Clinical trial NCT00793793: Safety, Antiviral Activity and PK of MRD of BI 201335 in Chronic Hepatitis C Patients Both Treatment Naive and -Experienced
Official title: Safety, Antiviral Activity, and Pharmacokinetics of Multiple Rising Oral Doses of BI 201335 NA in Treatment-naïve Patients With Chronic Hepatitis C Infection for 14 Days Monotherapy Followed by Combination With Pegylated Interferon and Ribavirin for an Additional 14 Days (Double-blind, Placebo Controlled), and in Treatment-experienced Patients With Chronic Hepatitis C Infection for 28 Days as Combination Therapy With Pegylated Interferon and Ribavirin (Open-label)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C, Chronic
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-11-19
Enrollment: 96
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will investigate safety, antiviral activity, and pharmacokinetics of BI 201335 NA in HCV genotype 1 infected patients treated for 14 days monotherapy followed by BI 201335 NA combination therapy with PegIFN/RBV for an additional 14 days for treatment-naïve patients; or for 28 days as BI 201335 NA combination therapy with PegIFN/RBV for treatment-experienced patients.

A secondary objective is to investigate antiviral activity, potential drug-drug interactions and safety of combination therapy of BI 201335 NA and PegIFN/RBV up to 28 days for treatment-naïve patients.


Eligibility criteria: Inclusion criteria:

1a. For treatment-naïve patients: no prior therapy with interferon, peginterferon, or ribavirin for acute or chronic hepatitis C infection

1b. For treatment-experienced patients: confirmed virological failure during or after combination treatment with an approved dose of alfa-2a or alfa-2b peginterferon combined with ribavirin; such patients must have received at least 12 weeks of therapy with a 90 day washout period prior to screening and must have documentation of medical history prior to enrolment in 1220.2 2. Age 18 years or older 3. Signed informed consent form prior to trial participation 4. Male or female with documented hysterectomy or menopausal female with last menstrual period at least 6 months prior to screening 5. Chronic hepatitis C infection of genotype 1, diagnosed by positive HCV serology test (HCV Ab positive) or detectable HCV RNA at least 6 months prior to screening 6. HCV viral load \>= 100,000 IU/mL at screening 7. TSH and T4 within normal limits or adequately controlled thyroid function 8. Histological evidence within 36 months prior to study enrolment of any degree of chronic necroinflammatory activity or the presence of fibrosis (Ishak Grade 1-4 or Metavir Grade 1-3)

Exclusion criteria:

1. Patients who have been previously treated with at least one dose of any protease inhibitor for acute or chronic hepatitis C infection
2. Evidence of liver disease due to causes other than chronic HCV infection
3. Positive ELISA for HIV-1 or HIV-2
4. Hepatitis B virus (HBV) infection based on presence of Hbs Ag or HBV DNA
5. Any previous liver biopsy consistent with cirrhosis
6. Decompensated liver diseases as evidenced by ascites, portal hypertension, jaundice or hepatic encephalopathy
7. Haemophilia
8. Hemoglobinopathy (e.g., thalassemia major or sickle cell anemia)
9. Severe pre-existing psychiatric disease
10. Poorly controlled diabetes mellitus
11. Ischaemic heart disease
12. Chronic obstructive airway disease
13. Autoimmune disease; including autoimmune hepatitis
14. History of alcohol abuse within the past 12 months
15. Hyperbilirubinemia (conjugated bilirubin) \>1.5x ULN
16. Alkaline phosphatase \>1.5x ULN
17. ALT and AST levels \>= 5 x ULN
18. Hemoglobin \< 12.0 g/dL for women and \< 13.0 g/dL for men
19. White blood cell count \< 2000 cells/mm3
20. Absolute Neutrophil Count \< 1500 cells/mm3
21. Platelet count \< 100,000 cells/mm3
22. Prothrombin time INR (Institutional Normalized Ratio) prolonged to \> 1.5 x ULN
23. Usage of any investigational drug within 30 days prior to enrolment; or the planned usage of an investigational drug during the course of the current study
24. Known hypersensitivity to study drugs

Primary outcomes:
measure: Efficacy: VR (Virologic Response) of >=2 log10 Reduction in Plasma Hepatitis C Virus (HCV) Ribonucleic Acid (RNA) From Baseline at Any Time up to Day 14 (naïve Patients) or Day 28 (Experienced Patients)
timeFrame: Baseline and up to 4 weeks
measure: Occurrence of Adverse Events (AEs) During BI201335 + Washout Period
timeFrame: from day 1 and up to 4 weeks + 4 days washout
measure: Occurrence of Serious Adverse Events (SAEs) During BI201335 + Washout Period
timeFrame: from day 1 and up to 4 weeks + 4 days washout
measure: Occurrence of Laboratory Test Abnormalities and With Respect to Division of AIDS (DAIDS) Classification and Laboratory Test Values Change Over Time
timeFrame: Baseline and up to 4 weeks
Secondary outcomes:
measure: Maximum Viral Load Reduction From Baseline up to Day 14 for Treatment-naïve Patients and Day 28 Treatment for Treatment-experienced Patients
timeFrame: Baseline and up to 4 weeks
measure: Change From Baseline in Viral Load on Day 14 for Treatment-naïve Patients and on Day 28 Treatment for Treatment-experienced Patients
timeFrame: Baseline and up to 4 weeks
measure: Rapid Virologic Response (RVR)
timeFrame: week 4
measure: Early Virologic Response (EVR)
timeFrame: week 12
measure: Complete EVR1 (cEVR1)
timeFrame: week 4 and week 12
measure: Complete EVR2 (cEVR2)
timeFrame: week 4 and week 12
measure: End of Treatment Response (ETR)
timeFrame: week 48
measure: Sustained Virologic Response (SVR)
timeFrame: week 72
measure: Achievement of an HCV RNA Level Below the Limit of Detection Over Time
timeFrame: from day 1 and up to 4 weeks
measure: Achievement of an HCV RNA Level Below the Limit of Quantification Over Time
timeFrame: from day 1 and up to 4 weeks
measure: Achievement of a >= 2 log10 Reduction in Plasma HCV RNA Level From Baseline Over Time
timeFrame: from day 1 and up to 4 weeks
measure: Occurrence of AEs, by Action Taken With Regard to Study Medication
timeFrame: from day 1 and up to 4 weeks
measure: Occurrence of Discontinuations Due to AEs During BI201335 or BI201335+PegIFN/RBV Combination Treatment Period
timeFrame: from day 1 and up to 4 weeks
measure: PK (Pharmacokinetic) Parameter After the First Dose: Cmax ( Maximum Measured Concentration of the Analyte in Plasma)
timeFrame: Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1)
measure: PK Parameter After the First Dose: Tmax (Time From (Last) Dosing to the Maximum Measured Concentration of the Analyte in Plasma)
timeFrame: Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1)
measure: PK Parameter After the First Dose: AUCτ,1 (Area Under the Concentration-time Curve of the Analyte in Plasma Over a Uniform Dosing Interval τ on Day 1)
timeFrame: Times of -0:15, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, and 16:00 h relative to first administration of trial medication (on day 1)
measure: PK Parameter at Steady State After the Last Dose: Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ)
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: Tmax,ss (Time From Last Dosing to the Maximum Measured Concentration of the Analyte in Plasma at Steady State )
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: Cmin,ss (Minimum Measured Concentration of the Analyte in Plasma)
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: AUCτ,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ)
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: t1/2,ss (Terminal Half-life of the Analyte in Plasma at Steady State )
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: MRTpo,ss (Mean Residence Time of the Analyte in the Body at Steady State After Oral Administration)
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: CL/F,ss (Apparent Clearance of the Analyte in Plasma at Steady State Following Multiple Oral Dose Administration )
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter at Steady State After the Last Dose: Vz/F,ss (Apparent Volume of Distribution During the Terminal Phase z at Steady State Following an Oral Administration )
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to last administration of trial medication (on day 28)
measure: PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): AUCτ,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval τ )
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14)
measure: PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmax,ss
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14)
measure: PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmin, ss
timeFrame: Times of -0:05, 0:30, 1:00, 2:00, 3:00, 4:00, 6:00. 8:00. 12:00, 16:00, 24:00 h relative to administration of trial medication in the morning of Day 14 (on day 14)
measure: Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAcmax
timeFrame: Day 1, Day 14, and Day 28
measure: Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAauc
timeFrame: Day 1, Day 14, and Day 28
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: 1220.2.10 Boehringer Ingelheim Investigational Site
state: California
city: San Francisco
country: United States
facility: 1220.2.15 Boehringer Ingelheim Investigational Site
state: California
city: Baltimore
country: United States
facility: 1220.2.17 Boehringer Ingelheim Investigational Site
state: Maryland
city: New York
country: United States
facility: 1220.2.11 Boehringer Ingelheim Investigational Site
state: New York
city: New York
country: United States
facility: 1220.2.12 Boehringer Ingelheim Investigational Site
state: New York
city: Austin
country: United States
facility: 1220.2.14 Boehringer Ingelheim Investigational Site
state: Texas
city: Lyon
country: France
facility: 1220.2.3304A Boehringer Ingelheim Investigational Site
city: Marseille
country: France
facility: 1220.2.3303A Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1220.2.3301A Boehringer Ingelheim Investigational Site
city: Paris
country: France
facility: 1220.2.3302A Boehringer Ingelheim Investigational Site
city: Berlin
country: Germany
facility: 1220.2.49002 Boehringer Ingelheim Investigational Site
city: Düsseldorf
country: Germany
facility: 1220.2.49005 Boehringer Ingelheim Investigational Site
city: Hannover
country: Germany
facility: 1220.2.49006 Boehringer Ingelheim Investigational Site
city: Kiel
country: Germany
facility: 1220.2.49004 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1220.2.49003 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1220.2.34001 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Berger KL, Lagace L, Triki I, Cartier M, Marquis M, Lawetz C, Bethell R, Scherer J, Kukolj G. Viral resistance in hepatitis C virus genotype 1-infected patients receiving the NS3 protease inhibitor Faldaprevir (BI 201335) in a phase 1b multiple-rising-dose study. Antimicrob Agents Chemother. 2013 Oct;57(10):4928-36. doi: 10.1128/AAC.00822-13. Epub 2013 Jul 22.
citation: Manns MP, Bourliere M, Benhamou Y, Pol S, Bonacini M, Trepo C, Wright D, Berg T, Calleja JL, White PW, Stern JO, Steinmann G, Yong CL, Kukolj G, Scherer J, Boecher WO. Potency, safety, and pharmacokinetics of the NS3/4A protease inhibitor BI201335 in patients with chronic HCV genotype-1 infection. J Hepatol. 2011 Jun;54(6):1114-22. doi: 10.1016/j.jhep.2010.08.040. Epub 2010 Nov 11.