Efficacy and Safety of Grazoprevir (MK-5172) and Uprifosbuvir (MK-3682) With Elbasvir (MK-8742) or Ruzasvir (MK-8408) for Chronic Hepatitis C Virus (HCV) Genotype (GT) 3, GT4, GT5, and GT6 Infection (MK-3682-012)
Condition: Hepatitis C
MeSH terms: Hepatitis A; Hepatitis C; Hepatitis
Intervention: Grazoprevir; Uprifosbuvir; Elbasvir; Ruzasvir; MK-3682B; Ribavirin (RBV)
Intervention description: Part A: one grazoprevir 100 mg tablet taken q.d. by mouth.; Part A: two or three uprifosbuvir 150 mg (300 or 450 mg total daily dose) tablets taken q.d. by mouth.; Part A: one elbasvir 50 mg tablet taken q.d. by mouth.; Part A: six ruzasvir 10 mg (60 mg total daily dose) capsules taken q.d. by mouth.; Part B and Part C: two FDC tablets, each containing grazoprevir 50 mg + elbasvir 225 mg + ruzasvir 30 mg, taken q.d. by mouth.; Part B and Part C: RBV 200 mg capsules taken b.i.d. by mouth at a total daily dose of 800 mg - 1400 mg based on participant body weight.
Intervention MeSH terms: Ribavirin; Grazoprevir; Ruzasvir; Uprifosbuvir
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 413.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a randomized, three-part, parallel-group, open-label trial of grazoprevir (MK-5172)
      (100 mg) and uprifosbuvir (MK-3682) (300 mg or 450 mg) with either elbasvir (MK-8742) (50 mg)
      or ruzasvir (MK-8408) (60 mg), and with or without ribavirin (RBV), in treatment-naive (TN)
      or treatment-experienced (TE) cirrhotic (C) or non-cirrhotic (NC) participants infected with
      hepatitis C virus (HCV) genotype (GT) 3, GT4, GT5, or GT6. Part A will consist of 4 arms to
      evaluate the safety of dose combinations. In Part B, participants will take 2 uprifosbuvir
      (+) grazoprevir (+) ruzasvir (MK-3682B) fixed dose combination (FDC) tablets once daily
      (q.d.) by mouth, with or without twice-daily (b.i.d.) RBV (200 mg capsules; weight-based
      dosing). Participants who relapse following completion of therapy in Part A will be offered
      the option of retreatment with 16 weeks of uprifosbuvir (+) grazoprevir (+) ruzasvir with RBV
      in Part C (data obtained from Part C will not be used in the analysis of outcome measures).
    

Eligibility criteria:

        Inclusion Criteria:

          -  Has documented chronic HCV GT3, GT4, GT5, or GT6 with no evidence of non-typeable or
             mixed GT infection

          -  Is otherwise healthy as determined by the medical history, physical examination,
             electrocardiogram (ECG), and clinical laboratory measurements performed at the time of
             screening

          -  Has cirrhosis of the liver (Part B only) or is non-cirrhotic (Part A and B)

          -  Is HCV treatment-naïve or has experienced virologic failure after completing a prior
             Pegylated Interferon/Ribavirin (Peg-IFN/RBV) regimen

          -  Is of non childbearing potential or agrees to avoid becoming pregnant or impregnating
             a partner beginning at least 2 weeks prior to administration of the initial dose of
             study drug and for 14 days after the last dose of study drug if not taking RBV, or for
             6 months after the last dose of study drug if taking RBV (or longer if dictated by
             local regulations). If not abstinent from heterosexual activity, participants in Part
             A must use 2 acceptable forms of barrier contraception whereas participants in Parts B
             and C must use 2 acceptable forms of contraception which may include oral
             contraceptives

        Part B only:

          -  If coinfected with human immunodeficiency virus (HIV) is not currently on
             antiretroviral therapy (ART) and has no plans to initiate ART treatment while
             participating in this study OR has well-controlled HIV on ART.

          -  Has at least 1 viable antiretroviral regimen alternative beyond their current regimen
             in the event of HIV virologic failure and the development of anti-retroviral drug
             resistance.

        Exclusion Criteria:

        Parts A, B, and C (unless otherwise specified):

          -  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.

          -  If cirrhotic (Part B only), is Child-Pugh Class B or C or has a Pugh-Turcotte (CPT)
             score >5.

          -  Is coinfected with hepatitis B virus (Parts A, B, and C) or is coinfected with HIV
             (Part A only; HIV coinfected participants are eligible for Parts B and C).

          -  If coinfected with HIV, has a history of opportunistic infection in the preceding 6
             months prior to screening.

          -  Has a history of malignancy ≤5 years prior to signing informed consent 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.

          -  Has clinically-relevant drug or alcohol abuse within 12 months of screening.

          -  Is female and is pregnant or breastfeeding, or expecting to conceive or donate eggs
             from at least 2 weeks prior to Day 1 and 6 months after the last dose of study
             medication, or longer if dictated by local regulations OR a male participant who is
             expecting to donate sperm from at least 2 weeks prior to day 1 until 6 months after
             the last dose of study medication.

          -  Has any of the following conditions:

          -  Organ transplants (including hematopoietic stem cell transplants) other than cornea
             and hair.

          -  Poor venous access that precludes routine peripheral blood sampling required for this
             trial.

          -  History of gastric surgery (e.g., stapling, bypass) or a history of malabsorption
             disorders (e.g., celiac sprue disease).

          -  Current or history of any clinically significant cardiac abnormalities/dysfunction,
             including but not limited to: angina, congestive heart failure, myocardial infarction,
             pulmonary hypertension, complex congenital heart disease, cardiomyopathy, significant
             arrhythmia, uncontrolled hypertension, a history of use of antianginal or
             anti-arrythmic agents for cardiac conditions, prolonged ECG QTc interval (>470 ms for
             males or >480 ms for females by either the Fridericia formula) at the screening visit,
             personal or family history of Torsade de pointes.

          -  Chronic pulmonary disease, including but not limited to: clinically significant
             chronic obstructive pulmonary disease, interstitial lung disease, pulmonary fibrosis,
             sarcoidosis.

          -  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).

          -  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 prescribed,
             and a normal neurological examination is documented in trial files within 6 months of
             Day 1.

          -  Has a history of stroke or transient ischemic attack.

          -  Has a history of a medical/surgical condition that resulted in hospitalization within
             the 3 months prior to enrollment, other than for minor elective procedures.

          -  Has medical/surgical conditions that may result in a need for hospitalization during
             the period of the study.

          -  Has 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.

          -  Has any condition, prestudy laboratory or ECG abnormality or history of any illness,
             which, in the opinion of the investigator, might confound the results of the study or
             pose additional risk in administering the study drugs to the participant.

          -  Has had a life-threatening serious adverse event (SAE) during the screening period.

          -  Has evidence of history of chronic hepatitis not caused by HCV, including but not
             limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis,
             hemochromatosis, Wilson's disease, α1-antitrypsin deficiency, alcoholic liver disease
             and autoimmune hepatitis Parts B and C only: is a male whose female partner(s) is/are
             pregnant