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Transplantation Using Hepatitis C Positive Donors, A Safety Trial

Primary Purpose

Lung Transplant Infection, Heart Transplant Infection, Kidney Transplant Infection

Status
Recruiting
Phase
Phase 3
Locations
Canada
Study Type
Interventional
Intervention
Glecaprevir 300 MG / Pibrentasvir 120 MG Oral Tablet
Ezetimibe 10Mg Oral Tablet
Ex Vivo Lung Perfusion
Sponsored by
Jordan Feld
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lung Transplant Infection focused on measuring Organ Transplant, Hepatitis C Virus, Direct-Acting Antivirals (DAAs)

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University Health Network Toronto General HospitalRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Non Randomized Intervention

Arm Description

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.

Outcomes

Primary Outcome Measures

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).
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).
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.

Secondary Outcome Measures

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.
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).
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).
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)
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.
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).
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)

Full Information

First Posted
July 2, 2019
Last Updated
July 11, 2019
Sponsor
Jordan Feld
Collaborators
University Health Network, Toronto
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1. Study Identification

Unique Protocol Identification Number
NCT04017338
Brief Title
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

2. Study Status

Record Verification Date
July 2019
Overall Recruitment Status
Recruiting
Study Start Date
August 6, 2018 (Actual)
Primary Completion Date
December 31, 2020 (Anticipated)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Jordan Feld
Collaborators
University Health Network, Toronto

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lung Transplant Infection, Heart Transplant Infection, Kidney Transplant Infection, Kidney Pancreas Infection, Hepatitis C
Keywords
Organ Transplant, Hepatitis C Virus, Direct-Acting Antivirals (DAAs)

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
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.
Masking
None (Open Label)
Allocation
N/A
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Non Randomized Intervention
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Glecaprevir 300 MG / Pibrentasvir 120 MG Oral Tablet
Other Intervention Name(s)
Maviret
Intervention Description
A potent and effective antiviral medication that has recently been approved for use in Canada with over 99% cure rates.
Intervention Type
Drug
Intervention Name(s)
Ezetimibe 10Mg Oral Tablet
Intervention Description
A cholesterol-lowering medication that also blocks entry of HCV into liver cells.
Intervention Type
Device
Intervention Name(s)
Ex Vivo Lung Perfusion
Other Intervention Name(s)
Normothermic EVLP
Intervention Description
A technology that allows for the assessment and treatment of lungs prior to transplant.
Primary Outcome Measure Information:
Title
Post-transplant Survival [Safety]
Description
Survival at 6 months post-transplantation in patients receiving organs from HCV-positive donors reported as a binary variable (survival: yes vs. no).
Time Frame
6 months
Title
Incidence of HCV transmission [Safety]
Description
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).
Time Frame
6 months
Title
Incidence of treatment-emergent adverse events [Safety and Tolerability]
Description
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.
Time Frame
30 days
Secondary Outcome Measure Information:
Title
Long-Term Organ Function using Spirometry for Lung Recipients
Description
Spirometry (also known as a pulmonary function test) will be used to assess lung function, measured as the Forced Vital Capacity (FVC) in liters.
Time Frame
1 year
Title
Long-Term Organ Function using Exercise Tolerance for Lung Recipients
Description
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).
Time Frame
1 year
Title
Long-Term Organ Function for Pancreas Recipients
Description
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).
Time Frame
1 year
Title
Long-Term Organ Function for Kidney Recipients
Description
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)
Time Frame
1 year
Title
Long-Term Organ Function for Heart Recipients
Description
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.
Time Frame
1 year
Title
Acute Cellular Rejection
Description
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).
Time Frame
1 year
Title
HCV Seroconversion
Description
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)
Time Frame
1 year

10. Eligibility

Sex
All
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jordan Feld, MD, MPH
Phone
416-340-4800
Ext
4584
Email
Jordan.Feld@uhn.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Nellie Kamkar, MSc
Phone
416-340-4800
Ext
6220
Email
Nellie.Kamkar@uhn.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jordan Feld, MD, MPH
Organizational Affiliation
University Health Network Toronto General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Health Network Toronto General Hospital
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M5G 2N2
Country
Canada
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jordan Feld, MD, MPH
Phone
416-340-4800
Ext
4584
Email
Jordan.Feld@uhn.ca
First Name & Middle Initial & Last Name & Degree
Nellie Kamkar, MSc
Phone
416-340-4800
Ext
6220
Email
Nellie.Kamkar@uhn.ca

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32389183
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. Erratum In: Lancet Gastroenterol Hepatol. 2020 Jul;5(7):e6.
Results Reference
derived

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Transplantation Using Hepatitis C Positive Donors, A Safety Trial

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