Clinical trial NCT04017338: Transplantation Using Hepatitis C Positive Donors, A Safety Trial
Official title: Transplantation Using Hepatitis C Positive Donors to Hepatitis C Negative Recipients: A Safety Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Lung Transplant Infection
Heart Transplant Infection
Kidney Transplant Infection
Kidney Pancreas Infection
Hepatitis C
Keywords: Organ Transplant
Hepatitis C Virus
Direct-Acting Antivirals (DAAs)
Lead sponsor: University Health Network, Toronto
Sponsor class: OTHER
Collaborators: name: University Health Network, Toronto
First posted: 2019-07-12
Enrollment: 40
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Investigators aim to transplant 40 recipients (20 lung; 20 other organs) on the transplant wait-list. Donor organs will be selected based on usual donor selection criteria. Recipients will be selected based on usual hospital protocol for selecting suitable recipients. After transplantation, recipients will receive highly effective antiviral prophylaxis using approved direct-acting antivirals (DAAs) Glecaprevir/Pibrentasvir (G/P) and they will also receive ezetimibe, a cholesterol-lowering medication. Additionally, lung transplant recipients will receive donor lungs treated with normothermic ex vivo lung perfusion (EVLP) prior to transplant.
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Post-transplant Survival [Safety]
timeFrame: 6 months
measure: Incidence of HCV transmission [Safety]
timeFrame: 6 months
measure: Incidence of treatment-emergent adverse events [Safety and Tolerability]
timeFrame: 30 days
Secondary outcomes:
measure: Long-Term Organ Function using Spirometry for Lung Recipients
timeFrame: 1 year
measure: Long-Term Organ Function using Exercise Tolerance for Lung Recipients
timeFrame: 1 year
measure: Long-Term Organ Function for Pancreas Recipients
timeFrame: 1 year
measure: Long-Term Organ Function for Kidney Recipients
timeFrame: 1 year
measure: Long-Term Organ Function for Heart Recipients
timeFrame: 1 year
measure: Acute Cellular Rejection
timeFrame: 1 year
measure: HCV Seroconversion
timeFrame: 1 year
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: University Health Network Toronto General Hospital
state: Ontario
Study officials:
affiliation: University Health Network Toronto General Hospital
name: Jordan Feld, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.