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

Hepatitis C, Chronic Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00793793
• Other study ID #: 1220.2
• Secondary ID: 2007-001158-19
• Status: Completed
• Phase: Phase 1
• Start date: September 2007
• Est. completion date: January 25, 2011

Study information

• Verified date: August 2018
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 96
• Est. completion date: January 25, 2011
• Est. primary completion date: January 2011
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• BI201335
patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
• BI201335
patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
• BI201335
patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days
• BI201335
patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days
• Placebo

Locations

Country	Name	City	State
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
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
Spain	1220.2.34001 Boehringer Ingelheim Investigational Site	Madrid
United States	1220.2.14 Boehringer Ingelheim Investigational Site	Austin	Texas
United States	1220.2.17 Boehringer Ingelheim Investigational Site	Baltimore	Maryland
United States	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	1220.2.10 Boehringer Ingelheim Investigational Site	San Francisco	California
United States	1220.2.15 Boehringer Ingelheim Investigational Site	San Francisco	California

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  France,  Germany,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	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).	Baseline and up to 4 weeks
Primary	Occurrence of Adverse Events (AEs) During BI201335 + Washout Period	Occurrence of Adverse Events (AEs) during BI201335 + washout period. For placebo patients include all AEs through 30 days after trial discontinuation.	from day 1 and up to 4 weeks + 4 days washout
Primary	Occurrence of Serious Adverse Events (SAEs) During BI201335 + Washout Period	Occurrence of Serious Adverse Events (SAEs)during BI201335 or BI201335+ washout period. For placebo patients include all SAEs through 30 days after trial discontinuation.	from day 1 and up to 4 weeks + 4 days washout
Primary	Occurrence of Laboratory Test Abnormalities and With Respect to Division of AIDS (DAIDS) Classification and Laboratory Test Values Change Over Time	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).	Baseline and up to 4 weeks
Secondary	Maximum Viral Load Reduction From Baseline up to Day 14 for Treatment-naïve Patients and Day 28 Treatment for Treatment-experienced Patients	Maximum viral load reduction from baseline up to Day 14 for treatment-naïve patients and Day 28 treatment for treatment-experienced patients.	Baseline and up to 4 weeks
Secondary	Change From Baseline in Viral Load on Day 14 for Treatment-naïve Patients and on Day 28 Treatment for Treatment-experienced Patients	Change from baseline in viral load on Day 14 for treatment-naïve patients and on Day 28 treatment for treatment-experienced patients.	Baseline and up to 4 weeks
Secondary	Rapid Virologic Response (RVR)	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.	week 4
Secondary	Early Virologic Response (EVR)	Early Virologic Response (EVR): >=2 log10 reduction in plasma HCV RNA level from baseline at week 12 (day 84)	week 12
Secondary	Complete EVR1 (cEVR1)	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	week 4 and week 12
Secondary	Complete EVR2 (cEVR2)	VL below the limit of detection at both 4 weeks and 12 weeks	week 4 and week 12
Secondary	End of Treatment Response (ETR)	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).	week 48
Secondary	Sustained Virologic Response (SVR)	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).	week 72
Secondary	Achievement of an HCV RNA Level Below the Limit of Detection Over Time	Achievement of an HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) over time	from day 1 and up to 4 weeks
Secondary	Achievement of an HCV RNA Level Below the Limit of Quantification Over Time	Achievement of an HCV RNA Level Below the Limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) Over Time	from day 1 and up to 4 weeks
Secondary	Achievement of a >= 2 log10 Reduction in Plasma HCV RNA Level From Baseline Over Time	Achievement of a >= 2 log10 reduction in plasma HCV RNA level from baseline over time.	from day 1 and up to 4 weeks
Secondary	Occurrence of AEs, by Action Taken With Regard to Study Medication	Occurrence of AEs, by action taken with regard to study medication.	from day 1 and up to 4 weeks
Secondary	Occurrence of Discontinuations Due to AEs During BI201335 or BI201335+PegIFN/RBV Combination Treatment Period	Occurrence of discontinuations due to AEs during BI201335 or BI201335+PegIFN/RBV combination treatment period.	from day 1 and up to 4 weeks
Secondary	PK (Pharmacokinetic) Parameter After the First Dose: Cmax ( Maximum Measured Concentration of the Analyte in Plasma)	PK (pharmacokinetic) parameter after the first dose: Cmax ( Maximum measured concentration of the analyte in plasma ).	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)
Secondary	PK Parameter After the First Dose: Tmax (Time From (Last) Dosing to the Maximum Measured Concentration of the Analyte in Plasma)	PK parameter after the first dose: tmax (Time from (last) dosing to the maximum measured concentration of the analyte in plasma).	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)
Secondary	PK Parameter After the First Dose: AUCt,1 (Area Under the Concentration-time Curve of the Analyte in Plasma Over a Uniform Dosing Interval t on Day 1)	PK parameter after the first dose: AUCt,1 (Area under the concentration-time curve of the analyte in plasma over a uniform dosing interval t on day 1).	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)
Secondary	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 t)	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 t).	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)
Secondary	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 )	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 ).	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)
Secondary	PK Parameter at Steady State After the Last Dose: Cmin,ss (Minimum Measured Concentration of the Analyte in Plasma)	PK parameter at steady state after the last dose: Cmin,ss (Minimum measured concentration of the analyte in plasma).	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)
Secondary	PK Parameter at Steady State After the Last Dose: AUCt,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t)	PK parameter at steady state after the last dose: AUCt,ss ((Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t).	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)
Secondary	PK Parameter at Steady State After the Last Dose: t1/2,ss (Terminal Half-life of the Analyte in Plasma at Steady State )	PK parameter at steady state after the last dose: t1/2,ss (Terminal half-life of the analyte in plasma at steady state [h] )	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)
Secondary	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)	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] )	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)
Secondary	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 )	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] )	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)
Secondary	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 )	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] )	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)
Secondary	PK Parameter for Drug-drug Interaction (naïve Patients With =1 Log Reduction on Day 10): AUCt,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State Over a Uniform Dosing Interval t )	PK parameter for drug-drug interaction (naïve patients with =1 log reduction on Day 10): AUCt,ss ( Area under the concentration-time curve of the analyte in plasma at steady state over a uniform dosing interval t ).	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)
Secondary	PK Parameter for Drug-drug Interaction (naïve Patients With =1 Log Reduction on Day 10): Cmax,ss	PK parameter for drug-drug interaction (naïve patients with =1 log reduction on Day 10): Cmax,ss.	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)
Secondary	PK Parameter for Drug-drug Interaction (naïve Patients With =1 Log Reduction on Day 10): Cmin, ss	PK parameter for drug-drug interaction (naïve patients with =1 log reduction on Day 10): Cmin, ss.	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)
Secondary	Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAcmax	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.	Day 1, Day 14, and Day 28
Secondary	Accumulation Ratio of the Analyte in Plasma Following Multiple Doses Over a Uniform Dosing Interval: RAauc	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.	Day 1, Day 14, and Day 28

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