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

Hepatitis C Clinical Trial

— C-WORTHy  

Official title:

A Phase II Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen MK-5172 and MK-8742 ± Ribavirin (RBV) in Subjects With Chronic Hepatitis C Virus Infection

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01717326
• Other study ID #: 5172-035
• Secondary ID: 2012-003354-89
• Status: Completed
• Phase: Phase 2
• Start date: February 7, 2013
• Est. completion date: May 6, 2015

Study information

• Verified date: January 2021
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 573
• Est. completion date: May 6, 2015
• Est. primary completion date: February 23, 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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%

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• Grazoprevir
100 mg tablet orally QD
• Elbasvir
Part A: 20 or 50 mg capsule orally QD Parts B, C, and D: 50 mg capsule orally QD
• Placebo to Elbasvir
Placebo to Elbasvir 20 or 50 mg capsule, orally, once daily for 12 weeks to maintain blind (Part A only)
• Ribavirin
Oral capsules BID at a total daily dose from 800 to 1400 mg based on participant weight

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.

References & Publications (2)

Lawitz E, Gane E, Pearlman B, Tam E, Ghesquiere W, Guyader D, Alric L, Bronowicki JP, Lester L, Sievert W, Ghalib R, Balart L, Sund F, Lagging M, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J, Robertson M, Barr E, Haber B. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1075-86. doi: 10.1016/S0140-6736(14)61795-5. Epub 2014 Nov 11. Erratum in: Lancet. 2015 Mar 21;385(9973):1074. — View Citation

Sulkowski M, Hezode C, Gerstoft J, Vierling JM, Mallolas J, Pol S, Kugelmas M, Murillo A, Weis N, Nahass R, Shibolet O, Serfaty L, Bourliere M, DeJesus E, Zuckerman E, Dutko F, Shaughnessy M, Hwang P, Howe AY, Wahl J, Robertson M, Barr E, Haber B. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet. 2015 Mar 21;385(9973):1087-97. doi: 10.1016/S0140-6736(14)61793-1. Epub 2014 Nov 11. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12)	Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). SVR12 was defined as HCV RNA <25 IU/ml at 12 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.	12 weeks after end of therapy (up to 30 weeks)
Primary	Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days	An AE was defined as any unfavorable 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 which is temporally associated with the use of the SPONSOR's product, was also an AE.	From Day 1 [post-dose] through 14 days following last dose of study drug (up to 20 weeks)
Primary	Percentage of Participants Discontinuing Study Therapy Due to an AE During the Treatment Period and First 14 Follow-up Days	An AE was defined as any unfavorable 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 which is temporally associated with the use of the SPONSOR's product, was also an AE.	From Day 1 [post-dose] through 14 days following last dose of study drug (up to 20 weeks)
Secondary	Mean Time to First Achievement of Undetectable Hepatitis C Virus Ribonucleic Acid (HCV RNA)	Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. Kaplan Meier summary statistics were used to characterize the time to first achievement of undetectable HCV RNA.	From first dose of study medication until first achievement of undetectable HCV RNA (up to 18 weeks of treatment)
Secondary	Percentage of Participants Achieving Undetectable HCV RNA at Week 2	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 various time points prior to, during, and after dosing. Undetectable HCV RNA was defined as below the 15.1 IU/ml limit of detection. The percentage of participants achieving undetectable HCV RNA and accompanying 95% CIs were reported at TW2 for each treatment arm of the PP Population. 95% confidence intervals provided based on the Clopper-Pearson method.	Week 2
Secondary	Percentage of Participants Achieving Undetectable HCV RNA at Week 4	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 various time points prior to, during, and after dosing. Undetectable HCV RNA was defined as below the 15.1 IU/ml limit of detection. The percentage of participants achieving undetectable HCV RNA and accompanying 95% CIs were reported at TW4 for each treatment arm of the PP Population. 95% confidence intervals provided based on the Clopper-Pearson method.	Week 4
Secondary	Percentage of Participants Achieving Undetectable HCV RNA at Week 12	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 various time points prior to, during, and after dosing. Undetectable HCV RNA was defined as below the 15.1 IU/ml limit of detection. The percentage of participants achieving undetectable HCV RNA and accompanying 95% CIs were reported at TW12 for each treatment arm of the PP Population (as applicable). 95% confidence intervals provided based on the Clopper-Pearson method.	Week 12
Secondary	Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 2	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 various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a LLoQ of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). The percentage of participants achieving HCV RNA levels <25 IU/ml and accompanying 95% CIs were reported at TW2 for each treatment arm of the PP Population. 95% confidence intervals provided based on the Clopper-Pearson method.	Week 2
Secondary	Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 4	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 various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a LLoQ of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). The percentage of participants achieving HCV RNA levels <25 IU/ml and accompanying 95% CIs were reported at TW4 for each treatment arm of the PP Population. 95% confidence intervals provided based on the Clopper-Pearson method.	Week 4
Secondary	Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 12	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 various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a LLoQ of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). The percentage of participants achieving HCV RNA levels <25 IU/ml and accompanying 95% CIs were reported at TW12 for each treatment arm of the PP Population (as applicable). 95% confidence intervals provided based on the Clopper-Pearson method.	Week 12
Secondary	Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Therapy (SVR4)	Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a LLoQ of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). SVR4 was defined as HCV RNA <25 IU/ml at 4 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.	4 weeks after end of therapy (up to 22 weeks)
Secondary	Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24)	Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 at various time points prior to, during, and after dosing. The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a LLoQ of 25 IU/mL and a limit of detection of 15.1 IU/mL (in plasma). SVR24 was defined as HCV RNA <25 IU/ml at 24 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.	24 weeks after end of therapy (up to 42 weeks)