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

Primary Purpose

Hepatitis C, Chronic

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

BI201335

Placebo

About this trial

This is an interventional treatment trial for Hepatitis C, Chronic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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:

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

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Placebo Comparator

Arm Label

20mg

48mg

120mg

240mg

Placebo

Arm Description

patient to receive 20mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

patient to receive 48mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

patient to receive 120mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Outcomes

Primary Outcome Measures

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).

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.

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.

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).

Secondary Outcome Measures

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.

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.

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.

Early Virologic Response (EVR)

Early Virologic Response (EVR): >=2 log10 reduction in plasma HCV RNA level from baseline at week 12 (day 84)

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

Complete EVR2 (cEVR2)

VL below the limit of detection at both 4 weeks and 12 weeks

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).

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).

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

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

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.

Occurrence of AEs, by Action Taken With Regard to Study Medication

Occurrence of AEs, by action taken with regard to study medication.

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.

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 ). .

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).

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)

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).

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)

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).

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 ).

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).

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)

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).

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] )

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] )

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] )

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] )

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 )

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 ).

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.

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.

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.

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.

Full Information

NCT ID

NCT00793793

First Posted

September 23, 2008

Last Updated

August 7, 2018

Sponsor

Boehringer Ingelheim

1. Study Identification

Unique Protocol Identification Number

NCT00793793

Brief Title

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

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Completed

Study Start Date

September 2007 (undefined)

Primary Completion Date

January 2011 (Actual)

Study Completion Date

January 25, 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Boehringer Ingelheim

4. Oversight

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hepatitis C, Chronic

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

Double

Allocation

Randomized

Enrollment

96 (Actual)

8. Arms, Groups, and Interventions

Arm Title

20mg

Arm Type

Experimental

Arm Description

patient to receive 20mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Arm Title

48mg

Arm Type

Experimental

Arm Description

patient to receive 48mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Arm Title

120mg

Arm Type

Experimental

Arm Description

patient to receive 120mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Arm Title

240mg

Arm Type

Experimental

Arm Description

patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Arm Title

Placebo

Arm Type

Placebo Comparator

Intervention Type

Drug

Intervention Name(s)

BI201335

Intervention Description

patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days

Intervention Type

Drug

Intervention Name(s)

BI201335

Intervention Description

patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days

Intervention Type

Drug

Intervention Name(s)

BI201335

Intervention Description

patient to receive rising doses of BI201335 solution qd +/- PegIFN/RBV fore 28 days

Intervention Type

Drug

Intervention Name(s)

BI201335

Intervention Description

patient to receive 240mg solution BI201335 qd +/- PegIFN/RBV fore 28 days

Intervention Type

Drug

Intervention Name(s)

Placebo

Primary Outcome Measure Information:

Title

Description

Time Frame

Baseline and up to 4 weeks

Title

Occurrence of Adverse Events (AEs) During BI201335 + Washout Period

Description

Occurrence of Adverse Events (AEs) during BI201335 + washout period. For placebo patients include all AEs through 30 days after trial discontinuation.

Time Frame

from day 1 and up to 4 weeks + 4 days washout

Title

Occurrence of Serious Adverse Events (SAEs) During BI201335 + Washout Period

Description

Occurrence of Serious Adverse Events (SAEs)during BI201335 or BI201335+ washout period. For placebo patients include all SAEs through 30 days after trial discontinuation.

Time Frame

from day 1 and up to 4 weeks + 4 days washout

Title

Occurrence of Laboratory Test Abnormalities and With Respect to Division of AIDS (DAIDS) Classification and Laboratory Test Values Change Over Time

Description

Time Frame

Baseline and up to 4 weeks

Secondary Outcome Measure Information:

Title

Maximum Viral Load Reduction From Baseline up to Day 14 for Treatment-naïve Patients and Day 28 Treatment for Treatment-experienced Patients

Description

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

Title

Change From Baseline in Viral Load on Day 14 for Treatment-naïve Patients and on Day 28 Treatment for Treatment-experienced Patients

Description

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

Title

Rapid Virologic Response (RVR)

Description

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.

Time Frame

week 4

Title

Early Virologic Response (EVR)

Description

Early Virologic Response (EVR): >=2 log10 reduction in plasma HCV RNA level from baseline at week 12 (day 84)

Time Frame

week 12

Title

Complete EVR1 (cEVR1)

Description

Time Frame

week 4 and week 12

Title

Complete EVR2 (cEVR2)

Description

VL below the limit of detection at both 4 weeks and 12 weeks

Time Frame

week 4 and week 12

Title

End of Treatment Response (ETR)

Description

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).

Time Frame

week 48

Title

Sustained Virologic Response (SVR)

Description

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).

Time Frame

week 72

Title

Achievement of an HCV RNA Level Below the Limit of Detection Over Time

Description

Achievement of an HCV RNA level below the limit of detection of the Roche COBAS Taqman HCV/HPS assay (10 IU/mL) over time

Time Frame

from day 1 and up to 4 weeks

Title

Achievement of an HCV RNA Level Below the Limit of Quantification Over Time

Description

Achievement of an HCV RNA Level Below the Limit of quantification of the Roche COBAS Taqman HCV/HPS assay (25 IU/mL) Over Time

Time Frame

from day 1 and up to 4 weeks

Title

Achievement of a >= 2 log10 Reduction in Plasma HCV RNA Level From Baseline Over Time

Description

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

Title

Occurrence of AEs, by Action Taken With Regard to Study Medication

Description

Occurrence of AEs, by action taken with regard to study medication.

Time Frame

from day 1 and up to 4 weeks

Title

Occurrence of Discontinuations Due to AEs During BI201335 or BI201335+PegIFN/RBV Combination Treatment Period

Description

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

Title

PK (Pharmacokinetic) Parameter After the First Dose: Cmax ( Maximum Measured Concentration of the Analyte in Plasma)

Description

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)

Title

PK Parameter After the First Dose: Tmax (Time From (Last) Dosing to the Maximum Measured Concentration of the Analyte in Plasma)

Description

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)

Title

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)

Description

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)

Title

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)

Description

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