Grazoprevir (MK-5172) Administered With Peginterferon and Ribavirin in Treatment-Naïve Participants With Chronic Hepatitis C (MK-5172-003)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier:
NCT01353911
First received: May 12, 2011
Last updated: February 3, 2016
Last verified: December 2015
  Purpose
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.

Condition Intervention Phase
Hepatitis C, Chronic
Drug: Grazoprevir
Drug: Boceprevir
Drug: Placebo for Grazoprevir
Drug: Placebo for Boceprevir
Drug: Peg-interferon alfa-2b
Drug: Ribavirin
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Merck Sharp & Dohme Corp.:

Primary Outcome Measures:
  • Percentage of Participants Achieving Complete Early Viral Response (cEVR) [ Time Frame: After 12 weeks of treatment with grazoprevir/boceprevir ] [ Designated as safety issue: No ]
    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 [ Time Frame: Treatment period plus the first 14 days of follow-up (up to 50 weeks) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: Treatment period plus the first 14 days of follow-up (up to 50 weeks) ] [ Designated as safety issue: Yes ]
    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 [ Time Frame: From first dose of study medication until first achievement of undetectable HCV RNA (up to 48 weeks of treatment) ] [ Designated as safety issue: No ]
    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) [ Time Frame: After 4 weeks of treatment with grazoprevir/boceprevir ] [ Designated as safety issue: No ]
    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) [ Time Frame: 12 weeks after the end of all treatment (up to 60 weeks) ] [ Designated as safety issue: No ]
    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) [ Time Frame: 24 weeks after the end of all treatment (up to 72 weeks) ] [ Designated as safety issue: No ]
    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 [ Time Frame: Week 72 ] [ Designated as safety issue: No ]
    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.


Enrollment: 368
Study Start Date: June 2011
Study Completion Date: March 2015
Primary Completion Date: March 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Placebo for Boceprevir
Four capsules orally three times daily.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Placebo for Boceprevir
Four capsules orally three times daily.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Placebo for Boceprevir
Four capsules orally three times daily.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Placebo for Boceprevir
Four capsules orally three times daily.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Active Comparator: 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.
Drug: Boceprevir
Four 200 mg capsules orally three times daily.
Other Name: Victrelis
Drug: Placebo for Grazoprevir
Orally once daily in AM.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol
Experimental: 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.
Drug: Grazoprevir
Orally once daily in AM. Blinded or open-label depending on treatment arm.
Drug: Peg-interferon alfa-2b
1.5 μg/kg/week subcutaneous injection.
Other Names:
  • PegIntron
  • Peg-IFN alfa-2b
Drug: Ribavirin
300 mg to 700 mg orally twice daily.
Other Name: Rebetol

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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01353911

Sponsors and Collaborators
Merck Sharp & Dohme Corp.
Investigators
Study Director: Medical Director Merck Sharp & Dohme Corp.
  More Information

Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01353911     History of Changes
Other Study ID Numbers: 5172-003  2011-000759-18 
Study First Received: May 12, 2011
Results First Received: February 3, 2016
Last Updated: February 3, 2016
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Interferons
Ribavirin
Interferon-alpha
Peginterferon alfa-2b
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 28, 2016