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

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ClinicalTrials.gov Identifier: NCT03146741
Recruitment Status : Active, not recruiting
First Posted : May 10, 2017
Last Update Posted : November 29, 2018
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Pennsylvania

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.

Condition or disease Intervention/treatment Phase
Heart Failure Drug: Zepatier Phase 1 Phase 2

Detailed Description:
Open-labelled pilot clinical trial of Zepatier (MK-5172 and MK-8742/Grazoprevir + Elbasvir) in 10 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.

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Open-Labeled Trial Of Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Heart Transplants From Hepatitis C-Positive Donors
Actual Study Start Date : May 16, 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Zepatier (grazoprevir 100mg and elbasvir 50 mg) o 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.




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 Zepatier therapy) / (number of subjects treated with Zepatier 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 ]


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Ages Eligible for Study:   40 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 40-65 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03146741


Locations
United States, Pennsylvania
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
University of Pennsylvania
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Peter Reese, MD, MSCE Perelman School of Medicine at the University of Pennsylvania
  Study Documents (Full-Text)

Documents provided by University of Pennsylvania:

Publications:
Reddy KR FS, et al. Ledipasvir/Sofosbuvir with Ribavirin for the Treatment of HCV in Patients with Post Transplant Recurrence: Preliminary Results of a Prospective, Multicenter Study. Hepatology. 2014;60:200A.
Van Deerlin, V. (December 2015). Hepatitis C Virus Genotyping (GenMark Assay) Validation Summary.
Pawlak R RJ, Maranan G, Michel-Treil V, Schutzbank T. A Comparative Evaluation of the Siemens VERSANT HCV Genotype 2.0 (LiPA) and GenMark eSensor HCV Direct Genotyping Tests. CVS 2013 Covance; 2013
Dahl A HD, Ogorek T, Hansen G. Comparison of the GenMark Direct Genotype Assay with the LiPA Genotype Assay Using a Diverse Spectrum of HCV Clinical Samples Encountered in a High Risk Inner City HCV Population. CVS 2013 Hennepin; 2013.
Woodberry M SK, Castor J, Cook L, Jerome K. Genotyping of Hepatitis C Virus by the Genmark DX Esensor HCVG Direct Test. CVS 2013 UW-Seattle 2013
U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. (June 2010). Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0.
Merck Sharp & Dohme Corporation (January 2016). ZEPATIER™ tablets. Highlights of Prescribing Information. 2016.
Merck Sharp & Dohme Corporation (July 2015). Elbasvir (MK-8742). Investigator's Brochure (8th Ed.). 2015.
Merck Sharp & Dohme Corporation (July 2015). Grazoprevir (MK-5172). Investigator's Brochure (10th Ed.). 2015.

Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT03146741     History of Changes
Other Study ID Numbers: 826708
First Posted: May 10, 2017    Key Record Dates
Last Update Posted: November 29, 2018
Last Verified: November 2018
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.: Yes

Keywords provided by University of Pennsylvania:
Heart Failure

Additional relevant MeSH terms:
Hepatitis
Hepatitis C
Hepatitis, Viral, Human
Heart Failure
Liver Diseases
Digestive System Diseases
Heart Diseases
Cardiovascular Diseases
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Elbasvir-grazoprevir drug combination
Antiviral Agents
Anti-Infective Agents