Zepatier For Treatment Of Hepatitis C-Negative Patients Who Receive Heart Transplants From Hepatitis C-Positive Donors (HCV)
NCT ID: NCT03146741
Last Updated: 2021-11-22
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE1/PHASE2
20 participants
INTERVENTIONAL
2017-05-16
2019-11-30
Brief Summary
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Detailed Description
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Conditions
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Keywords
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Zepatier (grazoprevir 100mg and elbasvir 50 mg)
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.
Interventions
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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.
Eligibility Criteria
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Inclusion Criteria
* 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
* Able to provide informed consent
Exclusion Criteria
* 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
18 Years
65 Years
ALL
No
Sponsors
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Merck Sharp & Dohme LLC
INDUSTRY
University of Pennsylvania
OTHER
Responsible Party
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Principal Investigators
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Peter Reese, MD, MSCE
Role: PRINCIPAL_INVESTIGATOR
Perelman School of Medicine at the University of Pennsylvania
Locations
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Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States
Countries
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References
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Sulkowski M, Hezode C, Gerstoft J, Vierling JM, Mallolas J, Pol S, Kugelmas M, Murillo A, Weis N, Nahass R, Shibolet O, Serfaty L, Bourliere M, DeJesus E, Zuckerman E, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J, Robertson M, Barr E, Haber B. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1087-97. doi: 10.1016/S0140-6736(14)61793-1. Epub 2014 Nov 11.
Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, Alric L, Bronowicki JP, Lester L, Sievert W, Ghalib R, Balart L, Sund F, Lagging M, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J, Robertson M, Barr E, Haber B. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11.
Forns X, Gordon SC, Zuckerman E, Lawitz E, Calleja JL, Hofer H, Gilbert C, Palcza J, Howe AY, DiNubile MJ, Robertson MN, Wahl J, Barr E, Buti M. Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent. J Hepatol. 2015 Sep;63(3):564-72. doi: 10.1016/j.jhep.2015.04.009. Epub 2015 Apr 18.
Zeuzem S, Ghalib R, Reddy KR, Pockros PJ, Ben Ari Z, Zhao Y, Brown DD, Wan S, DiNubile MJ, Nguyen BY, Robertson MN, Wahl J, Barr E, Butterton JR. Grazoprevir-Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Ann Intern Med. 2015 Jul 7;163(1):1-13. doi: 10.7326/M15-0785.
O'Leary JG, Neri MA, Trotter JF, Davis GL, Klintmalm GB. Utilization of hepatitis C antibody-positive livers: genotype dominance is virally determined. Transpl Int. 2012 Aug;25(8):825-9. doi: 10.1111/j.1432-2277.2012.01498.x. Epub 2012 May 30.
Reese PP, Abt PL, Blumberg EA, Goldberg DS. Transplanting Hepatitis C-Positive Kidneys. N Engl J Med. 2015 Jul 23;373(4):303-5. doi: 10.1056/NEJMp1505074. No abstract available.
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.
Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, Martin P, Pol S, Londono MC, Hassanein T, Zamor PJ, Zuckerman E, Wan S, Jackson B, Nguyen BY, Robertson M, Barr E, Wahl J, Greaves W. Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4-5 chronic kidney disease (the C-SURFER study): a combination phase 3 study. Lancet. 2015 Oct 17;386(10003):1537-45. doi: 10.1016/S0140-6736(15)00349-9. Epub 2015 Oct 5.
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). ZEPATIERâ„¢ 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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Other Identifiers
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826708
Identifier Type: -
Identifier Source: org_study_id