Efficacy and Safety of Grazoprevir (+) Uprifosbuvir (+) Ruzasvir (MK-3682B) (MK-5172 + MK-3682 + MK-8408) Fixed Dose Combination in Chronic HCV Participants Failing Prior Antiviral Treatment (MK-3682-021)

NCT02613403 | Terminated Phase 2 Results FDA Drug

• 3 other identifiers: 3682-021MK-3682-0212015-001483-19
• Study Type: interventional
• Target: 94
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a randomized, multicenter, 2-part, open-label trial of the combination regimen of grazoprevir (GZR \[MK-5172\]; 100mg), uprifosbuvir (UPR \[MK-3682\]; 450 mg) and ruzasvir (RZR \[MK-8408\]; 60 mg) with and without Ribavirin (RBV) in cirrhotic (C) or non-cirrhotic (NC) participants infected with hepatitis C virus (HCV) previously failing a direct-acting antiviral regimen (DAA). The combination regimen, referred to as MK-3682B, will be administered as two fixed-dose combination (FDC) tablets, given once-daily. The study will evaluate the efficacy of MK-3682B with or without RBV as assessed by the proportion of participants achieving Sustained Virologic Response 12 weeks (SVR12) after the end of all study therapy.

Conditions

Hepatitis; Hepatitis C; Digestive System Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Liver Diseases; RNA Virus Infections; Virus Diseases

Outcome Measures

Primary Outcomes (9)

• Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After The End of Study Therapy (SVR12)

  The percentage of participants achieving SVR12 was determined, defined as having a plasma HCV ribonucleic acid (RNA) level below the lower limit of quantification (LLOQ) 12 weeks after the end of study therapy. Plasma HCV RNA level was measured using the Roche COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay with a LLOQ of 15 IU/mL.

  12 weeks following final dose of study treatment ([MK-3682B + RBV Groups]: Study Week 28; [MK-3682B Groups]: Study Week 36)

• Number of Participants Who Experienced an Adverse Event

  The number of participants experiencing an adverse event (AE) was assessed. An AE is any unfavorable and unintended medical occurrence, symptom, or disease witnessed in a participant, regardless of whether or not a causal relationship with the study treatment can be demonstrated. Further, any worsening of a preexisting condition that is temporally associated with the use of the study treatment is also considered an AE.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Discontinued Study Drug Due to an Adverse Event

  The number of participants discontinuing study drug due to an AE was assessed.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced a Serious Adverse Event

  The number of participants experiencing a serious adverse event (SAE) was assessed. An SAE is an adverse event that: results in death; is life threatening; results in persistent or significant disability or incapacity; results in or prolongs a hospitalization; is a congenital anomaly or birth defect; is a cancer; or may jeopardize the participant, potentially require medical or surgical intervention.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced a Drug-Related Adverse Event

  The number of participants experiencing a drug-related AE was assessed. A drug-related AE was an AE thought to be possibly, probably, or definitely related to the study drug as determined by the investigator.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced a Serious and Drug-Related Adverse Event

  The number of participants experiencing a serious and drug-related AE was assessed.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced an Accidental or Intentional Overdose Without Adverse Effect

  The number of participants experiencing an accidental or intentional overdose without adverse effect was determined. Per study protocol, any occurrence of a participant receiving either MK-3682B or RBV at any dose higher than prescribed was considered an overdose. If this definition of overdose was met without any associated clinical symptoms or abnormal laboratory results, this occurrence of overdose was reported as an accidental or intentional overdose without adverse effect.

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced a Non-Overdose Event of Clinical Interest

  The number of participants experiencing a non-overdose event of clinical interest (ECI) was determined. Non-overdose ECIs, assessed from initiation of study therapy through 14 days following study treatment cessation, included the following: 1) aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \>500 IU/L; or 2) AST or ALT \>3x nadir value and \>3X upper limit normal (ULN).

  Up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

• Number of Participants Who Experienced AST/ALT >5x Upper Limit Normal (ULN)

  The number of participants experiencing AST / ALT \>5 times ULN from study week 4 until 2 weeks following completion of study therapy was determined.

  From Study Week 4 up to 2 weeks following cessation of study treatment ([MK-3682B + RBV Groups]: Up to Week 18; [MK-3682B Groups]: Up to Week 26)

Study Arms (5)

[Part A, Arm 1] Prior SOF/LDV Failure: MK-3682B + RBV

EXPERIMENTAL

C or NC HCV GT1 participants previously failing a DAA regimen of SOF/LDV receive MK-3682B, an FDC of GZR (MK-5172 \[50 mg\]) + UPR (MK-3682 \[225 mg\]) + RZR (MK-8408 \[30 mg\]), administered as 2 tablets once daily in combination with RBV twice daily for 16 weeks.

Drug: MK-3682B; Drug: Ribavirin

[Part A, Arm 2] Prior SOF/LDV Failure: MK-3682B

EXPERIMENTAL

C or NC HCV GT1 participants previously failing a DAA regimen of SOF/LDV receive MK-3682B, an FDC of GZR (MK-5172 \[50 mg\]) + UPR (MK-3682 \[225 mg\]) + RZR (MK-8408 \[30 mg\]), administered as 2 tablets once daily for 24 weeks.

Drug: MK-3682B

[Part A, Arm 3] Prior GZR/EBR Failure: MK-3682B + RBV

EXPERIMENTAL

C or NC HCV GT1 participants previously failing a DAA regimen of GZR/EBR (MK-5172/MK-8742) receive MK-3682B, an FDC of GZR (MK-5172 \[50 mg\]) + UPR (MK-3682 \[225 mg\]) + RZR (MK-8408 \[30 mg\]), administered as 2 tablets once daily in combination with RBV twice daily for 16 weeks.

Drug: MK-3682B; Drug: Ribavirin

[Part A, Arm 4] Prior GZR/EBR Failure: MK-3682B

EXPERIMENTAL

C or NC HCV GT1 participants previously failing a DAA regimen of GZR/EBR (MK-5172/MK-8742) receive MK-3682B, an FDC of GZR (MK-5172 \[50 mg\]) + UPR (MK-3682 \[225 mg\]) + RZR (MK-8408 \[30 mg\]), administered as 2 tablets once daily for 24 weeks.

Drug: MK-3682B

[Part B] Prior DAA (GT1-6) or SOF/PR (GT3) Failure: MK-3682B

EXPERIMENTAL

C or NC HCV participants previously failing any all-oral DAA regimen (GT1-6) or SOF/PR regimen (GT 3 only) receive MK-3682B, an FDC of GZR (MK-5172 \[50 mg\]) + UPR (MK-3682 \[225 mg\]) + RZR (MK-8408 \[30 mg\]), administered as 2 tablets once daily for 16 weeks.

Drug: MK-3682B

Interventions

MK-3682B DRUG

Two MK- 3682B 1,136 mg FDC tablets each containing 50 mg MK-5172 (GZR), 225 mg MK-3682 (UPR, formerly IDX21437), and 30 mg MK-8408 (RZR) taken once daily by mouth.

[Part A, Arm 1] Prior SOF/LDV Failure: MK-3682B + RBV; [Part A, Arm 2] Prior SOF/LDV Failure: MK-3682B; [Part A, Arm 3] Prior GZR/EBR Failure: MK-3682B + RBV; [Part A, Arm 4] Prior GZR/EBR Failure: MK-3682B; [Part B] Prior DAA (GT1-6) or SOF/PR (GT3) Failure: MK-3682B

Ribavirin DRUG

Ribavirin 200 mg capsules, taken twice daily by mouth as part of a weight-based dosing regimen. Depending on participant body weight, total daily dose of Ribavirin may be 800, 1000, 1200 or 1400 mg per day.

[Part A, Arm 1] Prior SOF/LDV Failure: MK-3682B + RBV; [Part A, Arm 3] Prior GZR/EBR Failure: MK-3682B + RBV

Eligibility Criteria

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

You may qualify if:

• Part A
• Has documented chronic HCV GT1 or HCV GT3 infection with no evidence of non-typeable or mixed genotype.
• Has documented relapse, defined as having HCV RNA target not detected at end-of-treatment, but HCV RNA quantifiable during follow-up, after treatment with one of the following DAA regimens either by approved dosage and duration or by completion of a clinical trial: GT1: SOF/LDV ± RBV; GT1: GZR/EBR ± RBV; GT3: SOF + RBV; GT3: SOF + PR; GT3: SOF + DCV ± RBV; GT3: SOF/LDV ± RBV.
• Is otherwise healthy.
• If male, be not of reproductive potential or agree to avoid impregnating a partner beginning at least 2 weeks prior to administration of the initial dose of study drug, through 6 months after taking the last dose of study drug (or longer if dictated by local regulations), by complying with one of the following: (1) practice abstinence from heterosexual activity or (2) use (or have their partner use) two forms of acceptable contraception during heterosexual activity which may include oral contraceptives.
• Part B
• Has documented chronic HCV GT1, GT2, GT3, GT4, GT5, GT6 infection with no evidence of non-typeable or mixed genotype.
• Has documented virologic failure, defined as having quantifiable HCV RNA at any time after completion of HCV therapy with a DAA regimen either by approved dosage and duration or by completion of a clinical trial that was not attributed to re-infection: GT1, GT2, GT4, GT5, or GT6: any prior all-oral DAA regimens; GT3: any prior all-oral DAA regimen or SOF/PR. Participants \[Parts A and B\] who previously failed PR treatment, with or without simepravir (SIM), boceprevir (BOC), or telaprevir (TPV), prior to receiving DAA therapy, may also be enrolled.
• Parts A and B
• Has HCV RNA ≥ 10,000 IU/mL in peripheral blood at enrollment.
• Has either absence of cirrhosis or presence of compensated cirrhosis.
• If female, be not of reproductive potential or agree to avoid becoming pregnant beginning at least 2 weeks prior to administration of the initial dose of study drug, through either 6 months \[Part A\] or 14 days \[Part B\] after taking the last dose of study drug (or longer if dictated by local regulations), by complying with one of the following: (1) practice abstinence from heterosexual activity or (2) use (or have their partner use) two forms of acceptable contraception during heterosexual activity which may include oral contraceptives.
• For HIV co-infected participants: 1) have documented HIV-1 infection \[Part A\] or HIV infection \[Part B\]; 2) either not be currently on antiretroviral therapy (ART) with no plans to initiate ART while participating in this study or have well controlled HIV on ART; and 3) have at least one viable antiretroviral regimen alternative beyond their current regimen in the event of HIV virologic failure and the development of anti-retroviral drug resistance \[Part A\].

You may not qualify if:

• Part A
• Has previously received a DAA containing regimen other than the permitted regimens listed above.
• Did not complete their prior DAA therapy due to intolerance to the DAA regimen or who failed the DAA regimen for reasons other than relapse (e.g., virologic breakthrough, rebound or non-response, non-compliance, lost to follow-up, withdrew consent).
• Is a male whose female partner(s) is/are pregnant or is a male who is expecting to donate sperm or planning to impregnate female partner(s) from at least two weeks prior to Day 1 through at least 6 months after last dose of study drug, or longer if dictated by local regulations.
• Has personal or family history of Torsade de pointes.
• Has chronic pulmonary disease.
• Has an hemoglobinopathy.
• Has central nervous system (CNS) trauma requiring intubation, intracranial pressure monitoring, brain meningeal or skull surgery, or resulting in seizure, coma, permanent neurologic deficits, abnormal brain imaging, or cerebral spinal fluid (CSF) leak; prior brain hemorrhage and/or intracranial aneurysms (whether adequately repaired or not).
• Has current or history of seizure disorder unless seizure was \>10 years ago, a single isolated event, no history of or current use of anti-seizure medications, and a documented normal neurological examination at Day 1.
• Has history of stroke or transient ischemic attack.
• Part B
• Did not complete their prior DAA therapy due to intolerance to the DAA regimen or who failed the DAA regimen for reasons other than virologic failure.
• Has any major medical condition, clinically-significant illness (other than HCV), pretrial laboratory or ECG abnormality, or history of any illness that might interfere with treatment, assessment, compliance or pose additional risk in administering study drug to the participant.
• Parts A and B
• Is under the age of legal consent, is 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.

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Wyles D, Wedemeyer H, Ben-Ari Z, Gane EJ, Hansen JB, Jacobson IM, Laursen AL, Luetkemeyer A, Nahass R, Pianko S, Zeuzem S, Jumes P, Huang HC, Butterton J, Robertson M, Wahl J, Barr E, Joeng HK, Martin E, Serfaty L; C-CREST Part C and C-SURGE Investigators. Grazoprevir, ruzasvir, and uprifosbuvir for hepatitis C virus after NS5A treatment failure. Hepatology. 2017 Dec;66(6):1794-1804. doi: 10.1002/hep.29358. Epub 2017 Oct 30.

  PMID: 28688129 RESULT

MeSH Terms

Conditions

Hepatitis; Hepatitis C; Digestive System Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Liver Diseases; RNA Virus Infections; Virus Diseases

Interventions

Ribavirin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections

Intervention Hierarchy (Ancestors)

Ribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 20, 2015
• First Posted: November 24, 2015
• Study Start: December 10, 2015
• Primary Completion: January 9, 2017
• Study Completion: March 27, 2017
• Last Updated: May 22, 2024
• Results First Posted: March 20, 2018

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share