A Study of the Combination Regimen Grazoprevir (MK-5172) and Elbasvir (MK-8742) ± Ribavirin in Participants With Chronic Hepatitis C (MK-5172-035) (C-WORTHy)

Merck Sharp & Dohme (MSD)

Status and phase: Completed; Phase 2

Conditions: Hepatitis C

Treatments: Drug: Placebo to Elbasvir; Drug: Grazoprevir; Drug: Elbasvir; Drug: Ribavirin

Study type: Interventional

Funder types: Industry

Identifiers

NCT01717326

5172-035

2012-003354-89 (EudraCT Number)

Details and patient eligibility

About

This is a study of the safety and efficacy of grazoprevir (MK-5172) in combination with elbasvir (MK-8742) ± ribavirin (RBV). The primary efficacy endpoint will be Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) in each of the treatment arms.

Full description

Part A is being done in treatment-naïve (TN), genotype 1 (GT1), interferon eligible, non-cirrhotic (N-C) participants with chronic hepatitis C (CHC). Participants will be assigned randomly to 1 of 2 treatment arms in which they will receive grazoprevir 100 mg once daily (QD) + elbasvir 20 mg or 50 mg QD and twice daily (BID) RBV, or to a treatment arm in which they will receive grazoprevir 100 mg QD + elbasvir 50 mg QD without RBV. Treatment will last 12 weeks.

In Part B, participants with hepatitis C virus (HCV) GT1 and HCV ribonucleic acid (RNA) levels of ≥10,000 IU/mL will be randomly assigned to a study arm, based on absence or presence of cirrhosis (C), whether they are TN or had poor response to previous antiviral therapy (null responders [NR]), or whether co-infected with human immunodeficiency virus (HIV); these participants will receive open-label grazoprevir (100 mg) in combination with elbasvir (50 mg) ± RBV. Treatment will last 8 to 18 weeks dependent on arm assignment.

In Part C, TN, N-C participants with HCV GT1b and HCV RNA levels of ≥10,000 IU/mL will be randomly assigned to receive open-label grazoprevir (100 mg) in combination with elbasvir (50 mg) ± RBV. Treatment will last 8 weeks.

In Part D, TN N-C participants with HCV GT3 and HCV RNA levels of ≥10,000 IU/mL will be randomly assigned to receive open-label grazoprevir (100 mg) in combination with elbasvir (50 mg) + RBV for 12 or 18 weeks.

Enrollment: 573 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

All participants

• CHC genotype 1 (GT1) virus infection (Parts A, B, and C) or GT3 virus infection (Part D)
• Female participants of childbearing potential or male participant with female partners of childbearing potential, must use two acceptable methods of birth control from ≥2 weeks prior to Day 1 until ≥6 months after last dose of study drug, or longer if dictated by local regulations

Part A - 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 advanced fibrosis, cirrhosis and/or hepatocellular carcinoma by biopsy or noninvasive testing (FibroScan and/or FibroTest)

Parts B, C, and D

• Treatment naïve with or without cirrhosis, or
• Prior treatment failure to Peg-IFN/Ribavirin with or without cirrhosis, or
• Co-infected with human immunodeficiency virus (HIV) without cirrhosis
• Absence (no medical history or physical findings) of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs or symptoms of advanced liver disease
• Liver disease staging assessment by liver biopsy or noninvasive testing (FibroScan and/or FibroTest)

Exclusion criteria

All participants

• Non-GT1 HCV infection (Part A, Part B, and Part C) or a non-GT3 HCV infection (Part D) including a mixed GT infection (with a non-GT1 [Part A, Part B, and Part C] or non-GT3 [Part D]) or a non-typeable genotype
• Evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC
• Currently participating or 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 study
• Diabetic and/or hypertensive with clinically significant ocular examination findings
• History of depression associated with hospitalization for depression, electroconvulsive therapy, or resulting in prolonged absence from work and/or significant disruption of daily functions
• Suicidal or homicidal ideations and/or attempt, or history of severe psychiatric disorders
• Clinical diagnosis of substance abuse
• Current history of seizure disorder, stroke, or transient ischemic attack
• Immunologically mediated disease
• Chronic pulmonary disease
• Clinically significant cardiac abnormalities/dysfunction
• Active clinical gout within the last year
• Hemoglobinopathy or myelodysplastic syndromes
• History of organ transplants including hematopoietic stem cell transplants
• Poor venous access
• Indwelling venous catheter
• History of gastric surgery or malabsorption disorders
• Severe concurrent disease
• Evidence of active or suspected malignancy, or a history of malignancy, ≤5 years before
• Pregnant, lactating, expecting to conceive or donate eggs
• Male participant with pregnant female partner
• Member/family member of the investigational study or sponsor staff directly involved with this study
• Evidence or history of chronic hepatitis not caused by HCV

Part A

• Not treatment-naïve
• Documented to be HIV positive
• Taking or planning to take significant inducers or inhibitors of CYP3A4 substrates or herbal supplements 2 weeks prior to start of study medications

Parts B, C, and D

• Previously received any HCV direct-acting antivirals
• Requiring, or likely to require, chronic systemic administration of corticosteroids during the course of the trial
• For participants diagnosed with diabetes mellitus, documented HbA1c >8.5%

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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573 participants in 20 patient groups

A1: TN NC Grazoprevir 100 mg + Elbasvir 20 mg + RBV-12 wk

Experimental group

Description:

GT1a and GT1b participants receive Grazoprevir 100 mg tablet orally once daily (QD) for 12 weeks, Elbasvir 20 mg capsule and Placebo capsule orally QD for 12 weeks, RBV capsules orally twice daily (BID) for 24 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Placebo to Elbasvir

Drug: Elbasvir

Drug: Grazoprevir

A2: TN NC Grazoprevir 100 mg + Elbasvir 50 mg + RBV-12 wk

Experimental group

Description:

GT1a and GT1b participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule and Placebo capsule orally QD for 12 weeks, RBV capsules orally BID for 24 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Placebo to Elbasvir

Drug: Elbasvir

Drug: Grazoprevir

A3: TN NC/GT1b Grazoprevir 100 mg + Elbasvir 50 mg-12 wk

Experimental group

Description:

GT1b only participants receive Grazoprevr 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B1: TN NC/GT1a Grazoprevir 100 mg + Elbasvir 50 mg + RBV-8 wk

Experimental group

Description:

GT1a only participants receive Grazoprevir 100 mg tablet orally QD for 8 weeks, Elbasvir 50 mg capsule orally QD for 8 weeks, RBV capsules orally BID for 8 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B2: TN NC Grazoprevir 100 mg + Elbasvir 50 mg + RBV-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks, RBV capsules orally BID for 12 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B3: TN NC/GT1a Grazoprevir 100 mg + Elbasvir 50 mg-12 wk

Experimental group

Description:

GT1a only participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B4: TN C Grazoprevir 100 mg + Elbasvir 50 mg + RBV-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks, RBV capsules orally BID for 12 weeks at a total daily dose from 800 to 1400 mg based on participant

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B5: TN C Grazoprevir 100 mg + Elbasvir 50 mg for 12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B6: TN C Grazoprevir 100 mg + Elbasvir 50 mg + RBV-18 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 18 weeks, Elbasvir 50 mg capsule orally QD for 18 weeks, RBV capsules orally BID for 18 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B7: TN C Grazoprevir 100 mg + Elbasvir 50 mg-18 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 18 weeks, Elbasvir 50 mg capsule orally QD for 18 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B8: NR Grazoprevir 100 mg + Elbasvir 50 mg +RBV-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks, RBV capsules orally BID for 12 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B9: NR Grazoprevir 100 mg + Elbasvir 50 mg-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B10: NR Grazoprevir 100 mg + Elbasvir 50 mg + RBV-8 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 18 weeks, Elbasvir 50 mg capsule orally QD for 18 weeks, RBV capsules orally BID for 18 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B11: NR Grazoprevir 100 mg + Elbasvir 50 mg-18 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 18 weeks, Elbasvir 50 mg capsule orally QD for 18 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

B12: TN HIV NC Grazoprevir 100 mg + Elbasvir 50 mg + RBV-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks, RBV capsules orally BID for 12 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

B13: TN HIV NC Grazoprevir 100 mg + Elbasvir 50 mg-12 wk

Experimental group

Description:

GT1a/non-a participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

C1: TN NC/GT1b Grazoprevir 100 mg + Elbasvir 50 mg + RBV-8 wk

Experimental group

Description:

GT1b participants receive Grazoprevir 100 mg tablet orally QD for 8 weeks, Elbasvir 50 mg capsule orally QD for 8 weeks, and RBV capsules orally BID for 8 weeks at a total daily dose from 800 to 1400 mg based on participant weight.

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

C2: TN NC/GT1b Grazoprevir 100 mg + Elbasvir 50 mg-8 wk

Experimental group

Description:

GT1b participants receive Grazoprevir 100 mg tablet orally QD for 8 weeks and Elbasvir 50 mg capsule orally QD for 8 weeks

Treatment:

Drug: Elbasvir

Drug: Grazoprevir

D1: TN NC/GT3 Grazoprevir 100 mg + Elbasvir 50 mg + RBV-12 wk

Experimental group

Description:

GT3 participants receive Grazoprevir 100 mg tablet orally QD for 12 weeks, Elbasvir 50 mg capsule orally QD for 12 weeks, and RBV capsules orally BID for 12 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir

D2: TN NC/GT3 Grazoprevir 100 mg + Elbasvir 50 mg + RBV-18 wk

Experimental group

Description:

GT3 participants receive Grazoprevir 100 mg tablet orally QD for 18 weeks, Elbasvir 50 mg capsule orally QD for 18 weeks, and RBV capsules orally BID for 18 weeks at a total daily dose from 800 to 1400 mg based on participant weight

Treatment:

Drug: Ribavirin

Drug: Elbasvir

Drug: Grazoprevir