Prophylaxis With Direct-acting Antivirals for Kidney Transplantation From HCV-Infected Donors to Uninfected Recipients

Study Overview
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Brief Summary
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This study is being done to find out the best time to start medication for Hepatitis C Virus (HCV) in HCV-negative recipients of HCV-positive (HCV D+/R-) kidney transplants. Participants will be randomized into one of two groups: Arm 1 - Prophylaxis: This group will start the HCV medication before transplant and will take a shorter course of HCV medication for 2 weeks. Arm 2 - Transmit and Treat: This group will start the HCV medication after transplant and will take the full course (12 weeks) of HCV medication.

Detailed Description
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In the past, HCV-positive (HCV+) kidneys were not given to HCV-negative recipients. But over the last few years, medications have been created that cure HCV in nearly 100% of patients. HCV+ transplants to HCV-negative recipients have become increasingly common now that HCV can be cured. There are two approaches to giving HCV medication to recipients of these transplants. The first is a prophylaxis approach. With prophylaxis, HCV medication is started before transplant and continued for a shorter course after transplant. The second is a transmit-and-treat approach. With transmit-and-treat, HCV medication is started after transplant and continued for the full, recommended course. Both approaches have successfully cured HCV in HCV-negative recipients of HCV+ organs. This research will use a study drug called sofosbuvir/velpatasvir (SOF/VEL). It contains two drugs for treating HCV in one pill. We will compare giving SOF/VEL for 2 weeks starting pre-transplant (prophylaxis) to giving SOF/VEL for 12 weeks starting no later than 14 days post-transplant (transmit-and-treat). SOF/VEL belongs to a group of medications called direct-acting antiviral agents (DAAs). These drugs prevent HCV from multiplying and spreading in the human body. SOF/VEL are already approved and used for 12 weeks to treat HCV infection. The use of SOF/VEL for 2 weeks in preventing HCV infection has not been studied. The FDA is allowing SOF/VEL to be used in this study.

Official Title
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Prophylaxis With Direct-acting Antivirals for Kidney Transplantation From Hepatitis C Virus-Infected Donors to Uninfected Recipients: a Randomized Controlled Trial

Conditions
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HCV

Intervention / Treatment
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* Other: Prophylaxis (P2W)
* Other: Transmit and Treat (T&T)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant meets the standard criteria for KT at local center. Participant is able to understand and provide informed consent. Participant is ≥ 18 years old. Exclusion Criteria: Participant has a history of HCV, defined as being HCV antibody positive. Participant has a Fibrosis-4 (FIB-4) score ≥ 1.45 at time of screening, or a history of cirrhosis or advanced liver fibrosis. Participant's aspartate aminotransferase (AST) or ALT > 2.5 times the upper limit of normal (ULN), within 60 days of screen. Participant has human immunodeficiency virus infection (HIV), or active hepatitis B (HBV) infection. Participant is unable to safely substitute or discontinue a medication that is contraindicated with the study medication. Past or current medical problems, which may pose additional risks from participation in the study, interfere with the participant's ability to comply with study, or impact the quality of the data obtained from the study. Participant is pregnant or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prophylaxis (P2W)<br>Prophylaxis is one dose of sofosbuvir/velpatasvir (SOF/VEL) pre-HCV D+/R- kidney transplant (KT), continued for 2 weeks. | Other: Prophylaxis (P2W)<br>* For participants enrolled in P2W arm, the initial dose of SOF/VEL will be administered to the recipient when called to the operating room for transplant (typically 1-3 hours prior to the start of surgery). Post-transplant, SOF/VEL will be continued daily for 13 days post-KT (a total of 14 doses administered).<br>|
| Experimental: Transmit and Treat (T&T)<br>T&T is study-supplied SOF/VEL for 12 weeks starting on post-HCV D+/R- kidney transplant day participant's insurance approves standard of care DAAs, or post-KT day 14, whichever comes first. | Other: Transmit and Treat (T&T)<br>* For participants enrolled in T&T arm, SOF/VEL will begin between post-KT day 0 and post-KT day 14. Participants will be clinically-prescribed DAAs once viremia is detected, and participant's insurance will be petitioned to obtain treatment as soon as possible. If insurance-provided DAAs are approved before post-KT day 14, participant will begin 12 weeks of study-provided SOF/VEL on date of insurance-provided DAAs approval. If insurance-provided DAAs are not approved by post-KT day 14, study-provided SOF/VEL will begin on post-KT day 14 and continue for 12 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite event of HCV-related or HCV treatment-related death, fibrosing cholestatic hepatitis, or HCV relapse | Proportion of events in each arm. | Within 26 weeks of transplant | 
| Number of participants with liver injury | Measured with a longitudinal model of Alanine aminotransferase (ALT). | The first 28 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant survival | Time to event (death) | At 6 months and 1 year post-transplant | 
| Graft survival | Time to event (graft loss) | At 6 months and 1 year post-transplant | 
| HCV plasma RNA | Based on local testing | At week 26 post-transplant | 
| Graft rejection | Cumulative incidence of rejection | At 6 months and 1 year post-transplant | 
| Prevalence of donor specific antibody (DSA) | Proportion of participants with a de novo donor-specific human leukocyte antigen (HLA) antibody as measured and reported by local sites' lab | At 4 weeks and 6 months post-transplant, and with any episode of clinically suspected or proven rejection. | 
| Graft function - eGFR <60 | Proportion of participants with glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI) < 60 mL/min/1.73 m2 | Months 3, 6, 9, and 12 post-transplant | 
| Graft function - mean eGFR | Mean calculated eGFR by CKD-EPI | Months 3, 6, 9, and 12 post-transplant | 
| Graft function - eGFR slope | The slope of eGFR by CKD-EPI, over time based on serum creatinine | Months 3, 6, 9, and 12 post-transplant | 
| Development of HCV resistance-associated variants (RAVs) | Proportion of participants with RAVs as measured and reported by local sites' lab | With any HCV viremia after P2W or T&T through end of follow up (at least 6 months, up to 3 years post-transplant) | 
| Incidence and severity of bacterial, fungal, viral, and opportunistic infections | Cumulative incidence of infections | From transplant through end of follow up (at least 6 months, up to 3 years post-transplant) | 
| Incidence of surgical and vascular complications | Number of surgical and vascular complications | During the first year post-transplant |