Heart Failure
Conditions
Keywords
Heart Failure
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.
Interventions
DRUGZepatier
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.
Sponsors
Merck Sharp & Dohme LLC
University of Pennsylvania
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Post-treatment Sustained Virologic Response (SVR) | 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 Zepatier therapy) / (number of subjects treated with Zepatier post-heart transplantation) |
| Number of Severe Adverse Events (SAE) Attributable to HCV Therapy Post-heart Transplant | Baseline to 52 weeks | — |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zepatier (Grazoprevir 100mg and Elbasvir 50 mg) 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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Awaiting txp | 2 |
| Overall Study | Listeted for MOT | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Txp with non-HCV+ heart | 4 |
Baseline characteristics
| Characteristic | Zepatier (Grazoprevir 100mg and Elbasvir 50 mg) |
|---|---|
| Age, Continuous | 52.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 10 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 10 |
| other Total, other adverse events | 10 / 10 |
| serious Total, serious adverse events | 6 / 10 |
Outcome results
Primary
Number of Participants With Post-treatment Sustained Virologic Response (SVR)
The primary analysis will be based on a calculation of SVR rates (number of subjects with SVR; negative HCV RNA after completing Zepatier therapy) / (number of subjects treated with Zepatier post-heart transplantation)
Time frame: Baseline to 24 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zepatier (Grazoprevir 100mg and Elbasvir 50 mg) | Number of Participants With Post-treatment Sustained Virologic Response (SVR) | 9 Participants |
Primary
Number of Severe Adverse Events (SAE) Attributable to HCV Therapy Post-heart Transplant
Time frame: Baseline to 52 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zepatier (Grazoprevir 100mg and Elbasvir 50 mg) | Number of Severe Adverse Events (SAE) Attributable to HCV Therapy Post-heart Transplant | 0 Severe adverse event |