Efficacy and Safety of Combination Grazoprevir (MK-5172) + Elbasvir (MK-8742) + Ribavirin (RBV) in Genotype 2 Hepatitis C Infection (MK-5172-047)

Study Overview
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Brief Summary
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This is a multi-site, open-label trial evaluating the safety and efficacy of 100 mg of grazoprevir (MK-5172) used in combination with or without 50 mg of elbasvir (MK-8742) and/or ribavirin (RBV) in treating non-cirrhotic treatment-naïve participants with chronic genotype (GT) 2, 4, 5, and 6 hepatitis C infection. In Part A there is no randomization or stratification; all GT2 participants will be assigned to arm A1. In Part B, all GT2 participants will be assigned to Arm B1 and all participants with GT4, GT5 and GT6 will be randomized in a 1:1 ratio to either Arm 3 or Arm 4 with stratification by genotype.

Official Title
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A Phase II Clinical Trial to Evaluate the Efficacy and Safety of a Combination Regimen of MK-5172 With/Without MK-8742 and/or Ribavirin (RBV) in Treatment-naive Subjects With Chronic Hepatitis C Genotype 2, 4, 5 and 6 Infection

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Grazoprevir
* Drug: Elbasvir
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Parts A and B: -Body weight ≥50 kg (111 lbs) and ≤ 125 kg (275 lbs) -Has absence of cirrhosis -Agrees to use two acceptable methods of birth control from at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations (for female participant who is of childbearing potential or male participant with female sexual partner who is of childbearing potential). Part A only: -Has chronic HCV GT2 infection Part B only: -Has chronic HCV GT2, GT4, GT5, or GT6 infection Exclusion Criteria: Parts A and B: -Is not treatment naïve (participant has had previous treatment with any interferon, RBV, approved or experimental direct acting antiviral(s), or other investigational therapies for HCV) -Is determined to be coinfected with hepatitis B virus (HBsAg positive) or HIV -Has evidence of, or is under evaluation for, hepatocellular carcinoma (HCC) -Has a clinical diagnosis of substance abuse including the following specified drugs within specified timeframes: Alcohol, intravenous drugs, inhalational, psychotropics, narcotics, cocaine use, prescription or over-the-counter drugs (within 1 year of the screening visit), is receiving opiate agonist substitution therapy (within 1 year of screening visit), or excessive historic marijuana use -Has evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years -Female participant who is pregnant, lactating, expecting to conceive or donate eggs, or is of childbearing potential and unwilling to commit to two methods of birth control throughout treatment and after the completion of all treatment, or male participant who is planning to impregnate or provide sperm donation or has a female sexual partner of childbearing potential and is unwilling to commit to using a two methods of birth control throughout treatment and after the completion of all treatment -Has evidence or history of chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis. -Has uncontrolled diabetes (documented HbA1c >8.5%) Part A only: -Has non GT2 HCV infection Part B only: -Has HCV infection with a genotype other than GT2, GT4, GT5 or GT6

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GT2: Grazoprevir + Elbasvir + RBV (Arm A1)<br>During Part A of the study, GT2 participants will receive 100 mg grazoprevir + 50 mg elbasvir + standard weight-based dosing of RBV for 12 weeks. | Drug: Grazoprevir<br>* 100 mg every day (QD) orally<br>* Other names: MK-5172;Drug: Elbasvir<br>* 50 mg QD orally<br>* Other names: MK-8742;Drug: Ribavirin<br>* Administered twice daily (BID) orally at a total daily dose of 800 mg to 1400 mg based on participant's weight on Day 1<br>* Other names: Rebetol™;|
| Experimental: GT2: Grazoprevir + RBV (Arm B1)<br>During Part B of the study, GT2 participants will receive 100 mg grazoprevir + standard weight-based dosing of RBV for 12 weeks. | Drug: Grazoprevir<br>* 100 mg every day (QD) orally<br>* Other names: MK-5172;Drug: Ribavirin<br>* Administered twice daily (BID) orally at a total daily dose of 800 mg to 1400 mg based on participant's weight on Day 1<br>* Other names: Rebetol™;|
| Experimental: GT 4,5,6: Grazoprevir + Elbasvir + RBV (Arm B2)<br>During Part B of the study, GT4/GT5/GT6 participants will receive 100 mg grazoprevir + 50 mg elbasvir + standard weight-based dosing of RBV for 12 weeks. | Drug: Grazoprevir<br>* 100 mg every day (QD) orally<br>* Other names: MK-5172;Drug: Elbasvir<br>* 50 mg QD orally<br>* Other names: MK-8742;Drug: Ribavirin<br>* Administered twice daily (BID) orally at a total daily dose of 800 mg to 1400 mg based on participant's weight on Day 1<br>* Other names: Rebetol™;|
| Experimental: GT 4,5,6: Grazoprevir + Elbasvir (Arm B3)<br>During Part B of the study, GT4/GT5/GT6 participants will receive 100 mg grazoprevir + 50 mg elbasvir for 12 weeks. | Drug: Grazoprevir<br>* 100 mg every day (QD) orally<br>* Other names: MK-5172;Drug: Elbasvir<br>* 50 mg QD orally<br>* Other names: MK-8742;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 12 Weeks After The End of Study Therapy (SVR12) | SVR12 was defined as Hepatitis C Virus ribonucleic acid (HCV RNA) <25 IU/mL, either target detected but unquantifiable (TD[u]) or target not detected (TND), at 12 weeks after the end of all study therapy. The percentage of participants with SVR12 and accompanying 95% confidence intervals (CIs) were reported for each treatment arm in the Per-Protocol (PP) Population. | 12 weeks after end of all therapy (Study Week 24) | 
| Percentage of Participants With Adverse Events (AEs), Serious AEs (SAEs), Drug-Related AEs, Drug-Related SAEs, or Discontinuation of Study Treatment Due to AE During the Treatment Period and First 14 Follow-up Days | 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 unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. An SAE was an AE that resulted in death, was life threatening, resulted in persistent or significant disability/incapacity, resulted in or prolonged an existing inpatient hospitalization, was a congenital anomaly/birth defect, was a cancer, was associated with an overdose, was another important medical event. The investigator determined the relationship of the AE to the treatment as unrelated or possibly, probably, or definitely related. | Treatment period plus the first 14 days of follow-up (up to 14 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Time to First Achievement of Undetectable HCV RNA During Treatment | HCV-RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test (v.2.0) on blood samples drawn from each participant during treatment at TWs 1, 2, 4, 8, and 12. Undetectable HCV RNA (or TND) was defined as below the 9.3 IU/ml limit of detection. Kaplan Meier summary statistics were calculated for each treatment arm in the Full Analysis Set (FAS). | From TW1 until first achievement of undetectable HCV RNA (up to 12 weeks) | 
| Percentage of Participants Achieving Undetectable HCV RNA During Treatment By Timepoint | HCV-RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test (v.2.0) on blood samples drawn from each participant during treatment at TWs 1, 2, 4, 8, and 12. Undetectable HCV RNA (or TND) was defined as below the 9.3 IU/ml limit of detection. The percentage of participants achieving undetectable HCV RNA and accompanying 95% CIs were reported at TW2, TW4, and TW12 for each treatment arm of the PP Population. | From TW 2 through TW 12 (up to 12 weeks) | 
| Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment By Timepoint | HCV-RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test (v.2.0) on blood samples drawn from each participant during treatment at TWs 1, 2, 4, 8, and 12. The Roche COBAS™ Taqman™ HCV Test (v.2.0) has a lower limit of quantification (LLoQ) of 25 IU/ml and a limit of detection of 9.3 IU/ml. The percentage of participants with HCV RNA levels <25 IU/ml (either TD[u] or TND) and accompanying 95% CIs were reported at TW2, TW4, and TW12 for each treatment arm of the PP Population. | From TW 2 through TW 12 (up to 12 weeks) | 
| Percentage of Participants Achieving SVR4 | SVR4 was defined as HCV RNA <25 IU/mL, either TD(u) or TND, at 4 weeks after the end of all study therapy. The percentage of participants with SVR4 and accompanying 95% CIs were reported for each treatment arm of the PP Population. | 4 weeks after end of all therapy (Study Week 16) | 
| Percentage of Participants Achieving SVR24 | SVR24 was defined as HCV RNA <25 IU/mL, either TD(u) or TND, at 24 weeks after the end of all study therapy. The percentage of participants with SVR24 and accompanying 95% CIs were reported for each treatment arm of the PP Population. | 24 weeks after end of all therapy (Study Week 36) |