Hepatitis C, Liver Cirrhosis
Conditions
Brief summary
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).
Interventions
DRUGBI 201335
single oral doses
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞). |
| Cmax | -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 | Maximum plasma concentration (Cmax). Individual Cmax values will be directly determined from the plasma concentration time profiles. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| t1/2 | -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 | Elimination half-life (t1/2). The terminal half-life will be calculated from the terminal rate constant. |
| CL/F | -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 | 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) |
| Vz/F | -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 | Apparent volume of distribution during the terminal phase (Vz/F) following an extravascular dose (at steady state). |
| Tmax | -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 | Time at which the maximum plasma concentration occurs (tmax). Individual tmax values will be directly determined from the plasma concentration time profiles. |
| Assessment of Tolerability by Investigator | Day 6 of period 1 and 2 | 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. |
| Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | from intake of the second dose Faldaprevir up to 9 days | 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. |
| 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 | Mean residence time of the analyte in the body after oral administration (MRTpo). |
| 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 | Area under the concentration-time curve over the time interval from 0 to the last quantifiable plasma concentration (AUC0-tz). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Subjects The trial was a nonrandomised, open-label, 2-period fixed-sequence trial to evaluate two single oral doses of Faldaprevir, separated by 14 days washout period. The dose levels were 120 mg and 240 mg.
A number of 12 entered patients with compensated liver cirrhosis was planned. | 2 |
| Total | 2 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | failed screening | 1 |
Baseline characteristics
| Characteristic | All Subjects |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 1 | 1 / 1 |
| serious Total, serious adverse events | 0 / 1 | 0 / 1 |
Outcome results
Primary
AUC 0-∞
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC 0-∞).
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | AUC 0-∞ | 7240 h*ng/mL |
| High Dose of Faldaprevir (Period 2) | AUC 0-∞ | 24700 h*ng/mL |
Primary
Cmax
Maximum plasma concentration (Cmax). Individual Cmax values will be directly determined from the plasma concentration time profiles.
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | Cmax | 308 ng/mL |
| High Dose of Faldaprevir (Period 2) | Cmax | 999 ng/mL |
Secondary
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.
Time frame: Day 6 of period 1 and 2
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | Assessment of Tolerability by Investigator | 1 units on a scale |
| High Dose of Faldaprevir (Period 2) | Assessment of Tolerability by Investigator | 1 units on a scale |
Secondary
AUC0-tz
Area under the concentration-time curve over the time interval from 0 to the last quantifiable plasma concentration (AUC0-tz).
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | AUC0-tz | 6770 h*ng/mL |
| High Dose of Faldaprevir (Period 2) | AUC0-tz | 23900 h*ng/mL |
Secondary
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)
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | CL/F | 276 mL/min |
| High Dose of Faldaprevir (Period 2) | CL/F | 162 mL/min |
Secondary
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.
Time frame: from intake of the second dose Faldaprevir up to 9 days
Population: Only one patient was treated and completed this study; he was the only patient analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | 0 participants |
| High Dose of Faldaprevir (Period 2) | Clinical Relevant Abnormalities for Vital Signs, Blood Chemistry, Haematology, Urinanalysis and ECG | 0 participants |
Secondary
MRTpo
Mean residence time of the analyte in the body after oral administration (MRTpo).
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | MRTpo | 39.3 hours |
| High Dose of Faldaprevir (Period 2) | MRTpo | 31.6 hours |
Secondary
t1/2
Elimination half-life (t1/2). The terminal half-life will be calculated from the terminal rate constant.
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | t1/2 | 33.8 hours |
| High Dose of Faldaprevir (Period 2) | t1/2 | 26.8 hours |
Secondary
Tmax
Time at which the maximum plasma concentration occurs (tmax). Individual tmax values will be directly determined from the plasma concentration time profiles.
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | Tmax | 8.00 hours |
| High Dose of Faldaprevir (Period 2) | Tmax | 8.00 hours |
Secondary
Vz/F
Apparent volume of distribution during the terminal phase (Vz/F) following an extravascular dose (at steady state).
Time frame: -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
Population: Only one patient was treated and completed this study; he was the only patient analysed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Dose of Faldaprevir (Period 1) | Vz/F | 809 Liter |
| High Dose of Faldaprevir (Period 2) | Vz/F | 376 Liter |