A Randomized, Active-Controlled, Dose-Ranging Estimation Study to Evaluate the Safety, Tolerability, and Efficacy of Different Regimens of MK-5172 When Administered Concomitantly With Peginterferon Alfa-2b and Ribavirin in Treatment-Naïve Patients With Chronic Genotype 1 Hepatitis C Virus Infection
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 368
- 主要终点
- Percentage of Participants Achieving Complete Early Viral Response (cEVR)
研究概览
简要总结
This study will evaluate the safety, tolerability, and antiviral activity of grazoprevir (MK-5172) when administered in combination with peginterferon alfa-2b (Peg-IFN) and ribavirin (RBV) in treatment-naïve (TN) participants with chronic hepatitis C.
详细描述
Amendment 4 unblinded treatment after an interim analysis for all subsequently enrolled TN participants (the Second Cohort) who were receiving grazoprevir 400 or 800 mg daily, and they were down-dosed to 100 mg daily between Treatment Week (TW) 3 and TW12 for the remainder of the 12-week treatment course.
Amendment 5 allowed treatment-naïve participants with chronic hepatitis C and compensated cirrhosis to be enrolled and receive open-label grazoprevir 100 mg in combination with Peg-IFN and RBV, without a corresponding control arm.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Has previously documented chronic hepatitis C genotype 1 (CHC GT 1) infection
- •Has hepatitis C virus (HCV) ribonucleic acid (RNA value) ≥10,000 IU/mL
- •Body weight ≥40 kg (88 lbs) and ≤125 kg (275 lbs)
- •Absence (no medical history or physical findings) of ascites, bleeding esophageal varices, hepatic encephalopathy, or other signs and symptoms of decompensated liver disease
- •Had a liver biopsy within 3 years of screening or between screening and Day 1 with histology consistent with CHC and no evidence of cirrhosis or hepatocellular carcinoma or no other cause for chronic liver disease (for participants with compensated cirrhosis, any liver biopsy demonstrating cirrhosis regardless of length of time since biopsy)
- •Female of childbearing potential or a male with female sexual partner who is of childbearing potential agrees to use two acceptable methods of birth control from at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug, or longer if dictated by local regulations
- •For participants with compensated cirrhosis, evidence of cirrhosis without evidence of hepatocellular carcinoma (confirmed by ultrasound within 4 weeks prior)
排除标准
- •Is pregnant, breastfeeding, or plans to become pregnant or donate eggs
- •Is human immunodeficiency virus (HIV) positive or known to be co-infected with hepatitis B virus
- •Has received prior approved or investigational treatment for hepatitis C
- •Has evidence of hepatocellular carcinoma or is under evaluation for hepatocellular carcinoma
- •For participants with compensated cirrhosis: alphafetoprotein level of ≥100 ng/mL
- •Has evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years
- •Has evidence or history of chronic hepatitis not caused by HCV
- •Is diabetic and/or hypertensive with clinically significant ocular examination findings: retinopathy, cotton wool spots, optic nerve disorder, retinal hemorrhage, or any other clinically significant abnormality
- •Has any known medical condition that could interfere with participation in and completion of the study
- •Pre-existing psychiatric condition including but not limited to moderate or severe depression, suicidal or homicidal ideation or attempt, schizophrenia, psychosis, bipolar disorder, post traumatic stress disorder, or mania
- •Is currently participating or has participated in a study with an investigational compound or device within 30 days of signing informed consent
- •Member or family member of study staff
研究组 & 干预措施
Grazoprevir 100 mg
TN non-cirrhotic (NC) participants receive Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Grazoprevir (Drug)
Grazoprevir 100 mg
TN non-cirrhotic (NC) participants receive Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Placebo for Boceprevir (Drug)
Grazoprevir 100 mg
TN non-cirrhotic (NC) participants receive Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 100 mg
TN non-cirrhotic (NC) participants receive Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
Grazoprevir 200 mg
TN NC participants receive Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Grazoprevir (Drug)
Grazoprevir 200 mg
TN NC participants receive Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Placebo for Boceprevir (Drug)
Grazoprevir 200 mg
TN NC participants receive Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 200 mg
TN NC participants receive Grazoprevir 200 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
Grazoprevir 400 mg
TN NC participants receive Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Grazoprevir (Drug)
Grazoprevir 400 mg
TN NC participants receive Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Placebo for Boceprevir (Drug)
Grazoprevir 400 mg
TN NC participants receive Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
Boceprevir 800 mg
TN NC participants start a 4 week lead-in with Peg-IFN + RBV, then receive Boceprevir 800 mg + Peg-IFN + RBV for 24 weeks followed by 0 or 20 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 400 mg
TN NC participants receive Grazoprevir 400 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
Grazoprevir 800 mg
TN NC participants receive Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Grazoprevir (Drug)
Grazoprevir 800 mg
TN NC participants receive Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Placebo for Boceprevir (Drug)
Grazoprevir 800 mg
TN NC participants receive Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 800 mg
TN NC participants receive Grazoprevir 800 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
Boceprevir 800 mg
TN NC participants start a 4 week lead-in with Peg-IFN + RBV, then receive Boceprevir 800 mg + Peg-IFN + RBV for 24 weeks followed by 0 or 20 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Boceprevir (Drug)
Boceprevir 800 mg
TN NC participants start a 4 week lead-in with Peg-IFN + RBV, then receive Boceprevir 800 mg + Peg-IFN + RBV for 24 weeks followed by 0 or 20 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Placebo for Grazoprevir (Drug)
Boceprevir 800 mg
TN NC participants start a 4 week lead-in with Peg-IFN + RBV, then receive Boceprevir 800 mg + Peg-IFN + RBV for 24 weeks followed by 0 or 20 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
Grazoprevir 400 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 400 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Grazoprevir (Drug)
Grazoprevir 400 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 400 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 400 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 400 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Ribavirin (Drug)
Grazoprevir 800 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 800 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Grazoprevir (Drug)
Grazoprevir 800 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 800 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Peg-interferon alfa-2b (Drug)
Grazoprevir 800 mg/100 mg
As the result of an interim analysis, TN NC participants assigned to the 800 mg grazoprevir group were unblinded and transitioned to 100 mg grazoprevir once daily + Peg-IFN + RBV and will remain in the study.
干预措施: Ribavirin (Drug)
OL Grazoprevir 100 mg
TN cirrhotic participants receive open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Grazoprevir (Drug)
OL Grazoprevir 100 mg
TN cirrhotic participants receive open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Peg-interferon alfa-2b (Drug)
OL Grazoprevir 100 mg
TN cirrhotic participants receive open-label Grazoprevir 100 mg + Peg-IFN + RBV for 12 weeks followed by 12 or 36 weeks of Peg-IFN + RBV, based on response guided therapy.
干预措施: Ribavirin (Drug)
结局指标
主要结局
Percentage of Participants Achieving Complete Early Viral Response (cEVR)
时间窗: After 12 weeks of treatment with grazoprevir/boceprevir
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 9.3 IU/mL (in plasma). cEVR was defined as undetectable HCV RNA (target not detected \[TND\]) at Week 12. 95% confidence intervals provided based on the Clopper-Pearson method.
Number of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days
时间窗: Treatment period plus the first 14 days of follow-up (up to 50 weeks)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. 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.
Number of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days
时间窗: Treatment period plus the first 14 days of follow-up (up to 50 weeks)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's product, whether or not considered related to the use of the product. 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.
次要结局
- Median Time to First Achievement of Undetectable HCV RNA During Treatment(From first dose of study medication until first achievement of undetectable HCV RNA (up to 48 weeks of treatment))
- Percentage of Participants Achieving Rapid Viral Response (RVR)(After 4 weeks of treatment with grazoprevir/boceprevir)
- Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)(12 weeks after the end of all treatment (up to 60 weeks))
- Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)(24 weeks after the end of all treatment (up to 72 weeks))
- Percentage of Participants Achieving Undetectable HCV RNA at Week 72(Week 72)