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

Hepatitis C, Chronic Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00774397
• Other study ID #: 1220.5
• Secondary ID: 2008-003538-11
• Status: Completed
• Phase: Phase 2
• First received: October 16, 2008
• Last updated: October 14, 2015
• Start date: October 2008

Study information

• Verified date: October 2015
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Argentina: A.N.M.A.T. (Administracion Nacional de Medicamentos, Alimentos y Tecnología Médica).Australia: Dept of Health and Ageing Therapeutic Goods AdminAustria: Federal Office for Safety in Health CareCanada: Health Canada - Therapeutic Products DirectorateCzech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10France: 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 AdministrationNetherlands: Central Committee on Research Involving Human Subjects (CCMO)Portugal: National Pharmacy and Medicines InstituteRomania: National Medicines Agency, BucharestSpain: Spanish Agency for Medicines and Health ProductsSwitzerland: SwissmedicUnited Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 719
• Est. primary completion date: November 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis C
• Hepatitis C, Chronic

Intervention

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
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
• BI 201335 NA 120mg QD / LI
120mg BI 201335 NA (Faldaprevir) once daily, for 24 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
• BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
• BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
• BI 201335 NA 240 mg BID
240mg BI 201335 NA (Faldaprevir) twice, 24 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d),48 weeks
• BI 201335 NA 240 mg QD
240mg BI 201335 NA (Faldaprevir) once daily, 24 weeks
• PegIFN/RBV
PegIFN (180 µg/wk) and RBV (1000/1200mg/d), 24 or 48 weeks
• Placebo
Placebo

Locations

Country	Name	City	State
Argentina	1220.5.5401 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1220.5.5403 Boehringer Ingelheim Investigational Site	Capital Federal
Argentina	1220.5.5405 Boehringer Ingelheim Investigational Site	Derqui, Pilar
Argentina	1220.5.5402 Boehringer Ingelheim Investigational Site	Rosario
Argentina	1220.5.5406 Boehringer Ingelheim Investigational Site	Rosario
Australia	1220.5.6110 Boehringer Ingelheim Investigational Site	Camperdown	New South Wales
Australia	1220.5.6102 Boehringer Ingelheim Investigational Site	Clayton	Victoria
Australia	1220.5.6107 Boehringer Ingelheim Investigational Site	Fitzroy	Victoria
Australia	1220.5.6103 Boehringer Ingelheim Investigational Site	Herston	Queensland
Australia	1220.5.6109 Boehringer Ingelheim Investigational Site	Kogarah	New South Wales
Australia	1220.5.6108 Boehringer Ingelheim Investigational Site	Parkville	Victoria
Australia	1220.5.6105 Boehringer Ingelheim Investigational Site	Randwick	New South Wales
Australia	1220.5.6101 Boehringer Ingelheim Investigational Site	Westmead	New South Wales
Australia	1220.5.6104 Boehringer Ingelheim Investigational Site	Woolloongabba	Queensland
Austria	1220.5.4303 Boehringer Ingelheim Investigational Site	Linz
Austria	1220.5.4301 Boehringer Ingelheim Investigational Site	Wien
Austria	1220.5.4302 Boehringer Ingelheim Investigational Site	Wien
Canada	1220.5.1003 Boehringer Ingelheim Investigational Site	Edmonton	Alberta
Canada	1220.5.1006 Boehringer Ingelheim Investigational Site	Hamilton	Ontario
Canada	1220.5.1004 Boehringer Ingelheim Investigational Site	Montreal	Quebec
Canada	1220.5.1001 Boehringer Ingelheim Investigational Site	Ottawa	Ontario
Canada	1220.5.1002 Boehringer Ingelheim Investigational Site	Toronto	Ontario
Canada	1220.5.1007 Boehringer Ingelheim Investigational Site	Vancouver	British Columbia
Czech Republic	1220.5.4202 Boehringer Ingelheim Investigational Site	Melnik
Czech Republic	1220.5.4203 Boehringer Ingelheim Investigational Site	Opava
France	1220.5.3301A Boehringer Ingelheim Investigational Site	Clichy
France	1220.5.3307A Boehringer Ingelheim Investigational Site	Creteil
France	1220.5.3309A Boehringer Ingelheim Investigational Site	Lyon
France	1220.5.3304A Boehringer Ingelheim Investigational Site	Marseille
France	1220.5.3306A Boehringer Ingelheim Investigational Site	Montpellier
France	1220.5.3302A Boehringer Ingelheim Investigational Site	Paris
France	1220.5.3303A Boehringer Ingelheim Investigational Site	Paris
France	1220.5.3308A Boehringer Ingelheim Investigational Site	Paris Cedex 20
France	1220.5.3305A Boehringer Ingelheim Investigational Site	Vandoeuvre Cedex
Germany	1220.5.4902 Boehringer Ingelheim Investigational Site	Berlin
Germany	1220.5.4903 Boehringer Ingelheim Investigational Site	Berlin
Germany	1220.5.4917 Boehringer Ingelheim Investigational Site	Berlin
Germany	1220.5.4914 Boehringer Ingelheim Investigational Site	Bochum
Germany	1220.5.4913 Boehringer Ingelheim Investigational Site	Bonn
Germany	1220.5.4915 Boehringer Ingelheim Investigational Site	Dortmund
Germany	1220.5.4905 Boehringer Ingelheim Investigational Site	Düsseldorf
Germany	1220.5.4912 Boehringer Ingelheim Investigational Site	Düsseldorf
Germany	1220.5.4906 Boehringer Ingelheim Investigational Site	Frankfurt/Main
Germany	1220.5.4908 Boehringer Ingelheim Investigational Site	Hamburg
Germany	1220.5.4904 Boehringer Ingelheim Investigational Site	Hannover
Germany	1220.5.4910 Boehringer Ingelheim Investigational Site	Leipzig
Germany	1220.5.4909 Boehringer Ingelheim Investigational Site	Mainz
Germany	1220.5.4907 Boehringer Ingelheim Investigational Site	Tübingen
Korea, Republic of	1220.5.8210 Boehringer Ingelheim Investigational Site	Busan
Korea, Republic of	1220.5.8205 Boehringer Ingelheim Investigational Site	Daegu
Korea, Republic of	1220.5.8201 Boehringer Ingelheim Investigational Site	Pusan
Korea, Republic of	1220.5.8202 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1220.5.8206 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1220.5.8207 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1220.5.8208 Boehringer Ingelheim Investigational Site	Seoul
Korea, Republic of	1220.5.8204 Boehringer Ingelheim Investigational Site	Seoungnam
Korea, Republic of	1220.5.8203 Boehringer Ingelheim Investigational Site	Sungnam
Korea, Republic of	1220.5.8209 Boehringer Ingelheim Investigational Site	Suwon
Korea, Republic of	1220.5.8211 Boehringer Ingelheim Investigational Site	Yangsan
Netherlands	1220.5.3101 Boehringer Ingelheim Investigational Site	Amsterdam
Netherlands	1220.5.3102 Boehringer Ingelheim Investigational Site	Leiden
Portugal	1220.5.3501 Boehringer Ingelheim Investigational Site	Coimbra
Portugal	1220.5.3504 Boehringer Ingelheim Investigational Site	Coimbra
Portugal	1220.5.3502 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1220.5.3503 Boehringer Ingelheim Investigational Site	Lisboa
Portugal	1220.5.3506 Boehringer Ingelheim Investigational Site	Porto
Portugal	1220.5.3507 Boehringer Ingelheim Investigational Site	Porto
Romania	1220.5.4001 Boehringer Ingelheim Investigational Site	Bucharest
Romania	1220.5.4002 Boehringer Ingelheim Investigational Site	Bucharest
Romania	1220.5.4003 Boehringer Ingelheim Investigational Site	Bucharest
Romania	1220.5.4004 Boehringer Ingelheim Investigational Site	Bucharest
Spain	1220.5.3402 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1220.5.3405 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1220.5.3401 Boehringer Ingelheim Investigational Site	Madrid
Spain	1220.5.3403 Boehringer Ingelheim Investigational Site	Madrid
Spain	1220.5.3404 Boehringer Ingelheim Investigational Site	Madrid
Spain	1220.5.3406 Boehringer Ingelheim Investigational Site	Madrid
Switzerland	1220.5.4104 Boehringer Ingelheim Investigational Site	Bern
Switzerland	1220.5.4102 Boehringer Ingelheim Investigational Site	La Chaux-de-Fonds
Switzerland	1220.5.4103 Boehringer Ingelheim Investigational Site	Lugano
Switzerland	1220.5.4101 Boehringer Ingelheim Investigational Site	Zürich
Switzerland	1220.5.4106 Boehringer Ingelheim Investigational Site	Zürich
United Kingdom	1220.5.4405 Boehringer Ingelheim Investigational Site	Bristol
United Kingdom	1220.5.4401 Boehringer Ingelheim Investigational Site	London
United Kingdom	1220.5.4402 Boehringer Ingelheim Investigational Site	London
United Kingdom	1220.5.4406 Boehringer Ingelheim Investigational Site	London
United Kingdom	1220.5.4409 Boehringer Ingelheim Investigational Site	London
United Kingdom	1220.5.4410 Boehringer Ingelheim Investigational Site	London
United Kingdom	1220.5.4408 Boehringer Ingelheim Investigational Site	Nottingham
United Kingdom	1220.5.4403 Boehringer Ingelheim Investigational Site	Southampton
United States	1220.5.0004 Boehringer Ingelheim Investigational Site	Austin	Texas
United States	1220.5.0005 Boehringer Ingelheim Investigational Site	Chicago	Illinois
United States	1220.5.0010 Boehringer Ingelheim Investigational Site	Germantown	Tennessee
United States	1220.5.0006 Boehringer Ingelheim Investigational Site	Lutherville	Maryland
United States	1220.5.0009 Boehringer Ingelheim Investigational Site	Nashville	Tennessee
United States	1220.5.0002 Boehringer Ingelheim Investigational Site	New York	New York
United States	1220.5.0003 Boehringer Ingelheim Investigational Site	New York	New York
United States	1220.5.0007 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1220.5.0001 Boehringer Ingelheim Investigational Site	San Francisco	California
United States	1220.5.0008 Boehringer Ingelheim Investigational Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Canada,  Czech Republic,  France,  Germany,  Korea, Republic of,  Netherlands,  Portugal,  Romania,  Spain,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Virological Response 4 Weeks After the End of Treatment With BI 201335 or Placebo	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'.	Week 28	No
Primary	Sustained Virological Response 24 Weeks (SVR24) After Completion of All Therapy	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.	Day 155 after the end of all treatment	No
Secondary	Virological Response at Week 2	Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 2 (< 25 IU/ml, detectable or undetectable)	Week 2	No
Secondary	Virological Response at Week 4	Viral load (plasma HCV RNA level) below the lower limit of quantification at Week 4 (< 25 IU/ml, detectable or undetectable)	Week 4	No
Secondary	Early Virological Response (EVR)	Early Virological Response (EVR) is defined as = 2 log 10 reduction in plasma HCV RNA level from baseline at Week 12	Baseline and Week 12	No
Secondary	Extended Rapid Virological Response (eRVR)	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	Week 4 and Week 12	No
Secondary	Complete Early Virological Response (cEVR)	Complete Early Virological Response (cEVR) is defined as plasma HCV RNA level below the lower limit of detection at Week 12	Week 12	No
Secondary	End of Treatment Response at Week 24	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.	Week 24	No
Secondary	End of Treatment Response at End of All Therapy	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	Week 24 or Week 48	No
Secondary	Sustained Virological Response 12 Weeks (SVR12) After Completion of All Therapy	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	Week 36 or Week 60	No
Secondary	Time to Reach a Plasma HCV RNA Level Below the Lower Limit of Detection	Summary of time (i.e Median number of days) to reach a plasma HCV RNA level below limit of detection (BLD)	On or after day 155 post end of all treatment	No
Secondary	Time to Loss of Virological Response	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.	Week 24	No
Secondary	Virological Rebound	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.	Week 24 or Week 48	No
Secondary	Breakthrough on BI 201335/Placebo (Rebound While All 3 Treatments Were Still Ongoing)	Number of patients with Unconfirmed rebound ( = 1log10 increase in HCV mRNA) while on BI201335/placebo + 5 days washout.	Up to Week 24	No
Secondary	Breakthrough on PegIFN/RBV (Rebound While Only PegIFN/RBV Treatment Alone Was Still Ongoing)	Number of patients with Unconfirmed rebound (= 1log10 increase in HCV mRNA) while on PegIFN/RBV treatment + 5 days washout.	Week 24 through Week 48	No
Secondary	Relapse	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.	post-End of treatment (i.e. post 48 weeks)	No
Secondary	Change From Baseline to Week 24 in Diastolic Blood Pressure and Systolic Blood Pressure	Baseline is defined as the last value before the initial drug administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Change From Baseline to Week 24 in Pulse Rate	Baseline is defined as the last value before the administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Change From Baseline to Week 24 in Weight of the Patients	Baseline is defined as the last value before the administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Global Assessment of Tolerability	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'.	Week 24	No
Secondary	Change From Baseline to Week 24 in Haemoglobin of the Patients	Baseline is defined as the last value before the administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Haemoglobin	Number of patients with normal or high baseline moved to low .	Baseline and Week 24	No
Secondary	Change From Baseline to Week 24 in Absolute Neutrophils of the Patients	Baseline is defined as the last value before the administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Absolute Neutrophils	Number of patients with normal or high baseline moved to low .	Baseline and Week 24	No
Secondary	Change From Baseline to Week 24 in ALT/GPT,SGPT of the Patients	Baseline is defined as the last value before the drug administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter ALT/GPT,SGPT	Number of patients with normal or low baseline moved to high .	Baseline and Week 24	No
Secondary	Change From Baseline to Week 24 in Total Bilirubin of the Patients	Baseline is defined as the last value before the administration of BI 201335 or placebo.	Baseline and Week 24	No
Secondary	Number of Patients [N(%)] With Transitions Relative to Reference Range for Laboratory Parameter Total Bilirubin	Number of patients with normal or low baseline moved to high .	Baseline and Week 24	No
Secondary	Trough Concentration (Cpre,ss) of Faldaprevir at Steady State	C(pre,ss) is defined as pre-dose (trough) concentration of Faldaprevir in plasma at steady state immediately before administration of the next dose.	Week 8, week 10, week 12, week 24	No
Secondary	Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1000 mg/Day RBV)	C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose.	Week 8, week 10, week 12, week 24	No
Secondary	Trough Concentration (Cpre,ss) of Ribavirin at Steady State (Receiving 1200 mg/Day RBV)	C(pre,ss) is defined as pre-dose (trough) concentration of Ribavirin in plasma at steady state immediately before administration of the next dose.	Week 8, week 10, week 12, week 24	No
Secondary	Trough Concentration (Cpre,ss) of PegIFN at Steady State	C(pre,ss) is defined as pre-dose (trough) concentration of PegIFN in plasma at steady state immediately before administration of the next dose.	Week 8, week 10, week 12, week 24	No

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