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A Pharmacokinetics/Pharmacodynamics Study of SCH 900518 in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C (Protocol No. P05104AM2)(COMPLETED) (NEXT-1)

Primary Purpose

Hepatitis C, Chronic

Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
peginterferon alfa 2b
ribavirin
SCH 900518
ritonavir
Sponsored by
Merck Sharp & Dohme LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C, Chronic focused on measuring genotype 1 infection

Eligibility Criteria

18 Years - 55 Years (Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Adult subjects with CHC HCV genotype 1 with no previous treatment for CHC
  • 18 to 55 years of age
  • Weight between 40 and 125 kg
  • Previously documented CHC genotype 1 infection
  • Liver biopsy within 2 years of Screening with histology consistent with chronic hepatitis C and no evidence of bridging fibrosis or cirrhosis
  • Subject and subject's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug
  • Subjects must be willing to give written informed consent

Exclusion Criteria:

  • Prior treatment for hepatitis C other than herbal remedies
  • HIV positive or known to be co-infected with hepatitis B
  • Medically significant gallbladder or hepatobiliary findings on Screening ultrasound
  • Use of any known significant inducers or substrates of CYP3A4 two weeks prior to start of study medications
  • Use of herbal supplements (Milk Thistle permitted)
  • Diabetic and hypertensive subjects with clinically significant ocular examination findings
  • Current moderate or severe depression

  • History of depression associated with any of the following:

    • Hospitalization for depression
    • Electroconvulsive therapy for depression.
    • Depression that resulted in a prolonged absence from work and/or significant disruption of daily functions
  • Suicidal or homicidal ideation and/or attempt
  • History of severe psychiatric disorders
  • Past history or current use of lithium
  • Clinical diagnosis of substance abuse of alcohol, intravenous drugs, inhalational (not including marijuana), psychotropics, narcotics, cocaine use, prescription or over-the-counter drugs within 5 years of Day 1
  • Past or current use of opiate agonist substitution therapy
  • Any known pre-existing medical condition (CNS, cardiac, pulmonary, immune mediated) that could interfere with the subject's participation in and completion of the study
  • Active clinical gout within the last year
  • Hemoglobinopathy or coagulopathy
  • Myelodysplastic syndromes
  • Organ transplants other than cornea and hair
  • Poor venous access that precludes routine peripheral blood sampling or an indwelling venous catheter
  • Subjects with a history of gastric surgery (eg, stapling, banding, bypass) or subjects with a history of malabsorption disorders (eg, celiac sprue disease)
  • Evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible.
  • Subjects who are pregnant or nursing
  • Subjects who intend to become pregnant during the study period
  • Male subjects with partners who are, or intend to become, pregnant during the study period

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm 5

    Arm 6

    Arm 7

    Arm Type

    Active Comparator

    Experimental

    Experimental

    Experimental

    Experimental

    Experimental

    Experimental

    Arm Label

    Standard of Care

    2

    3

    4

    5

    6

    7

    Arm Description

    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily for 48 weeks. Subjects with >= 1 log decrease from baseline in HCV-RNA levels after 12 weeks, but still above the lower limit of quantitation, have the option of crossing over to PegIntron, ribavirin plus SCH 900518 400 mg and ritonavir 100 mg daily for 12 weeks. This is followed by standard of care, PegIntron and ribavirin, for a total treatment duration of up to 48 weeks.

    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 200 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 400 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 200 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 400 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 100 mg twice daily plus ritonavir 100 mg twice daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 600 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.

    Outcomes

    Primary Outcome Measures

    The primary efficacy endpoint is the proportion of subjects with undetectable HCV-RNA after 4 weeks of treatment with SCH 900518.

    Secondary Outcome Measures

    Rate of viral decline during the first 4 weeks of dosing with SCH 900518
    Proportion of subjects with undetectable HCV-RNA at both 4 and 12 weeks of dosing with SCH 900518
    Proportion of subjects with undetectable HCV-RNA at end of treatment (EOT) and follow-up week 24 (FW24)

    Full Information

    First Posted
    November 24, 2008
    Last Updated
    January 21, 2015
    Sponsor
    Merck Sharp & Dohme LLC
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    1. Study Identification

    Unique Protocol Identification Number
    NCT00797745
    Brief Title
    A Pharmacokinetics/Pharmacodynamics Study of SCH 900518 in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C (Protocol No. P05104AM2)(COMPLETED)
    Acronym
    NEXT-1
    Official Title
    A Study of SCH 900518 in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C (Protocol No. P05104)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2015
    Overall Recruitment Status
    Completed
    Study Start Date
    November 2008 (undefined)
    Primary Completion Date
    July 2009 (Actual)
    Study Completion Date
    September 2010 (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
    SCH 900518 is a potent oral inhibitor of HCV NS3 protease which disrupts hepatitis C virus (HCV) polyprotein processing. SCH 900518, when added to the current standard of care (SOC), peginterferon-alfa plus ribavirin, would likely increase the proportion of patients achieving undetectable HCV-RNA levels and sustained virologic response (SVR). In this study, SCH 900518 would be used in combination with low doses of ritonavir to enhance the levels of SCH 900518 within the body and reduce the number of daily SCH 900518 tablets required. The purpose of this study is to identify the optimal dose and schedule (once or twice a day) of SCH 900518 plus ritonavir in previously untreated patients with genotype 1 chronic hepatitis C when given in combination with SOC. The study compares SOC to 6 experimental arms. In the experimental arms, SOC plus SCH 900518 doses of 200, 400 and 600 mg once daily or 100 mg twice daily with ritonavir 100 mg once or twice daily will be explored. The benefits of a 4 week lead-in with PegIntron and ribavirin prior to the addition of SCH 900518 will also be explored.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Hepatitis C, Chronic
    Keywords
    genotype 1 infection

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 2
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    111 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Standard of Care
    Arm Type
    Active Comparator
    Arm Description
    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily for 48 weeks. Subjects with >= 1 log decrease from baseline in HCV-RNA levels after 12 weeks, but still above the lower limit of quantitation, have the option of crossing over to PegIntron, ribavirin plus SCH 900518 400 mg and ritonavir 100 mg daily for 12 weeks. This is followed by standard of care, PegIntron and ribavirin, for a total treatment duration of up to 48 weeks.
    Arm Title
    2
    Arm Type
    Experimental
    Arm Description
    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 200 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Arm Title
    3
    Arm Type
    Experimental
    Arm Description
    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 400 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Arm Title
    4
    Arm Type
    Experimental
    Arm Description
    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 200 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Arm Title
    5
    Arm Type
    Experimental
    Arm Description
    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 400 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Arm Title
    6
    Arm Type
    Experimental
    Arm Description
    PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily plus SCH 900518 100 mg twice daily plus ritonavir 100 mg twice daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 12 or 36 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Arm Title
    7
    Arm Type
    Experimental
    Arm Description
    4 week lead-in with PegIntron 1.5 mcg/kg SC weekly plus ribavirin 600 to 1400 mg daily (weight-based) by mouth twice daily followed by PegIntron plus ribavirin plus SCH 900518 600 mg daily plus ritonavir 100 mg daily for 12 weeks. Depending on HCV-RNA levels after 4 weeks of SCH 900518, patients will receive an additional 8 or 32 weeks of PegIntron/ribavirin. Total treatment duration will be 24 or 48 weeks.
    Intervention Type
    Biological
    Intervention Name(s)
    peginterferon alfa 2b
    Other Intervention Name(s)
    PegIntron
    Intervention Description
    1.5 mcg/kg subcutaneously weekly for up to 24 or 48 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    ribavirin
    Other Intervention Name(s)
    REBETOL
    Intervention Description
    ribavirin 600 to 1400 mg daily (weight-based dosing) by mouth twice daily for up to 24 or 48 weeks
    Intervention Type
    Drug
    Intervention Name(s)
    SCH 900518
    Intervention Description
    SCH 900518 100 mg tablets taken as 200 mg PO QD, 100 mg PO BID, 400 mg PO QD, or 600 mg PO QD for 12 weeks.
    Intervention Type
    Drug
    Intervention Name(s)
    ritonavir
    Other Intervention Name(s)
    Norvir
    Intervention Description
    Ritonavir 100 mg capsules taken as 100 mg PO QD or 100 mg PO BID for 12 weeks.
    Primary Outcome Measure Information:
    Title
    The primary efficacy endpoint is the proportion of subjects with undetectable HCV-RNA after 4 weeks of treatment with SCH 900518.
    Time Frame
    After 4 weeks of treatment with SCH 900518
    Secondary Outcome Measure Information:
    Title
    Rate of viral decline during the first 4 weeks of dosing with SCH 900518
    Time Frame
    After 4 and 12 weeks of treatment with SCH 900518, at EOT and FW 24
    Title
    Proportion of subjects with undetectable HCV-RNA at both 4 and 12 weeks of dosing with SCH 900518
    Time Frame
    After 4 and 12 weeks of treatment with SCH 900518, at EOT and FW 24
    Title
    Proportion of subjects with undetectable HCV-RNA at end of treatment (EOT) and follow-up week 24 (FW24)
    Time Frame
    After 4 and 12 weeks of treatment with SCH 900518, at EOT and FW 24

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    55 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Adult subjects with CHC HCV genotype 1 with no previous treatment for CHC 18 to 55 years of age Weight between 40 and 125 kg Previously documented CHC genotype 1 infection Liver biopsy within 2 years of Screening with histology consistent with chronic hepatitis C and no evidence of bridging fibrosis or cirrhosis Subject and subject's partner(s) must each agree to use acceptable methods of contraception for at least 2 weeks prior to Day 1 and continue until at least 6 months after last dose of study drug Subjects must be willing to give written informed consent Exclusion Criteria: Prior treatment for hepatitis C other than herbal remedies HIV positive or known to be co-infected with hepatitis B Medically significant gallbladder or hepatobiliary findings on Screening ultrasound Use of any known significant inducers or substrates of CYP3A4 two weeks prior to start of study medications Use of herbal supplements (Milk Thistle permitted) Diabetic and hypertensive subjects with clinically significant ocular examination findings Current moderate or severe depression History of depression associated with any of the following: Hospitalization for depression Electroconvulsive therapy for depression. Depression that resulted in a prolonged absence from work and/or significant disruption of daily functions Suicidal or homicidal ideation and/or attempt History of severe psychiatric disorders Past history or current use of lithium Clinical diagnosis of substance abuse of alcohol, intravenous drugs, inhalational (not including marijuana), psychotropics, narcotics, cocaine use, prescription or over-the-counter drugs within 5 years of Day 1 Past or current use of opiate agonist substitution therapy Any known pre-existing medical condition (CNS, cardiac, pulmonary, immune mediated) that could interfere with the subject's participation in and completion of the study Active clinical gout within the last year Hemoglobinopathy or coagulopathy Myelodysplastic syndromes Organ transplants other than cornea and hair Poor venous access that precludes routine peripheral blood sampling or an indwelling venous catheter Subjects with a history of gastric surgery (eg, stapling, banding, bypass) or subjects with a history of malabsorption disorders (eg, celiac sprue disease) Evidence of active or suspected malignancy, or a history of malignancy, within the last 5 years (except adequately treated basal cell carcinoma of the skin). Subjects under evaluation for malignancy are not eligible. Subjects who are pregnant or nursing Subjects who intend to become pregnant during the study period Male subjects with partners who are, or intend to become, pregnant during the study period

    12. IPD Sharing Statement

    Learn more about this trial

    A Pharmacokinetics/Pharmacodynamics Study of SCH 900518 in Previously Untreated Subjects With Genotype 1 Chronic Hepatitis C (Protocol No. P05104AM2)(COMPLETED)

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