Transplantation Using Hepatitis C Positive Donors, A Safety Trial

Transplantation Using Hepatitis C Positive Donors to Hepatitis C Negative Recipients: A Safety Trial

The success of transplantation is significantly hindered by the lack of sufficient number of available donors. Many potential donor organs cannot be utilized in clinical transplantation because donors have chronic viral infections such as hepatitis C (HCV) infection. This study will test the possibility of safely transplanting organs from HCV-infected donors into HCV-uninfected recipients. Prior to transplantation, recipients will receive an initial dose of highly effective antiviral prophylaxis using approved direct-acting antivirals (DAAs) Glecaprevir/Pibrentasvir (G/P) and they will also receive ezetimibe, a cholesterol-lowering medication that also blocks entry of HCV into liver cells. They will then receive daily dosing of the same medications for 7 days after transplant. The aim of the study is to show that transplantation of organs from HCV+ donors is safe in the era of DAAs. The investigators hypothesize that rates of HCV transmission to recipients will be prevented by the use of DAA prophylaxis and any HCV transmission that does occur will be readily treatable and curable. If successful, the knowledge from this study can have a large impact to patients with end stage organ diseases by providing a large novel source of donors for organ transplantations.

Study Overview

• Status: Recruiting
• Conditions: Hepatitis C; Kidney Transplant Infection; Heart Transplant Infection; Lung Transplant Infection; Kidney Pancreas Infection
• Intervention / Treatment: Drug: Glecaprevir 300 MG / Pibrentasvir 120 MG Oral Tablet; Drug: Ezetimibe 10Mg Oral Tablet; Device: Ex Vivo Lung Perfusion

Detailed Description

The investigators aim to transplant 40 recipients with end-stage organ disease (20 lung, and 20 other organs) using organs from HCV+ donors. Lungs to be used for transplantation will be exposed to ex vivo lung perfusion with use of ultraviolet C light during perfusion if clinically indicated for lung-related outcomes (ie. not determined by the study investigators). Ex vivo organ perfusion will not be used for other organs. Recipients who are scheduled to receive an HCV-infected organ will receive glecaprevir (300mg)/pibrentasvir (120mg) supplied as three fixed-dose combination tablets once a day starting prior to the transplant as soon the patient is in the hospital and it is confirmed that the transplant is proceeding. HCV treatment will continue for 7 days post-transplant (total 8 doses). Recipients will also receive ezetimibe (10 mg) once daily starting at the same time as G/P and continued until 7 days post-transplant. Recipients will have blood samples taken daily for the first 2 weeks and then weekly until 12 weeks post-transplant for HCV PCR (with additional final sample taken at 6 months post-transplant). The investigators hypothesize that HCV transmission to recipients will be prevented by the use of potent DAA prophylaxis plus ezetimibe with or without ex vivo organ perfusion in the immediate peri-operative period.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Jordan Feld, MD, MPH; Phone Number: 4584 416-340-4800; Email: Jordan.Feld@uhn.ca
• Study Contact Backup: Name: Nellie Kamkar, MSc; Phone Number: 6220 416-340-4800; Email: Nellie.Kamkar@uhn.ca

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2N2
      • Recruiting
      • University Health Network Toronto General Hospital
      • Contact: Jordan Feld, MD, MPH; Phone Number: 4584 416-340-4800; Email: Jordan.Feld@uhn.ca
      • Contact: Nellie Kamkar, MSc; Phone Number: 6220 416-340-4800; Email: Nellie.Kamkar@uhn.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Donor Inclusion Criteria:

• Age <70
• NAT+ HCV donor

Donor Exclusion Criteria:

• HIV positive or HTLV 1/2 positive
• Hepatitis B surface Antigen positive
• Any medical issues in the donor that would normally clinically exclude the donor (e.g. history of cancer, evidence of organ dysfunction, etc)
• Age>70

Recipient Inclusion Criteria:

• Recipients listed for kidney, kidney-pancreas, pancreas transplant alone, heart, or lung transplant
• HCV NAT negative
• Provides written informed consent

Recipient Exclusion Criteria:

• Chronic liver disease with > stage 2 fibrosis
• Participating in another interventional clinical trial
• Recipient listed for liver transplant
• Known allergy or contraindication to Glecaprevir/Pibrentasvir or ezetimibe

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Non Randomized Intervention; Intervention description: recipients on the wait-list for lung, heart, kidney, and/or pancreas transplants will all receive antiviral treatment in the form of 8 total doses of oral tablets. Lung recipients will also receive donor lungs that are treated with normothermic EVLP (details of both described below). Drug: All recipients will receive glecaprevir (300mg)/pibrentasvir (120mg) supplied as three tablets per dose 6-12 hours prior to transplant, and for 7 days post-transplant. Other Names: Maviret. Patients will also receive ezetimibe (10mg), supplied as one tablet per dose to be taken at the same time as Maviret tablets (6-12 hours prior to transplant in addition to 7 daily doses post-transplant). Ex Vivo Lung Perfusion (EVLP): Normothermic EVLP is a method of donor lung preservation, assessment, treatment, and repair of injured organs. This method allows donor lungs to be treated for at least 12h under protective physiological conditions. Other names: Normothermic EVLP.

Drug: Glecaprevir 300 MG / Pibrentasvir 120 MG Oral Tablet; A potent and effective antiviral medication that has recently been approved for use in Canada with over 99% cure rates.; Other Names: Maviret; Drug: Ezetimibe 10Mg Oral Tablet; A cholesterol-lowering medication that also blocks entry of HCV into liver cells.; Device: Ex Vivo Lung Perfusion; A technology that allows for the assessment and treatment of lungs prior to transplant.; Other Names: Normothermic EVLP

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Post-transplant Survival [Safety]	Survival at 6 months post-transplantation in patients receiving organs from HCV-positive donors reported as a binary variable (survival: yes vs. no).	6 months
Incidence of HCV transmission [Safety]	Incidence of HCV transmission following organ transplantation using HCV-positive donors. The proportion who are HCV RNA positive by PCR at 6 months post-transplantation will be reported as a binary variable (transmission: yes vs. no).	6 months
Incidence of treatment-emergent adverse events [Safety and Tolerability]	The number and type of adverse events that are related to treatment with glecaprevir/pibrentasvir or ezetimibe in the opinion of the investigator will be reported at 30 days.	30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-Term Organ Function using Spirometry for Lung Recipients	Spirometry (also known as a pulmonary function test) will be used to assess lung function, measured as the Forced Vital Capacity (FVC) in liters.	1 year
Long-Term Organ Function using Exercise Tolerance for Lung Recipients	A 6-minute walk test will also be used to assess lung function, measured as the total distance the patient can walk during the span of 6 minutes in meters).	1 year
Long-Term Organ Function for Pancreas Recipients	Insulin dependency will be used to assess pancreas function in patients with diabetes, measured as the status of insulin freedom (not needing insulin) after the first year post transplantation. The outcome will be reported as a binary variable (insulin freedom: yes vs. no).	1 year
Long-Term Organ Function for Kidney Recipients	Creatinine levels will be used to assess kidney function and will be collected with a blood test. The estimated glomerular filtration rate (eGFR) will then be calculated in milliliters per minute using serum creatinine (Scr). The formula used to calculate eGFR will be using the Modification of Diet in Renal Disease (MDRD) equation, GFR (mL/min/1.73 m2) = 175 x (Scr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if African American)	1 year
Long-Term Organ Function for Heart Recipients	Left ventricular ejection fraction (the amount of blood leaving the heart during each contraction) will be measured by echocardiography and will be expressed as a percentage.	1 year
Acute Cellular Rejection	The incidence of acute cellular rejection following transplantation will be measured as the proportion of patients with biopsy-proven acute cellular rejection of the transplanted organ and will be reported as a binary variable (yes vs. no).	1 year
HCV Seroconversion	HCV seroconversion will be measured as the proportion of patients who test positive for antibodies to HCV at 1 year post-transplant and will be reported as a binary variable (HCV antibody positive: yes vs. no)	1 year

Collaborators and Investigators

• Sponsor: Jordan Feld
• Collaborators: University Health Network, Toronto
• Investigators: Principal Investigator: Jordan Feld, MD, MPH, University Health Network Toronto General Hospital

Publications and helpful links

General Publications

• Feld JJ, Cypel M, Kumar D, Dahari H, Pinto Ribeiro RV, Marks N, Kamkar N, Bahinskaya I, Onofrio FQ, Zahoor MA, Cerrochi O, Tinckam K, Kim SJ, Schiff J, Reichman TW, McDonald M, Alba C, Waddell TK, Sapisochin G, Selzner M, Keshavjee S, Janssen HLA, Hansen BE, Singer LG, Humar A. Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study. Lancet Gastroenterol Hepatol. 2020 Jul;5(7):649-657. doi: 10.1016/S2468-1253(20)30081-9. Epub 2020 May 6. Erratum In: Lancet Gastroenterol Hepatol. 2020 Jul;5(7):e6.

Study record dates

Study Major Dates

• Study Start (Actual): August 6, 2018
• Primary Completion (Anticipated): December 31, 2020
• Study Completion (Anticipated): December 31, 2024

Study Registration Dates

• First Submitted: July 2, 2019
• First Submitted That Met QC Criteria: July 11, 2019
• First Posted (Actual): July 12, 2019

Study Record Updates

• Last Update Posted (Actual): July 12, 2019
• Last Update Submitted That Met QC Criteria: July 11, 2019
• Last Verified: July 1, 2019

More Information

Terms related to this study

• Keywords: Hepatitis C Virus; Organ Transplant; Direct-Acting Antivirals (DAAs)
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Blood-Borne Infections; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Infections; Communicable Diseases; Hepatitis; Hepatitis A; Hepatitis C; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Ezetimibe
• Other Study ID Numbers: JF-8-2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No