Clinical trial NCT01717326: A Study of the Combination Regimen Grazoprevir (MK-5172) and Elbasvir (MK-8742) ± Ribavirin in Participants With Chronic Hepatitis C (MK-5172-035)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2012-10-30
Enrollment: 573
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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%

Primary outcomes:
measure: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of All Study Therapy (SVR12)
timeFrame: 12 weeks after end of therapy (up to 30 weeks)
measure: Percentage of Participants Experiencing at Least One Adverse Event (AE) During the Treatment Period and First 14 Follow-up Days
timeFrame: From Day 1 [post-dose] through 14 days following last dose of study drug (up to 20 weeks)
measure: Percentage of Participants Discontinuing Study Therapy Due to an AE During the Treatment Period and First 14 Follow-up Days
timeFrame: From Day 1 [post-dose] through 14 days following last dose of study drug (up to 20 weeks)
Secondary outcomes:
measure: Mean Time to First Achievement of Undetectable Hepatitis C Virus Ribonucleic Acid (HCV RNA)
timeFrame: From first dose of study medication until first achievement of undetectable HCV RNA (up to 18 weeks of treatment)
measure: Percentage of Participants Achieving Undetectable HCV RNA at Week 2
timeFrame: Week 2
measure: Percentage of Participants Achieving Undetectable HCV RNA at Week 4
timeFrame: Week 4
measure: Percentage of Participants Achieving Undetectable HCV RNA at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 2
timeFrame: Week 2
measure: Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 4
timeFrame: Week 4
measure: Percentage of Participants Achieving HCV RNA <25 IU/mL at Week 12
timeFrame: Week 12
measure: Percentage of Participants Achieving Sustained Virologic Response 4 Weeks After the End of All Therapy (SVR4)
timeFrame: 4 weeks after end of therapy (up to 22 weeks)
measure: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of All Study Therapy (SVR24)
timeFrame: 24 weeks after end of therapy (up to 42 weeks)
Other outcomes:
Locations:
Study officials:
References:
citation: 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.
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.
citation: Gane E, Nahass R, Luketic V, Asante-Appiah E, Hwang P, Robertson M, Wahl J, Barr E, Haber B. Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naive, noncirrhotic HCV genotype 3-infected patients. J Viral Hepat. 2017 Oct;24(10):895-899. doi: 10.1111/jvh.12719. Epub 2017 Jun 23.
citation: Jacobson IM, Lawitz E, Kwo PY, Hezode C, Peng CY, Howe AYM, Hwang P, Wahl J, Robertson M, Barr E, Haber BA. Safety and Efficacy of Elbasvir/Grazoprevir in Patients With Hepatitis C Virus Infection and Compensated Cirrhosis: An Integrated Analysis. Gastroenterology. 2017 May;152(6):1372-1382.e2. doi: 10.1053/j.gastro.2017.01.050. Epub 2017 Feb 11.