Clinical trial NCT03146741: Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Heart Transplants From Hepatitis C-Positive Donors (HCV)
Official title: Open-Labeled Trial Of Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Heart Transplants From Hepatitis C-Positive Donors
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Heart Failure
Keywords: Heart Failure
Lead sponsor: University of Pennsylvania
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2017-05-10
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is being conducted to determine safety and effectiveness of transplanting hearts from Hepatitis C-positive donors into Hepatitis C-negative patients on the heart transplant waitlist, who will then be treated with Zepatier after transplantation.

Detailed description: Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir) in at least 20 HCV-negative subjects receiving a heart transplant from a HCV-positive donor. Eligible subjects will receive a heart transplant from a deceased-donor with genotype 1 or 4 HCV, and then will receive 12 weeks of Zepatier after heart transplantation when infection with HCV is confirmed in these heart transplant recipients. Treatment will be complete after 12 weeks.

Eligibility criteria: Inclusion Criteria:

* New York Heart Association (NYHA) Class III or IV CHF refractory to maximal medical therapy (ACE inhibitor, B-blocker, digoxin and diuretics, resynchronization therapy or Implantable Cardioverter Defibrillator when applicable) and/or conventional surgery.
* Inoperable coronary artery disease with intractable anginal symptoms
* Malignant ventricular arrhythmias unresponsive to medical or surgical therapy
* 18-65 years of age
* Obtained agreement for participation from the transplant cardiology team
* No evident contraindication to liver transplantation other than the underlying cardiac disorder
* Able to travel to the University of Pennsylvania for routine post-transplant visits and study visits for a minimum of 6 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-heart transplantation
* Able to provide informed consent

Exclusion Criteria:

* Hepatocellular carcinoma
* HIV positive
* HCV antibody positive and/or RNA positive
* Hepatitis B surface antigen, core antibody, and/or DNA positive
* Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal liver enzymes
* Persistently elevated liver transaminases
* Congenital heart disease
* Fibrosis by liver biopsy or total bilirubin \> 2.5 with associated evidence of synthetic dysfunction.
* 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
* Waitlisted for a multi-organ transplant
* 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.
* Chronic bronchitis, chronic obstructive pulmonary disease, inability to stop smoking.
* Hematologic: Significant coagulation abnormalities, bleeding diatheses.
* Psychosocial: Profound neurocognitive impairment with absence of social support.
* Active mental illness or psychosocial instability
* Inadequate insurance or financial support for post-transplant care.
* Evidence of drug, tobacco or alcohol abuse within the past six months and completion of recommended therapy/services or meets satisfied parameters as indicated by social work staff and/or consult team.
* History of chronic non-compliance.
* Amyloidosis (restricted to cardiac only, without evidence of extra cardiac involvement)
* BMI ≥38
* Active peptic ulcer disease.
* Severe malnutrition.
* Major chronic disabling illness (e.g. lupus, severe arthritis, neurologic diseases, previous stroke with profound residual).
* Pulmonary infarction within the past 6 weeks
* Severe pulmonary hypertension as evidenced by a fixed pulmonary vascular resistance of greater than 4 Wood units on appropriate medical therapy.
* Patient refusal to receive blood products or transfusions during heart transplant surgery.
* Severe chronic obstructive pulmonary disease
* Current clinical sepsis.
* Symptomatic or severe vascular disease.
* Chronic Kidney Disease Stage IV, Glomerular Filtration Rate \< 30
* History of Mantle radiation.
* Asymptomatic renal cell carcinoma \<1 year from curative treatment.
* Symptomatic renal cell carcinoma \<5 years from curative treatment.
* Prostate cancer \<2 years from curative treatment.
* Uterine or cervical cancer \<2 years from curative treatment.
* Any other cancer other than the above including malignant melanoma, \< 5 years from treatment apart from other skin malignancies.

Donor Organ Selection Criteria:

General criteria (although there can be exceptions on a case-by-case basis)

* Detectable HCV RNA
* Genotype 1 or 4 HCV
* Age \<=55 years
* No history of coronary artery disease
* No congenital heart disease except a repaired atrial septal defect (ASD) provided the patient has normal right ventricular function
* No history of arrhythmia (atrial fibrilation, atrial flutter or VT) except during resuscitation from fatal event.
* No evidence of cirrhosis

Echocardiographic criteria:

* Left ventricular ejection fraction (LVEF) \>=50%
* Normal right ventricular function
* No left ventricular hypertrophy (LVH) - septal wall thickness \<1 cm
* No left ventricular hypertrophy (LVH)- posterior wall thickness \<1 cm
* No significant valvular heart disease - more than mild tricuspid regurgitation, more than mild mitral regurgitation, more than trace aortic regurgitation. No mitral or aortic stenosis.
* No congenital heart disease - transposition of the great vessels, ventricular septal defect (VSD), ASD, and/or single ventricle (Fontan)

Right heart catheterization criteria:

* Right atrial pressure \<=10mmHg
* Pulmonary capillary wedge pressure \<=18mmHg
* CI \>=2.1 l/min/m2
* Pulmonary hypertension is allowed if the patient has normal right ventricular function and a normal tricuspid valve

Primary outcomes:
measure: Number of Participants With Post-treatment Sustained Virologic Response (SVR)
timeFrame: Baseline to 24 weeks
measure: Number of Severe Adverse Events (SAE) Attributable to HCV Therapy Post-heart Transplant
timeFrame: Baseline to 52 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
Study officials:
affiliation: Perelman School of Medicine at the University of Pennsylvania
name: Peter Reese, MD, MSCE
role: PRINCIPAL_INVESTIGATOR
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