Study of Grazoprevir (MK-5172) and Elbasvir (MK-8742) in Japanese Participants With Chronic Hepatitis C (MK-5172-058)

NCT02203149 | Completed Phase 2 Results DMC

• 2 other identifiers: 5172-058142638
• Study Type: interventional
• Target: 399
• Locations: 0 countries
• Sites: N/A

Brief Summary

This is a two-part study of grazoprevir (MK-5172) + elbasvir (MK-8742) in Japanese participants with chronic hepatitis C virus (HCV) genotype 1 (GT1). Part I is a dose-finding study; in Part II, participants will be randomly assigned to receive grazoprevir at the dose determined in Part I in combination with elbasvir. The primary study hypothesis is that the percentage of treatment-naïve participants in the Immediate Treatment Arm of Part II who achieve sustained viral response at 12 weeks after the end of all treatment (SVR12) will be greater than the reference rate of 75%. A separate study arm for cirrhotic participants will also be included in Part II; these participants will receive grazoprevir at the determined dose in combination with elbasvir.

Conditions

Hepatitis C

Outcome Measures

Primary Outcomes (5)

• Part 2: Percentage of Treatment-naïve Participants in the Immediate Treatment Arm Achieving Sustained Viral Response at 12 Weeks After The End of All Treatment (SVR12)

  Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS® Taqman quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, v2.0, which had a lower limit of quantification (LLoQ) of 1.2 Log IU/mL (15 IU/mL) and a lower limit of detection (LLoD) below 15 IU/ml (no specific value). SVR12 was defined as undetectable HCV RNA (target not detected) at 12 weeks after the end of all study therapy. The Clopper-Pearson method was used to construct 95% confidence intervals (CIs) for the SVR12 rate. The lower limit of the 95% CI was compared to the reference rate of 75%; a lower CI limit that was higher than the reference rate would confirm the primary hypothesis and indicate that that the treatment combination was efficacious. As pre-specified in the protocol, only the Immediate Treatment Arm of Part 2 (treatment naïve participants) was included in the primary efficacy analysis.

  12 weeks after end of all therapy in Part 2 (Study Week 24 of Part 2)

• Part 1: Percentage of Participants Experiencing an Adverse Event (AE) During Treatment and First 4 Follow-Up Weeks

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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, was also an AE. The primary safety evaluation was limited to the initial treatment period through Follow-up Week 4 (FUWK4).

  Up to 4 weeks post last dose in Part 1 (Up to total of 16 weeks)

• Part 1: Percentage of Participants That Discontinued Treatment Due to an AE

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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, was also an AE. The primary safety evaluation was limited to the initial treatment period through FUWK4.

  Up to Study Week 12 in Part 1

• Part 2: Percentage of Participants Experiencing an AE During Initial Treatment and First 4 Follow-Up Weeks

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, was also an AE. The primary safety evaluation was limited to the initial treatment period and first 4 follow-up weeks, and the primary safety statistical analysis compared the percentage of participants with events between the Part 2 Immediate Treatment Arm and the Part 2 Deferred Treatment Arm while receiving placebo.

  Up to 4 weeks following initial treatment in Part 2 (Up to total of 16 weeks)

• Part 2: Percentage of Participants That Discontinued Initial Treatment Due to an AE

  An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign, 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 of a preexisting condition that is temporally associated with the use of the Sponsor's product, was also an AE. The primary safety evaluation was limited to the initial treatment period and first 4 follow-up weeks, and the primary safety statistical analysis compared the percentage of participants with events between the Part 2 Immediate Treatment Arm and the Part 2 Deferred Treatment Arm while receiving placebo.

  Up to Study Week 12 in Part 2

Secondary Outcomes (4)

• Part 1: Percentage of Participants Achieving Undetectable HCV RNA Over Time

  Part 1 Treatment Weeks (TW)2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24

• Part 1: Percentage of Participants Achieving HCV RNA Below the Lower Limit of Quantitation (<LLoQ) Over Time

  Part 1 TW2, TW4, TW12, EOT, FUWK4, FUWK12, FUWK24

• Part 2: Percentage of Participants Achieving Undetectable HCV RNA Over Time After Active Treatment

  Part 2: Active TW2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24

• Part 2: Percentage of Participants Achieving HCV RNA <LLoQ Over Time After Active Treatment

  Part 2: Active TW2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24

Study Arms (5)

Part 1 Grazoprevir 50 mg + Elbasvir

EXPERIMENTAL

Non-cirrhotic participants take 50 mg grazoprevir in combination with 50 mg elbasvir by mouth (p.o.) once daily (q.d.) for 12 weeks during the blinded period of Part 1 and are followed-up for 24 weeks during the open-label period of Part 1.

Drug: Grazoprevir; Drug: Elbasvir; Drug: Placebo to Grazoprevir

Part 1 Grazoprevir 100 mg + Elbasvir

EXPERIMENTAL

Non-cirrhotic participants take 100 mg grazoprevir in combination with 50 mg elbasvir p.o. q.d. for 12 weeks during the blinded period of Part 1 and are followed-up for 24 weeks during the open-label period of Part 1.

Drug: Grazoprevir; Drug: Elbasvir

Part 2 Non-cirrhotic Immediate: Grazoprevir + Elbasvir

EXPERIMENTAL

Non-cirrhotic participants take grazoprevir (50 mg or 100 mg dose selected from Part I) and 50 mg elbasvir p.o. q.d. for 12 weeks during the blinded period of Part 2 and are followed-up for 24 weeks during the open-label period of Part 2.

Drug: Grazoprevir; Drug: Elbasvir

Part 2 Non-cirrhotic Deferred: Placebo► Grazoprevir + Elbasvir

PLACEBO COMPARATOR

Non-cirrhotic participants take dose-matched placebo p.o. q.d. for 12 weeks during the blinded period of Part 2 followed by a 4-week follow-up. Afterwards, participants take grazoprevir (50 mg or 100 mg dose selected from Part I) and 50 mg elbasvir p.o. q.d. for 12 weeks and are followed-up for 24 weeks during the open-label period of Part 2.

Drug: Grazoprevir; Drug: Elbasvir; Drug: Placebo to Grazoprevir; Drug: Placebo to Elbasvir

Part 2 Cirrhotic: Grazoprevir + Elbasvir

EXPERIMENTAL

Cirrhotic participants take grazoprevir (50 mg or 100 mg dose selected from Part 1) and 50 mg elbasvir p.o. q.d. for 12 weeks during the blinded period of Part 2, and are followed-up for 24 weeks during the open-label period of Part 2.

Drug: Grazoprevir; Drug: Elbasvir

Interventions

Grazoprevir DRUG

One or two 50 mg tablets (depending on randomization) taken orally once daily for 12 weeks.

Part 1 Grazoprevir 100 mg + Elbasvir; Part 1 Grazoprevir 50 mg + Elbasvir; Part 2 Cirrhotic: Grazoprevir + Elbasvir; Part 2 Non-cirrhotic Deferred: Placebo► Grazoprevir + Elbasvir; Part 2 Non-cirrhotic Immediate: Grazoprevir + Elbasvir

Elbasvir DRUG

One 50 mg tablet taken orally once daily for 12 weeks.

Part 1 Grazoprevir 100 mg + Elbasvir; Part 1 Grazoprevir 50 mg + Elbasvir; Part 2 Cirrhotic: Grazoprevir + Elbasvir; Part 2 Non-cirrhotic Deferred: Placebo► Grazoprevir + Elbasvir; Part 2 Non-cirrhotic Immediate: Grazoprevir + Elbasvir

Placebo to Grazoprevir DRUG

One tablet of placebo matched to grazoprevir, taken orally once daily for 12 weeks.

Part 1 Grazoprevir 50 mg + Elbasvir; Part 2 Non-cirrhotic Deferred: Placebo► Grazoprevir + Elbasvir

Placebo to Elbasvir DRUG

One tablet of placebo matched to elbasvir, taken orally once daily for 12 weeks.

Part 2 Non-cirrhotic Deferred: Placebo► Grazoprevir + Elbasvir

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Has documented chronic Japanese HCV genotype (GT) 1 with no evidence of non-typeable or mixed GT infection
• Is treatment-naïve, or intolerant or non-responder to prior anti-HCV interferon (IFN)-based treatment without direct acting antiviral (DAA) therapy, prior IFN-based treatment with DAA therapy, or prior DAA therapy
• Agrees to the use of contraception if a female of reproductive potential

You may not qualify if:

• Has evidence of decompensated liver disease manifested by the presence of or history of ascites, esophageal or gastric variceal bleeding, hepatic encephalopathy or other signs or symptoms of advanced liver disease
• Is coinfected with hepatitis B virus or human immunodeficiency virus (HIV)
• Has a history of malignancy ≤5 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or carcinoma in situ
• Has cirrhosis and liver imaging within 6 months of Day 1 showing evidence of hepatocellular carcinoma (HCC) or is under evaluation for HCC (Part 2 only)
• Has clinically-relevant drug or alcohol abuse within 12 months of screening
• Is a female and is pregnant or breast-feeding, or expecting to conceive or donate eggs from Day 1 and continue throughout treatment and follow-up (or longer if dictated by local regulations)
• Has any of the following conditions:
• Organ transplants (including hematopoietic stem cell transplants) other than cornea and hair
• Poor venous access
• History of gastric surgery (e.g., stapling, bypass) or subject with a history of malabsorption disorders (e.g., celiac sprue disease)
• History of a medical/surgical condition that resulted in hospitalization within the 3 months prior to enrollment, other than for minor elective procedures
• Medical/surgical conditions that may result in a need for hospitalization during the period of the study
• Any medical condition requiring, or likely to require, chronic systemic administration of corticosteroids, TNF antagonists, or other immunosuppressant drugs during the course of the trial
• Has chronic hepatitis not caused by HCV, including but not limited to nonalcoholic steatohepatitis (NASH), drug-induced hepatitis, and autoimmune hepatitis

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (1)

• Kumada H, Suzuki Y, Karino Y, Chayama K, Kawada N, Okanoue T, Itoh Y, Mochida S, Toyoda H, Yoshiji H, Takaki S, Yatsuzuka N, Yodoya E, Iwasa T, Fujimoto G, Robertson MN, Black S, Caro L, Wahl J. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. J Gastroenterol. 2017 Apr;52(4):520-533. doi: 10.1007/s00535-016-1285-y. Epub 2016 Nov 21.

  PMID: 27873094 RESULT

MeSH Terms

Conditions

Hepatitis C

Interventions

grazoprevir; elbasvir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 25, 2014
• First Posted: July 29, 2014
• Study Start: August 1, 2014
• Primary Completion: October 2, 2015
• Study Completion: May 16, 2016
• Last Updated: September 24, 2018
• Results First Posted: October 11, 2016

Record last verified: 2018-08

Data Sharing

• IPD Sharing: Will share