Transplanting Hepatitis C Lungs Into Negative Lung Recipients

NCT ID: NCT03724149

Last Updated: 2023-04-14

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-12-12
• Study Completion Date: 2022-12-31

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.

Conditions

Lung Diseases

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Direct-acting antiviral treatment for HCV

Group Type: EXPERIMENTAL

Zepatier

Intervention Type: DRUG

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.

Epclusa

Intervention Type: DRUG

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.

Interventions

Zepatier

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

Epclusa

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.

Intervention Type: DRUG

Eligibility 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
• Able to provide informed consent

• 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)

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.

• Donation after circulatory death determination (DCDD)
• HIV positive

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 67 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Merck Sharp & Dohme LLC

INDUSTRY

Sponsor Role: collaborator

University of Pennsylvania

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Peter Reese, MD, MSCE

Role: STUDY_DIRECTOR

Perelman School of Medicine at the University of Pennsylvania

Locations

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

829397

Identifier Type: -

Identifier Source: org_study_id