Transplanting Hepatitis C Lungs Into Negative Lung Recipients (SHELTER)
Primary Purpose
Lung Diseases
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Zepatier
Epclusa
Sponsored by
About this trial
This is an interventional treatment trial for Lung Diseases focused on measuring Lung Disease
Eligibility Criteria
Subject Selection Criteria
Inclusion Criteria:
- 18-67 years of age
- Obtained agreement for participation from the lung transplant team
- No evident contraindication to lung transplantation other than the underlying lung disorder
- Able to travel to the University of Pennsylvania for routine post-transplant visits and study visits for a minimum of 12 months after transplantation
- No active illicit substance abuse
- Women must agree to use birth control in accordance with Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) following transplant due to the increased risk of birth defects and/or miscarriage
- Both men and women must agree to use at least one barrier method of birth control or remain abstinent following transplant due to risk of HCV transmission
- Inclusion criteria for treatment (not for entry as study patient) will include any detectable HCV RNA by week 4 post-lung transplantation
- Able to provide informed consent
Exclusion Criteria:
- Hepatocellular carcinoma
- HIV positive
- HCV RNA positive
- Hepatitis B surface antigen and/or DNA positive
- Any chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD)) that is occurring in the setting of persistently elevated liver enzymes (patients with Alpha-1-antitrypsin lung disease without hepatic involvement are eligible)
- Significant fibrosis (≥F2 on the Fibroscan)-for patients with cystic fibrosis, the cutoff will be 11kPa (cutoff for F2 for patients with chronic cholestatic liver disease), whereas for all other patients the cutoff will be 8kPa (the cutoff for fatty liver disease used in the THINKER study).
- Pregnant or nursing (lactating) women
- Known allergy or intolerance to tacrolimus that would require post-transplant administration of cyclosporine, rather than tacrolimus given the drug-drug interaction between cyclosporine and Zepatier/Epclusa
- Pre-transplant treatment with amiodarone given the drug-drug interaction between amiodarone and Epclusa
- Waitlisted for a multi-organ transplant
- Patients with underlying liver disease with or without liver cirrhosis
- Patients with cystic fibrosis who have underlying liver disease
- Re-transplant candidate
- Use of ECMO or mechanical ventilation as a bridge to lung transplantation
- Inability to provide study consent
- Chronic kidney disease with GFR<50 ml/min/1.73 m^2
Relative contraindications for study subjects that will be reviewed on a case-by-case basis by the Lung Transplant Selection Committee and the Principal Investigators:
- Evidence of end organ damage due to diabetes (e.g. retinopathy, nephropathy, ulcerations) and /or brittle diabetes mellitus (e.g. history of diabetic ketoacidosis) and/or uncontrolled diabetes as evidence by a HgbA1C of 7.5-8.5.
- Hematologic: Significant coagulation abnormalities, and/or bleeding diatheses.
- Active or recent solid or liquid malignancy in the past 5 years (apart from select skin malignancies).
- Patient refusal to receive blood products or transfusions during lung transplant surgery.
- Psychosocial: Profound neurocognitive impairment with absence of social support.
- Active mental illness or psychosocial instability
- Inadequate insurance and/or financial support for post-transplant care.
- Evidence of drug, tobacco or alcohol abuse within the past six months and failure to satisfy recommended therapy/services/parameters as indicated by social work staff and/or consult team.
- History of chronic non-adherence to medical recommendations and/or medications
- PRA >10%.
- Severe malnutrition, BMI <18
- Major chronic disabling comorbidity (e.g. lupus, severe arthritis, neurologic diseases, previous stroke with profound residual).
- Symptomatic or severe vascular disease (History of CABG, Aorta-femoral surgery)
Donor Organ Selection Criteria
Broad goal: To include donors with confirmed HCV expected to have acceptable post-transplant graft outcomes based on large retrospective lung transplant studies.
Inclusion criteria for donors:
- Detectable HCV RNA
- Age ≤55 years
- PaO2/FiO2 ≥300 on FiO2 = 100% and PEEP=5
- Cigarette use history ≤20 pack years
- No evidence of cirrhosis
- No prior treatment of HCV with a DAA-based therapy
- Can be isolated hepatitis B Core IgG positive, but cannot have a detectable HBV Core IgM, HBSAg, and/or HBV DNA (positive HBV NAT test)
Donor Exclusion Criteria:
- Donation after circulatory death determination (DCDD)
- HIV positive
Sites / Locations
- Hospital of the University of Pennsylvania
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Direct-acting antiviral treatment for HCV
Arm Description
Outcomes
Primary Outcome Measures
Subject Sustained Virologic Response (SVR-12) at 12-weeks Post-treatment
The primary outcome measure is Sustained Virologic Response (SVR) rate at 12 weeks (number of subjects with SVR; negative HCV RNA after completing therapy) / (number of subjects treated post-lung transplantation).
SVR will be based on the standard definition of SVR-12, defined as an undetectable HCV RNA in a subject's serum 12 weeks after completing treatment for HCV (12 weeks after the subject takes the last dose of Zepatier, Epclusa, or another appropriate antiviral treatment).
Major Adverse Events Attributable to HCV Therapy in Post-lung Transplant Patients Post-lung Transplant Patients
Secondary Outcome Measures
Full Information
NCT ID
NCT03724149
First Posted
October 26, 2018
Last Updated
April 13, 2023
Sponsor
University of Pennsylvania
Collaborators
Merck Sharp & Dohme LLC
1. Study Identification
Unique Protocol Identification Number
NCT03724149
Brief Title
Transplanting Hepatitis C Lungs Into Negative Lung Recipients
Acronym
SHELTER
Official Title
Open-Labeled Trial Of Direct-acting Antiviral Treatment Of Hepatitis C-Negative Patients Who Receive Lung Transplants From Hepatitis C-Positive Donors
Study Type
Interventional
2. Study Status
Record Verification Date
April 2023
Overall Recruitment Status
Completed
Study Start Date
December 12, 2018 (Actual)
Primary Completion Date
December 31, 2021 (Actual)
Study Completion Date
December 31, 2022 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Pennsylvania
Collaborators
Merck Sharp & Dohme LLC
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This study is being conducted to determine safety and effectiveness of transplanting lungs from Hepatitis C-positive donors into Hepatitis C-negative patients on the lung transplant waitlist, who will then be treated with appropriate direct-acting antiviral (DAA) after transplantation.
Detailed Description
Open-labelled pilot clinical trial of Zepatier (Grazoprevir + Elbasvir), Epclusa (Sofosbuvir + Velpatasvir), or another appropriate DAA in at least 10 HCV-negative subjects receiving a lung transplant from a hepatitis C (HCV)-positive donor. Eligible subjects will receive a lung transplant from a deceased-donor, and then will receive treatment after lung transplantation when infection with HCV is confirmed in these lung transplant recipients. Treatment will be complete after 12 weeks for most subjects.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lung Diseases
Keywords
Lung Disease
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Direct-acting antiviral treatment for HCV
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Zepatier
Intervention Description
Zepatier (grazoprevir 100mg and elbasvir 50 mg once daily) is taken by mouth for 12 weeks unless a genetic variation is detected. In this case treatment with Zepatier will be extended to 16 weeks. Study subjects with treatment failure will be provided open-label Zepatier + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.
Intervention Type
Drug
Intervention Name(s)
Epclusa
Intervention Description
Epclusa (sofosbuvir 400mg and velpatasvir 100mg once daily) is taken by mouth for 12 weeks. Study subjects with treatment failure will be provided an alternative DAA + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.
Primary Outcome Measure Information:
Title
Subject Sustained Virologic Response (SVR-12) at 12-weeks Post-treatment
Description
The primary outcome measure is Sustained Virologic Response (SVR) rate at 12 weeks (number of subjects with SVR; negative HCV RNA after completing therapy) / (number of subjects treated post-lung transplantation).
SVR will be based on the standard definition of SVR-12, defined as an undetectable HCV RNA in a subject's serum 12 weeks after completing treatment for HCV (12 weeks after the subject takes the last dose of Zepatier, Epclusa, or another appropriate antiviral treatment).
Time Frame
Baseline to 12 weeks
Title
Major Adverse Events Attributable to HCV Therapy in Post-lung Transplant Patients Post-lung Transplant Patients
Time Frame
Baseline to 52 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
67 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Subject Selection Criteria
Inclusion Criteria:
18-67 years of age
Obtained agreement for participation from the lung transplant team
No evident contraindication to lung transplantation other than the underlying lung disorder
Able to travel to the University of Pennsylvania for routine post-transplant visits and study visits for a minimum of 12 months after transplantation
No active illicit substance abuse
Women must agree to use birth control in accordance with Mycophenolate Risk Evaluation and Mitigation Strategy (REMS) following transplant due to the increased risk of birth defects and/or miscarriage
Both men and women must agree to use at least one barrier method of birth control or remain abstinent following transplant due to risk of HCV transmission
Inclusion criteria for treatment (not for entry as study patient) will include any detectable HCV RNA by week 4 post-lung transplantation
Able to provide informed consent
Exclusion Criteria:
Hepatocellular carcinoma
HIV positive
HCV RNA positive
Hepatitis B surface antigen and/or DNA positive
Any chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD)) that is occurring in the setting of persistently elevated liver enzymes (patients with Alpha-1-antitrypsin lung disease without hepatic involvement are eligible)
Significant fibrosis (≥F2 on the Fibroscan)-for patients with cystic fibrosis, the cutoff will be 11kPa (cutoff for F2 for patients with chronic cholestatic liver disease), whereas for all other patients the cutoff will be 8kPa (the cutoff for fatty liver disease used in the THINKER study).
Pregnant or nursing (lactating) women
Known allergy or intolerance to tacrolimus that would require post-transplant administration of cyclosporine, rather than tacrolimus given the drug-drug interaction between cyclosporine and Zepatier/Epclusa
Pre-transplant treatment with amiodarone given the drug-drug interaction between amiodarone and Epclusa
Waitlisted for a multi-organ transplant
Patients with underlying liver disease with or without liver cirrhosis
Patients with cystic fibrosis who have underlying liver disease
Re-transplant candidate
Use of ECMO or mechanical ventilation as a bridge to lung transplantation
Inability to provide study consent
Chronic kidney disease with GFR<50 ml/min/1.73 m^2
Relative contraindications for study subjects that will be reviewed on a case-by-case basis by the Lung Transplant Selection Committee and the Principal Investigators:
Evidence of end organ damage due to diabetes (e.g. retinopathy, nephropathy, ulcerations) and /or brittle diabetes mellitus (e.g. history of diabetic ketoacidosis) and/or uncontrolled diabetes as evidence by a HgbA1C of 7.5-8.5.
Hematologic: Significant coagulation abnormalities, and/or bleeding diatheses.
Active or recent solid or liquid malignancy in the past 5 years (apart from select skin malignancies).
Patient refusal to receive blood products or transfusions during lung transplant surgery.
Psychosocial: Profound neurocognitive impairment with absence of social support.
Active mental illness or psychosocial instability
Inadequate insurance and/or financial support for post-transplant care.
Evidence of drug, tobacco or alcohol abuse within the past six months and failure to satisfy recommended therapy/services/parameters as indicated by social work staff and/or consult team.
History of chronic non-adherence to medical recommendations and/or medications
PRA >10%.
Severe malnutrition, BMI <18
Major chronic disabling comorbidity (e.g. lupus, severe arthritis, neurologic diseases, previous stroke with profound residual).
Symptomatic or severe vascular disease (History of CABG, Aorta-femoral surgery)
Donor Organ Selection Criteria
Broad goal: To include donors with confirmed HCV expected to have acceptable post-transplant graft outcomes based on large retrospective lung transplant studies.
Inclusion criteria for donors:
Detectable HCV RNA
Age ≤55 years
PaO2/FiO2 ≥300 on FiO2 = 100% and PEEP=5
Cigarette use history ≤20 pack years
No evidence of cirrhosis
No prior treatment of HCV with a DAA-based therapy
Can be isolated hepatitis B Core IgG positive, but cannot have a detectable HBV Core IgM, HBSAg, and/or HBV DNA (positive HBV NAT test)
Donor Exclusion Criteria:
Donation after circulatory death determination (DCDD)
HIV positive
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Peter Reese, MD, MSCE
Organizational Affiliation
Perelman School of Medicine at the University of Pennsylvania
Official's Role
Study Director
Facility Information:
Facility Name
Hospital of the University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Plan to Share IPD
Undecided
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Transplanting Hepatitis C Lungs Into Negative Lung Recipients
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