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)
Condition: Hepatitis; Hepatitis C; Digestive System Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Liver Diseases; RNA Virus Infections; Virus Diseases
MeSH terms: Infections; Communicable Diseases; Hepatitis A; Virus Diseases; Hepatitis C; RNA Virus Infections; Hepatitis, Viral, Human; Flaviviridae Infections; Hepatitis; Liver Diseases; Digestive System Diseases; Gastrointestinal Diseases
Intervention: MK-3682B; Ribavirin
Intervention description: 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.; 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.
Intervention MeSH terms: Ribavirin; Uprifosbuvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 94.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        Inclusion Criteria:

        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].

        Exclusion Criteria:

        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.

          -  Has evidence of decompensated liver disease manifested by the presence of or history
             of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other
             signs or symptoms of advanced liver disease.

          -  Has cirrhosis classified as Child-Pugh Class B or C or has a Pugh-Turcotte score >6

          -  Is co-infected with hepatitis B virus (HBV)

          -  For participants with HIV, has a history of opportunistic infection in the 6 months
             prior to screening.

          -  Has a history of malignancy ≤5 years prior to enrollment except for adequately treated
             basal cell or squamous cell skin cancer or in situ cervical cancer or carcinoma in
             situ; or is under evaluation for other active or suspected malignancy.

          -  Has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of
             hepatocellular carcinoma (HCC) or is under evaluation for HCC.

          -  Is currently participating or has participated in a study with an investigational
             compound within 30 days of signing informed consent and is not willing to refrain from
             participating in another such study during the course of this study (trial treatment
             period). Participants participating in MK-5172-017 (NCT01667081) may be enrolled in
             this study, MK- 3682-021.

          -  Has clinically-relevant drug or alcohol abuse within 12 months of screening

          -  Is a female and is pregnant or breastfeeding or expecting to conceive or donate eggs
             from at least 2 weeks prior to Day 1 through at least 6 months [Part A] or 14 days
             [Part B] after last dose of study drug, or longer if dictated by local regulations.

          -  Has organ transplants (including hematopoietic stem cell transplants) other than
             cornea and hair.

          -  Has history of gastric surgery or history of malabsorption disorders.

          -  Has current or history of any clinically significant cardiac
             abnormalities/dysfunction.

          -  Has medical/surgical conditions that may result in a need for hospitalization during
             the period of the study.

          -  Has a 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 study

          -  Has evidence of history of chronic hepatitis not caused by HCV. Participants with
             history of acute non-HCV-related hepatitis, that resolved >6 months before study
             entry, may be enrolled.