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

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

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).

Study Overview

• Status: Completed
• Conditions: Liver Cirrhosis; Hepatitis C
• Intervention / Treatment: Drug: BI 201335

• Study Type: Interventional
• Enrollment (Actual): 2
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Mainz, Germany
    • 1220.15.49006 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

1. 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.
2. 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)
3. Age 18 years or older
4. 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
5. 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:

1. 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)
2. 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
3. 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
4. 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)
5. ALT or AST levels > 5xULN, Alkaline Phosphatase > 2xULN
6. Liver cirrhosis due to primary or secondary biliary cirrhosis, sclerosing cholangitis, vanishing bile duct disease
7. History of alcohol abuse within the past 3 months
8. Known hypersensitivity to any content of the study drug
9. Pregnant or breast feeding females
10. 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
11. 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)
12. Evidence of chronic kidney failure (i.e. serum creatinine > ULN)
13. Haemoglobinopathy (e.g., thalassaemia major or sickle cell anaemia)
14. 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.
15. 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI 201335; BI 201335 two single oral doses, separated by 14 days washout period	Drug: BI 201335; single oral doses

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): October 1, 2008
• Study Completion (Actual): October 1, 2008

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: July 26, 2013
• First Posted (Estimate): July 29, 2013

Study Record Updates

• Last Update Posted (Estimate): August 10, 2015
• Last Update Submitted That Met QC Criteria: August 3, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Hepatitis; Fibrosis; Hepatitis C; Liver Cirrhosis
• Other Study ID Numbers: 1220.15; 2007-007776-42 (EudraCT Number: EudraCT)