Administration of Zepatier (Grazoprevir Plus Elbasvir) in Chronic Hemodialysis (HD) Patients With Hepatitis C (HD)

Tracking Information
First Submitted Date ICMJE	November 29, 2017
First Posted Date ICMJE	December 7, 2017
Last Update Posted Date	May 8, 2018
Estimated Study Start Date ICMJE	June 15, 2018
Estimated Primary Completion Date	January 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: December 6, 2017)	SVR - Sustained Virologic Response [ Time Frame: 12 weeks after completion of Elbasivir/Grazoprevir treatment ]; Absence of HCV by viral RNA quantitation at 12 weeks post treatment
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT03365635 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: December 6, 2017)	Approval for DAA by third party payers [ Time Frame: Within one month of last patient enrolled ]; The percent of applications made to third party payers for DAA which are approved
Original Secondary Outcome Measures ICMJE	Same as current
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Administration of Zepatier (Grazoprevir Plus Elbasvir) in Chronic Hemodialysis (HD) Patients With Hepatitis C
Official Title ICMJE	"Real World" Administration of Zepatier (Grazoprevir Plus Elvasvir) in Chronic Hemodialysis Patients With Hepatitis C Infection. Strategies for Identification of Patients, Insurance Approval, Treatment , and Laboratory Monitoring
Brief Summary	This is a study to define strategies for Nephrologists to directly supervise and apply direct acting antivirals to cure hepatitis C in hemodialysis patients. Strategies will include identification of candidate patients, application for insurance approval, specifics of direct acting antiviral therapy (Zepatier with or without ribavirin) and laboratory monitoring during and after therapy.
Detailed Description	Background - Hepatitis C (HCV) is common in hemodialysis (HD) patients with reported prevalences of 25%, By 2020, predicted 775,000 hemodialysis patients in the US, of whom 109,000 will have HCV. Hepatitis C is associated with increased mortality in HD patients, decreased kidney allograft survival, and a source of nosocomial infection in hemodialysis units. Currently drugs to cure HCV - direct acting antivirals (DAA) which can be safely given to HD patients are now available. A significant portion of the medical care provided to HD patients is by Nephrologists and HD staff. Goals of Protocol - 1. Provide guidelines for implementation and monitoring of DAA therapy in HD patients with HCV 2. Provide Nephrologists strategies for identification of candidate HD patients, obtainment of third party approval for DAA payment, specific drug dosing protocols based on genome type of HCV, and laboratory and clinical monitoring during DDA therapy. 3, By reducing the pool of HCV patients in a HD Unit, the risk of nosocomial transmission of HCV t o other patients and staff will be reduced Study Design - an interventional, prospective, non-randomized, non-blinded trial to evaluate real world strategies to identify and treat HCV infected patients with Zepatier Study Procedures 1. Patients who meet inclusion criteria without exclusion criteria be assigned treatment with Zepatier with or without Ribavirin according to following schedule: (a) Genotype 1a - treatment naive without NS5A polymorphism - Zepatier one tablet (100 mg grazoprevir and 50 mg elbasvir) per day for 12 weeks (b) Genotype 1a - treatment naiive with NS5A polymorphism - Zepatier one tablet daily and ribavirin (200 mg) daily for 16 weeks (c) Genotype 1b-treatment naive - Zepatier one daily for 12 weeks (d) Genotype 1a or 1b - prior treatment with INF or HCV NS3/4A protease inhibitor - Zepatier and ribavirin each once daily for 12 weeks (e) Genotype 4 - treatment naive - Zepatier one daily for 12 weeks (f)Genotype 4 -prior treatment - Zepatier and ribavirin each once per day for 16 weeks Baseline/Screening Testing: 1. HCV genotype testing 2. HCV viral RNA load 3. Liver function tests 4, Protime, Partial Thromboplastin time 5. HIV - if positive, then determine viral RNA and CD4 and T cell count 6. Liver biopsy (within 24 mo of treatment) or Fibroscan within 12 mo of treatment 7. Hepatitis BsAg 8. For patients with HCV genotype 1a, test fro NS5A mutation Treatment of HIV/HCV co-infected patients will be done in collaboration with the HIV treating physician to determine if any adjustments in the HIV drug regimen will be required Testing/Evaluations during Active DAA Treatment - 1. LFT and RNA HCV viral load at week 4, 8, and 12. For patients on 16 weeks of treatment, LFT at week 16 as well 2. For patients on combination Zepatier and ribavirin, hemoglobin monitoring every week during treatment 3. Clinical pharmacology evaluation for compliance and adverse events at week 4,8,and 12 (and week 16 for patients on 16 week treatment) Testing/Evaluation Post DAA Treament - 1, RNA viral load at 12 weeks post treatment 2. Clinical Pharmacologoy evaluation 12 weeks post treatment for adverse events 3. patients who achieve sustained viral remission at 12 weeks will be identified in HD records as HCV ab positive but HCV viral load RNA negative
Study Type ICMJE	Interventional
Study Phase	Phase 4
Study Design ICMJE	Intervention Model: Single Group Assignment; Intervention Model Description: An interventional, prospective, non-randomized, non-blinded trial to evaluate real world strategies to identify and treat hepatitis C infected hemodialysis patients with Zepatier Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Hepatitis C; Hemodialysis; Nosocomial Infection
Intervention ICMJE	Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Same as described in arm description; Other Name: Ribavirin 200 mg
Study Arms	Experimental: Genotype 1a -Rx naive -no NS5A polymorph Genotype 1a - treatment naive without NS5A polymorphism - Drug Intervention : Oral administration Elbasvir (50mg)/Grazoprevir (100mg) one tablet per day for 12 weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Experimental: Genotype 1a, Rx naive + NS5A polymorph Genotype 1a - treatment naiive with NS5A polymorphism - Oral administration of Elbasvir/Grazoprevir one tablet daily and ribavirin (200 mg) daily for 16 weeks weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Experimental: Genotype 1b - Rx naive Genotype 1b-treatment naive - Oral administration of Elbasvir/Grazoprevir one daily for 12 weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Experimental: Genotype 1a/1b -prior INF or NS3/4A Genotype 1a or 1b - prior treatment with INF or HCV NS3/4A protease inhibitor - oral administration of Elbasvir/Grazoprevir and ribavirin each once daily for 12 weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Experimental: Genotype4 - treatment naive (e) Genotype 4 - treatment naive - oral administration of Elbasvir/Grazoprevir one daily for 12 weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]; Experimental: Genotype 4- prior treatment Genotype 4 -prior treatment - oral administration of Elbasvir/Grazoprevir and ribavirin each once per day for 16 weeks Intervention: Drug: Elbasvir 50 MG / Grazoprevir 100 MG [Zepatier]
Publications *	Roth D, Nelson DR, Bruchfeld A, Liapakis A, Silva M, Monsour H Jr, Martin P, Pol S, Londoño 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.; Goodkin DA, Bieber B, Jadoul M, Martin P, Kanda E, Pisoni RL. Mortality, Hospitalization, and Quality of Life among Patients with Hepatitis C Infection on Hemodialysis. Clin J Am Soc Nephrol. 2017 Feb 7;12(2):287-297. doi: 10.2215/CJN.07940716. Epub 2016 Dec 1.; Zaki MSE. The effect of Hepatitis C Virus infection on cardiovascular complications in end stage kidney disease patients on regular hemodialysis. Electron Physician. 2017 Feb 25;9(2):3857-3861. doi: 10.19082/3857. eCollection 2017 Feb.; Jadoul M, Horsmans Y. Towards eradication of hepatitis C virus from dialysis units. Lancet. 2015 Oct 17;386(10003):1514-5. doi: 10.1016/S0140-6736(15)00381-5. Epub 2015 Oct 5.; Lo Re V. Extrahepatic Complications of Hepatitis C Virus Infection in HIV and the Impact of Successful Antiviral Treatment. Clin Infect Dis. 2017 Feb 15;64(4):498-500. doi: 10.1093/cid/ciw814.; Cacoub P, Desbois AC, Isnard-Bagnis C, Rocatello D, Ferri C. Hepatitis C virus infection and chronic kidney disease: Time for reappraisal. J Hepatol. 2016 Oct;65(1 Suppl):S82-S94. doi: 10.1016/j.jhep.2016.06.011. Review.; Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int Suppl. 2008 Apr;(109):S1-99. doi: 10.1038/ki.2008.81.; Rao AK, Luckman E, Wise ME, MacCannell T, Blythe D, Lin Y, Xia G, Drobeniuc J, Noble-Wang J, Arduino MJ, Thompson ND, Patel PR, Wilson LE. Outbreak of hepatitis C virus infections at an outpatient hemodialysis facility: the importance of infection control competencies. Nephrol Nurs J. 2013 Mar-Apr;40(2):101-10, 164; quiz 111.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Not yet recruiting
Estimated Enrollment ICMJE; (submitted: December 6, 2017)	18
Original Estimated Enrollment ICMJE	Same as current
Estimated Study Completion Date	April 2019
Estimated Primary Completion Date	January 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Hemodialysis patient; > age 18 years old; Hepatitis C antibody positive and Hepatitis C RNA Quantification positive; Hepatitis C genomes 1a, 1b, or 4; Prior Interferon , ribavirin treatment failures , partial responders, or intolerance to these treatment allowed to enroll; Not of reproductive potential - hemodialysis patients must have no menses for 12 months; Males with partners of reproductive potential as along a 2 reliable forms of contraception are used simultaneously during treatment and for 6 months after completion of treatment; Ability to understand the study procedures, alternative treatments available, risks of participating in the study, and voluntarily agree to participate Exclusion Criteria: Currently undergoing active treatment for HCV with a direct acting antiviral or have previously successfully been treated with a direct acting antiviral; Have moderate or severe hepatic disease - Child-Pugh B or C; Have evidence of decompensated liver disease manifested by ascites, gastric or variceal bleeding, hepatic encephalopathy, or other signs/symptoms of advanced liver disease; Co-administration of known heaptotoxic drugs including but not limited to : etofoxine, isoniazid, nitrofurantoin, phenytoin; Use of strong CYP3A/P-gp inhibitors, organic acid transporting polypeptide 1B1/3 inhibitors, strong inducers of cytochrome 450 3A (CYP3A), efavirenz, or other drugs which may interact with elbasvir/grazoprevir as per package insert; history of substance abuse with alcohol, intravenous drugs, psychotropics, narcotics, cocaine use within 1 year of screening for study; history of any condition, pre-study lab abnormality, or ECG abnormality or history of any illness which in the opinion of the investigators might confound the results of the study or pose additional risks from the administration of elbasvir/grazoprevir; Have evidence of history of chronic hepatitis not caused by HCV including but not limited to nonalcoholic steatohepatitis (NASH), drug induced hepatitis, and autoimmune hepatitis
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years and older (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Michael R Rudnick, MD 215-662-8730 rudnickm@uphs.upenn.edu Contact: Deirdre Sawinski, MD 215-662-7934 Deirdre.Sawinski@uphs.upenn.edu
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT03365635
Other Study ID Numbers ICMJE	828322
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	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
IPD Sharing Statement	Plan to Share IPD: No Plan Description: No research reason to share IPD to other researchers
Responsible Party	Michael Rudnick, University of Pennsylvania
Study Sponsor ICMJE	University of Pennsylvania
Collaborators ICMJE	Merck Sharp & Dohme Corp.
Investigators ICMJE	Principal Investigator: Michael R Rudnick, MD University of Pennsylvania Health System
PRS Account	University of Pennsylvania
Verification Date	February 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP