Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Heart Transplants From Hepatitis C-Positive Donors (HCV)

Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir)
in up to 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.

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