Transplanting Hepatitis C Lungs Into Negative Lung Recipients (SHELTER)

• ClinicalTrials.gov Identifier: NCT03724149
• Recruitment Status: Recruiting
• First Posted: October 30, 2018
• Last Update Posted: November 18, 2019
• Sponsor: University of Pennsylvania
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): University of Pennsylvania

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.

Condition or disease	Intervention/treatment	Phase
Lung Diseases	Drug: Zepatier; Drug: Epclusa	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-Labeled Trial Of Direct-acting Antiviral Treatment Of Hepatitis C-Negative Patients Who Receive Lung Transplants From Hepatitis C-Positive Donors
• Actual Study Start Date: December 12, 2018
• Estimated Primary Completion Date: November 2020
• Estimated Study Completion Date: November 2021

Arms and Interventions

Arm

Intervention/treatment

Experimental: Direct-acting antiviral treatment for HCV

Drug: 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.; 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.

Outcome Measures

Primary Outcome Measures :

1. Post-treatment Sustained Virologic Response (SVR) [ Time Frame: Baseline to 24 weeks ]
   The primary analysis will be based on a calculation of SVR rates (number of subjects with SVR; negative HCV RNA after completing therapy) / (number of subjects treated post-heart transplantation)
2. Major Adverse Events Attributable to HCV Therapy in Post-heart Transplant Patients Post-heart Transplant Patients [ Time Frame: Baseline to 52 weeks ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Subject Selection Criteria

Inclusion Criteria:

• 18-65 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

Contacts and Locations

Contacts

Contact: Stacey Prenner, MD; (307) 22-THINK; thinker@med.upenn.edu

Contact: Joshua Diamond, MD, MHSE; (307) 22-THINK; thinker@med.upenn.edu

Locations

United States, Pennsylvania

Hospital of the University of Pennsylvania; Recruiting

Philadelphia, Pennsylvania, United States, 19104

Contact: Adam Mussell, MA 215-746-4177 adam.mussell@uphs.upenn.edu

Principal Investigator: Stacey Prenner, MD

Principal Investigator: Peter Reese, MD, MSCE

Sponsors and Collaborators

University of Pennsylvania

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Peter Reese, MD, MSCE; Perelman School of Medicine at the University of Pennsylvania

More Information

• Responsible Party: University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT03724149 History of Changes
• Other Study ID Numbers: 829397
• First Posted: October 30, 2018
• Last Update Posted: November 18, 2019
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Keywords provided by University of Pennsylvania:

Lung Disease

Additional relevant MeSH terms:

Hepatitis C; Hepatitis; Lung Diseases; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Respiratory Tract Diseases; Sofosbuvir-velpatasvir drug combination; Elbasvir-grazoprevir drug combination; Antiviral Agents; Anti-Infective Agents