Clinical trial NCT02203149: Study of Grazoprevir (MK-5172) and Elbasvir (MK-8742) in Japanese Participants With Chronic Hepatitis C (MK-5172-058)
Official title: A Phase II, Randomized Clinical Trial to Study the Safety, Tolerability, and Efficacy of the Combination Regimen of MK-5172 and MK-8742 in Japanese Subjects With Chronic Hepatitis C and a Phase III, Randomized Placebo-Controlled Clinical Trial to Study the Safety, Tolerability, and Efficacy of the Combination Regimen of MK-5172 and MK-8742 in Japanese Subjects With Chronic Hepatitis C
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Hepatitis C
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2014-07-29
Enrollment: 399
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Detailed description: In Part 1, HCV GT1 participants are randomized into one of two arms: 50 mg grazoprevir plus 50 mg elbasvir for 12 weeks during the double blinded (DB) period followed by 24 weeks of follow-up (FU) during an open-label (OL) period \[Arm 1\]; or 100 mg grazoprevir plus 50 mg elbasvir for 12 weeks during the DB followed by 24 weeks of FU during the OL \[Arm 2\]. Unblinding will occur after all participants complete FU Week 4 at which time the grazoprevir dose will be selected.

In Part 2, non-cirrhotic HCV GT1 participants and GT1 participants with compensated liver cirrhosis all receive the selected dose of grazoprevir (50 mg or 100 mg from Part 1) with 50 mg elbasvir for 12 weeks. Non-cirrhotic GT1 participants are randomized to receive either a) 12 weeks of active treatment immediately during the DB with 24 weeks of FU in the OL \[Arm 1/Immediate Arm\] or b) placebo for 12 weeks with 4 weeks of follow-up during the DB followed by 12 weeks of active treatment and 24 weeks of follow-up during the OL \[Arm 2/Deferred Arm\]. All cirrhotic participants \[Arm 3/Cirrhotic\] receive the selected dose immediately for 12 weeks during the DB with 24 weeks of FU during the OL.

Safety analyses for Part 1 and Part 2 arms will focus on the 12 week treatment phase plus the first 4 FU weeks. For the Part 2 Deferred Arm this will include the initial 12 week placebo treatment and first 4 weeks of FU. Efficacy analyses for Parts 1 and 2 will evaluate active treatment only (Weeks 1-12 for all arms except for Part 2 Deferred Arm which is weeks 16-28).

Part 1:

50 mg grazoprevir + 50 mg elbasvir treatment for 12 weeks, 24 weeks follow-up (Arm 1) 100 mg grazoprevir + 50 mg elbasvir treatment for 12 weeks, 24 weeks follow-up (Arm 2)

Part 2:

Selected dose of grazoprevir + 50 mg elbasvir treatment for 12 weeks, 24 weeks follow-up (Arm 1/Immediate) Placebo treatment for 12 weeks, 4 weeks follow-up, selected dose of grazoprevir + 50 mg elbasvir treatment for 12 weeks, 24 weeks follow-up (Arm 2/Deferred) Selected dose of grazoprevir + 50 mg elbasvir treatment for 12 weeks, 24 weeks follow-up (Arm 3/Cirrhotic)

Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: 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)
timeFrame: 12 weeks after end of all therapy in Part 2 (Study Week 24 of Part 2)
measure: Part 1: Percentage of Participants Experiencing an Adverse Event (AE) During Treatment and First 4 Follow-Up Weeks
timeFrame: Up to 4 weeks post last dose in Part 1 (Up to total of 16 weeks)
measure: Part 1: Percentage of Participants That Discontinued Treatment Due to an AE
timeFrame: Up to Study Week 12 in Part 1
measure: Part 2: Percentage of Participants Experiencing an AE During Initial Treatment and First 4 Follow-Up Weeks
timeFrame: Up to 4 weeks following initial treatment in Part 2 (Up to total of 16 weeks)
measure: Part 2: Percentage of Participants That Discontinued Initial Treatment Due to an AE
timeFrame: Up to Study Week 12 in Part 2
Secondary outcomes:
measure: Part 1: Percentage of Participants Achieving Undetectable HCV RNA Over Time
timeFrame: Part 1 Treatment Weeks (TW)2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24
measure: Part 1: Percentage of Participants Achieving HCV RNA Below the Lower Limit of Quantitation (<LLoQ) Over Time
timeFrame: Part 1 TW2, TW4, TW12, EOT, FUWK4, FUWK12, FUWK24
measure: Part 2: Percentage of Participants Achieving Undetectable HCV RNA Over Time After Active Treatment
timeFrame: Part 2: Active TW2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24
measure: Part 2: Percentage of Participants Achieving HCV RNA <LLoQ Over Time After Active Treatment
timeFrame: Part 2: Active TW2, TW4, TW12, End of Treatment (EOT), FUWK4, FUWK12, FUWK24
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.