Transplanting Hepatitis C Kidneys Into Negative Kidney Recipients

End Stage Renal Disease Clinical Trial

— THINKER  

Official title:

Open-Labeled Trial Of Direct-Acting Antiviral Treatment Of Hepatitis C-Negative Patients Who Receive Kidney Transplants From Hepatitis C-Positive Donors

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02743897
• Other study ID #: 823833
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: May 1, 2016
• Est. completion date: December 2022

Study information

• Verified date: June 2023
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

Open-labelled pilot clinical trial of Zepatier (Grazoprevir + Elbasvir), Mavyret (Glecaprevir + Pibrentasvir), Epclusa (Sofosbuvir + Velpatasvir), or another appropriate DAA in at least 75 HCV-negative subjects with end-stage renal disease receiving a kidney transplant from a HCV-positive donor. Eligible subjects will receive a kidney transplant from a deceased-donor, and then will receive DAA treatment after kidney transplantation when infection with HCV is confirmed in these kidney transplant recipients. Treatment will be complete after 12 weeks for most subjects.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 62
• Est. completion date: December 2022
• Est. primary completion date: March 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 30 Years to 70 Years

Eligibility

Subject:

Inclusion criteria

• 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

• Inclusion criteria for treatment (not for entry as study patient) will include any detectable HCV RNA

• Able to provide informed consent

Exclusion criteria

• 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

Donor Organ Selection:

Inclusion Criteria

• Detectable HCV RNA

• Age =60 years

• Study modified Kidney donor profile index (KDPI) score =0.856 - calculated as if the kidney were HCV-negative (https://optn.transplant.hrsa.gov/resources/allocation-calculators/kdpi-calculator/)

Exclusion Criteria

• Anatomical issues in the kidney allograft that raise the risk of post-transplant complications (e.g., number or length of renal arteries or veins)

• Confirmed HIV positive

• Confirmed HBV positive (positive Hepatitis B surface antigen and/or HBV DNA)

• Known previously failed treatment for HCV using a regimen with a direct-acting antiviral (can have received interferon monotherapy and/or interferon + ribavirin combination therapy)

Related Conditions & MeSH terms

• End Stage Renal Disease
• Hepatitis
• Hepatitis C
• Kidney Diseases
• Kidney Failure, Chronic

Intervention

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.
• Mavyret
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.

Locations

Country	Name	City	State
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
University of Pennsylvania	Merck Sharp & Dohme LLC

Country where clinical trial is conducted

United States, 

References & Publications (16)

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.

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. — View Citation

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. Erratum In: Lancet. 2015 Mar 21;385(9973):1074. — View Citation

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.

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. — View Citation

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

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

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. — View Citation

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. Erratum In: Lancet. 2015 Nov 7;386(10006):1824. — View Citation

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. — View Citation

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.

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

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

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. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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

External 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.