meeting enrollment eligibility criteria related 
to the subject as a candidate for kidney transplantation. After being centrally verified as 
meeting the eligibility criteria, subjects will be entered centrally via the study system. At the 
time of transplantation, final eligibility of the subject and the organ will be made by the 
responsible site PI. The local study site will inform the MGH lead clinical site staff and the 
DCC about each transplant event within 24 hours of the transplant (preferably sooner). 
 
Once a patient has consented to study participation and approved by the CCC as meeting 
criteria, study drug will be shipped as a bulk supply from AbbVie to that study site so that 
G/P may be provided to any patient subsequently offered an eligible kidney from an HCV 
RNA-positive donor.  
 
5.5.5 Selection and Timing of Dose for Each Subject 
G/P study drug is a fixed-dose combination tablet of 100 mg glecaprevir and 40 mg 
pibrentasvir. The dose used for all subjects in this study is 300 mg/120 mg G/P, 3 tablets 
given together once daily with food. The maximum dose of G/P will not exceed 300 
mg/120 mg per day for 8 weeks (i.e. 56 daily doses) for initial treatment.   
 
Kidney transplant recipients of kidneys from deceased donors that are HCV RNA-positive 
should be administered G/P starting on day 3 after transplantation. Subjects will receive a 


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supply of G/P, with dosing instructions. The default approach will be to provide a supply of 
4 weeks of pills at the time that G/P is first prescribed. 
 
5.5.6 Blinding 
This is an open-label study. 
 
5.5.7 Treatment Compliance 
The investigator or his/her designated and qualified representatives will administer/ dispense 
study drug only to subjects enrolled in the study in accordance with the protocol. The study 
drug must not be used for reasons other than that described in the protocol. 
 
At the start of the study, each subject should receive counselling regarding the importance of 
dosing compliance with the treatment regimen with regard to virologic response and 
potential development of resistance due to poor compliance. 
 
At each post baseline visit during the Treatment Period denoted in Table 5, subjects will be 
instructed to bring all study drug containers (full, partial or empty) for assessment of 
treatment compliance by pill count and the site will discuss adherence with the subject. At 
Weeks 4 and 8 only, study site personnel will assess subject compliance by pill count (where 
available) or by talking to participants about their adherence history, and, where possible, record 
the exact number of remaining tablets of G/P in the source. In between the Week 4 and 
Week 8 study visits, a Week 6 phone call will be conducted to discuss ongoing compliance 
with the subject.  
 
5.5.8 Drug Accountability & Destruction 
The investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts. A current and accurate inventory of study drug will be 
kept by the investigator or his/her representative and will include lot number, kit number, 
number of tablets dispensed, subject number, initials of person who dispensed study drug, 


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and date dispensed for each subject. An overall accountability of the study drug will be 
performed and verified by the study monitor. Final accountability will be verified by the 
monitor at the end of study drug treatment at the site or via alternate approved method (e.g. 
video conferencing). 
 
Study drug start dates for each drug and the last dose of the regimen will be documented in 
the subject's source documents. Upon completion of or discontinuation of G/P therapy, all 
original study drug bottles containing unused study drugs will be destroyed at the study site, 
or returned to AbbVie (or its designee). All unused study drugs can only be destroyed after 
being inspected and reconciled by clinical site staff and verified by the Clinical 
Coordinating Center. The number of tablets of each type of study drug returned will be 
noted in a drug accountability log. Labels must remain attached to the containers. 
 
On-site destruction is preferred, provided the following minimal standards are met: 
• On-site disposal practices must not expose humans to risks from the drug. 
• On-site disposal practices and procedures are in agreement with applicable laws and 
regulations, including any special requirements for controlled or hazardous 
substances. 
• Written procedures for on-site disposal are available and followed. The procedures 
must be filed with the site’s SOPs and a copy provided to the Clinical Coordinating 
Center. 
• Records are maintained that allow for traceability of each container, including the 
date disposed of, quantity disposed, and identification of the person disposing the 
containers. The method of disposal, i.e., incinerator, licensed sanitary landfill, or 
licensed waste disposal vendor must be documented. 
• Accountability and disposal records are complete, up-to-date, and available for the 
Monitor to review throughout the clinical trial period. 
 


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If conditions for destruction cannot be met, the responsible Study Monitor will make 
arrangements for return of all unused and/or partially used study drug to AbbVie. 
 
It is the investigator’s responsibility to arrange for disposal of all empty containers, 
provided that procedures for proper disposal have been established according to 
applicable federal, state, local, and institutional guidelines and procedures, and provided 
that appropriate records of disposal are kept. Empty containers can only be destroyed on-
site after being inspected and reconciled by the Study Monitor at the site or via alternate 
approved method (e.g. video conferencing).   
 
5.5.8.1 Risk of Development of Resistance-Associated Substitutions During 
Combination DAA Trials 
In subjects treated with a DAA, variants with amino acid substitution(s) in the targeted 
protein conferring resistance to the DAA can be selected. Among the 2258 TN and TE-PRS 
subjects chronically infected with GT1-6 and treated with G/P 300/120 mg included in the 
integrated resistance analysis from the Phase 2 and Phase 3 studies, only 22 (0.97%) 
experienced virologic failure. Among these 22 subjects, treatment-emergent substitutions 
were detected in NS3 in 54.5% (12/22) and in NS5A in 81.8% (18/22). Subjects frequently 
had multiple substitutions in NS5A at the time of failure indicating that, in contrast to first 
generation NS5A inhibitors, single substitutions in NS5A do not confer sufficient resistance 
to allow the virus to overcome PIB drug pressure. These results support the prediction that 
the risk of development of resistance-associated variants with glecaprevir and pibrentasvir 
combination treatment is low. 
6.0  Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, reliability, 
safety, effectiveness, or performance of a product after it is released for distribution. 
Complaints associated with any component of G/P must be reported to the Sponsor (Section 


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6.2.2). For adverse events, please refer to Section 6.1. For product complaints, please refer 
to Section 6.2. 
 
6.1 Medical Complaints 
The investigator will monitor each subject for clinical and laboratory evidence of adverse 
events on a routine basis throughout the study in accordance with standard medical practice 
and the AASLD HCV treatment guidelines as well as kidney transplant protocols at the 
clinical centers. The adverse events and actions taken (concomitant therapy, etc.) identified 
centrally in the submitted medical records generated as part of clinical care will entered into study 
CRFs using the electronic interface that will be developed by the DCC. The DCC Abstraction 
Conventions manual will be used to assign adverse event start dates for any event without a 
specific start date noted. After adverse event data are submitted, the site investigator/clinician 
designee will be provided an adverse event listing to assess relationship of the adverse event to 
study drug. Site investigator/designee will also be provided an adverse event listing to 
determine adverse event stop dates/continuation for any adverse events for which no end 
date is evident in the submitted medical records during the treatment period and up to 30 
days post treatment.  
 
6.1.1 Definitions 
6.1.1.1 Adverse Event 
 
Adverse event (AE):  Any untoward medical occurrence associated with the protocol 
procedures, whether or not considered product or process related. Any symptom, sign, 
illness or experience that develops or worsens in severity during the course of the study.  
Inter-current illnesses or injuries should be regarded as AEs.  Abnormal results of 
diagnostic procedures are considered to be AEs if the abnormality: 
• results in study withdrawal 
• is associated with a serious AE 
• is associated with clinical signs or symptoms 


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• leads to additional treatment or to further diagnostic tests 
• is considered by the investigator to be of clinical significance 
 
 
6.1.1.2 
Serious Adverse Events 
If an adverse event meets any of the following criteria, it is to be reported to the sponsor as a 
SAE within 24 hours of the site being made aware of the serious adverse event: 
Death of Subject 
 
An event that results in the death of a subject. 
Life-Threatening 
 
An event that, in the opinion of the investigator, would 
have resulted in immediate fatality if medical intervention 
had not been taken. This does not include an event that 
would have been fatal if it had occurred in a more severe 
form. 
Hospitalization or 
Prolongation of 
Hospitalization 
 
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay. This 
does not include an emergency room visit or admission to 
an outpatient facility. 
Congenital Anomaly 
 
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss. 
Persistent or 
Significant 
Disability/Incapacity 
 
 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject. Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental 
trauma (e.g., sprained ankle). 
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome 
 
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 


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of the outcomes listed above (i.e., death of subject, life-
threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity). Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. 
 
Note that criteria as described above apply to all SAEs that occur after consent for the trial. 
All SAEs in the trial will be categorized as pre-transplant vs post-transplant, as well as pre-
study drug vs post study drug. 
 
 
Sites will use the SAE reporting template provided by the sponsor to report all SAEs.  If 
an SAE is observed in the submitted clinical records during data abstraction that was not 
previously reported by the site, the site will be queried for the report and supporting 
records.  The query must be responded to within 24hrs. 
 
Minimum supporting records required for all SAE reports: 
1. Admit and Discharge note 
2. Consults with VS/PE as available 
3. All labs 
4. Imaging/procedure reports 
5. Medication administration record 
 
For serious adverse events with the outcome of death, the date and cause of death (if known) 
will be recorded on the appropriate case report form. The site will make all reasonable 
efforts to obtain a death or autopsy certificate, if available. 
 
The following hospitalizations are not considered SAEs: 


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• a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status 
(e.g., routine colonoscopy) 
• medical/surgical admission other than to remedy ill health and planned prior to 
entry into the study. Appropriate documentation is required in these cases 
• admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (e.g., lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason) 
6.1.2 Adverse Event Severity 
The investigator will rate the severity of each adverse event according to the mild-
moderate-severe severity scale below.  Adverse events will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) using the following definitions:  
 
1. MILD: Adverse events and/or symptoms recorded in the medical record where no 
therapy was given to treat the event or where an over-the-counter 
medication/intervention ONLY was given to treat the event.   
 
2. MODERATE: Adverse events and/or symptoms recorded in the medical record 
requiring prescription medication treatment. 
 
3. SEVERE: Adverse events and/or symptoms requiring any study drug 
discontinuation will be defined and coded as severe.  ANEMIA events requiring 
blood transfusion will be coded as severe. 
 


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6.1.3 Relationship to Study Drug 
Assessment of relatedness will be made with respect to the stage of the trial that the subject 
is in (screening, waiting list, or post-transplantation) and further with respect to whether the 
event was related to G/P where applicable. The investigator will use the following 
definitions to assess the relationship of the adverse event to the use of G/P: 
 
Reasonable 
Possibility 
 
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event. 
No Reasonable 
Possibility 
 
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event. 
 
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated." Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated." In 
addition, when the investigator has not reported a causality or deemed it not assessable, the 
sponsor will consider the event associated. 
 
For serious adverse events, if an investigator's opinion of relatedness is "no reasonable 
possibility of being related to study drug" an "Other" cause of event must be provided by the 
investigator. After adverse event data is abstracted from the submitted records, the site 
investigator/ clinician designee will be provided an adverse event listing to assess relationship 
of the adverse event to study drug.   
6.1.4 Adverse Event Reporting  
 For this study, the AE reporting period will be divided based on the three phases of the 
study. 
Pre-Treatment Phase  


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Screening phase: When all screening tests have been done, we will assess for any AEs 
related to the screening tests at the time of communication with the subject about whether 
he/she is official eligible or ineligible for the study.  
Pre-existing Condition: A pre-existing condition is one that is present at the start of the 
study. A pre-existing condition should be recorded as an AE if the frequency, intensity, or 
the character of the condition worsens during the study period. 
Waitlist phase: We will only capture AEs that are pertinent to the study. Specifically, the 
following will be captured:  
 
1. Patient death,  
 
2. Patient develops a condition that would exclude that subject from the study,  
 
3. Patient is de-listed (taken off the kidney transplant waitlist)  
 
4. Patient is made inactive on the transplant waitlist  
5. Serious Adverse events and non-SAE hospitalizations; these will be categorized 
as “pre-transplant” (vs. “post-transplant”) and “pre-study drug” (vs. “post-study 
drug”) 
 
In order to ascertain these events, we will review the patient’s medical history by phone 
every 2 months and in person every 6 months that they are on the wait list.  
 
Treatment Phase in Arm 1 
Immediate Post-transplant phase:  
From the date of transplant with a HCV RNA-positive kidney to 1 day before first 
administration of the study drug, we will collect SAEs and clinical outcomes and data, 
including death, graft failure, acute allograft rejection, delayed graft function, eGFR, ALT 
elevation > 5 x ULN, SAEs. 
 
 HCV Treatment Phase 
The following additional data will be collected from Day 1 of HCV treatment to 30 days 
following last dose of HCV treatment:  


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All adverse events will be collected and clinical outcomes, including death, graft failure, 
acute allograft rejection, delayed graft function, ALT elevation > 5 x ULN, SAEs, 
sclerosing cholestatic hepatitis and extrahepatic manifestations of HCV, and data of eGFR 
and proteinuria. An assessment for causality to transplant, HCV infection, or study drug 
G/P will be made. Grade 3 or greater treatment-emergent laboratory abnormalities from the 
first dose of G/P through 2 days post dosing will also be collected and summarized. Events 
of sclerosing cholestatic hepatitis and extrahepatic manifestions of HCV infection will only 
be collected in ARM 1 subjects and subset of ARM 2A subjects who develop HCV 
viremia.  
 
Post-Treatment Phase in Arm 1 
Post HCV treatment Phase: From 30 days post last dose of HCV treatment to 1 year post 
kidney transplant (last study visit), the following outcomes and other data will be collected: 
death, graft failure, acute allograft rejection, delayed graft function, ALT elevation > 5 x 
ULN, SAEs, sclerosing cholestatic hepatitis and extrahepatic manifestations of HCV. eGFR 
and proteinuria will be collected at specific visits. All SAEs will be assessed at every clinic 
visit when the subject is seen by a member of the study team.  
 
All unresolved AEs considered possibly, probably, or definitely related to the study drug or 
to HCV infection should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the AE is otherwise explained.   
 
The investigator will notify the IRB of any death or SAE occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to 
this study.  The IRB will also be notified if the investigator should become aware of the 
development of cancer or of a congenital anomaly in a subsequently conceived offspring of 
a subject that has participated in this study. 
 
6.1.5 Serious Adverse Event Reporting 


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In the event of a serious adverse event, whether associated with study drug or not, the 
Investigator will notify the Sponsor within 24 hours of the site being made aware of the 
serious adverse event by submitting the available serious adverse event data to:   
 
 
For safety concerns, contact the physician listed below: 
Hannah Gilligan, MD 
Office:  617-643-2257 
  Mobile: 781-552-1870 
Email:  Hgilligan@mgh.harvard.edu 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be submitted within 24 
hours using the same procedure used for transmitting the initial SAE report. All SAEs 
should be followed to resolution or stabilization. 
The MGH designated Medical Monitor or delegate from the sponsor must also report any 
serious adverse event in a subjects on G/P treatment (on G/P treatment period includes day 
1 of G/P dosing to 30 days after last G/P dose) to AbbVie within 24 hours after receipt of 
the serious adverse event information from the study site.  
 
6.1.6 Pregnancy 
Female subjects should avoid pregnancy starting with screening and through 30 days after 
completion of study drug.  
 
Pregnancy in a study subject must be reported to the sponsor within 1 working day of the 
site becoming aware of the pregnancy. Administration of study drug may be continued at 
the investigator's discretion after discussion with the subject, if the benefit of continuing 
therapy is felt to outweigh the risk (Section 5.4.1). If a subject is discontinued, the subject 
will be monitored for SVR in the Post-Treatment Period as described in Section 5.1.3. 
 
Email to: mythicSAE@mgh.harvard.edu 


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Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected for pregnancies occurring up to 30 days after the end of 
treatment.  
 
Pregnancy in a study subject is not considered an adverse event. However, the medical 
outcome of an elective or spontaneous abortion, stillbirth or congenital anomaly is 
considered a serious adverse event and must be reported to the sponsor within 24 hours of 
the site becoming aware of the event. 
 
In the peri-transplant and post-kidney transplantation period, standard of care is to avoid 
pregnancy during the first year because of potential negative effects on the allograft and 
because of the common utilization of teratogenic medications such as mycophenolate 
mofetil. In the post-transplant period, clinical sites will follow their own standard of care 
protocols regarding screening for pregnancy and robust contraceptive counselling. 
 
6.1.7 Toxicity Management 
For the purpose of medical management, all adverse events and laboratory abnormalities 
that occur during the study must be evaluated by the investigator. Only lab abnormalities 
that are deemed clinically significant or require intervention are classified as adverse 
events. All adverse events and laboratory abnormalities will be managed and followed to a 
satisfactory clinical resolution. A toxicity is deemed "clinically significant" based on the 
medical judgment of the investigator.  
 
To facilitate this process in a pragmatic study, after adverse event data is abstracted from the 
submitted records, the site investigator/clinician designee will be provided an adverse event 
listing to assess relationship of the adverse event to study drug. The site will also upload 
signed central lab reports where the investigator completed the evaluation of clinical 
significance of abnormal results. Actions taken for clinically significant abnormal 


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laboratory results and/or adverse events will be recorded in the site medical record or 
source, and entered into the eCRFs. 
 
6.1.8. 
Management of ALT elevations while on study drug G/P 
 
If a subject experiences a post-baseline increase in ALT to > 5 × ULN which is also 
> 2 × baseline value, the subject should have a confirmatory ALT measurement 
performed.  
If the ALT increase is confirmed to be > 5 × ULN which is also > 2 × baseline value, 
the recommendations below should be followed: 
●   Evaluate for alternate etiology of ALT elevation; document in the source, update the 
medical history and concomitant medications eCRF (if applicable), and obtain 
additional testing as appropriate (e.g., hepatitis B panel). 
●   Manage the subject as medically appropriate. 
●   Repeat ALT, AST, total and fractionated bilirubin, alkaline phosphatase and 
INR within 1 week. Repeat liver chemistries as indicated until resolution. 
●   Discontinue study drugs if any of the following is observed at any time: 
○   ALT level is ≥ 20 × ULN in the absence of an alternate etiology. 
○   Increasing direct bilirubin or INR or onset of symptoms/signs of hepatitis. 
 At the discretion of the investigator alternate management of ALT increases is 
permitted with approval of the Principal Investigator (Ray Chung) at MGH. 
 
6.1.9. 
Management of suspected kidney rejection while on study 
drug G/P 
If at any time a site investigator suspects rejection of the transplanted kidney while 
the subject is receiving study drug, then dose adjustment of immunosuppressants may 
be performed per the site investigator's usual practice and the event captured on eCRF. 
If the abnormality is non-responsive to immunosuppressant adjustment and/or if the site 
investigator wishes to empirically augment the immunosuppressive regimen, e.g., by 


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commencement of high dose steroids or to add specific anti-rejection agents but without 
the availability of a biopsy of the transplanted organ confirming rejection, then change 
in follow-up procedures and antiviral treatments may be considered by the site 
investigator, as appropriate. 
 
If the site investigator wishes to pursue alternative management of study drugs in this 
setting the Principal Investigator should be contacted to obtain approval. 
 
If a biopsy of the transplanted kidney is performed as part of the evaluation of rejection 
and the histologic findings are consistent with rejection as determined by the local 
pathologist, the site investigator should follow the usual management of rejection and 
continuation of study drugs should be per investigator discretion. If the site investigator 
wishes to pursue alternative management of study drugs in the setting of histologically 
confirmed rejection, then the Principal Investigator should be contacted to obtain 
approval. Biopsy tissue from the transplanted organ obtained during the trial to evaluate 
rejection or other pathologic process should be read locally and the result recorded in 
the subject source documents. Because of the potential impact of discontinuation (or 
interruption) of study drugs on immunosuppressant levels, investigators should ensure 
that a plan for appropriate immunosuppressant dose modification is in place and that 
this plan is communicated to the subject. 
 
6.2. Product Complaint 
6.2.1 Definition 
A product complaint is any complaint (see Section 6.0 for the definition) related to the study 
drug product(s). For a product this may include, but is not limited to, damaged/broken 
product or packaging, product appearance whose color/markings do not match the labelling, 
labelling discrepancies/inadequacies in the labelling/instructions (e.g. printing illegible), or 
missing components/product, or packaging issues.  Any product complaints identified 
centrally in the submitted medical records will be abstracted into the study database. 


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6.2.2 Reporting 
Product complaints concerning the investigational product must be reported to the sponsor 
within 24 hours of the time it is observed. If the data is abstracted centrally from the 
submitted medical records, it should be reported via the product complaint form. Product 
complaints occurring during the study will be followed up to a satisfactory conclusion via 
specific query to the site for any available clinical information. All follow up information is 
to be reported to the sponsor and documented in the source medical record.  Product 
complaints associated with adverse events will be reported in the study summary. All other 
complaints will be monitored on an ongoing basis. 
 
Product complaints may require return of the product with the alleged complaint condition. 
In instances where a return is requested, every effort should be made by the investigator/site 
to return the product within 30 days. If returns cannot be accommodated within 30 days, the 
site will need to provide justification and an estimated date of return. 
 
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required. 
 
7.0 Major Protocol Deviations 
The investigator should not implement any major deviation from the protocol without prior 
review and agreement by the Sponsor and in accordance with the Independent Ethics 
Committee (IEC)/Independent Review Board (IRB) and local regulations, except when 
necessary to eliminate an immediate hazard to study subjects. When a deviation from the 
protocol is deemed necessary for an individual subject, the investigator must contact the 
following personnel:  
Hannah Gilligan, M.D. 
If by e-mail: hgilligan@mgh.harvard.edu 
If by phone: 617-643-2257 
  
 


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Such contact must be made as soon as possible to permit a review by the sponsor to 
determine the impact of the deviation on the subject and/or the study. Any significant 
protocol deviations affecting subject eligibility and/or safety must be reviewed and/or 
approved by the IEC/IRB and regulatory authorities, as applicable, prior to implementation. 
 
8.0 Statistical Methods and Determination of Sample Size 
In some analyses below, Arm 2 will be further broken down by category: 
A. subjects who receive a kidney from a study-eligible  HCV RNA-negative/ HCV 
Ab-positive donor 
B. subjects who receive a standard of care kidney transplant 
C. subjects who were not transplanted within 1 year of consent 
8.1 Statistical and Analytical Plans 
The data analysis will be generated using SAS version 9.4 or higher for windows and/or 
STATA software version 14.0 or higher (StataCorp LP, College Station, TX). SAS Institute 
Inc. SAS and all other SAS Institute Inc. product or service names are registered 
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA. All statistical tests (if 
applicable) and confidence intervals will be two-sided with an alpha level of 0.05. 
Descriptive statistics will be provided, such as the number of observations (N), mean, and 
standard deviation (SD) for continuous variables and counts and percentages for discrete 
variables. 
 
The efficacy and safety of the “reactive” G/P treatment of patients who become HCV 
RNA-positive after receiving a kidney from a study eligible HCV RNA-negative/HCV Ab-
positive donor in Arm 2A are not an objective of this study, and they are not included in 
assessments of efficacy or safety described below. The time to transplant and clinical 
outcomes and data post-transplant from patients in Arm 2A are included in those secondary 
endpoints. 
 


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The primary analysis will occur after all recipients of HCV RNA-positive kidneys in Arm 1 
have completed post-treatment week 12 visit (corresponding to SVR12 data collection) or 
prematurely discontinued study. The primary analysis of SVR12 will be performed on the 
intention-to-treat (ITT) population defined as all enrolled subjects who received a study 
eligible HCV RNA-positive kidney and received at least one dose of G/P according to actual 
treatment received (Arm 1).  
 
No data will be imputed for any efficacy or safety analysis except for analyses of SVR 
endpoints (HCV RNA data). HCV RNA values will be selected for the analyses of all SVR 
endpoints (e.g., SVR4 and SVR12, SVR24) based on defined visit windows. A backward 
imputation method will be used to impute missing responses for SVR analyses. 
Additional details of analyses to be performed will be specified in the Statistical Analysis 
Plan. 
 
8.1.1 Demographics 
Demographics and baseline characteristics will be summarized for all enrolled subjects by 
arm (Arm 1 and Arm 2) with further breakdown by categories of Arm 2 (2A, 2B and 2C), 
and overall. Baseline characteristics include age, weight, height, BMI, gender, race, 
ethnicity, cause of end-stage kidney disease, dialysis vintage, prior solid organ 
transplantation, liver fibroscan results, and any HCV treatment history (for participants 
previously cured of HCV infection) and match run position f or kidney transplant 
recipients.  For subjects in Arm 2B, further breakdown by the subgroups allowed in Arm 
2B will be summarized  - 2B1 to 2B5. 
 
Donor variables will include donor age, sex, race, terminal serum creatinine, cause of death, 
PHS increased risk status, KDPI score, cold ischemia time, and where available, 
characteristics of the donor HCV including genotype.  
 


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Summary statistics (N, mean, median, SD, and range) will be generated for continuous 
variables (e.g., age and BMI), and the number and percentage of subjects will be presented 
for categorical variables (e.g., sex and race). 
 
Study drug G/P exposure and compliance will be summarized for Arm 1. Treatment 
compliance to study drug will be calculated based on the percentage of tablets taken relative 
to the total tablets expected to be taken, where these data are available. A subject is 
considered to be compliant if the percentage is between 80% and 120%. Compliance will 
be calculated for each subject and summarized with the mean, median, standard deviation, 
minimum, and maximum. The percentage of compliant subjects will be summarized. 
 
8.1.2 Efficacy 
All efficacy analyses will be performed on the ITT population, unless otherwise specified. 
Plasma HCV RNA levels will be determined for each sample and measured using standard 
of care in the clinical site labs. HCV RNA ≥ the lower limit of quantification (LLOQ) are all 
quantifiable values. 
 
8.1.2.1 Primary Efficacy Endpoint 
The primary efficacy endpoints is the proportion of ITT subjects who achieved SVR12 
(HCV RNA < LLOQ 12 weeks after the last actual dose of study drug).  
The number and percentage of subject achieving SVR12 will be summarized along with a 
two-sided 95% confidence interval calculated using Wilson’s score method. A summary of 
reasons for SVR12 non-response (e.g., on-treatment virologic failure, relapse, other) will be 
provided. 
 
8.1.2.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints to be summarized for all ITT subjects who are: 
 


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o the number and percentage of subjects with on-treatment virologic failure 
(confirmed increase of > 1 log10 IU/mL above nadir during treatment, confirmed 
HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA 
≥ LLOQ at the end of treatment with at least 6 weeks of treatment); 
o the number and percentage of subjects with post-treatment relapse (defined as 
confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after the last 
dose of study drug among subjects who completed treatment as planned with HCV 
RNA < LLOQ at the end of treatment, excluding subjects with reinfection).  
 
For the analysis of relapse, completion of treatment is defined as any subject with study 
drug duration of 49 days or greater for 8-week treatment. 
 
8.1.2.3 Sensitivity Analysis 
As a sensitivity analysis, the percentage of subjects in the modified intention-to-treat-virologic-
failure (VF) population (ITT population excluding those who did not achieve SVR12 for 
reasons other than on treatment VF and relapse) achieving SVR12, will be summarized. 
8.1.2.4 Subgroup Analysis 
The percentage of ITT subjects with SVR12 will be calculated, as will the corresponding 
two-sided 95% Wilson score intervals by the following subgroups: 
o HCV GT 
o Timing of HCV treatment initiation after transplant 
o Study drug compliance 
Further details about subgroup analyses will be described in the Statistical Analysis 
Plan 
8.1.2.5 Additional Efficacy Endpoints 
The following additional efficacy endpoints will be summarized for the ITT population: 
 


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o The percentage of subjects with HCV RNA < LLOQ at each post-baseline visit in 
the Treatment Period (using data as observed); 
o The percentage of subjects with SVR4; 
o The percentage of subjects with SVR24 and the concordance between SVR12 and 
SVR24 
 
In the above analyses for SVR, the percentage of subjects and a two-sided 95% Wilson 
score interval will be summarized. 
 
8.1.3 Resistance Analyses 
The following analyses will be performed for subjects in Arms 1 and 2A who do not achieve 
SVR 12 and who have post-baseline resistance data available: The HCV NS3 and NS5A 
amino acid sequences from the sample closest in time after virologic failure or treatment 
discontinuation with an HCV RNA level of ≥ 1000 IU/mL will be determined by population 
sequencing or NGS, and a listing by subject of all substitutions at GLE and PIB signature 
amino acid positions relative to the appropriate prototypic reference sequence of NS3 and 
NS5A will be provided. 
 
8.1.4 Secondary Clinical Outcomes 
Secondary clinical outcome analyses will be performed for subjects prior to kidney 
transplant in both Arms 1 and 2, and post kidney transplant for those who receive a kidney 
transplant in Arms 1 and 2.  For details on safety reporting and periods of safety reporting 
see section 6.1.4.  
The cumulative incidence function curves of time to kidney transplant will be created for 
each type of kidney transplant (Arms 1, 2A, 2B), and cumulative incidence and standard 
error (SE) will be calculated for each type of kidney transplant.  
An exploratory analysis will create cumulative incidence function curves of time to kidney 
transplant for the subgroups of Arm 2B if sufficient subjects are enrolled in Arm 2B. 
 


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The number and percentage of subjects with clinical outcomes while on waitlist and after 
study consent (SAEs, delisting from waitlist, death) among subjects who receive an HCV 
RNA-positive kidney (Arm 1) and among those subjects who do not receive an HCV RNA-
positive kidney (all Arm 2 subjects) overall and with breakdown by category of Arm 2 (2A, 
2B, 2C).  In addition, the total number of inpatient hospital days while on waitlist in those 
who did receive an HCV RNA-positive kidney (Arm 1) and total inpatient hospital days in 
those who did not (Arm 2) overall and with breakdown by category of Arm 2 with be 
summarized descriptively with mean, median, standard deviation (SD), minimum and 
maximum.  
 
We will match MYTHIC trial participants 1:3 to comparators derived from the Organ 
Procurement and Transplantation Network database. Matching will be based on 
demographics and baseline characteristics known to influence waiting time, including 
waiting list priority, blood group, geographic region, and sensitization. A comparison of 
time to kidney transplantation between the kidney transplant candidates enrolled in the 
MYTHIC trial and OPTN comparators will be performed using a Cox proportional hazards 
model. 
 
Clinical outcomes post-transplant will include death, graft failure, acute allograft rejection, 
delayed graft function,  ALT elevation > 5 times the upper limit of normal, and SAEs. In 
addition,  HCV-infection related events of fibrosing cholestatic hepatitis and extrahepatic 
manifestations of HCV infection collected for Arm 1 subjects and only for Arm 2A subjects 
who develop HCV viremia will also count as clinical outcomes.  The number and 
percentage of subjects with each and any clinical outcomes will be summarized for those 
who receive an HCV RNA-positive kidney (Arm 1) versus Arm 2 subjects combined and 
broken down (2A and 2B) as applicable. The difference in the overall percentage of 
subjects with clinical outcomes post-transplant in Arm 1 vs Arm 2A + 2B will be assessed 
by logistic regression with Arm as a factor and including appropriate covariates to adjust 
for possible differences between Arms including waiting list priority, blood group, 


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geographic region and sensitization, as appropriate given sample size and other statistical 
considerations. In addition, to include any clinical outcomes due to being treated with G/P, 
another summary of clinical outcomes post-transplant will include any study drug (G/P) 
related severe treatment emergent adverse events for Arm 1 subjects, and another will 
include events of treatment emergent Grade ≥ 3 laboratory values and related severe 
treatment emergent adverse events as clinical outcomes for Arm 1 subjects.  
 
Analyses of the eGFR outcome will be calculated eGFR using the 4-variable MDRD 
equation. Mean (SD) eGFR will be summarized at appropriate visits and compared between 
Arms.  Specifically, mean eGFR at 24 weeks/6-months post-transplant and 1 year post 
transplant will be compared between Arm 1 transplant recipients and the combined group 
of Arm 2A and 2B transplant recipients (2B1-2B4). As a secondary approach, mean eGFR 
at 24 weeks/6-months post-transplant will be compared between Arm 1 recipients and Arm 
2A and 2B kidney recipients limited to those 2A and 2B recipients who did not develop 
HCV infection.  
 
We will also compare estimated proteinuria between Arms 1 and 2A, including a count of 
individuals with >1000 mg/day estimated proteinuria. Proteinuria will be estimated using 
spot protein:Cr ratio. 
 
An exploratory analysis will summarize the number and percentage of subjects with clinical 
outcomes post kidney transplant for the subgroups of Arm 2B. 
Exploratory analyses will also make comparisons between groups in which recipients of 
non study-eligible HCV RNA-positive and non study-eligible RNA-negative/HCV Ab-
positive kidneys are censored at transplantation. 
 
These clinical outcomes post-transplant will be further summarized by relatedness to study 
drug or HCV infection for Arm 1 subjects, and relatedness to transplant for each group Arm 
1, Arm 2A, and Arm 2B subjects. 


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In addition, for subjects in study Arm 2 receiving HCV antibody-positive/ HCVRNA-
negative kidneys, the rate and timing of HCV transmission will be summarized.  
 
8.1.5 
Safety Analyses for Arm 1 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Subjects reporting more than one adverse event for a given MedDRA preferred 
term will be counted only once for that term using the most severe grade for the severity 
grade table and the most related for the relationship to study drug table. Subjects reporting 
more than one type of event within a SOC will be counted only once for that SOC. An 
adverse event will be considered treatment-emergent if it begins or worsens in severity after 
initiation of study drug through 30 days post-study drug dosing. Related adverse events are 
those considered at least possibly related to study. 
 
Laboratory data will be summarized from the first dose of G/P through 2 days post dosing.  
Laboratory values will be rated according to the National Cancer Institute Common 
Terminology Criteria for Adverse Events (NCI CTCAE Version 4) which is available on 
the Cancer Therapy Evaluation Program (CTEP) website at:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf 
Grade 3+ laboratory values are those that are Grade 3 or 4.  
8.1.6 
Additional Adverse Event Analyses for Arm 1 
 
For subjects treated with G/P, the number and percentage of subjects with treatment-
emergent adverse events (i.e., any event that begins or worsens in severity after initiation of 
study drug through 30 days post-study drug dosing) will be tabulated by primary MedDRA 
System Organ Class (SOC) and preferred term (PT) for each treatment arm. The tabulation 
of the number of subjects with treatment-emergent adverse events by severity grade and 
relationship to study drug, kidney transplantation, or HCV infection also will be provided.  


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8.1.7 Additional Clinical Laboratory Data for Arm 1 
Clinical laboratory tests will be summarized by transplant phase (e.g., awaiting a transplant, 
after receipt of a transplant) and treatment arm. Additional evaluations will be performed for 
subjects who received study drug as part of the protocol (Arm 1). The baseline value will 
be the last non-missing measurement prior to the initial dose of study drug. Mean changes 
from baseline to each post-baseline visit, including the Final Treatment Visit, will be 
summarized descriptively for Arm 1 as feasible.  
In addition, the number and percentage of subjects with post-baseline laboratory values of 
interest equal or greater than Grade 3 of the CTCAE scale will be summarized overall and by 
Arm.  
 
8.2 Determination of Sample Size 
This study is primarily designed to demonstrate feasibility and to generate preliminary data 
related to cure rates (defined as SVR12) from treating donor-derived HCV infection post 
kidney transplantation using G/P. For this reason, the sample size was not determined with 
reference to power to detect differences between groups for the primary objective. The 
lower bound of a one-sided 95% confidence interval using the Wilson’s score method, for 
various SVR12 rates with a total sample size of 30 subjects are provided in Table 10.  
 
Table 10: Estimated Lower Bound for 95% Confidence Interval for Cure Rate Based 
on Observed Number of Cures 
Sample Size 
No. of 
Observed 
Cures 
Observed Cure 
Rate 
Lower Bound for 95% 
CI of Cure (Wilson’s 
Score) 
30 
30 
100.0% 
93.8% 
30 
29 
96.7% 
85.4% 
30 
28 
93.3% 
81.0% 
30 
27 
90.0% 
76.9% 
30 
26 
86.7% 
73.0% 
As a secondary objective, we will compare time to kidney transplantation between the 
estimated 75 - 90 kidney transplant candidates enrolled in this trial with 225-270 matched 
kidney transplant candidates from the OPTN list (1:3 match). We estimate that at least 40 


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patients (44%) of 90 enrolled patients will undergo kidney transplantation versus 20% (or 
less) of comparators from OPTN list during an estimated 6 months of follow-up, with 80% 
power to detect a difference between groups. 
 
8.3 Assignment of Participants to Study Arms: Methods 
This is a two-arm study. All eligible subjects who entered the study will be observed. 
Observed subjects who accept a study-eligible HCV RNA-positive kidney allograft offer 
will be assigned to the G/P treatment Arm 1 and followed in that Arm up until 1 year post-
transplant. All other enrolled study subjects will remain in Arm 2 of the study (see Figure 
1A). 
 
9.0 Ethics 
9.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB) 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the MAVYRET USPI,10  the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB at each site will review the ethical, 
scientific and medical appropriateness of the study before it is conducted. IEC/IRB approval 
of the protocol, informed consent and subject information and/or advertising, as relevant, 
will be obtained prior to the authorization of drug shipment to a study site. 
 
Any amendments to the protocol will require IEC/IRB approval prior to implementation of 
any changes made to the study design. The investigator will be required to submit, maintain 
and archive study essential documents according to ICH GCP. 
 
Any serious adverse events that meet the reporting criteria, as dictated by local regulations, 
will be reported to both responsible Ethics Committees and Regulatory Agencies, as 
required by local regulations. During the conduct of the study, the investigator should 
promptly provide written reports (e.g., ICH Expedited Reports, and any additional reports 


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required by local regulations) to the IEC/IRB of any changes that affect the conduct of the 
study and/or increase the risk to subjects. Written documentation of the submission to the 
IEC/IRB should also be provided to the sponsor 
 
9.2 Ethical Conduct of the Study 
The study will be conducted in accordance with the protocol, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of Helsinki. 
Responsibilities of the clinical investigator are specified in Appendix A. 
 
9.2.1 Ethics Analysis 
The main ethical considerations in this trial are non-maleficence, respect for persons, and 
autonomy. Our selection criteria are designed to select subjects who are at substantial risk 
of death and health complications because of end-stage renal disease and chronic dialysis 
treatment. Transplantation with a HCV RNA-positive kidney and then treatment for HCV 
also involve risks, but it is plausible that survival and quality of life will still improve after 
transplantation compared to the alternative of additional years on dialysis. Our informed 
consent procedures are designed to enable individuals to make decisions that are consistent 
with their values. We will enumerate the many possible risks and plausible benefits. The 
processes of informed consent in this study will be conducted so that patients can ask 
questions, confer with their primary nephrologists and develop a full understanding of the 
trial procedures and risks, all of which is consistent with respect for persons. Lastly, 
subjects in the trial will retain the ability to consider organ offers and decide whether to 
accept an organ based on their own judgment about the value of that particular organ and 
after getting advice from their transplant team.   
 
9.3 Subject Information and Consent 
The processes of informed consent in this study are designed to give potential participants 
several opportunities to learn about HCV, the study and to understand risks and benefits. As 


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described in section 5.1.3 Screening, study staff will discuss the study during an initial 
phone call, a subsequent educational session and finally during the informed consent 
session when subjects will have the opportunity to sign the informed consent document. 
 
The investigator or his/her representative will explain the nature of the study to the subject, 
and answer all questions regarding this study. Prior to any study -related screening 
procedures being performed on the subject, the informed consent statement will be reviewed 
and signed and dated by the subject, the person who administered the informed consent, and 
any other signatories according to local requirements. A signed copy of the informed 
consent form will be given to the subject and the original will be placed in the subject's 
medical record. An entry must also be made in the subject's dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that 
the subject received a signed copy. 
 
9.4 Potential Risks and Benefits 
9.4.1 Risks of Study Procedures  
There are several areas of potential risk in this study.  We will obtain several blood samples 
from each subject. There is a risk of bruising, hematoma, and infection after phlebotomy, 
which are possible but not considered serious AEs. Fainting may occur, which is unlikely 
but considered a serious AE. The removal of <70 cc of blood every 1-4 weeks during the 
40-week post-transplant period is a potential risk; however this amount is routinely taken 
from subjects for clinical indications without adverse effect. Study medications will be 
delayed until after phlebotomy on each study day. 
 
Because we may store subjects’ blood samples, there may be confidentiality risks 
associated with the storage and analysis of those samples or the information resulting from 
the analysis of those samples. Samples may be used for genetic testing. Under some 
circumstances, it can be a risk for genetic information to be known. To help ensure 
confidentiality, samples will be coded and stored in a secured facility. While situations 


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cannot be foreseen where potentially sensitive genetic information is revealed or where 
people who should not have this information could obtain it (representing a loss of 
confidentiality), however, it is possible that presently unforeseen situations may arise where 
this could happen. 
 
The risk of undergoing screening includes potential identification of new health problems 
that subjects were unaware of. If we discover new health problems, we will answer 
subjects’ questions and try to arrange appropriate treatment if any is needed. If new health 
problems are discovered, it is possible that subjects would not be able to enter this study. It 
is also possible that subjects would no longer be eligible for kidney transplantation based 
on the results. 
 
The risks associated with a Fibroscan are that the probe used on the abdomen during the 
Fibroscan may lead to mild soreness in the area for about a day.  
 
The risks of any kidney transplant surgery include blood loss, infections, and deep vein 
thrombosis. There are also risks related to immunosuppression and standard anti-infective 
therapy. The risks of any kidney transplant also include primary graft non-function, delayed 
graft function, acute rejection, and death. Re-admissions within 30 days after a kidney 
transplant are expected in approximately 40% of patients. 
 
There may also be a small risk of developing Focal and Segmental Glomerulosclerosis 
(FSGS) after receiving a kidney from HCV-RNA-positive donor and/or being treated for 
HCV after transplantation. However, this condition can also develop in patients who do not 
have HCV.  There have been case reports of FSGS among patients receiving treatment for 
HCV after kidney and liver transplantation. It is possible that such cases were related to 
HCV treatment. After transplant, we will monitor all patients for FSGS and similar 
conditions by checking proteinuria at every study visit post-transplant. 


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There may also be a small risk of developing symptoms of acute HCV infection, or 
extrahepatic manifestations of HCV infection if the start of HCV treatment is delayed. 
After transplant, we will monitor all patients and will initiate HCV treatment as early as 
feasible on or after day 3 post-transplant. 
 
Taking part in a research study may cause psychological distress or excess worry. A subject 
may experience discomfort if asked questions about the subject’s medical history that the 
subject deems to be private.  
 
9.4.2 Risk of Study Drugs and Mycophenolate Mofetil 
Glecaprevir/Pibrentasvir  
In subjects receiving G/P for 8, 12, or 16 weeks, the most commonly reported adverse 
reactions of all intensity (greater than or equal to 5% were headache, fatigue and nausea.10 
The majority of subjects experienced an AE, which were mostly considered to be mild in 
severity by the investigator (Grade 1).   
 
For this trial, the greatest risk is failure to achieve SVR12 after treatment with G/P, leading 
to chronic HCV. 
Glecaprevir/Pibrentasvir and/or Mycophenolate Mofetil 
It is not known whether G/P causes fetal harm in humans. There is a risk of fetal harm and 
birth defects should any woman taking G/P.  Mycophenolate mofetil can cause fetal harm 
and birth defects. To mitigate this risk, all pre-menopausal women with a uterus will be 
screened for pregnancy before enrollment and instructed to use a highly effective form of 
birth control (e.g. abstinence, intrauterine device, etc.). The applicable methods of birth 
control that are required in this protocol are outlined in Appendix D, and based on whether 
the subjects will take mycophenolate mofetil after kidney transplantation or not.  
 
9.4.3 Risk of Developing HCV Infection 


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The risks of chronic HCV include severe acute inflammation of the liver that could lead to 
liver failure requiring a liver transplant. HCV may also cause a severe type of acute 
infection called fibrosing cholestatic HCV, that can cause severe liver injury, jaundice 
(yellowing of the eyes and skin), and progressive liver dysfunction, and may cause damage 
to other organs, including and not limited to the kidneys, heart, skin. Chronic HCV 
infection has also been associated with certain cancers, autoimmune diseases, and 
depression. 
 
There is a small risk of transmission of HCV from the study subject to intimate partners 
during sexual activity. This risk is very low and should be reduced even further due to 
requirements for subjects to use barrier protection during sexual activity. 
 
9.4.4 Potential benefits 
The results from the study could be applied in the future to subjects (including those in the 
study) who stand to benefit from the information. Subjects will experience clinical benefits 
as their kidney function and quality of life should vastly improve following transplant. The 
study involves the risks of phlebotomy, echocardiography, Fibroscan, development of 
chronic HCV, and loss of confidentiality, but there is a potential for future benefit for both 
subjects in the study and for future subjects, the risk/benefit ratio is favorable. 
 
9.4.5 Alternatives 
The use of the medications for this study requires that certain other medications not be used 
(Table 7). Therefore, the alternative is to not participate in this study and to continue having 
the option to take these medications. 
 
 
 
 


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10.0 Study Administration, Data Handling, and Record Keeping  
10.1 Confidentiality  
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA). 
Those regulations require a signed subject authorization informing the subject of the 
following:  
• What protected health information (PHI) will be collected from subjects in this study  
• Who will have access to that information and why  
• Who will use or disclose that information  
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect at least vital status (i.e. that the 
subject is alive) at the end of their scheduled study period.  
 
10.2 Source Documents  
Source data is all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Source data are contained in source documents. Examples of these original documents, and 
data records include: hospital records, clinical and office charts, laboratory notes, 
memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing records, 
recorded data from automated instruments, copies or transcriptions certified after 
verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial as 
appropriate and applicable to the study.  
 
 


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10.3 Case Report Forms  
The study case report form (CRF) is the primary data collection instrument for the study. 
Data will be collected using CRFs developed specifically for the (study name) trial as well 
as standardized instruments. Forms will be made available for completion on paper as well 
as directly into the electronic data management system. Data will be collected from in-
person and telephone interviews with study participants, and from clinical information 
contained in medical records. When possible during the follow-up phase of telephone 
interviewing, data collected will be entered directly into the electronic data management 
system. Hard copy CRFs will be available in case of the electronic data management 
system (DMS) is inaccessibility.  
 
10.4 Data Collection and Management  
Data Collection Procedures. All data collection procedures for this Multi 
Center, Open-Label Study of Glecaprevir/Pibrentasvir to Treat Recipients of 
Transplanted Kidneys from Deceased Donors with Hepatitis C Virus are outlined in  
Section 5.0 (“Investigational Plan”)  
Figure 2 shows flow of patients through the 4 patient scenarios, data collection and data 
transfer activities. The first diagram depicts patient and data flow for enrolled subject who 
receive a study-eligible HCV RNA positive kidneys (left, ARM 1) and subjects who 
receive a study-eligible HCV RNA-negative/HCV Ab-positive kidney (right, ARM 2A). 
The second diagram shows patient and data flow for enrolled subject who receive a 
standard-of- care kidney (left, ARM 2B) and subject who are not transplanted during the 
duration of the trial (right, ARM 2C). 
  
Figure 2: Subject flow, data collection and data transfer activities during the trial  
 


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*A “standard of care” transplant is defined as any of the following kidney transplants: a deceased 
donor HCV RNA-positive kidney transplant that did not meet donor criteria for Arm 1 or HCV 
RNA-positive kidney transplant that place after last transplant allowed for Arm 1 but met criteria 
for Arm 1 inclusion (2B1); a deceased donor  HCV RNA-negative/HCV Ab-positive kidney 
transplant that either did not meet donor criteria or took place > 6 months after the last Arm 1 
transplant (2B2); a deceased donor HCV RNA-negative/HCV Ab-negative transplant at a MYTHIC 


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clinical site (2B3); any living donor kidney transplant at a MYTHIC clinical site (2B4); or 
any kidney transplant at a different center than the 7 clinical sites (2B5). 
Arm 2B5 recipients will be censored at transplantation. 
 
Data management procedures. The Data Coordinating Center (DCC) at the University of 
Pennsylvania will develop a data management system for the collection, validation, storage 
and management of trial data. The data management system will use a combination of tools 
to perform the following study functions:  
• Subject tracking – to monitor screening and enrollment and produce subject visit 
schedules  
• Eligibility determination - to evaluate screening data to determine subject eligibility  
• Comprehensive data collection modules to accommodate all types of trial data  
 
Data management system. All research data for this trial will be stored in an electronic 
database that is managed by the Clinical Research Computing Unit (CRCU) of the 
University of Pennsylvania Center for Clinical Epidemiology and Biostatistics (CCEB). 
The Data Management System will be developed using Oracle Corporation’s suite of 
pharmaceutical applications, including Oracle Clinical® and Oracle Clinical Remote Data 
Capture®. The Oracle Clinical system, which has been installed, tested and validated in 
compliance with the FDA part 11 of Title 21 of the Code of Federal Regulations; Electronic 
Records; Electronic Signatures (21 CFR Part 11), meets the requirement for IND/IDE 
studies. The database will be hosted on secure computing servers and will be restricted to 
only those individuals who are authorized to work on the trial. Individual user accounts 
with passwords will be used to restrict access to the database. Specific privilege 
assignments within the database will also be employed to limit the types of functions that 
authorized users can perform to those functions that are appropriate for their role in the 
trial. Additional measures to prevent unauthorized external access to the database 
environment will be employed using network firewall technologies.  
 


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The DMS will exist within an appropriate database structure to support the requirements of 
the DMS and to promote data security and integrity. Electronic audit trails of changes to 
database contents will be incorporated into the design and will capture and record those 
changes automatically. In addition to the trial database where actual results will be 
maintained, a development database will be created. The development database is a 
working environment that facilitates the development, testing, troubleshooting, 
enhancement, and training for the DMS without adversely affecting the integrity of the 
collected project data. CRCU servers exist within highly secure computing environments of 
the CCEB that are the responsibility of the Penn Medicine Academic Computing Services 
group. This group focuses on providing hardware and software services, systems 
administration, business continuity, and security services to research projects within the 
CCEB and other departments in Penn Medicine.  
 
Data Security Measures: The research computing environment has a security component 
required due to HIPAA; federal, state, and research compliance regulations; and CCEB best 
practices for safeguarding research data. The CCEB secures its logical network using 
virtual private network (VPN) protocols and network address translation (NAT) protocols 
layered on top of the single logical virtual local area network (VLAN). The VPN protocols 
provide encrypted “data in motion” protections and “fire-walled” connections between each 
of the physical network segments of the logical network. Applying VPN/VLAN encrypted 
connections allow all internal CCEB data to “tunnel through” and traverse the University’s 
thus ensuring the privacy of the CCEB data and the availability of the data to only CCEB 
managed resources and users.  
 
In addition to the VLAN and VPN technologies, the CCEB network utilizes the NAT 
protocols to provide private network addressing within the logical CCEB network. This 
additional precaution ensures that all network protocols running into or out of the logical 
CCEB network are essentially “proxy” connections that are only passed through one of 
several CCEB firewall devices. Providing a proxy service allows the CCEB to monitor, log 


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and control all data and network protocols coming into and going out of its logical network.  
The physical building environment for supporting the computing environments required by 
the CRCU is co-located within a formal data center facility that is managed by University 
of Pennsylvania; Penn Medicine and Information Systems and Computing personnel. The 
data center also has uninterrupted power supply (UPS)/diesel subsystems to ensure that 
adequate and constant electrical power requirements are met at all times, even during 
prolonged power outages. The data center has secured and limited physical access and is 
constructed with walls and doors to prevent break-through efforts and/or illegal entry.  
 
Data entry. The CRCU will configure the Oracle Clinical® remote data capture (RDC) 
module to allow remote data entry from the participating trial sites. The RDC module will 
be available to any computer with a persistent internet connection and will be run using 
standard web browser software. The data entry screens will look like the data collection 
forms as closely as possible to allow visual referencing during data entry, enhancing 
accuracy and efficiency. Data entry checks will be included in the entry screen designs 
where appropriate to limit the opportunity for erroneous entries due to mistyping. Such data 
entry checks would include value range comparisons, valid data type checks, required value 
checks, and skip pattern enforcement. This data entry module will be configured for single 
data entry. 
 
Data Quality Module: The CRCU will configure a module to assess data entered in to the 
database in relation to a set of rules that describe expectations for those data items. This set 
of data validation rules will be defined by CRCU clinical data management personnel and 
the study PI and Biostatistician to identify data items that may have been collected 
incorrectly or entered into the database inaccurately. The module will run automatically to 
inspect all newly entered or modified data. Clinical site personnel will review the results of 
the data validation and take any required corrective action for invalid data. Queries will be 
recorded and tracked in the data quality module. Corrections identified for individual data 


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items will be managed by the clinical sites. All changes made will be recorded in an 
electronic audit trail and documented using change control procedures.  
 
The DCC and CCC teams will establish specific training and certification procedures to 
ensure that all study personnel are well trained in the performance of study procedures, data 
collection and data entry processes. 
A Manual of Procedures (MOP) will provide detailed instruction for the performance of 
screening, enrollment, treatment, and follow-up procedures. The MOP will provide 
instruction in data collection, case report form completion, and use of the electronic data 
management system. 
  
Reports Module: The CRCU will develop a set of standard reports to clearly illustrate the 
results of trial recruitment efforts and study events, and to document any safety concerns 
that have occurred during the study. Additional reports may be developed where regular 
feedback is desirable. Such additional reports may include data entry timeliness and data 
quality assessments. 
 
10.5 Medical record review/verification  
Clinical Site RCs will complete a detailed chart abstraction to include all original clinic 
notes, telephone notes, safety and efficacy labs/evaluations collected during standard of 
care treatment and in the post treatment observation period. Data required by the protocol 
will be entered into the online Data Management System. Hard copy forms will be stored in 
secure locked cabinets within offices controlled by study personnel and locked when not in 
use.  
As needed, clinical site staff will provide medical record/source documents with identifying 
information redacted to the CCC to confirm eligibility of all screened patients, as soon as 
possible after the screening process. The CCC will assess the accuracy of eligibility 
determination and provide feedback to the clinical site staff. The CCC may determine that 


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additional documentation and/or training may be may be required, as determined by the 
results of the chart review. Sites will redact all personal identifying information prior to 
sending. All documentation from medical charts will be permanently disposed of by 
shredding. Eligibility will be confirmed again by the site PI immediately before transplant. 
The CCC may request the corresponding medical records of treated patients in order to 
further verify data accuracy.  
 
10.6 HIPAA Privacy Rule for Elements of PHI and Uploaded Records  
Established in 1996, the U.S. Department of Health and Human services issued the 
Privacy Rule as part of the Health Insurance Portability and Accountability Act to 
establish a national set of standards for the protection of certain health information.  This 
rule protects all “individually identifiable health information” held or transmitted by a 
covered entity or its business associate in any form or media whether electronic, paper, or 
oral.  A list of 18 Identifiers was established: 
1. Names 
2. All geographical subdivisions smaller than a State, including street address, city, 
county, precinct, zip code, and their equivalent geocodes, except for the initial 
three digits of a zip code, if according to the current publicly available data from 
the Bureau of the Census: (1) The geographic unit formed by combining all zip 
codes with the same three initial digits contains more than 20,000 people; and (2) 
The initial three digits of a zip code for all such geographic units containing 
20,000 or fewer people is changed to 000. 
3. All elements of dates (except year) for dates directly related to an individual, 
including birth date, admission date, discharge date, date of death; and all ages 
over 89 and all elements of dates (including year) indicative of such age, except 
that such ages and elements may be aggregated into a single category of age 90 or 
older 
4. Phone numbers 
5. Fax numbers 


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6. Electronic mail addresses 
7. Social Security numbers 
8. Medical record numbers 
9. Health plan beneficiary numbers 
10.  Account numbers 
11.  Certificate/license numbers 
12.  Vehicle identifiers and serial numbers, including license plate numbers 
13.  Device identifiers and serial numbers 
14.  Web Universal Resource Locators (URLs) 
15.  Internet Protocol (IP) address numbers 
16.  Biometric identifiers, including finger and voice prints 
17.  Full face photographic images and any comparable images 
18. Any other unique identifying number, characteristic, or code (note this does not 
mean the unique code assigned by the investigator to code the data) 
 
Records submitted for Centralized Abstraction and through RED-I are redacted for these 
PHI identifiers except for dates of service/activities. In instances where a PHI identifier 
other than a date of service is present on a redacted record delegated CCC personnel will 
redact that information. 
 
11.0 Monitoring 
The study monitor – to be selected by MGH leadership - will review data centrally 
(remote monitoring) to identify potential issues to determine a schedule of on-site visits 
for targeted review of study records.  
 
The study monitor must be allowed to visit all study site locations periodically to assess 
the data quality and study integrity. On-site they will review study records, the 
Investigator Site File, and study medication; discuss the conduct of the study with the 
investigator; and verify that the facilities remain acceptable. 


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The investigator must notify the sponsor promptly of any inspections scheduled by 
regulatory authorities, and promptly forward copies of inspection reports to the sponsor. 
 
12.0 Records Retention 
The investigator must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, or for 
the period specified by the sponsor, whichever is longer. The investigator must contact 
the sponsor prior to destroying any records associated with the study.  The sponsor will 
notify the investigator when the study records are no longer needed. 
 
If the investigator withdraws from the study (e.g., relocation, retirement), the records 
shall be transferred to a mutually agreed upon designee (e.g., another investigator, IRB). 
Notice of such transfer will be given in writing to the sponsor. 
 
13.0  Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of 
study drug (inventoried and dispensed) is maintained at the study site to include 
investigational product. Records or logs must comply with applicable regulations and 
guidelines and should include: 
• amount received and placed in storage area 
• amount currently in storage area 
• label identification number or batch number 
• amount dispensed to and returned by each subject, including unique subject 
identifiers 
• amount transferred to another area/site for dispensing or storage 
• nonstudy disposition (eg, lost, wasted) 
• amount destroyed at study site, if applicable 


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• amount returned to AbbVie, if applicable 
• dates and initials of person responsible for Investigational Product dispensing/ 
accountability, as per the Delegation of Authority Form. 
 
The sponsor will provide forms to facilitate inventory control if the investigational site 
does not have an established system that meets these requirements. 
 
14.0 Data Quality Assurance 
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates. Any necessary corrections will be made to the electronic CRF. 
 
15.0 Data Safety Monitoring Committee 
An independent DSMB will be constituted by the sponsor. The DSMB will be comprised of 
3 members who have current experience in the management of kidney- and/or liver 
transplant patients, clinical trials, GCP, HCV treatment with direct acting antivirals, and 
preferably have prior DSMC experience (not required).  After the 5th kidney transplant 
from an HCV RNA-positive donor, the DSMC will have at least one interim meeting 
during which efficacy and safety, including adverse events data as well as data related to 
response of HCV infection to therapy, will be reviewed. The DSMC will continue monitor 
ongoing efficacy and safety data during the study until the time of its conclusion. The 
DSMC charter will outline DSMC constitution, scope, operation, and function per relevant 
FDA Guidance Documents.  
 
16.0 Completion of the Study 
The investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the investigator and sponsor. 
Continuation of this study beyond this date must be mutually agreed upon in writing by both 
the investigator and sponsor. The investigator will provide a final report to the IEC/IRB 


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following conclusion of the study, and will forward a copy of this report to AbbVie or their 
representative. 
 
The investigator must retain any records related to the study according to local 
requirements. If the investigator is not able to retain the records, he/she must notify the 
sponsor to arrange alternative archiving options. 
 
The end-of-study is defined as the date of the last subject’s last visit.  
 
 
 


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17.0 Investigator's Agreement 
1. I have received and reviewed the MAVYRET USPI. 
2. I have read this protocol and agree that the study is ethical. 
3. I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines. 
4. I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol. 
5. I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding. 
 
Protocol Title: 
A Multi-Center, Open-Label Study of Glecaprevir/Pibrentasvir to 
Treat Recipients of Transplanted Kidneys from Deceased Donors with Hepatitis C Virus 
 
Protocol Date: 
February 13, 2019 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
Name of Principal Investigator (printed or typed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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18.0 Reference List 
References 
 
1. Centers for Disease Control and Prevention. Viral Hepatitis 
Statistics and Surveillance. URL: https://www.cdc.gov/hepatitis/statistics/index.htm. Accessed 
September 26 2017. 
2. World Health Organization Global Hepatitis Report 2017: Executive Summary URL: 
http://appswhoint/iris/bitstream/10665/255017/1/WHO-HIV-201706-engpdf?ua=1 Accessed 
September 26, 2017. 
3. Cardoso A-C, Moucari R, Figueiredo-Mendes C, et al. Impact of peginterferon and ribavirin 
therapy on hepatocellular carcinoma: incidence and survival in hepatitis C patients with 
advanced fibrosis. Journal of Hepatology 2010;52:652-7. 
4. Backus LI, Boothroyd DB, Phillips BR, Belperio P, Halloran J, Mole LA. A sustained virologic 
response reduces risk of all-cause mortality in patients with hepatitis C. Clinical 
Gastroenterology and Hepatology 2011;9:509-16. e1. 
5. Pawlotsky JM. New hepatitis C therapies: the toolbox, strategies, and challenges. 
Gastroenterology 2014;146:1176-92. 
6. Organ Procurement and Transplant Network. National Data on Kidney Transplant US Waiting 
List. Accessed September 18, 2017. Available at:  https://optn.transplant.hrsa.gov/data/view-
data-reports/national-data/#. . 
7. Veatch RM, Ross LF. Transplantation Ethics. 2nd ed. Washington, D.C.: Georgetown University 
Press; 2015. 
8. Bloom RD, Sayer G, Fa K, Constantinescu S, Abt P, Reddy KR. Outcome of hepatitis C virus‐
infected kidney transplant candidates who remain on the waiting list. American journal of 
transplantation 2005;5:139-44. 
9. Goldberg DS, Blumberg E, McCauley M, Abt P, Levine M. Improving Organ Utilization to Help 
Overcome the Tragedies of the Opioid Epidemic. Am J Transplant 2016;16:2836-41. 
10. Mavyret US Package Insert, AbbVie Inc., 2017. URL: 
http://www.rxabbvie.com/pdf/mavyret_pi.pdf. Accessed October 11 2017 
11. Gane EJ, Lawitz E, Pugatch D, et al. Glecaprevir and Pibrentasvir in patients with HCV and 
severe renal impairment.  NEJM 2017; 377:1448-55. 
12. Hall IE, Reese PP, Doshi MD, et al. Delayed Graft Function Phenotypes and 12-Month Kidney 
Transplant Outcomes. Transplantation 2017;101:1913-23. 
13. Davis MI, Chute DF, Chung RT, Sise ME. When and how can nephrologists treat hepatitis C 
virus infection in dialysis patients? Semin Dial 2 2018 31(1):26-36. 
14. Reau N, Kwo P, Rhee S, et al. LBO-03-MAGELLAN-2: safety and efficacy of rentasvir in liver or 
renal transplant adults with chronic hepatitis C genotype 1–6 infection. Journal of Hepatology 
2017;66:S90-S1. 
15. Goldberg DS, Abt PL, Blumberg EA, et al. Trial of Transplantation of HCV-Infected Kidneys into 
Uninfected Recipients. N Engl J Med 2017;376:2394-5. 
16. Levitsky J, Formica RN, Bloom RD, et al. The American Society of Transplantation Consensus 
Conference on the Use of Hepatitis C Viremic Donors in Solid Organ Transplantation. Am J 
Transplant 2017;17:2790-802. 


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17. Zeuzem S, Foster GR, Asatryan A, Gane E, Feld JJ et al. Glecaprevir-Pibrentasvir for 8 and 12 
weeks in HCV genotype 1 or 3 infection. New England Journal of Medicine 2018: 378: 354-69.A  
18. Asselah T, Kowdley CV, Zadeikis N, Wang S, etal. Effiacy of glecaprevir/pibrentasvir for 8 or 12 
weeks in patients with hepatitis C virus genotype 2,4,5 or 6 infection without cirrhosis. Clin 
Gatroenterol H epatol. 2018 in press.   DOI: https://doi.org/10.1016/j.cgh.2017.09.027  
19. Wolfe RA, Ashby VB, Milford EL, et al. Comparison of mortality in all patients on dialysis, 
patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N 
Engl J Med 1999;341:1725-30. 
20. Merion RM, Ashby VB, Wolfe RA, et al. Deceased-donor characteristics and the survival benefit 
of kidney transplantation. JAMA 2005;294:2726-33. 
21. Reese PP, Shults J, Bloom RD, et al. Functional status, time to transplantation, and survival 
benefit of kidney transplantation among wait-listed candidates. Am J Kidney Dis 2015;66:837-
45. 
22. Reese PP, Abt PL, Blumberg EA, Goldberg DS. Transplanting Hepatitis C-Positive Kidneys. N 
Engl J Med 2015;373:303-5. 
23. Durand C, Brown D, Wesson R, et al. EXPANDER-1: Exploring Renal Transplants Using Hepatitis-
C Infected Donors for HCV-Negative Recipients. American Journal of Transplantation 2017;17 
(suppl 3). 
24.  Cacoub P, Comarmond C, DomontF, et al Extrahepatic manifesations of chronic hepatitis C 
virus infection. Ther Adv Infect Dis. 2016 3:(1) 3-14. 
25.  Sherman AC and Sherman KE. Extrahepatic manifestations of hepatitis C infection: navigating 
CHASM. Curr HIV/AIDS Rep. 2015 12(3): 353-361. 
26.  American Association for the Study of the Liver Disease (AASLD) Clinical Practice Guidelines: 
Recommendations for Testing, Managing, and Treating Hepatitis C. Available at: 
http://www.hcvguidelines.org. Accessed August 15, 2017. 
 


134 
 
 
Appendix A: Educational material to be distributed at MYTHIC trial 
education session 
What is hepatitis C infection?  
Hepatitis C is a virus that circulates in the blood, attacks liver cells, changes the way that 
the liver functions and causes inflammation of the liver.  
 
How can a person get hepatitis C infection?  
Hepatitis C virus is passed by blood to blood contact with another person who has Hepatitis 
C virus infection. The most common way that it is passed from one person to the next is by 
intravenous drug use and sharing needles.  Some people may get Hepatitis C virus infection 
by sexual contact.  After the virus is passed, it moves through the bloodstream and 
replicates and lives in blood and the liver.  
 
What happens when you get hepatitis C? 
Once you are infected with hepatitis C, the virus begins to grow.  Some people’s immune 
system can fight off Hepatitis C virus, but for most people the virus remains active in their 
body.  Liver cells are the most commonly affected cells. With the virus present, liver cells 
become injured and inflamed. Once Hepatitis C virus has lived in your body for many years 
(usually more than 20 years), the liver may not be able to function and Hepatitis C virus can 
cause cirrhosis of the liver, which can lead to liver failure and liver cancer. Cirrhosis can 
cause yellowing of the skin, fluid retention, confusion, gastrointestinal bleeding, and may 
lead to the need for a liver transplant or death. 
 
 
Are there any other effects of Hepatitis C on other parts of the body? 
Rarely, hepatitis C can cause inflammation in other parts of the body, including the joints 
(arthritis), skin (rashes), nerves (numbness or nerve pain), or kidney (kidney failure).   
 
Could you get hepatitis C from being in this study? 
Yes, if the donor you receive has virus circulating in their blood then when the kidney is 
transplanted to you, you would likely catch their hepatitis C virus if you didn’t take any 
treatment. We believe that starting medication right away at the time of transplant will kill 
the virus and that by the time the treatment is done there is only a small chance that you 
would still have Hepatitis C virus circulating in your body. The study medications are being 
used are more than 95% effective at curing Hepatitis C.  
 
What is a Hepatitis C antibody test?  What is a Hepatitis C viral load test? 


135 
 
 
A Hepatitis C antibody test detects if you have ever been exposed to the virus.  Even if you 
had the virus but your body or a medicine cured it, your antibody test will stay positive in 
your blood for the rest of your life. The Hepatitis C viral load test will measure if the virus 
is still circulating in your blood. If your viral load test is positive then you have an active 
Hepatitis C infection.  If your viral load test is negative then you do not have a Hepatitis C 
infection.  
 
Why would a donor have a positive Hepatitis C antibody test but a negative viral 
load?   Can I still catch Hepatitis C from this donor? 
A donor with a positive Hepatitis C antibody but negative virus 1) may be false positive 
antibody test, or 2) may have had the infection in the past but cleared by either their 
immune system or by taking Hepatitis C treatment or 3) may have a false negative viral 
load test.  You are unlikely to catch Hepatitis C from this donor, even without treatment, 
but there is still a small chance, so we will carefully test you for Hepatitis C virus at regular 
intervals. You will be tested 1 week, 4 weeks, 24 weeks and 1 year after the kidney 
transplant from a Hep C antibody positive but HCV RNA negative donor. If you were 
going to get Hepatitis C from such transplant, we expect it would happen right away.   If 
you are clear 24 weeks after your transplant then there is almost no chance the virus will 
spread to you from the transplant.   
 
Are there any treatments for hepatitis C infection?  
Yes, there are many therapies that have been approved by the FDA as safe and effective for 
treating chronic hepatitis C. Newer medications are curing more than 95 out of 100 people 
who get treatments. Even patients who fail their first round of Hepatitis C treatment can be 
treated with an alternative treatment and be cured.  
 
Can people with hepatitis C donate a kidney? 
Yes, but right now a person with hepatitis C can only donate to another person who already 
has hepatitis C infection.  Right now patients who are on dialysis and have hepatitis C 
usually have a much shorter wait time because they can accept these donors. 
 
How do you know that a kidney donor has hepatitis C infection? 
Any potential deceased kidney transplant donor goes through many blood tests to determine 
if they have infections that may be spread.  The hospital tests the blood of the donor for 
Hepatitis C virus. 
 
Why are there many donors with Hepatitis C infection? 


136 
 
 
One of the major causes of Hepatitis C virus is sharing needles during intravenous drug use.  
There are many people now taking opioid medications and using injection drugs. There has 
been a large increase in the number of people who die from opioid overdose and have 
hepatitis C. This is part of the reason why there are so many kidneys available with 
Hepatitis C.  
 
What are the different types of hepatitis C? 
There are six common types of Hepatitis C. These variations are categorized into groups 
known as genotypes. There are a total of 6 common genotypes seen throughout the world. 
Genotype 1 is the most common in the United States. Approximately 75% of Americans 
infected with hepatitis C have a genotype 1 viral infection. 
 
Does glecaprevir/pibrentasvir (G/P) treat all types of Hepatitis C? 
The study medication, glecaprevir and pibrentasvir (G/P), is approved to treat all 6 common 
genotypes of hepatitis C. The use of G/P in patients receiving organs from donors with 
HCV infection is investigational.   
 
When would the G/P treatment begin? 
If you receive a transplant from a donor with HCV infection, then you will take your first 
dose of G/P within the first week of transplant. Your doctors and study team will decide 
when you are ready to start G/P given as oral tablets. 
 
If you receive a transplant from a donor with a positive HCV antibody but a negative viral 
load then you will be monitored after transplant and you will only start G/P if your 
Hepatitis C viral load test becomes positive within 24 weeks after the transplant. 
 
How long will I take G/P? 
You will take 3 G/P tablets at one time with food daily for 8 weeks 
 
What are the side effects of G/P? 
The most common side effects were fatigue, headache and nausea (occurring in 
approximately 1 in 10 patients). Less than 1 in 100 patients had side effects so severe that 
had to stop treatment due to a side effect. 
 
What happens if G/P doesn’t work and the Hepatitis C comes back? 
If, after taking G/P for 8 weeks the Hepatitis C virus is detected in your blood you will have 
the option to be given an additional course of Hep C treatment at no cost to you.  The study 
investigators will choose which kind of therapy is best for you at the time.  


137 
 
 
 
 
 
How long will I be a part of this study? 
You will start the screening process soon after you sign the consent form.  You will meet 
with the transplant team and we will ensure you are healthy enough for a kidney transplant, 
once you pass these tests you will be accepted into the study. We estimate that you will 
receive a kidney transplant within 6 months after enrolling into the study.  Once you 
received the transplant, we will follow you for one year. We estimate your total time in the 
study will be 1.5 years.  
 
When will my study visits take place? 
You will schedule your screening visits with our study team at your convenience and meet 
in the transplant clinic. Your visits after the transplant will take place after your regularly 
scheduled medical visits to the transplant clinic. 
 
Will participating in this study effect my transplant medications or my transplant 
care? 
Your transplant doctor will know that you are participating in this study, but your care after 
the transplant should not be affected by being a part of this study. You will get the same 
transplant immunosuppression drugs that are most commonly used at our transplant 
program.  
 
Does being a part of this study affect my standing on the kidney transplant list?  If I 
decide not to participate does this affect my standing on the kidney transplant list? 
You will still be eligible to receive a kidney transplant from a donor without Hepatitis C 
should one become available for you.  However, if you decide to participate in this study it 
is more likely that you will be called about a transplant from a Hepatitis C donor first.   If 
you decide not to participate, this will not affect your standing on the regular transplant list. 
 
Has anyone like me who does not have Hepatitis C ever received a kidney transplant 
from a patient with Hepatitis C before? 
Yes, patients have previously received kidney transplants from patients with hepatitis C and 
the virus was transmitted from the donor to the recipient.  Recently, 20 patients at the 
University of Pennsylvania (as well as 10 patients at Johns Hopkins and other patients at 
Massachusetts General Hospital) had a kidney transplant from donors with Hepatitis C and 
they all developed the Hepatitis C virus in their system within 3 days. They were treated 


138 
 
 
with a different combination of Hep C medicines for 12 weeks and all were cured of 
Hepatitis C virus.  
 
 
 
 
What are the risks to being in this study? 
 
Risks include contracting Hepatitis C from the donor kidney. You may experience liver 
disease right after the transplant or years later if you have Hepatitis C, however we would 
not expect you to have liver disease from Hepatitis C as long as the G/P treatment works to 
cure Hepatitis C.  The study procedures including blood draw may lead to bruising. 
Although G/P is generally well tolerated, it is possible you experience a more severe side 
effect. There is also a possibility of detecting a new health problem during screening for 
this study that you may need to address. Participating in a study may lead to psychological 
stress. Risks will be reviewed again in the informed consent session.  
 
What are the benefits to being in this study? 
Participation in this study may allow you to receive a good quality kidney and shorten your 
wait time on the kidney transplant list. If you are willing to accept a kidney from a donor 
who has hepatitis C virus infection we expect you will wait 6 months.  This is much shorter 
than you would otherwise be expected to have to wait. 
 
 


139 
 
 
Appendix B: Responsibilities of the Clinical Investigator 
Clinical research studies sponsored by MGH are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location. In 
signing the Investigator Agreement in Section 17.0 of this protocol, the investigator is 
agreeing to the following: 
 
Conducting the study in accordance with the relevant, current protocol, making changes in a 
protocol only after notifying the sponsor, except when necessary to protect the safety, rights 
or welfare of subjects. 
Personally conducting or supervising the described investigation(s). 
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent 
and ethics committees (e.g., independent ethics committee [IEC] or institutional review 
board [IRB]) review and approval of the protocol and amendments. 
Reporting adverse experiences that occur in the course of the investigation(s) to the sponsor 
and the site director. 
Reading the information in the Mavyret US package insert/safety material provided, including 
the instructions for use and the potential risks and side effects of the study drug(s) 
Informing all associates, colleagues, and employees assisting in the conduct of the study 
about their obligations in meeting the above commitments. 
Maintaining adequate and accurate records of the conduct of the study, making those 
records available for inspection by representatives of the sponsor and/or the appropriate 
regulatory agency, and retaining all study-related documents until notification from the 
sponsor. 
Maintaining records demonstrating that an ethics committee reviewed and approved the 
initial clinical investigation and all amendments. 
Reporting promptly, all changes in the research activity and all unanticipated problems 
involving risks to human subjects or others, to the appropriate individuals (e.g., coordinating 
investigator, institution director) and/or directly to the ethics committees and the sponsor. 


140 
 
 
Following the protocol and not make any changes in the research without ethics committee 
approval, except where necessary to eliminate apparent immediate hazards to human 
subjects. 
 
 


141 
 
 
Appendix C: Medicare National Coverage Decision for Clinical Trials 
This national coverage policy is based upon the authority found in §1862(a)(1)(E) of the 
Social Security Act (Act). It is binding on all Medicare carriers, fiscal intermediaries, Peer 
Review Organizations, Health Maintenance Organizations, Competitive Medical Plans, 
Health Care Prepayment Plans, and Medicare+Choice organizations (§1852(a)(1)(A) of the 
Act). In addition, an administrative law judge may not disregard, set aside, or otherwise 
review a national coverage decision issued under §1862(a)(1) of the Act. 42 C.F.R. 
§405.860. 
 
Clinical Trials 
Effective for items and services furnished on or after September 19, 2000, Medicare covers 
the routine costs of qualifying clinical trials, as such costs are defined below, as well as 
reasonable and necessary items and services used to diagnose and treat complications 
arising from participation in all clinical trials. All other Medicare rules apply. 
 
Routine costs of a clinical trial include all items and services that are otherwise generally 
available to Medicare beneficiaries (i.e., there exists a benefit category, it is not statutorily 
excluded, and there is not a national noncoverage decision) that are provided in either the 
experimental or the control arms of a clinical trial except: 
• 
the investigational item or service, itself, 
• 
items and services provided solely to satisfy data collection and analysis needs and 
that are not used in the direct clinical management of the patient (e.g., monthly CT scans 
for a condition usually requiring only a single scan); and 
• 
items and services customarily provided by the research sponsors free of charge for 
any enrollee in the trial. 
 
Routine costs in clinical trials include: 
• 
Items or services that are typically provided absent a clinical trial (e.g., conventional 
care); 


142 
 
 
• 
Items or services required solely for the provision of the investigational item or 
service (e.g., administration of a noncovered chemotherapeutic agent), the clinically 
appropriate monitoring of the effects of the item or service, or the prevention of 
complications; and 
• 
Items or services needed for reasonable and necessary care arising from the 
provision of an investigational item or service--in particular, for the diagnosis or treatment 
of complications. 
  
This policy does not withdraw Medicare coverage for items and services that may be 
covered according to local medical review policies or the regulations on category B 
investigational device exemptions (IDE) found in 42 C.F.R. §405.201-405.215 and §411.15 
and §411.406. For information about LMRPs, refer to www.lmrp.net, a searchable database 
of Medicare contractors' local policies. 
 
For noncovered items and services, including items and services for which Medicare 
payment is statutorily prohibited, Medicare only covers the treatment of complications 
arising from the delivery of the noncovered item or service and unrelated reasonable and 
necessary care. (Refer to MCM 2300.1 and MIM 3101.) However, if the item or service is 
not covered by virtue of a national noncoverage policy in the Coverage Issues Manual and 
is the focus of a qualifying clinical trial, the routine costs of the clinical trial (as defined 
above) will be covered by Medicare but the noncovered item or service, itself, will not. 
 
Requirements for Medicare Coverage of Routine Costs 
Any clinical trial receiving Medicare coverage of routine costs must meet the following 
three requirements: 
1. 
The subject or purpose of the trial must be the evaluation of an item or service that 
falls within a Medicare benefit category (e.g., physicians' service, durable medical 
equipment, diagnostic test) and is not statutorily excluded from coverage (e.g., cosmetic 
surgery, hearing aids). 


143 
 
 
2. 
The trial must not be designed exclusively to test toxicity or disease 
pathophysiology. It must have therapeutic intent. 
3. 
Trials of therapeutic interventions must enroll patients with diagnosed disease rather 
than healthy volunteers. Trials of diagnostic interventions may enroll healthy patients in 
order to have a proper control group. 
 
The three requirements above are insufficient by themselves to qualify a clinical trial for 
Medicare coverage of routine costs. Clinical trials also should have the following desirable 
characteristics; however, some trials, as described below, are presumed to meet these 
characteristics and are automatically qualified to receive Medicare coverage: 
 
1. 
The principal purpose of the trial is to test whether the intervention potentially 
improves the participants' health outcomes; 
2. 
The trial is well-supported by available scientific and medical information or it is 
intended to clarify or establish the health outcomes of interventions already in common 
clinical use; 
3. 
The trial does not unjustifiably duplicate existing studies; 
4. 
The trial design is appropriate to answer the research question being asked in the 
trial; 
5. 
The trial is sponsored by a credible organization or individual capable of executing 
the proposed trial successfully;  
6. 
The trial is in compliance with Federal regulations relating to the protection of 
human subjects; and 
7. 
All aspects of the trial are conducted according to the appropriate standards of 
scientific integrity. 
 
Qualification Process for Clinical Trials 
Using the authority found in §1142 of the Act (cross-referenced in §1862(a)(1)(E) of the 
Act), the Agency for Healthcare Research and Quality (AHRQ) will convene a multi- 


144 
 
 
agency Federal panel (the "panel") composed of representatives of the Department of 
Health and Human Services research agencies (National Institutes of Health (NIH), Centers 
for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), 
AHRQ, and the Office of Human Research Protection), and the research arms of the 
Department of Defense (DOD) and the Department of Veterans Affairs (VA) to develop 
qualifying criteria that will indicate a strong probability that a trial exhibits the desirable 
characteristics listed above. These criteria will be easily verifiable, and where possible, 
dichotomous. Trials that meet these qualifying criteria will receive Medicare coverage of 
their associated routine costs. This panel is not reviewing or approving individual trials. 
The multi-agency panel will meet periodically to review and evaluate the program and 
recommend any necessary refinements to CMS. 
 
Clinical trials that meet the qualifying criteria will receive Medicare coverage of routine 
costs after the trial's lead principal investigator certifies that the trial meets the criteria. This 
process will require the principal investigator to enroll the trial in a Medicare clinical trials 
registry, currently under development. 
 
Some clinical trials are automatically qualified to receive Medicare coverage of their 
routine costs because they have been deemed by AHRQ, in consultation with the other 
agencies represented on the multi-agency panel to be highly likely to have the above- listed 
seven desirable characteristics of clinical trials. The principal investigators of these 
automatically qualified trials do not need to certify that the trials meet the qualifying 
criteria, but must enroll the trials in the Medicare clinical trials registry for administrative 
purposes, once the registry is established. 
 
Effective September 19, 2000, clinical trials that are deemed to be automatically qualified 
are: 
 
1. 
Trials funded by NIH, CDC, AHRQ, CMS, DOD, and VA; 


145 
 
 
2. 
Trials supported by centers or cooperative groups that are funded by the NIH, CDC, 
AHRQ, CMS, DOD and VA; 
3. 
Trials conducted under an investigational new drug application (IND) reviewed by 
the FDA; and 
4. 
Drug trials that are exempt from having an IND under 21 CFR 312.2(b)(1) will be 
deemed automatically qualified until the qualifying criteria are developed and the 
certification process is in place. At that time the principal investigators of these trials must 
certify that the trials meet the qualifying criteria in order to maintain Medicare coverage of 
routine costs. This certification process will only affect the future status of the trial and will 
not be used to retroactively change the earlier deemed status. 
 
Medicare will cover the routine costs of qualifying trials that either have been deemed to be 
automatically qualified or have certified that they meet the qualifying criteria unless CMS's 
Chief Clinical Officer subsequently finds that a clinical trial does not meet the qualifying 
criteria or jeopardizes the safety or welfare of Medicare beneficiaries. 
 
Should CMS find that a trial's principal investigator misrepresented that the trial met the 
necessary qualifying criteria in order to gain Medicare coverage of routine costs, Medicare 
coverage of the routine costs would be denied under §1862(a)(1)(E) of the Act. In the case 
of such a denial, the Medicare beneficiaries enrolled in the trial would not be held liable 
(i.e., would be held harmless from collection) for the costs consistent with the provisions of 
§1879, §1842(l), or §1834(j)(4) of the Act, as applicable. Where appropriate, the billing 
providers would be held liable for the costs and fraud investigations of the billing providers 
and the trial's principal investigator may be pursued. 
 
Medicare regulations require Medicare+Choice (M+C) organizations to follow CMS's 
national coverage decisions. This NCD raises special issues that require some modification 
of most M+C organizations' rules governing provision of items and services in and out of 
network. The items and services covered under this NCD are inextricably linked to the 


146 
 
 
clinical trials with which they are associated and cannot be covered outside of the context 
of those clinical trials. M+C organizations therefore must cover these services regardless of 
whether they are available through in-network providers. M+C organizations may have 
reporting requirements when enrollees participate in clinical trials, in order to track and 
coordinate their members' care, but cannot require prior authorization or approval. For the 
initial implementation, Medicare contractors will pay providers directly on a fee for service 
basis for covered clinical trial services for beneficiaries enrolled in M+C plans. 
 
 


147 
 
 
Appendix D: Methods of Contraceptives 
D1 Contraception requirement for all subjects who will not receive mycophenolate 
mofetil following transplantation.  
The below listed methods meet the requirements for contraception as per the CTFG 
guidance.18 
 
If female, subject must be either postmenopausal defined as: 
● Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause. 
● Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 IU/L. 
OR 
● Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 
OR for Women of Childbearing Potential who do not receive mycophenolate mofetil 
immunosuppressant after kidney transplantation 
 
 ● Agreeing to practice one effective method of birth control while receiving G/P (as 
outlined in the subject information and consent form or other subject information 
documents), starting with Day of transplant and for  at least 30 days after stopping G/P.  
○ Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 1 month prior to 
Study Day 1. 
○ Bilateral tubal occlusion/ligation. 
○ Vasectomized partner(s), provided the vasectomized partner has received 
medical assessment of the surgical success and is the sole sexual partner of 
the WOCBP trial participant. 
○ Non-ethinyl estradiol hormone-releasing Intrauterine device (IUD) 
○ Non-ethinyl estradiol hormone-releasing Intrauterine hormone-releasing system 
(IUS) 
o Male or female condom with spermicide (male and female condom must 
not be used together) 
o Diaphragm with spermicide 
o Cervical cap with spermicide 
o Contraceptive sponge with spermicide 


148 
 
 
○ True abstinence:  
 
 
Refraining from heterosexual intercourse when this is in 
 
line with the preferred and usual lifestyle of the subject (periodic abstinence, 
 
e.g., calendar, ovulation, symptothermal, post-ovulation methods, “rhythm  
    method,” or pre-ejaculation withdrawal,are not acceptable forms of 
 
contraception). 
o Sexually active with female partners only 
 
Male Subjects 
Subject must be surgically sterile (vasectomy with medical assessment confirming 
surgical success)  
      OR   
Have a female partner who is postmenopausal or permanently sterile 
                  (bilateral oophorectomy, bilateral salpingectomy or hysterectomy) 
      OR  
if sexually active with female partner(s) of CBP must agree to practice one effective 
method of birth control while receiving G/P (as outlined in the subject information and 
consent form or other subject information documents), starting with Day 1 and for 30 days 
after stopping G/P. 
• 
Any approved and commercially available hormonal contraception for 
female partners  
• Any approved and commercially available, including any hormone-
eluting, devices for female partners of male subjects 
• Male or female condom with spermicide (male and female condom must 
not be used together) 
• Female partner using a diaphragm with spermicide 
• Female partner using a cervical cap with spermicide 
• 
Female partner using a contraceptive sponge with spermicide 
• True abstinence: Refraining from heterosexual intercourse-when this is 
in line with the preferred and usual lifestyle of the subject. (Note: 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods, “rhythm method”, or pre-ejaculation withdrawal are 
not acceptable forms of contraception). 
• 
Sexually active with male partners only 
 
 


149 
 
 
D2 Contraception requirements for all subjects who will receive mycophenolate 
mofetil post kidney transplant  
 
All Women of child bearing potential subjects or male subjects with child bearing potential 
women partners   who receive mycophenolate mofetil following kidney transplantation 
are required to utilize highly effective methods of birth control as per transplant center 
standard of care and consistent with the transplant center mycophenolate mofetil Risk 
Evaluation and Mitigation Strategy (REMS).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


150 
 
 
Appendix E: Extrahepatic Manifestations of HCV infection 
Infection with hepatitis C virus (HCV) can lead to both acute and chronic hepatitis. The 
hepatitis C virus mainly affects the liver, but there are many other conditions that are 
associated with hepatitis C. Extrahepatic manifestation of HCV infection denotes diseases 
or conditions that affect organs other than the liver. Extrahepatic manifestations of hepatitis 
C infection can be found in the skin, eyes, joints, immune system, nervous system and 
kidneys.24,25 Some of the extrahepatic manifestations of HCV infection are more common-
such as cryoglobulinemia, while others are not common. Furthermore, it is not well 
understood whether extrahepatic manifestations of HCV can already manifest during the 
phase of acute HCV infection. In this study the below listed diseases/conditions are 
recognized as extrahepatic manifestations of HCV infection and new onset/diagnosis of 
respective diseases/conditions following the transplant of an HCV-positive kidney during 
the study will be collected:  
 
-Mixed cryoglobulinemia 
-B cell non-hodgkin’s lymphoma 
-Monoclonal gammopathy 
-Sjögren syndrome/sicca symptoms 
-Polyarteritis 
-Autoimmune thyroiditis 
- Immune thrombocytopenia (ITP) 
-membranoproliferative glomerulonephritis type 1 
-Porphyria cutanea tarda 
-Lichen planus 
 

SAP_001.pdf: 
Summary of Statistical Analysis Plan for MYTHIC Study 
[Draft: April 26, 2020] 
 
Part 
 
Patient Group(s) 
Outcome 
Statistical Analysisa 
1 
Arm 1 (ITT) 
SVR12 
- estimated probability of SVR12 and 95% confidence interval (CI)  
- exact binomial calculations  
2 
Arm 1 (ITT) 
Virologic failure (VF) 
- estimated probability of SVR12 and 95% confidence interval (CI)  
- exact binomial calculations 
3 
Arm 1 (ITT) 
Post-treatment 
virologic relapse  
- estimated probability of SVR12 and 95% confidence interval (CI)  
- exact binomial calculations 
4 
All patients 
HCV-viremic kidney 
transplant (KT); i.e., 
Arm 1 KT 
- cumulative incidence and 95% CI  
- death and other KT types treated as competing risk 
- estimate non-parametrically, using Lin (1997) which proceeds through the 
cause-specific hazards, or Fan (2013) which uses Inverse Probability of Censoring 
Weighting (IPCW).  
5 
All patients 
Non-HCV-viremic KT; 
i.e., Arm 2A-2B KT 
- same as for component (4).  
6 
All, by Arm 
Hospital admissions  
- Arm treated as a time-dependent treatment 
- crude hospitalization rate per 100 patient-years (PY) and 95% CI 
- use robust variance estimator, to account for correlation among hospital 
admissions within-patient 
7 
All, by Arm 
Hospital admissions  
- Arm treated as a time-dependent treatment 
- proportional rates model (Lin et al., 2000)  
- robust SEs, to account for clustering within-patient 
 
8(a) 
All, and SRTR* 
controls  
Kidney transplant   
 
- exclude, from SRTR, all patients who indicated consent to receive an HCV-
viremic KT (hereafter: SRTR*) 
- estimate prognostic score using SRTR* patients: KT as event  
- 1:5 matching (MYTHIC : SRTR*) based on prognostic score with caliper 
- Cox regression, with MYTHIC as lone covariate, stratified by matched set  


 
8(b) 
All, and SRTR* 
controls 
Kidney transplant   
 
Same as 9(a), but using exact matching on small set of predictors, with prognostic 
score used to break ties among potential matches 
9 
Arm 1 – ITT 
Compliance 
Treated as repeated binary (0/1) data, with 1 indicating compliance (i.e., having 
taken 80-120% of prescribed pills) 
10 
Arm 1 – ITT 
Death 
Time to event; Cox regression 
11 
Arm 1 – ITT 
Graft failure 
Time to event; Cox regression 
12 
Arm 1 
Delayed graft 
function 
DGF: binary (0/1) response. 
Compute OBS/EXP, where OBS=observed number of DGFs for Arm 1 and EXP= 
expected count based on logistic regression model fitted to HCV-negative UNOS 
patients from large academic centers  
13  
Arm 1 
Acute allograft 
rejection 
AAR: Binary (0/1) response. 
Compute OBS/EXP, where OBS=observed number of AARs for Arm 1 and EXP= 
expected cunt based on logistic regression model fitted to HCV-negative UNOS 
patients from large academic centers 
14  
Arm 1 
ALT elevation 
Binary (0/1), with ‘1’ corresponding to peak ALT > 5 x ULN, where ULN=upper 
limit of ‘normal’. 
15 
All, by arm 
Serious Adverse 
Event 
SAE: recurrent event 
Arm treated as a time-dependent factor 
Proportional rates model, robust SEs to account for within-patient clustering 
16 
Arm 1, 2AB 
eGFR 
Repeated continuous response 
Linear mixed model, to account for clustering by patient  
17 
Arm 1, 2AB 
Proteinuria  
Binary response; logistic regression 
18 
Arm 1, 2AB 
BK virus 
Binary response; logistic regression 
 
Notes: 
a)  Each of the above-listed analyses will be accompanied by appropriate summary statistics (e.g., mean, median, IQR, etc).