Antiviral Effect, Safety, and Pharmacokinetics of BI201335 +PegIFN/RBV in HCV-GT1 (SILEN-C1&2)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00774397
First received: October 16, 2008
Last updated: October 14, 2015
Last verified: October 2015
  Purpose
The objective was to investigate the antiviral effect, safety, and pharmacokinetics of BI 201335 (Faldaprevir), given as a soft gelatine capsule, in patients with hepatitis C virus (HCV) genotype 1 infection. Combination therapy of BI 201335 (Faldaprevir) with pegylated interferon α-2a (PegIFN) and ribavirin (RBV), with or without a 3-day lead-in, was assessed in treatment-naïve (TN) and treatment experienced (TE) patients.

Condition Intervention Phase
Hepatitis C, Chronic
Drug: BI 201335 NA 240 mg QD / LI
Drug: PegIFN/RBV
Drug: BI 201335 NA 120mg QD / LI
Drug: BI 201335 NA 240 mg QD
Drug: BI 201335 NA 240 mg BID
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double-Blind
Primary Purpose: Treatment
Official Title: Antiviral Effect, Safety and Pharmacokinetics of BI 201335 NA in Hepatitis C Virus Genotype 1 Infected Treatment-naïve and Treatment-experienced Patients for 24 Weeks as Combination Therapy With Pegylated Interferon-alpha 2a and Ribavirin (Double-blinded, Randomised, Placebo-controlled, Phase II)

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Virological Response 4 Weeks After the End of Treatment With BI 201335 or Placebo [ Time Frame: Week 28 ] [ Designated as safety issue: No ]

    An achieved virological response is defined as the plasma Hepatitis C Virus RiboNucleic Acid (HCV RNA) level below the lower limit of detection (BLD).

    This data was only collected for patients, who stopped trial participation at Week 24 and did not continue with PegIFN/RBV until Week 48.

    The lower limit of quantification (BLQ) of this assay was 25 IU/mL and the lower limit of detection (BLD) was 10 IU/mL at the time of the protocol finalisation. During the course of the trial, the manufacturer defined BLD as '< 25 IU/mL, not detectable' and BLQ as '< 25 IU/mL, detectable'.


  • Sustained Virological Response 24 Weeks (SVR24) After Completion of All Therapy [ Time Frame: Day 155 after the end of all treatment ] [ Designated as safety issue: No ]

    Virological (VL) response was defined as the plasma HCV RNA level below the lower limit of detection.

    The first VL measurement that occurred in the time window ≥ Day 155 (from End Of Treatment on) was selected for the determination of SVR24.

    Therefore, patients with virological load BLD 24 weeks after completion of therapy, who had a rebound after this time point (outside the defined time window of 155 days after end of all treatments) were identified as SVR24 achieved.



Secondary Outcome Measures:
  • Virological Response at Week 2 [ Time Frame: Week 2 ] [ Designated as safety issue: No ]
    Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 2 (< 25 IU/ml, detectable or undetectable)

  • Virological Response at Week 4 [ Time Frame: Week 4 ] [ Designated as safety issue: No ]
    Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 4 (< 25 IU/ml, detectable or undetectable)

  • Early Virological Response (EVR) [ Time Frame: Baseline and Week 12 ] [ Designated as safety issue: No ]
    Early Virological Response (EVR) is defined as ≥ 2 log 10 reduction in plasma HCV RNA level from baseline at Week 12

  • Extended Rapid Virological Response (eRVR) [ Time Frame: Week 4 and Week 12 ] [ Designated as safety issue: No ]
    Extended Rapid Virological Response (eRVR) is defined as plasma HCV RNA levels below the lower limit of quantification at Week 4 and below the lower limit of detection at Week 12

  • Complete Early Virological Response (cEVR) [ Time Frame: Week 12 ] [ Designated as safety issue: No ]
    Complete Early Virological Response (cEVR) is defined as plasma HCV RNA level below the lower limit of detection at Week 12

  • End of Treatment Response at Week 24 [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    End of Treatment Response of BI 201335 or placebo (ETR BI 201335/placebo ) is defined as plasma HCV RNA level below the lower limit of detection at Week 24.

  • End of Treatment Response at End of All Therapy [ Time Frame: Week 24 or Week 48 ] [ Designated as safety issue: No ]
    End of Treatment Response (ETR) is defined as plasma HCV RNA level below the lower limit of detection at end of all therapy, i.e. at Week 24 or Week 48

  • Sustained Virological Response 12 Weeks (SVR12) After Completion of All Therapy [ Time Frame: Week 36 or Week 60 ] [ Designated as safety issue: No ]
    Sustained Virological Response 12 Weeks (SVR12) after completion of all therapy is defined as plasma HCV RNA level below the lower limit of detection at 12 weeks after completion of all therapy, i.e. at Week 36 or 60

  • Time to Reach a Plasma HCV RNA Level Below the Lower Limit of Detection [ Time Frame: On or after day 155 post end of all treatment ] [ Designated as safety issue: No ]
    Summary of time (i.e Median number of days) to reach a plasma HCV RNA level below limit of detection (BLD)

  • Time to Loss of Virological Response [ Time Frame: Week 24 ] [ Designated as safety issue: No ]

    Time to loss of virological response, defined as the last value below the lower limit of detection in a patient who subsequently had 2 consecutive plasma HCV RNA level measurements ≥100 IU/mL. Patients that did not achieve suppression of plasma HCV RNA levels below the lower limit of detection until Week 24 were defined as having a time to failure of zero.

    Time is expressed in Median number of days.


  • Virological Rebound [ Time Frame: Week 24 or Week 48 ] [ Designated as safety issue: No ]

    Virological rebound is defined as increase of ≥ 1 log 10 in plasma HCV RNA level from a quantifiable nadir, or to ≥ 250 IU/mL after previous nadir < 25 IU/mL (detectable), or to ≥ 100 IU/mL after a previous viral load below the lower limit of detection.

    Note that this is numerical rebound, not requiring confirmation with a re-measurement.


  • Breakthrough on BI 201335/Placebo (Rebound While All 3 Treatments Were Still Ongoing) [ Time Frame: Up to Week 24 ] [ Designated as safety issue: No ]
    Number of patients with Unconfirmed rebound ( ≥ 1log10 increase in HCV mRNA) while on BI201335/placebo + 5 days washout.

  • Breakthrough on PegIFN/RBV (Rebound While Only PegIFN/RBV Treatment Alone Was Still Ongoing) [ Time Frame: Week 24 through Week 48 ] [ Designated as safety issue: No ]
    Number of patients with Unconfirmed rebound (≥ 1log10 increase in HCV mRNA) while on PegIFN/RBV treatment + 5 days washout.

  • Relapse [ Time Frame: post-End of treatment (i.e. post 48 weeks) ] [ Designated as safety issue: No ]

    Relapse was rebound after the viral load at end of all treatment had been below the lower limit of detection, or, if the value at end of all treatment was missing, after both the last value before End of Treatment (EOT) and the first value after End of Treatment were below the lower limit of detection.

    Patients could experience relapse at any point post-treatment.


  • Change From Baseline to Week 24 in Diastolic Blood Pressure and Systolic Blood Pressure [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the initial drug administration of BI 201335 or placebo.

  • Change From Baseline to Week 24 in Pulse Rate [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the administration of BI 201335 or placebo.

  • Change From Baseline to Week 24 in Weight of the Patients [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the administration of BI 201335 or placebo.

  • Global Assessment of Tolerability [ Time Frame: Week 24 ] [ Designated as safety issue: No ]

    The investigator was to assess the tolerability of trial medication based on adverse events (AEs) and the laboratory evaluation.

    Tolerability was assessed by the investigator according to the categories 'good', 'satisfactory', 'not satisfactory', and 'bad'.


  • Change From Baseline to Week 24 in Haemoglobin of the Patients [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the administration of BI 201335 or placebo.

  • Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Haemoglobin [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Number of patients with normal or high baseline moved to low .

  • Change From Baseline to Week 24 in Absolute Neutrophils of the Patients [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the administration of BI 201335 or placebo.

  • Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Absolute Neutrophils [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Number of patients with normal or high baseline moved to low .

  • Change From Baseline to Week 24 in ALT/GPT,SGPT of the Patients [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the drug administration of BI 201335 or placebo.

  • Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter ALT/GPT,SGPT [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Number of patients with normal or low baseline moved to high .

  • Change From Baseline to Week 24 in Total Bilirubin of the Patients [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Baseline is defined as the last value before the administration of BI 201335 or placebo.

  • Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Total Bilirubin [ Time Frame: Baseline and Week 24 ] [ Designated as safety issue: No ]
    Number of patients with normal or low baseline moved to high .

  • Trough Concentration (Cpre,ss) of Faldaprevir at Steady State [ Time Frame: Week 8, week 10, week 12, week 24 ] [ Designated as safety issue: No ]
    C(pre,ss) is defined as pre-dose (trough) concentration of Faldaprevir in plasma at steady state immediately before administration of the next dose.

  • Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1000 mg/Day RBV) [ Time Frame: Week 8, week 10, week 12, week 24 ] [ Designated as safety issue: No ]
    C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose.

  • Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1200 mg/Day RBV) [ Time Frame: Week 8, week 10, week 12, week 24 ] [ Designated as safety issue: No ]
    C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose.

  • Trough Concentration (Cpre,ss) of PegIFN at Steady State [ Time Frame: Week 8, week 10, week 12, week 24 ] [ Designated as safety issue: No ]
    C(pre,ss) is defined as pre-dose (trough) concentration of PegIFN in plasma at steady state immediately before administration of the next dose.


Enrollment: 719
Study Start Date: October 2008
Primary Completion Date: November 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 240 mg QD TN
240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients
Drug: BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
Other Name: Faldaprevir
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
Experimental: 240 mg QD / LI-TN
240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients
Drug: BI 201335 NA 240 mg QD / LI
240mg BI 201335 NA (Faldaprevir) once daily with a 3 days lead-in phase of PegIFN/RB, 24 weeks
Other Name: Faldaprevir
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
Placebo Comparator: Placebo
Placebo once daily combined with PegIFN/RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV in treatment-naive (TN) patients
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
Drug: Placebo
Placebo
Experimental: 120 mg QD / LI-TN
120 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in (LI) phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), followed by an additional 24 weeks of PegIFN/RBV in treatment naive (TN) patients
Drug: BI 201335 NA 120mg QD / LI
120mg BI 201335 NA (Faldaprevir) once daily, for 24 weeks
Other Name: Faldaprevir
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
Experimental: 240 mg QD TE
240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, followed by an additional 24 weeks of PegIFN/RBV in treatment experienced (TE) patients
Drug: BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
Other Name: Faldaprevir
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
Experimental: 240 mg QD / LI-TE
240 mg BI 201335 NA (Faldaprevir) once daily (QD) combined with PegIFN/RBV for 24 weeks, with a 3-day lead-in phase of PegIFN/RBV (i.e. initiation of BI 201335 (Faldaprevir) three days after first administration of PegIFN/RBV), success-dependently followed by re-randomisation to stop or to an additional 24 weeks of PegIFN/RBV in treatment-experienced (TE) patients
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
Drug: BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
Other Name: Faldaprevir
Experimental: 240 mg BID / LI-TE
240mg BI 201335 NA (Faldaprevir) twice daily combined with PegIFN/RBV for 24 or 48 weeks, with 3-day lead-in phase of PegIFN/RBV, in treatment-experienced patients
Drug: BI 201335 NA 240 mg BID
240mg BI 201335 NA (Faldaprevir) twice, 24 weeks
Other Name: Faldaprevir
Drug: PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion criteria:

chronic HCV GT1; therapy-naive to IFN, PegIFN, or RBV; HCV VL >=100,000 IU/mL Liver biopsy within 2 years prior to study enrolment showing necroinflammatory activity or presence of fibrosis Normal retinal finding on fundoscopy within 6 months prior to Day 1 age 18-65 years Females and males with adequate contraception

Exclusion criteria:

Mixed genotype (1/2, 1/3, or 1/4), diagnosed by genotypic testing at screening Previous treatment with protease inhibitor Evidence of liver disease due to causes other than chronic HCV infection HIV-1 or HIV-2 positive HBV positive Decompensated liver disease, or history of decompensated liver disease Active or suspected malignancy or history of malignancy within the last 5 years History of alcohol or drug abuse within the past 12 months. Usage of any investigational drug within 30 days prior to enrolment, or 5 half-lives, whichever is longer Known hypersensitivity to any ingredient of the study drugs Condition that is defined as one which in the opinion of the investigator may put the patient at risk because of participation in the study or may influence the results of the study or the patient's ability to participate in the study Alpha-fetoprotein value > 100ng/mL at screening; if >20ng/mL and <=100ng/mL, patients can be included if there is no evidence of liver cancer in two congruent imaging studies Total bilirubin > 1.5x ULN wiht ratio of direct/indirect >1. ALT or AST levels > 5x ULN INR prolonged to >1.5x ULN Exclusion criteria related to PegIFN and/or RBV restrictions.

  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: NCT00774397

  Show 100 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00774397     History of Changes
Other Study ID Numbers: 1220.5  2008-003538-11 
Study First Received: October 16, 2008
Results First Received: July 3, 2015
Last Updated: October 14, 2015
Health Authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos y Tecnología Médica).
Australia: Dept of Health and Ageing Therapeutic Goods Admin
Austria: Federal Office for Safety in Health Care
Canada: Health Canada - Therapeutic Products Directorate
Czech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: BfArM (Bundesagentur für Arzneimittel und Medizinalproduke)
Korea, Republic of: Korea Food and Drug Administration
Netherlands: Central Committee on Research Involving Human Subjects (CCMO)
Portugal: National Pharmacy and Medicines Institute
Romania: National Medicines Agency, Bucharest
Spain: Spanish Agency for Medicines and Health Products
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Additional relevant MeSH terms:
Hepatitis
Hepatitis C
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Flaviviridae Infections
RNA Virus Infections
Hepatitis, Chronic
Antiviral Agents
Peginterferon alfa-2a
Anti-Infective Agents

ClinicalTrials.gov processed this record on August 25, 2016