A Study of Different Doses of Grazoprevir (MK-5172) Given With Pegylated Interferon Alfa-2b and Ribavirin to Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-038)

Study Overview
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Brief Summary
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This is a study designed to compare the safety and efficacy of 3 different doses of grazoprevir (MK-5172) combined with pegylated interferon alfa-2b (PEG-IFN) and ribavirin (RBV) in treatment-naïve participants with genotype 1 (GT1) chronic hepatitis C (CHC). Participants will receive 12 weeks of treatment with grazoprevir combined with Peg-IFN and RBV, and depending on response at Week 4 may go on to receive an additional 12 weeks of treatment with Peg-IFN and RBV.

Official Title
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A Phase II Randomized, Dose Ranging, Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of Different Doses of MK-5172 When Administered Concomitantly With Peginterferon Alfa-2b and Ribavirin in Treatment Naïve Subjects With Chronic Hepatitis C Virus Infection

Conditions
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Chronic Hepatitis C (CHC)

Intervention / Treatment
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* Drug: Grazoprevir
* Biological: pegylated interferon alfa-2b
* Drug: Ribavirin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment naive Chronic, compensated HCV GT1 infection Absence (no medical history or physical findings) of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs or symptoms of advanced liver disease, or cirrhosis No evidence of cirrhosis or hepatocellular carcinoma by biopsy or noninvasive testing (e.g. FibroScan and/or FibroTest) Must agree to use two acceptable methods of birth control from at least 2 weeks prior to first dose and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations Exclusion Criteria: Non-GT1 HCV infection, including a mixed GT infection (with a non-GT1) or a non-typeable genotype. Documented to be Human Immunodeficiency Virus (HIV) positive or co-infected with hepatitis B virus Hepatocellular carcinoma (HCC) or under evaluation for HCC Participating in or has participated in a study with an investigational compound or device within 30 days of signing informed consent Diabetic and/or hypertensive with clinically significant ocular examination findings Current or history of central nervous system trauma, seizure disorder, stroke or transient ischemic attack Chronic pulmonary disease Current or history of any clinically significant cardiac abnormalities/dysfunction Active clinical gout within the last year History of gastric surgery or history of malabsorption disorders Active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated carcinoma in situ and basal cell carcinoma of the skin) Pregnant, lactating, expecting to conceive or donate eggs, or male participant planning to impregnate or provide sperm donation or with a female partner who is pregnant Current moderate or severe depression or history of depression associated with hospitalization, electroconvulsive therapy, or severe disruption of daily functions, or suicidal or homicidal ideation and/or attempt, or history of severe psychiatric disorders Evidence or 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: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Grazoprevir 25 mg + PEG-IFN + RBV<br>After a maximum of a 45 day screening window, randomized participants receive 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by Response Guided Therapy (RGT). Participants may receive an additional 12 weeks of PEG-IFN plus RBV depending on their Hepatitis C virus ribonucleic acid (HCV RNA) level at Treatment Week (TW) 4. | Drug: Grazoprevir<br>* Grazoprevir tablet, orally, once per day at assigned dose<br>* Other names: MK-5172;Biological: pegylated interferon alfa-2b<br>* 1.5 mcg/kg/week, administered as a weekly subcutaneous (SC) injection<br>* Other names: PEG-IFN;Drug: Ribavirin<br>* Ribavirin capsule, orally, twice daily, at a dose of 800 to 1400 mg based on participant weight<br>* Other names: RBV;Drug: Placebo<br>* Placebo to match grazoprevir tablets to maintain dose blinding<br>|
| Experimental: Grazoprevir 50 mg + PEG-IFN + RBV<br>After a maximum of a 45 day screening window, randomized participants receive 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by RGT. Participants may receive an additional 12 weeks of PEG-IFN plus RBV depending on their HCV RNA level at TW 4. | Drug: Grazoprevir<br>* Grazoprevir tablet, orally, once per day at assigned dose<br>* Other names: MK-5172;Biological: pegylated interferon alfa-2b<br>* 1.5 mcg/kg/week, administered as a weekly subcutaneous (SC) injection<br>* Other names: PEG-IFN;Drug: Ribavirin<br>* Ribavirin capsule, orally, twice daily, at a dose of 800 to 1400 mg based on participant weight<br>* Other names: RBV;Drug: Placebo<br>* Placebo to match grazoprevir tablets to maintain dose blinding<br>|
| Experimental: Grazoprevir 100 mg + PEG-IFN + RBV<br>After a maximum of a 45 day screening window, randomized participants receive 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up as determined by RGT. Participants may receive an additional 12 weeks of PEG-IFN plus RBV depending on their HCV RNA level at TW 4. | Drug: Grazoprevir<br>* Grazoprevir tablet, orally, once per day at assigned dose<br>* Other names: MK-5172;Biological: pegylated interferon alfa-2b<br>* 1.5 mcg/kg/week, administered as a weekly subcutaneous (SC) injection<br>* Other names: PEG-IFN;Drug: Ribavirin<br>* Ribavirin capsule, orally, twice daily, at a dose of 800 to 1400 mg based on participant weight<br>* Other names: RBV;Drug: Placebo<br>* Placebo to match grazoprevir tablets to maintain dose blinding<br>|

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 at 12 Weeks After the End of Treatment (SVR12) | Hepatitis C virus ribonucleic acid (HCV RNA) was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR12 was defined as HCV RNA <25 IU/mL (either target detected, unquantifiable or target not detected) 12 weeks after the end of all study therapy. | 12 weeks after end of treatment (up to 36 weeks total) | 
| Number of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol -specified procedure, whether or not considered related to the medicinal product or protocol -specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | 14 days following last dose of study drug (up to 26 weeks) | 
| Number of Participants Discontinued From Study Treatment Due to AEs During the Treatment Period and First 14 Follow-up Days | An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event can therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol -specified procedure, whether or not considered related to the medicinal product or protocol -specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an adverse event. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Undetectable HCV RNA During Treatment by Time Point | HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. Undetectable HCV RNA was defined as HCV RNA < 9.3 IU/mL. | From Treatment Week (TW) 2 through end of treatment (up to 24 weeks) | 
| Percentage of Participants Achieving HCV RNA <25 IU/mL During Treatment by Time Point | HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. | From TW 2 through end of treatment (up to 24 weeks) | 
| Percentage of Participants Achieving SVR4 | HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR4 was defined as HCV RNA <25 IU/mL (either target detected, unquantifiable or target not detected) 4 weeks after the end of all study therapy. | 4 weeks after end of treatment (up to 28 weeks total) | 
| Percentage of Subjects Achieving SVR24 | HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR24 was defined as HCV RNA <25 IU/mL (either target detected, unquantifiable or target not detected) 24 weeks after the end of all study therapy. | 24 weeks after end of treatment (up to 48 weeks total) | 
| Number of Participants Developing Post-baseline Antiviral Resistance to Grazoprevir Among Participants Not Achieving SVR24 Response | Post-baseline resistance associated variants (RAV) analysis was conducted by comparing the amino acid sequences at virologic failure time points to those at baseline (BL): Day 1, pre-dose. A post-BL variant was defined as an amino acid substitution within HCV NS3/4A that was present after the first dose at virologic failure and follow-up visits but not at BL. Post-BL variant analysis was conducted for participants who did not achieve SVR24 who had sequence data available. | From Day 1 up to Follow-up Week 24 (up to 48 weeks total) |