Open Label Single Dose Phase I Trial of BI 201335 to Study Pharmacokinetics and Safety in Patients With Compensated Liver Cirrhosis

Study Overview
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Brief Summary
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This trial was intended to investigate the pharmacokinetics, safety and tolerability of BI 201335 NA soft-gel capsules in patients with compensated liver cirrhosis, i.e. grade A according to Child-Pugh classification (< 7 points).

Official Title
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An Open Label Single Dose Phase I Trial of 120 mg and 240 mg BI 201335 Soft Gel Capsules to Study Pharmacokinetic Properties and Safety in Patients With Compensated Liver Cirrhosis in Historical Comparison With 1220.2

Conditions
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Hepatitis C, Liver Cirrhosis

Intervention / Treatment
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* Drug: BI 201335


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients with liver cirrhosis, that is histologically proven in a previous liver biopsy; possible aetiologies are: cured HCV infection, former alcohol abuse, genetic haemochromatosis, non-alcoholic steatohepatitis or others. Compensated liver disease, as indicated by Prothrombin time or INR prolonged to <1.7 x ULN, serum bilirubin < 2 mg/dl, albumin > 3.5 g/dl, no ascites or encephalopathy (Child-Pugh grade A, score < 7) Age 18 years or older Male patients, or female with documented hysterectomy, ovariectomy or tubal ligation OR menopausal female with last menstrual period at least 12 months prior to screening OR female of childbearing potential with a negative serum pregnancy test at screening and day 1 and willing to ensure consistent and correct contraception Written informed consent prior to study enrolment which must be consistent with international conference on harmonisation ¿ good clinical practice (ICH-GCP) and local legislation. Exclusion criteria: Serological evidence of active HBV, HCV or HIV infection (i.e. seropositivity for HBs antigen, anti-HIV-1 or -2 antibodies; if anti-HCV antibody positive, patients must have documented negative HCV RNA for at least 12 months) Usage of any drug within 7 days or 5 halftimes, whichever is longer, prior to treatment; or the planned usage of a drug during the course of the current study Usage of any investigational drug within 30 days prior to treatment; or the planned usage of an investigational drug during the course of the current study Decompensated liver disease within past 12 months, as indicated by variceal bleeding, ascites, encephalopathy, Prothrombin time or INR prolonged to > 1,7 x ULN, serum bilirubin > 2 mg/dl or albumin < 3,5 g/dl (i.e. Child-Pugh grade B) ALT or AST levels > 5xULN, Alkaline Phosphatase > 2xULN Liver cirrhosis due to primary or secondary biliary cirrhosis, sclerosing cholangitis, vanishing bile duct disease History of alcohol abuse within the past 3 months Known hypersensitivity to any content of the study drug Pregnant or breast feeding females Females of childbearing potential who are not willing to ensure consistent and correct use of condoms and at least one additional medically accepted method of contraception (diaphragm with spermicidal substance, cervical caps) or who are unwilling to comply to complete abstinence, from the date of screening until 6 months after the last dose of study drug AFP value > 100 ng/ml; if AFP is > 20 and <= 100 ng/ml, patients can be included if liver cancer is excluded by two congruent imaging studies (i.e. ultrasound plus CT scan or MRI) Evidence of chronic kidney failure (i.e. serum creatinine > ULN) Haemoglobinopathy (e.g., thalassaemia major or sickle cell anaemia) Concomitant intercurrent illnesses including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness or social situation that would limit compliance with trial requirement or which are considered relevant for the evaluation of the pharmacokinetic parameters or safety of the trial drug. Active or suspected malignancy or history of malignancy within the last 2 years (with the exception of appropriately treated basal cell carcinoma or in situ carcinoma of the uterine cervix)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 201335<br>BI 201335 two single oral doses, separated by 14 days washout period | Drug: BI 201335<br>* single oral doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC 0-∞ | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h (hours) after drug administration on day 1 and day 15 | 
| Cmax | Maximum plasma concentration (Cmax). Individual Cmax values will be directly determined from the plasma concentration time profiles. | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax | Time at which the maximum plasma concentration occurs (tmax). Individual tmax values will be directly determined from the plasma concentration time profiles. | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| AUC0-tz | Area under the concentration-time curve over the time interval from 0 to the last quantifiable plasma concentration (AUC0-tz). | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| t1/2 | Elimination half-life (t1/2). The terminal half-life will be calculated from the terminal rate constant. | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| CL/F | Apparent clearance of the analyte in plasma following extravascular administration (CL/F). The apparent clearance after oral administration will be determined according to the following equation: CL or CL/F=dose/AUC0-∞. (F=absolute bioavailability factor) | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| Vz/F | Apparent volume of distribution during the terminal phase (Vz/F) following an extravascular dose (at steady state). | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| MRTpo | Mean residence time of the analyte in the body after oral administration (MRTpo). | -0:15, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 8:00, 12:00, 16:00, 20:00, 24:00, 48:00, 72:00, 96:00, 120:00 h after drug administration on day 1 and day 15 | 
| Assessment of Tolerability by Investigator | The investigator has assessed tolerability based on adverse events and the laboratory evaluation. Tolerability was assessed by the investigator according to the categories 1=good, 2=satisfactory, 3=not satisfactory, and 4=bad. | Day 6 of period 1 and 2 | 
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG. New abnormal findings or worsening of baseline conditions were reported as Adverse Events. | from intake of the second dose Faldaprevir up to 9 days |