Safety, Antiviral Activity and PK of MRD of BI 201335 in Chronic Hepatitis C Patients Both Treatment Naive and -Experienced

• ClinicalTrials.gov Identifier: NCT00793793
• Recruitment Status: Completed
• First Posted: November 19, 2008
• Results First Posted: September 17, 2015
• Last Update Posted: September 5, 2018
• Sponsor: Boehringer Ingelheim
• Information provided by (Responsible Party): Boehringer Ingelheim

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: BI201335; Drug: Placebo	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double
• Primary Purpose: Treatment
• 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 Start Date: September 2007
• Actual Primary Completion Date: January 2011
• Actual Study Completion Date: January 25, 2011

Arms and Interventions

Arm	Intervention/treatment
Experimental: 20mg; patient to receive 20mg solution BI201335 qd +/- PegIFN/RBV fore 28 days	Drug: BI201335; patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days
Experimental: 48mg; patient to receive 48mg solution BI201335 qd +/- PegIFN/RBV fore 28 days	Drug: BI201335; patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
Experimental: 120mg; patient to receive 120mg solution BI201335 qd +/- PegIFN/RBV fore 28 days	Drug: BI201335; patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
Experimental: 240mg; patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days	Drug: BI201335; patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
Placebo Comparator: Placebo	Drug: Placebo

Outcome Measures

Primary Outcome Measures :

1. 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) [ Time Frame: Baseline and up to 4 weeks ]
   Efficacy endpoint: 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).
2. Occurrence of Adverse Events (AEs) During BI201335 + Washout Period [ Time Frame: from day 1 and up to 4 weeks + 4 days washout ]
   Occurrence of Adverse Events (AEs) during BI201335 + washout period. For placebo patients include all AEs through 30 days after trial discontinuation.
3. Occurrence of Serious Adverse Events (SAEs) During BI201335 + Washout Period [ Time Frame: from day 1 and up to 4 weeks + 4 days washout ]
   Occurrence of Serious Adverse Events (SAEs)during BI201335 or BI201335+ washout period. For placebo patients include all SAEs through 30 days after trial discontinuation.
4. Occurrence of Laboratory Test Abnormalities and With Respect to Division of AIDS (DAIDS) Classification and Laboratory Test Values Change Over Time [ Time Frame: Baseline and up to 4 weeks ]

   Occurrence of laboratory test abnormalities and with respect to Division of AIDS (DAIDS) classification and laboratory test values change over time.

   ALT=Alanine transaminase (SGPT), AST=Aspartate transaminase (SGOT).

Secondary Outcome Measures :

1. Maximum Viral Load Reduction From Baseline up to Day 14 for Treatment-naïve Patients and Day 28 Treatment for Treatment-experienced Patients [ Time Frame: Baseline and up to 4 weeks ]
   Maximum viral load reduction from baseline up to Day 14 for treatment-naïve patients and Day 28 treatment for treatment-experienced patients.
2. Change From Baseline in Viral Load on Day 14 for Treatment-naïve Patients and on Day 28 Treatment for Treatment-experienced Patients [ Time Frame: Baseline and up to 4 weeks ]
   Change from baseline in viral load on Day 14 for treatment-naïve patients and on Day 28 treatment for treatment-experienced patients.
3. Rapid Virologic Response (RVR) [ Time Frame: week 4 ]
   Rapid virologic response (RVR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) on Day 28 for all patients.
4. Early Virologic Response (EVR) [ Time Frame: week 12 ]
   Early Virologic Response (EVR): >=2 log10 reduction in plasma HCV RNA level from baseline at week 12 (day 84)
5. Complete EVR1 (cEVR1) [ Time Frame: week 4 and week 12 ]
   VL (Viral load) below the limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) at 4 weeks and below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at 12 weeks
6. Complete EVR2 (cEVR2) [ Time Frame: week 4 and week 12 ]
   VL below the limit of detection at both 4 weeks and 12 weeks
7. End of Treatment Response (ETR) [ Time Frame: week 48 ]
   End of Treatment Response (ETR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at week 48 (Day 336).
8. Sustained Virologic Response (SVR) [ Time Frame: week 72 ]
   Sustained Virologic Response (SVR): Plasma HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) at week 72 (Day 504).
9. Achievement of an HCV RNA Level Below the Limit of Detection Over Time [ Time Frame: from day 1 and up to 4 weeks ]
   Achievement of an HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) over time
10. Achievement of an HCV RNA Level Below the Limit of Quantification Over Time [ Time Frame: from day 1 and up to 4 weeks ]
    Achievement of an HCV RNA Level Below the Limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) Over Time
11. Achievement of a >= 2 log10 Reduction in Plasma HCV RNA Level From Baseline Over Time [ Time Frame: from day 1 and up to 4 weeks ]
    Achievement of a >= 2 log10 reduction in plasma HCV RNA level from baseline over time.
12. Occurrence of AEs, by Action Taken With Regard to Study Medication [ Time Frame: from day 1 and up to 4 weeks ]
    Occurrence of AEs, by action taken with regard to study medication.
13. Occurrence of Discontinuations Due to AEs During BI201335 or BI201335+PegIFN/RBV Combination Treatment Period [ Time Frame: from day 1 and up to 4 weeks ]
    Occurrence of discontinuations due to AEs during BI201335 or BI201335+PegIFN/RBV combination treatment period.
14. PK (Pharmacokinetic) Parameter After the First Dose: Cmax ( Maximum Measured Concentration of the Analyte in Plasma) [ Time Frame: 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) ]

    PK (pharmacokinetic) parameter after the first dose: Cmax ( Maximum measured concentration of the analyte in plasma ).

    .

15. PK Parameter After the First Dose: Tmax (Time From (Last) Dosing to the Maximum Measured Concentration of the Analyte in Plasma) [ Time Frame: 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) ]
    PK parameter after the first dose: tmax (Time from (last) dosing to the maximum measured concentration of the analyte in plasma).
16. 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) [ Time Frame: 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) ]
    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).
17. 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) [ Time Frame: 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) ]
    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).
18. 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 ) [ Time Frame: 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) ]
    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 ).
19. PK Parameter at Steady State After the Last Dose: Cmin,ss (Minimum Measured Concentration of the Analyte in Plasma) [ Time Frame: 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) ]
    PK parameter at steady state after the last dose: Cmin,ss (Minimum measured concentration of the analyte in plasma).
20. 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) [ Time Frame: 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) ]
    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).
21. PK Parameter at Steady State After the Last Dose: t1/2,ss (Terminal Half-life of the Analyte in Plasma at Steady State ) [ Time Frame: 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) ]
    PK parameter at steady state after the last dose: t1/2,ss (Terminal half-life of the analyte in plasma at steady state [h] )
22. 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) [ Time Frame: 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) ]
    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 [h] )
23. 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 ) [ Time Frame: 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) ]
    PK parameter at steady state after the last dose (if applicable): CL/F,ss (ss Apparent clearance of the analyte in plasma at steady state following multiple oral dose administration [mL/min] )
24. 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 ) [ Time Frame: 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) ]
    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 [L] )
25. 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 ) [ Time Frame: 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) ]
    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 ).
26. PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmax,ss [ Time Frame: 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) ]
    PK parameter for drug-drug interaction (naïve patients with ≥1 log reduction on Day 10): Cmax,ss.
27. PK Parameter for Drug-drug Interaction (naïve Patients With ≥1 Log Reduction on Day 10): Cmin, ss [ Time Frame: 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) ]
    PK parameter for drug-drug interaction (naïve patients with ≥1 log reduction on Day 10): Cmin, ss.
28. Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAcmax [ Time Frame: Day 1, Day 14, and Day 28 ]
    For TN patients, comparing exposure on Day 14 to the first dose on Day 1; for TE patients, comparing exposure on Day 28 to the first dose on Day 1.
29. Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAauc [ Time Frame: Day 1, Day 14, and Day 28 ]
    For TN patients, comparing exposure on Day 14 to the first dose on Day 1; for TE patients, comparing exposure on Day 28 to the first dose on Day 1.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

1220.2.10 Boehringer Ingelheim Investigational Site

San Francisco, California, United States

1220.2.15 Boehringer Ingelheim Investigational Site

San Francisco, California, United States

United States, Maryland

1220.2.17 Boehringer Ingelheim Investigational Site

Baltimore, Maryland, United States

United States, New York

1220.2.11 Boehringer Ingelheim Investigational Site

New York, New York, United States

1220.2.12 Boehringer Ingelheim Investigational Site

New York, New York, United States

United States, Texas

1220.2.14 Boehringer Ingelheim Investigational Site

Austin, Texas, United States

France

1220.2.3304A Boehringer Ingelheim Investigational Site

Lyon, France

1220.2.3303A Boehringer Ingelheim Investigational Site

Marseille, France

1220.2.3301A Boehringer Ingelheim Investigational Site

Paris, France

1220.2.3302A Boehringer Ingelheim Investigational Site

Paris, France

Germany

1220.2.49002 Boehringer Ingelheim Investigational Site

Berlin, Germany

1220.2.49005 Boehringer Ingelheim Investigational Site

Düsseldorf, Germany

1220.2.49006 Boehringer Ingelheim Investigational Site

Hannover, Germany

1220.2.49004 Boehringer Ingelheim Investigational Site

Kiel, Germany

1220.2.49003 Boehringer Ingelheim Investigational Site

Mainz, Germany

Spain

1220.2.34001 Boehringer Ingelheim Investigational Site

Madrid, Spain

Sponsors and Collaborators

Boehringer Ingelheim

Investigators

• Study Chair: Boehringer Ingelheim; Boehringer Ingelheim

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Berger KL, Lagacé 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.

Manns MP, Bourlière 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.

• Responsible Party: Boehringer Ingelheim
• ClinicalTrials.gov Identifier: NCT00793793
• Other Study ID Numbers: 1220.2; 2007-001158-19 ( EudraCT Number )
• First Posted: November 19, 2008
• Results First Posted: September 17, 2015
• Last Update Posted: September 5, 2018
• Last Verified: August 2018

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Hepatitis, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections