Study of Efficacy and Safety of Grazoprevir (MK-5172) + Elbasvir (MK-8742) in Chronic Hepatitis C Participants With Child-Pugh (CP)-B Hepatic Insufficiency (MK-5172-059)

Study Overview
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Brief Summary
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This study is being done to evaluate the efficacy and safety of the drug combination grazoprevir (GZR; MK-5172) + elbasvir (EBR; MK-8742) in participants with chronic hepatitis C virus (HCV) genotype (GT) 1, 4, or 6 infection and who have cirrhosis and Child-Pugh (CP) score 7-9 moderate hepatic insufficiency (CP-B). The primary hypothesis is that the percentage of HCV-infected participants with hepatic insufficiency (the CP-B population) achieving sustained viral response (SVR) 12 weeks after the end of all treatment (SVR12) will be greater than 60%. Additionally, ten non-cirrhotic (NC) HCV-infected GT1 participants will also be given GZR + EBR at the beginning of the study; this will be done for the purpose of collecting plasma pharmacokinetic (PK) data in HCV GT1-infected participants who do not have hepatic insufficiency.

Detailed Description
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The study will be conducted sequentially in 3 Parts. Each participant will participate in only one Part. Participants will be enrolled in either Part A, Part B, or Part C: Part A: CP-B participants will receive GZR 50 mg+ EBR 50 mg; NC participants will receive GZR 100 mg/EBR 50 mg. Part B: CP-B participants will receive GZR 100 mg + EBR 50 mg. Part C: CP-B participants will receive either GZR 50 mg or 100 mg + EBR 50 mg. Study progression from Part A to Part B and from Part B to Part C will be based upon a review of safety and efficacy in Parts A and B, respectively. Depending upon safety and efficacy in Part A, the study may progress directly from Part A to Part C using GZR 50 mg + EBR 50 mg, without performing Part B.

Official Title
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A Phase II/III Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-8742 in Subjects With Chronic Hepatitis C Virus Infection With Advanced Cirrhosis and Child-Pugh (CP)-B Hepatic Insufficiency

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: Grazoprevir
* Drug: Elbasvir
* Drug: MK-5172A


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Has documented chronic HCV GT1 infection (for Arm 4 participants may have GT4 or GT6 infection) with no evidence of non-typable or mixed genotype infection Has clinical evidence of hepatic cirrhosis with a score on the Child-Pugh scale from 7 to 9 and not anticipated to receive a liver transplant within the next 36 weeks (for Arm 1, Arm 3, and Arm 4) Has no evidence of cirrhosis (only for Arm 2 ) Agrees to remain truly abstinent or use (or have their partner use) an acceptable method of birth control from at least 2 weeks prior to Day 1 and continue until at least 14 days after last dose of study drug, or longer if dictated by local regulations Exclusion criteria: Is co-infected with hepatitis B virus or human immunodeficiency virus (HIV) Has previously received direct-acting antiviral therapy for HCV 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 under evaluation for other active or suspected malignancy Has cirrhosis and liver imaging results within 4 weeks prior to screening 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 Has clinically-relevant drug or alcohol abuse within 12 months of screening Is pregnant or breast-feeding, or expecting to conceive or donate eggs or sperm from at least 2 weeks prior to Day 1 and continue throughout treatment and follow up, or longer if dictated by local regulations Has received organ transplants (including hematopoietic stem cell transplants) other than cornea and hair Has poor venous access Has a history of gastric surgery (e.g., stapling, bypass) or history of malabsorption disorders (e.g., celiac sprue disease) Requires, or likely to require, chronic systemic administration of corticosteroids during the course of the trial 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

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: Part A: CP-B GZR 50 mg + EBR 50 mg<br>CP-B participants take GZR 50 mg + EBR 50 mg once daily (q.d.) by mouth for 12 weeks. | Drug: Grazoprevir<br>* GZR was supplied as two 25 mg tablets in the Part A CP-B arm, or as either one GZR 100 mg tablet or one fixed-dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg in a single tablet (MK-5172A) in the Part A NC arm. GZR was taken q.d. by mouth.<br>* Other names: MK-5172;Drug: Elbasvir<br>* EBR was supplied as 50 mg tablets and was taken q.d. by mouth.<br>* Other names: MK-8742;|
| Experimental: Part A: NC GZR 100 mg + EBR 50 mg<br>NC participants take GZR 100 mg + EBR 50 mg q.d. by mouth for 12 weeks. | Drug: Grazoprevir<br>* GZR was supplied as two 25 mg tablets in the Part A CP-B arm, or as either one GZR 100 mg tablet or one fixed-dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg in a single tablet (MK-5172A) in the Part A NC arm. GZR was taken q.d. by mouth.<br>* Other names: MK-5172;Drug: Elbasvir<br>* EBR was supplied as 50 mg tablets and was taken q.d. by mouth.<br>* Other names: MK-8742;Drug: MK-5172A<br>* MK-5172A FDC tablet containing GZR 100 mg + EBR 50 mg taken q.d. by mouth.<br>|
| Experimental: Part B: CP-B GZR 100 mg + EBR 50 mg<br>CP-B participants take GZR 100 mg + EBR 50 mg q.d. by mouth for 12 weeks. | Drug: Grazoprevir<br>* GZR was supplied as two 25 mg tablets in the Part A CP-B arm, or as either one GZR 100 mg tablet or one fixed-dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg in a single tablet (MK-5172A) in the Part A NC arm. GZR was taken q.d. by mouth.<br>* Other names: MK-5172;Drug: Elbasvir<br>* EBR was supplied as 50 mg tablets and was taken q.d. by mouth.<br>* Other names: MK-8742;Drug: MK-5172A<br>* MK-5172A FDC tablet containing GZR 100 mg + EBR 50 mg taken q.d. by mouth.<br>|
| Experimental: Part C: CP-B GZR 50 mg or 100 mg + EBR 50 mg<br>CP-B participants take GZR 50 mg or GZR 100 mg + EBR 50 mg q.d. by mouth for 12 weeks (GZR dose chosen based on results of Part A CP-B arm). | Drug: Grazoprevir<br>* GZR was supplied as two 25 mg tablets in the Part A CP-B arm, or as either one GZR 100 mg tablet or one fixed-dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg in a single tablet (MK-5172A) in the Part A NC arm. GZR was taken q.d. by mouth.<br>* Other names: MK-5172;Drug: Elbasvir<br>* EBR was supplied as 50 mg tablets and was taken q.d. by mouth.<br>* Other names: MK-8742;Drug: MK-5172A<br>* MK-5172A FDC tablet containing GZR 100 mg + EBR 50 mg taken q.d. by mouth.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Achieving Sustained Viral Response 12 Weeks After Completing Study Therapy (SVR12) | SVR12 was defined as hepatitis C virus (HCV) ribonucleic acid (RNA) levels below the lower limit of quantification (LLoQ) 12 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. | Week 24 | 
| Number of Participants Experiencing an Adverse Event (AE) During Treatment and First 14 Follow-up Days | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 14 weeks | 
| Number of Participants Discontinuing Study Drug Due to an AE | An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. | Up to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Model for End-Stage Liver Disease (MELD) Scores in CP-B Participants | The MELD score provides an objective and granular assessment of liver improvement as a continuous variable. The calculation of MELD score is based on three biochemical variables (serum bilirubin, creatinine and international normalized ratio [INR] of prothrombin time). The MELD equation is as follows: 9.57 x ln(creatinine mg/dL) +3.78 x ln(bilirubin mg/dL) +11.2 x ln (INR) + 6.43. Scores are multiplied by 10 and rounded to the nearest whole number and range from 6 (less ill) to 40 (gravely ill). MELD scores were determined at Baseline (Day 1) and again at Week 12, Follow-up (FU) Week 12 (Week 24), and FU Week 24 (Week 36). Change from baseline in MELD score = Post-baseline MELD score - baseline MELD score. | Baseline and Weeks 12, 24, and 36 | 
| Percentage of Participants With HCV RNA Undetectable at Weeks 2, 4, and 12 | HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. | Week 2, 4, and 12 | 
| Percentage of Participants With HCV RNA <LLoQ at Weeks 2, 4, and 12 | HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. | Weeks 2, 4, and 12 | 
| Percentage of Participants Achieving Sustained Viral Response 4 Weeks After Completing Study Therapy (SVR4) | SVR4 was defined as HCV RNA levels <LLoQ 4 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. | Week 16 | 
| Percentage of Participants Achieving Sustained Viral Response 24 Weeks After Completing Study Therapy (SVR24) | SVR24 was defined as HCV RNA levels <LLoQ 24 weeks after completing study therapy. HCV RNA was measured with the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0 ® assay which has a LLoQ of 15 IU/mL and a limit of detection of 15 IU/mL. | Week 36 |