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) (C-EDGE CO-STAR)

• ClinicalTrials.gov Identifier: NCT02105688
• Recruitment Status: Completed
• First Posted: April 7, 2014
• Results First Posted: July 11, 2016
• Last Update Posted: December 5, 2019
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: April 2, 2014
• First Posted Date: April 7, 2014
• Results First Submitted Date: May 26, 2016
• Results First Posted Date: July 11, 2016
• Last Update Posted Date: December 5, 2019
• Actual Study Start Date: September 2, 2014
• Actual Primary Completion Date: June 10, 2015 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 11, 2019)

• Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12) [ Time Frame: 12 weeks after end of all therapy (Study Week 24 for Immediate Treatment Arm and Study Week 40 for Deferred Treatment Arm) ]
  Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which had a lower limit of quantification of 15 IU/mL. SVR12 was defined as HCV RNA below the lower limit of detection (<LLOQ) at 12 weeks after the end of all study therapy for baseline infection, or HCV RNA≥ LLOQ demonstrated to be due to reinfection (after clearance of baseline infection). The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR12 rate. The primary efficacy analysis for Part A was the percentage of participants in the immediate treatment arm (ITA) who achieved SVR12. SVR12 was also calculated for the Deferred Treatment Arm.
• Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Double-Blind (DB) Treatment Period and First 14 Follow-up Days [ Time Frame: DB Treatment period plus first 14 follow-up days (up to Study Week 14) ]
  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants experiencing an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period.
• Percentage of Participants Discontinued From Study Therapy Due to AEs During the DB Treatment Period [ Time Frame: DB Treatment period (up to Study Week 12) ]
  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the Sponsor's product, was also an AE. For this outcome measure, the primary safety analysis compared the percentage of participants discontinuing study therapy due to an AE in the Immediate Treatment Arm during the double-blinded active treatment period to that of the Deferred Treatment Arm during the double-blinded placebo treatment period.

Original Primary Outcome Measures (submitted: April 2, 2014)

• Percentage of partcipants achieving Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) [ Time Frame: Follow-up Week 12 (Up to 24 weeks) ]
• Percentage of participants experiencing adverse events [ Time Frame: Up to 36 weeks ]
• Percentage of participants discontinuing study drug due to adverse events [ Time Frame: Up to 12 weeks ]

Current Secondary Outcome Measures (submitted: November 11, 2019)

Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24) [ Time Frame: 24 weeks after end of all therapy (Study Week 36 for Immediate Treatment Arm and Study Week 52 for Deferred Treatment Arm) ]

Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS® AmpliPrep/COBAS® Taqman HCV Test, v2.0, which has an LLOQ of 15 IU/mL. SVR24 was defined as HCV RNA <LLOQ at 24 weeks after the end of all study therapy. The Clopper-Pearson method was used to construct 95% confidence intervals for the SVR24 rate. The secondary efficacy analysis for Part A evaluated the percentage of participants in the immediate treatment arm (ITA) who achieved SVR24. SVR24 was also calculated for the Deferred Treatment Arm.

• Original Secondary Outcome Measures (submitted: April 2, 2014): Percentage of participants achieving Sustained Virologic Response 24 weeks after the end of all study therapy (SVR24) [ Time Frame: Follow-up Week 24 (Up to 36 weeks) ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Chronic Hepatitis C

Intervention

• Drug: Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet (MK-5172A)
  Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet, taken once daily by mouth for 12 weeks.
  Other Name: MK-5172A
• Drug: Placebo to Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet
  Placebo Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet, taken once daily by mouth for 12 weeks.

Study Arms

• Experimental: Immediate Treatment Arm: Grazoprevir/Elbasvir
  In Part A, participants receive grazoprevir 100 mg plus elbasvir 50 mg FDC (MK-5172A) once daily for 12 weeks (blinded) and were followed-up for 24 weeks. In Part B, participants could enroll in a 3-year follow-up period where they were followed every 6 months for 3 years in an observational cohort (no treatment was administered during Part B).
  Intervention: Drug: Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet (MK-5172A)
• Placebo Comparator: Deferred Treatment Arm: Placebo > Grazoprevir/Elbasvir
  In Part A, participants receive placebo to MK-5172A once daily for 12 weeks (blinded), followed by 4 weeks of follow-up. Afterwards, participants received 12 weeks of open-label treatment with the MK-5172A FDC and were followed-up for 24 weeks. In Part B, participants could enroll in a 3-year follow-up period where they were followed every 6 months for 3 years in an observational cohort (no treatment was administered during Part B).
  Interventions:

  • Drug: Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet (MK-5172A)
  • Drug: Placebo to Grazoprevir 100 mg/Elbasvir 50 mg FDC tablet

Publications *

• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 26, 2015): 301
• Original Estimated Enrollment (submitted: April 2, 2014): 200
• Actual Study Completion Date: December 4, 2018
• Actual Primary Completion Date: June 10, 2015 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Not Provided
• Removed Location Countries: Australia, Canada, France, Germany, Israel, Netherlands, New Zealand, Norway, Puerto Rico, Romania, Spain, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT02105688
• Other Study ID Numbers: 5172-062; 2014-000343-32 ( EudraCT Number ); MK-5172-062 ( Other Identifier: Merck )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Responsible Party: Merck Sharp & Dohme Corp.
• Study Sponsor: Merck Sharp & Dohme Corp.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: November 2019