Efficacy and Safety of Uprifosbuvir (MK-3682) With Ruzasvir (MK-8408) in Adults With Chronic Hepatitis C Genotype 1, 2, 3, 4, 5 or 6 Infection (MK-3682-035)

Study Overview
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Brief Summary
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This study is an open-label, multi-center trial to evaluate the novel 2-drug regimen of uprifosbuvir (MK-3682) 450 mg and ruzasvir (MK-8408) 60 mg in participants with chronic hepatitis C virus (HCV) genotype (GT)1, GT2, GT3, GT4, GT5, or GT6 infection. The impact of the study treatment regimen on the percentage of participants with undetectable HCV ribonucleic acid [RNA] 12 weeks after completing study treatment (SVR12) will be evaluated.

Official Title
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A Phase II, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-3682 + MK-8408 in Subjects With Chronic HCV Genotype 1, 2, 3, 4, 5 or 6 Infection

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: Uprifosbuvir 450 mg
* Drug: Ruzasvir 60 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has hepatitis C virus (HCV) ribonucleic acid (RNA) at the time of screening Has documented chronic HCV genotype (GT)1, GT2, 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 absence of cirrhosis or has compensated cirrhosis Is HCV treatment-naïve or has experienced virologic failure after completing a prior interferon-containing 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 For human immunodeficiency virus (HIV) co-infected participants: 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 Exclusion Criteria: Is mentally or legally incapacitated, has significant emotional problems (at screening or expected during the study) or has a history of a clinically significant psychiatric disorder that 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 Is Child-Pugh Class B or C or has a Pugh-Turcotte (CPT) score >6 if cirrhotic Is co-infected with Hepatitis B Virus Has a history of opportunistic infection in the preceding 6 months prior to screening if co-infected with HIV Has a history of malignancy ≤5 years prior to study start (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 prior to study start showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC Is taking any medications or herbal supplements restricted by the study entry criteria in the period from ≤2 weeks prior to study start through 2 weeks after the last dose of study drug Has clinically-relevant drug or alcohol abuse within 12 months of study start Has participated in any clinical study of an investigational product within 30 days prior to the first dose of study drug Is female and is pregnant or breastfeeding, or expecting to conceive or donate eggs from at least 2 weeks prior to study start and 14 days after the last dose of study drug Is male and is expecting to donate sperm from at least 2 weeks prior to Day 1 until 14 days after the last dose of study drug Has or has had any of the following: organ transplants (including hematopoietic stem cell transplants) other than cornea and hair; poor venous access; history of gastric surgery; or history of malabsorption disorders Has any cardiac abnormalities/dysfunction including but not limited to: unstable angina; unstable congestive heart failure; or unstable arrhythmia Has a history of a medical/surgical condition that resulted in hospitalization within 3 months prior to study start, other than for minor elective procedures 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 study Has evidence of history of chronic hepatitis not caused by HCV

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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GT1: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT1 Arm is sub-divided into GT1a and GT1b Arms. GT1a Arm will enroll approximately 35 participants including up to 10 participants who are compensated cirrhotics and GT1b Arm will enroll approximately 15 participants including up to 5 participants who are compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|
| Experimental: GT2: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT2 Arm of the study will enroll approximately 50 participants including up to 15 participants who are compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|
| Experimental: GT3: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT3 Arm of the study will enroll approximately 50 participants including up to 15 participants who are compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|
| Experimental: GT4: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT4 Arm of the study will enroll approximately 50 participants including up to 15 participants who are compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|
| Experimental: GT5: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT5 Arm of the study will enroll approximately 25 participants including both non- cirrhotics and compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|
| Experimental: GT6: Uprifosbuvir 450 mg + Ruzasvir 60 mg<br>Participants will receive an oral dose of 450 mg uprifosbuvir (3 x 150 mg tablets) and 60 mg ruzasvir (6 x 10 mg capsules) following an overnight fast and at least one hour before a meal, once a day, for 12 weeks. The GT6 Arm of the study will enroll approximately 25 participants including both non- cirrhotics and compensated cirrhotics. | Drug: Uprifosbuvir 450 mg<br>* 450 mg administered as 3 x 150 mg oral tablets<br>* Other names: MK-3682;Drug: Ruzasvir 60 mg<br>* 60 mg administered as 6 x 10 mg oral capsules<br>* Other names: MK-8408;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After Completing Study Therapy (SVR12) | The percentage of participants in each arm achieving SVR12 was determined. SVR12 was defined as HCV ribonucleic acid (RNA) levels in plasma < lower limit of quantification (LLOQ) 12 weeks after completing study treatment. Plasma levels of HCV RNA were measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL. | Week 24 (12 weeks after completing study therapy) | 
| Percentage of Participants With ≥1 Adverse Events (AEs) | The percentage of participants experiencing an AE during the treatment period and first 2 weeks of follow-up was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to Week 14 (up to 2 weeks after completing study therapy) | 
| Percentage of Participants Withdrawing From Study Therapy Due to an AE | The percentage of participants discontinuing from study therapy during the treatment period was determined. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to Week 12 | 
| Percentage of Participants With ≥1 Events of Clinical Interest (ECIs) | The percentage of participants with ECIs was determined. ECIs were defined as the following: 1) an overdose of study drug; 2) first instance of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >500 IU/L; 3) first instance of ALT or AST >3x nadir and >3x upper limit of normal (ULN); 4) first instance of estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2; or 4) first instance of serum creatinine >1.3x ULN and elevated from baseline. | Up to Week 14 (up to 2 weeks after completing study therapy) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After Completing Study Therapy (SVR24) | The percentage of participants in each arm achieving SVR24 was determined. SVR24 was defined as HCV RNA levels in plasma < LLOQ 24 weeks after completing study treatment. Plasma levels of HCV RNA were measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL. For SVR24, participants with GT1 infection were separated into GT1a or GT1b infection. | Week 36 (24 weeks after completing study therapy) | 
| Percentage of Participants With Virologic Failure (VF) | The percentage of participants in each arm experiencing VF was determined. VF was defined as: 1) non-response (HCV RNA detected at end of treatment without HCV RNA < LLOQ while on treatment); 2) rebound (>1 log 10 IU/mL increase in HCV RNA from nadir while on treatment); 3) virologic breakthrough (HCV RNA ≥LLOQ after being <LLOQ on treatment); or 4) relapse (HCV RNA ≥LLOQ after end of all study therapy after being undetectable at end of treatment); virologic failure could occur either on-treatment or relapse post-treatment. For VF, participants with GT1 infection were separated into GT1a or GT1b infection | 12 weeks after the end of all study therapy (24 weeks) | 
| Percentage of Participants With Baseline Resistance-Associated Substitutions (RAS) Achieving SVR12 | The percentage of participants in each arm with baseline RAS achieving SVR12 was determined. Analysis of RAS in NS5A or NS5B at baseline was determined. SVR12 was defined as HCV RNA levels in plasma < LLOQ 24 weeks after completing study treatment. Plasma levels of HCV RNA were measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay, which has a LLOQ of 15 IU/mL. | 12 weeks after the end of all study therapy (24 weeks) |