Clinical trial NCT02105688: An Efficacy and Safety Study of Grazoprevir (MK-5172) + Elbasvir (MK-8742) in the Treatment of Chronic Hepatitis C Virus (HCV) Genotype (GT)1, 4, or 6 Infection in Treatment-Naïve Participants Who Are on Opiate Substitution Therapy (MK-5172-062)
Official title: A Phase III Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172/MK-8742 in Treatment-Naïve Subjects With Chronic HCV GT1, GT4, and GT6 Infection Who Are on Opiate Substitution Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chronic Hepatitis C
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-04-07
Enrollment: 301
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a 2-part study. The purpose of Part A is to assess the efficacy and safety of grazoprevir (MK-5172) 100 mg in combination with elbasvir (MK-8742) 50 mg for 12 weeks in the treatment of chronic HCV GT1, GT4, or GT6 infection in treatment-naïve participants who are on opiate substitution therapy (OST). The primary hypothesis is that the percentage of participants who receive grazoprevir/elbasvir fixed-dose combination (FDC) in the Immediate Treatment Arm and achieve a Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) will be superior to 67%. In addition, participants who received at least 1 dose of grazoprevir/elbasvir in Part A will be eligible to participate in Part B, which is a 3-year observational follow-up.


Eligibility criteria: Inclusion Criteria:

Part A

* Documented chronic HCV GT1, GT4, or GT6 infection with no evidence of GT2, GT3, GT5 or non-typeable genotypes and HCV ribonucleic acid (RNA) confirmed by screening lab results prior to randomization
* On opiate substitution therapy (OST; methadone, levamethadone, buprenorphine, naloxone, naltrexone) for at least 3 months prior to screening
* Treatment naïve to all HCV therapies
* Human Immunodeficiency Virus (HIV)-infected participants enrolled in this study must meet following criteria:
* Documented HIV infection
* Naïve to treatment with any antiretroviral therapy (ART) OR on HIV ART for at least 8 weeks prior to study entry using a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone of tenofovir or abacavir and either emtricitabine or lamivudine PLUS raltegravir (or dolutegravir or rilpivirine). Dose modifications or changes in ART during the 4 weeks prior to study entry (Day 1) are not permitted
* Cluster of differentiation 4 (CD4+) T-cell count \>200 cells/mm\^3 if on ART or \>500 cell/mm\^3 if ART treatment naïve
* Undetectable plasma HIV-1 RNA at least 8 weeks prior to screening if on ART or \<50,000 copies/mL if ART treatment naïve
* Participants with HIV-1 infection and on ART must have at least one viable antiretroviral regimen alternative beyond their current regimen in the event of HIV virologic failure or the development of anti-retroviral drug resistance
* Females who are of reproductive potential must agree to avoid becoming pregnant while receiving study drug and for 14 days after the last dose of study drug by complying with one of the following: (1) practice abstinence from heterosexual activity OR (2) use (or have her partner use) acceptable contraception during heterosexual activity

Part B

* Received at least one dose of grazoprevir in combination with elbasvir in Part A. Receiving OST and keeping \>80% of scheduled appointments while on OST were not required for Part B.

Exclusion Criteria:

Part A

* Evidence of decompensated liver disease
* For participants with cirrhosis, participants who are Child-Pugh Class B or C or who have a Pugh-Turcotte (CPT) score \>6
* Is co-infected with hepatitis B virus
* Has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC
* Currently using or intends to use barbiturates during the treatment period of this study
* Is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs from Day 1 or anytime during treatment, and 14 days after the last dose of study medication, or longer if dictated by local regulations
* Any medical condition requiring or likely to require chronic systemic administration of corticosteroids, Tumor Necrosis Factor (TNF) antagonists, or other immunosuppressant drugs during the course of the trial
* Evidence or history of chronic hepatitis not caused by HCV

Part B

* Mentally or legally incapacitated, has significant emotional problems at the time of pre-study screening visit or expected during the conduct of the study or has a history of a clinically significant psychiatric disorder which, in the opinion of the investigator, would interfere with the study procedures
* Has a medical condition or personal circumstance which, in the opinion of the investigator and/or Sponsor, places the participant at unnecessary risk through continued participation in the trial or does not allow the participant to adhere to the requirements of the protocol

Primary outcomes:
measure: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12)
timeFrame: 12 weeks after end of all therapy (Study Week 24 for Immediate Treatment Arm and Study Week 40 for Deferred Treatment Arm)
measure: Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and First 14 Follow-up Days
timeFrame: DB Treatment period plus first 14 follow-up days (up to Study Week 14)
measure: Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period
timeFrame: DB Treatment period (up to Study Week 12)
Secondary outcomes:
measure: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24)
timeFrame: 24 weeks after end of all therapy (Study Week 36 for Immediate Treatment Arm and Study Week 52 for Deferred Treatment Arm)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Dore GJ, Altice F, Litwin AH, Dalgard O, Gane EJ, Shibolet O, Luetkemeyer A, Nahass R, Peng CY, Conway B, Grebely J, Howe AY, Gendrano IN, Chen E, Huang HC, Dutko FJ, Nickle DC, Nguyen BY, Wahl J, Barr E, Robertson MN, Platt HL; C-EDGE CO-STAR Study Group. Elbasvir-Grazoprevir to Treat Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy: A Randomized Trial. Ann Intern Med. 2016 Nov 1;165(9):625-634. doi: 10.7326/M16-0816. Epub 2016 Aug 9.
citation: Grebely J, Dore GJ, Altice FL, Conway B, Litwin AH, Norton BL, Dalgard O, Gane EJ, Shibolet O, Nahass R, Luetkemeyer AF, Peng CY, Iser D, Gendrano IN, Kelly MM, Hwang P, Asante-Appiah E, Haber BA, Barr E, Robertson MN, Platt H. Reinfection and Risk Behaviors After Treatment of Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy : A Cohort Study. Ann Intern Med. 2022 Sep;175(9):1221-1229. doi: 10.7326/M21-4119. Epub 2022 Aug 9.
citation: Asselah T, Reesink H, Gerstoft J, de Ledinghen V, Pockros PJ, Robertson M, Hwang P, Asante-Appiah E, Wahl J, Nguyen BY, Barr E, Talwani R, Serfaty L. Efficacy of elbasvir and grazoprevir in participants with hepatitis C virus genotype 4 infection: A pooled analysis. Liver Int. 2018 Sep;38(9):1583-1591. doi: 10.1111/liv.13727. Epub 2018 Mar 31.
citation: Reau N, Robertson MN, Feng HP, Caro L, Yeh WW, Nguyen BT, Wahl J, Barr E, Hwang P, Klopfer SO. Concomitant proton pump inhibitor use does not reduce the efficacy of elbasvir/grazoprevir: A pooled analysis of 1,322 patients with hepatitis C infection. Hepatol Commun. 2017 Aug 22;1(8):757-764. doi: 10.1002/hep4.1081. eCollection 2017 Oct.