Transplanting Hepatitis C Kidneys Into Negative Kidney Recipients

NCT02743897 | Completed Phase 1 Results DMC

• 1 other identifier: 823833
• Study Type: interventional
• Target: 62
• Locations: 1 country
• Sites: 1

Brief Summary

This study is being conducted to determine safety and effectiveness of transplanting kidneys from Hepatitis C-positive donors into Hepatitis C-negative patients on the kidney transplant waitlist, who will then be treated with the appropriate direct-acting antiviral (DAA) after the single kidney transplantation.

Conditions

End Stage Renal Disease

Keywords

end-stage renal disease

Outcome Measures

Primary Outcomes (2)

• Number of Subjects Cured

  Subjects with post-treatment sustained virologic response (SVR) = Number of subjects with negative HCV RNA 12 weeks after completing therapy / number of subjects treated post-kidney transplantation

  Baseline to 24 weeks

• Number of Subjects With SAE Attributable to HCV Therapy

  Number of subjects with major adverse events attributable to HCV therapy in post-kidney transplant

  Baseline to 52 weeks

Study Arms (1)

Direct-acting antiviral treatment for HCV

EXPERIMENTAL

Drug: Zepatier; Drug: Mavyret

Interventions

Zepatier DRUG

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.

Direct-acting antiviral treatment for HCV

Mavyret DRUG

Mavyret (glecaprevir 100 mg and pibrentasvir 40 mg) is taken by mouth for 8 weeks. Study subjects with treatment failure will be provided an alternative DAA + sofosbuvir (sovaldi) 400mg + Ribavirin (generic), renally dosed based on creatinine clearance per the manufacturer guidelines.

Direct-acting antiviral treatment for HCV

Eligibility Criteria

• Age: 30 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Must be waitlisted for a kidney transplant (dialysis is not a requirement if a patient is waitlisted)
• Listed for an isolated kidney transplant with ≤2555 days of accrued transplant waiting time and/or ≤2555 days of dialysis time for blood group A, B, or O, by enrollment
• Listed for an isolated kidney transplant with ≤1825 days of accrued transplant waiting time and/or ≤1825 days of dialysis time for blood group AB, by enrollment
• No available living kidney donor
• Between 30-70 years of age, by enrollment
• Have a panel reactive antibody level ≤97%
• eGFR \<15ml/min/1.73m2 as calculated using the 4 variable MDRD equation
• Obtained agreement for participation from the patient's treating transplant nephrologist
• 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
• Weigh at least 50kg
• 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 to prevent any secretion exchange
• Able to provide informed consent

You may not qualify if:

• Hepatocellular carcinoma
• Patients with primary focal segmental glomerulosclerosis (FSGS), FSGS recurring after previous transplant, or disease process with increased risk of causing early graft failure as per the treating nephrologist
• HIV positive
• HCV RNA positive (can be isolated HCV antibody positive provided the subject has no history of previously treated HCV)
• Hepatitis B surface antigen positive
• Any other chronic liver disease (excluding non-alcoholic fatty liver disease (NAFLD) with abnormal liver enzymes
• Persistently elevated liver transaminases
• Significant hepatic fibrosis on screening elastography (≥f2 fibrosis)
• 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 (e.g., pancreas-kidney, heart-kidney, etc.)
• Significant cardiomyopathy defined as either:
• Left ventricular ejection fraction \<40% on most recent echocardiogram
• Left ventricular ejection fraction ≥40% but \<50% on most recent echocardiogram with an \<5 METS of exercise tolerance
• Reversible ischemia on stress testing without revascularization

Sponsors & Collaborators

• University of Pennsylvania: lead
• Merck Sharp & Dohme LLC: collaborator

Study Sites (1)

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (18)

• 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.

  PMID: 25467560 BACKGROUND

• 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.

  PMID: 25467591 BACKGROUND

• 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.

  PMID: 25895428 BACKGROUND

• 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.

  PMID: 25909356 BACKGROUND

• 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.

  PMID: 22643162 BACKGROUND

• 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.

  PMID: 26456905 BACKGROUND

• 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.

  PMID: 26200976 BACKGROUND

• 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

  BACKGROUND

• Van Deerlin, V. (December 2015). Hepatitis C Virus Genotyping (GenMark Assay) Validation Summary

  BACKGROUND

• 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

  BACKGROUND

• 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.

  BACKGROUND

• 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

  BACKGROUND

• 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.

  BACKGROUND

• Merck Sharp & Dohme Corporation (January 2016). ZEPATIER™ tablets. Highlights of Prescribing Information. 2016.

  BACKGROUND

• Merck Sharp & Dohme Corporation (July 2015). Elbasvir (MK-8742). Investigator's Brochure (8th Ed.). 2015.

  BACKGROUND

• Merck Sharp & Dohme Corporation (July 2015). Grazoprevir (MK-5172). Investigator's Brochure (10th Ed.). 2015.

  BACKGROUND

• Sawinski D, Forde KA, Lo Re V 3rd, Goldberg DS, Cohen JB, Locke JE, Bloom RD, Brensinger C, Weldon J, Shults J, Reese PP. Mortality and Kidney Transplantation Outcomes Among Hepatitis C Virus-Seropositive Maintenance Dialysis Patients: A Retrospective Cohort Study. Am J Kidney Dis. 2019 Jun;73(6):815-826. doi: 10.1053/j.ajkd.2018.11.009. Epub 2019 Jan 29.

  PMID: 30704882 DERIVED

• Reese PP, Abt PL, Blumberg EA, Van Deerlin VM, Bloom RD, Potluri VS, Levine M, Porrett P, Sawinski D, Nazarian SM, Naji A, Hasz R, Suplee L, Trofe-Clark J, Sicilia A, McCauley M, Gentile C, Smith J, Niknam BA, Bleicher M, Reddy KR, Goldberg DS. Twelve-Month Outcomes After Transplant of Hepatitis C-Infected Kidneys Into Uninfected Recipients: A Single-Group Trial. Ann Intern Med. 2018 Sep 4;169(5):273-281. doi: 10.7326/M18-0749. Epub 2018 Aug 7.

  PMID: 30083748 DERIVED

Related Links

• Quest Diagnostics, Inc. (December 2014). Test summary guide. Hepatitis C Viral RNA Genotype 1 NS5a Drug Resistance.
• Sandoz, Inc. (May 2015) Ribavirin capsule. Highlights of Prescribing Information. 2015.

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

elbasvir-grazoprevir drug combination; glecaprevir and pibrentasvir

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Results Point of Contact

• Title: Dr. Peter Reese
• Organization: Perelman School of Medicine

amussell@upenn.edu

215-900-3782

Study Officials

• Stacey Prenner, MD

  University of Hospital of Pennsylvania

  PRINCIPAL INVESTIGATOR

• Peter Reese, MD, MSCE

  University of Hospital of Pennsylvania

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 15, 2016
• First Posted: April 19, 2016
• Study Start: May 1, 2016
• Primary Completion: March 1, 2022
• Study Completion: December 1, 2022
• Last Updated: June 15, 2023
• Results First Posted: June 15, 2023

Record last verified: 2023-06

Locations

US (1)