Back to resultsGrazoprevir (MK-5172) Administered With Peginterferon and Ribavirin in Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-003)
Primary Purpose
Hepatitis C, Chronic
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Grazoprevir
Boceprevir
Placebo for Grazoprevir
Placebo for Boceprevir
Peg-interferon alfa-2b
Ribavirin
Sponsored by
About this trial
This is an interventional treatment trial for Hepatitis C, Chronic
Eligibility Criteria
Inclusion Criteria:
- 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)
Exclusion Criteria:
- 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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
Arm 7
Arm 8
Arm Type
Experimental
Experimental
Experimental
Experimental
Active Comparator
Experimental
Experimental
Experimental
Arm Label
Grazoprevir 100 mg
Grazoprevir 200 mg
Grazoprevir 400 mg
Grazoprevir 800 mg
Boceprevir 800 mg
Grazoprevir 400 mg/100 mg
Grazoprevir 800 mg/100 mg
OL Grazoprevir 100 mg
Arm Description
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.
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.
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.
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.
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.
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.
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.
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.
Outcomes
Primary Outcome Measures
Percentage of Participants Achieving Complete Early Viral Response (cEVR)
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
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
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.
Secondary Outcome Measures
Median Time to First Achievement of Undetectable HCV RNA During Treatment
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. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. Kaplan Meier summary statistics were calculated for each treatment arm.
Percentage of Participants Achieving Rapid Viral Response (RVR)
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). RVR was defined as undetectable (TND) HCV RNA at Week 4 of study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of 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 9.3 IU/mL (in plasma). SVR12 was defined as undetectable (TND) HCV RNA at 12 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of 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 lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). SVR24 was defined as undetectable (TND) HCV RNA at 24 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Percentage of Participants Achieving Undetectable HCV RNA at Week 72
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. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. 95% confidence intervals provided based on the Clopper-Pearson method.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01353911
Brief Title
Grazoprevir (MK-5172) Administered With Peginterferon and Ribavirin in Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-003)
Official Title
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
Study Type
Interventional
2. Study Status
Record Verification Date
August 2018
Overall Recruitment Status
Completed
Study Start Date
June 27, 2011 (Actual)
Primary Completion Date
January 20, 2013 (Actual)
Study Completion Date
March 10, 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Merck Sharp & Dohme LLC
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
Detailed Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C, Chronic
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
368 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Grazoprevir 100 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Grazoprevir 200 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Grazoprevir 400 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Grazoprevir 800 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Boceprevir 800 mg
Arm Type
Active Comparator
Arm Description
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.
Arm Title
Grazoprevir 400 mg/100 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
Grazoprevir 800 mg/100 mg
Arm Type
Experimental
Arm Description
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.
Arm Title
OL Grazoprevir 100 mg
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Grazoprevir
Intervention Description
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Intervention Type
Drug
Intervention Name(s)
Boceprevir
Other Intervention Name(s)
Victrelis
Intervention Description
Four 200 mg capsules orally three times daily.
Intervention Type
Drug
Intervention Name(s)
Placebo for Grazoprevir
Intervention Description
Orally once daily in AM.
Intervention Type
Drug
Intervention Name(s)
Placebo for Boceprevir
Intervention Description
Four capsules orally three times daily.
Intervention Type
Drug
Intervention Name(s)
Peg-interferon alfa-2b
Other Intervention Name(s)
PegIntron, Peg-IFN alfa-2b
Intervention Description
1.5 μg/kg/week subcutaneous injection.
Intervention Type
Drug
Intervention Name(s)
Ribavirin
Other Intervention Name(s)
Rebetol
Intervention Description
300 mg to 700 mg orally twice daily.
Primary Outcome Measure Information:
Title
Percentage of Participants Achieving Complete Early Viral Response (cEVR)
Description
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.
Time Frame
After 12 weeks of treatment with grazoprevir/boceprevir
Title
Number of Participants Experiencing Adverse Events (AEs) During the Treatment Period and First 14 Follow-up Days
Description
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.
Time Frame
Treatment period plus the first 14 days of follow-up (up to 50 weeks)
Title
Number of Participants Who Discontinued Study Medication Due to AEs During the Treatment Period and First 14 Follow-up Days
Description
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.
Time Frame
Treatment period plus the first 14 days of follow-up (up to 50 weeks)
Secondary Outcome Measure Information:
Title
Median Time to First Achievement of Undetectable HCV RNA During Treatment
Description
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. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. Kaplan Meier summary statistics were calculated for each treatment arm.
Time Frame
From first dose of study medication until first achievement of undetectable HCV RNA (up to 48 weeks of treatment)
Title
Percentage of Participants Achieving Rapid Viral Response (RVR)
Description
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). RVR was defined as undetectable (TND) HCV RNA at Week 4 of study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Time Frame
After 4 weeks of treatment with grazoprevir/boceprevir
Title
Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After the End of Study Therapy (SVR12)
Description
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). SVR12 was defined as undetectable (TND) HCV RNA at 12 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Time Frame
12 weeks after the end of all treatment (up to 60 weeks)
Title
Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After the End of Study Therapy (SVR24)
Description
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). SVR24 was defined as undetectable (TND) HCV RNA at 24 weeks after the end of all study therapy. 95% confidence intervals provided based on the Clopper-Pearson method.
Time Frame
24 weeks after the end of all treatment (up to 72 weeks)
Title
Percentage of Participants Achieving Undetectable HCV RNA at Week 72
Description
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. Undetectable HCV RNA (target not detected [TND]) was defined as below the 9.3 IU/ml limit of detection. 95% confidence intervals provided based on the Clopper-Pearson method.
Time Frame
Week 72
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
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)
Exclusion Criteria:
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Director
Organizational Affiliation
Merck Sharp & Dohme LLC
Official's Role
Study Director
12. IPD Sharing Statement
Plan to Share IPD
Yes
IPD Sharing Plan Description
https://www.merck.com/clinical-trials/pdf/ProcedureAccessClinicalTrialData.pdf
IPD Sharing URL
http://engagezone.msd.com/ds_documentation.php
Citations:
PubMed Identifier
24727022
Citation
Manns MP, Vierling JM, Bacon BR, Bruno S, Shibolet O, Baruch Y, Marcellin P, Caro L, Howe AY, Fandozzi C, Gress J, Gilbert CL, Shaw PM, Cooreman MP, Robertson MN, Hwang P, Dutko FJ, Wahl J, Mobashery N. The combination of MK-5172, peginterferon, and ribavirin is effective in treatment-naive patients with hepatitis C virus genotype 1 infection without cirrhosis. Gastroenterology. 2014 Aug;147(2):366-76.e6. doi: 10.1053/j.gastro.2014.04.006. Epub 2014 Apr 12.
Results Reference
result
PubMed Identifier
25266289
Citation
Howe AY, Black S, Curry S, Ludmerer SW, Liu R, Barnard RJ, Newhard W, Hwang PM, Nickle D, Gilbert C, Caro L, DiNubile MJ, Mobashery N. Virologic resistance analysis from a phase 2 study of MK-5172 combined with pegylated interferon/ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection. Clin Infect Dis. 2014 Dec 15;59(12):1657-65. doi: 10.1093/cid/ciu696. Epub 2014 Sep 28.
Results Reference
derived
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Grazoprevir (MK-5172) Administered With Peginterferon and Ribavirin in Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-003)
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