Hepatic Insufficiency
Conditions
Brief summary
This study is open to adults aged 18 years and older. People without liver problems and people who have mild or moderate liver problems can join the study. The purpose of this study is to find out how a medicine called BI 1015550 is taken up in the blood of people with and without liver problems. Liver problems may change how a medicine is processed in the body. Participants are in the study for about 2 weeks. During this time, they visit the study site 6 times. On the second visit, participants stay overnight at the study site for 4 nights. At the visits, doctors take blood samples to measure the levels of BI 1015550 in participants' blood. Then they compare the results between the groups of participants with and without liver problems. The doctors also check participants' health and take note of any unwanted effects.
Interventions
DRUGBI 1015550
BI 1015550
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
applicable to all participants * Male or female participants * Age 18-79 years (inclusive) * Body Mass Index (BMI) of 18.5 to 35 kilogram per square meter (kg/m2) (inclusive) * Signed and dated written informed consent in accordance with Guideline for Guideline for Good Clinical Practice - Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial * Male participants are not required to use contraception * Women of childbearing potential are allowed to participate provided they use a highly effective contraception from at least 30 days before the administration of trial medication until 7 days after trial completion. Of note, oral hormonal contraceptives are not considered as highly effective in this study due to the potential CYP3A induction by BI 1015550. Methods of contraception considered adequate for female participants of childbearing potential are listed in the protocol. Inclusion criteria applying only to participants with impaired hepatic function * Hepatic impairment classified as Child-Pugh A (score 5-6 points) or Child-Pugh B (score 7-9 points) * further inclusion criteria apply Inclusion criteria applying only to participants with normal hepatic function * Individually matched to participants with hepatic impairment according to sex, age, and weight * further inclusion criteria apply
Exclusion criteria
applying to all participants * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetic(s) (PK) of the trial medication (except appendectomy or simple hernia repair) * Diseases of the central nervous system (CNS) (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders (including but not limited to major depressive disorder) * History of relevant orthostatic hypotension, fainting spells, or blackouts * Relevant chronic or acute infections * Any documented active or suspected malignancy or history of malignancy within 5 years prior to screening, except appropriately treated basal cell carcinoma of the skin or squamous cell carcinoma in situ of the skin or in situ carcinoma of uterine cervix * further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration. | Area under the concentration-time curve of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups. |
| Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax) | Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration. | Maximum measured concentration of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration. | Area under the concentration-time curve of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups. |
Countries
Germany
Participant flow
Recruitment details
The trial was performed as a non-randomised, single-dose, open-label, parallel, individual matched design in order to investigate pharmacokinetic(s) of BI 1015550, as well as safety and tolerability of BI 1015550 in male and female participants with mild and moderate hepatic impairment compared to individually matched control participants.
Pre-assignment details
All participants were screened for eligibility prior to participation in the trial. Participants attended a specialist site which ensured that the participants strictly met all inclusion and none of the exclusion criteria. Participants were not to be entered in the trial if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| BI 1015550 Mild Hepatic Impairment Participants with mild hepatic impairment, classified as Child-Pugh A (score 5 to 6 points), administered orally one film-coated tablet of 18 milligram of BI 1015550 with 240 milliliter of water after an overnight fast of at least 10 hours. | 8 |
| BI 1015550 Moderate Hepatic Impairment Participants with moderate hepatic impairment, classified as Child-Pugh B (score 7 to 9 points), administered orally one film-coated tablet of 18 milligram of BI 1015550 with 240 milliliter of water after an overnight fast of at least 10 hours. | 8 |
| BI 1015550 Normal Hepatic Function Participants with normal hepatic function administered orally one film-coated tablet of 18 milligram of BI 1015550 with 240 milliliter of water after an overnight fast of at least 10 hours.
Participants with normal hepatic function were individually matched to participants with mild and/or moderate hepatic impairment. The matching criteria were age (± 10 years), sex and weight (± 15%). One participant with normal hepatic function could match one participant in one or both groups of participants with hepatic impairment. | 12 |
| Total | 28 |
Baseline characteristics
| Characteristic | BI 1015550 Mild Hepatic Impairment | BI 1015550 Moderate Hepatic Impairment | BI 1015550 Normal Hepatic Function | Total |
|---|---|---|---|---|
| Age, Continuous | 65.9 Years STANDARD_DEVIATION 5.5 | 61.0 Years STANDARD_DEVIATION 7.4 | 64.7 Years STANDARD_DEVIATION 9.04 | 64.0 Years STANDARD_DEVIATION 7.7 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 8 Participants | 12 Participants | 28 Participants |
| Sex: Female, Male Female | 4 Participants | 4 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 6 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 8 | 2 / 8 | 1 / 8 | 2 / 8 |
| serious Total, serious adverse events | 0 / 8 | 0 / 8 | 0 / 8 | 0 / 8 |
Outcome results
Primary
Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups.
Time frame: Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration.
Population: The pharmacokinetic parameter analysis set (PKS) included all participants in the treated set who provided at least 1 primary or secondary PK endpoint and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.~Thus, a participant was to be included in the PKS even if they contributed only 1 of the main PK parameter value to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 mild hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2913.55 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 moderate hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2837.74 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 normal hepatic function matched to mild hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2786.43 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 normal hepatic function matched to moderate hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 2168.11 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [91.89, 118.98]
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [89.34, 191.75]
Primary
Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax)
Maximum measured concentration of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma (Cmax) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups.
Time frame: Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration.
Population: The pharmacokinetic parameter analysis set (PKS) included all participants in the treated set who provided at least 1 primary or secondary PK endpoint and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.~Thus, a participant was to be included in the PKS even if they contributed only 1 of the main PK parameter value to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 mild hepatic impairment | Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax) | 409.35 nanomole/liter (nmol/L) |
| BI 1015550 moderate hepatic impairment | Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax) | 277.67 nanomole/liter (nmol/L) |
| BI 1015550 normal hepatic function matched to mild hepatic impairment | Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax) | 491.48 nanomole/liter (nmol/L) |
| BI 1015550 normal hepatic function matched to moderate hepatic impairment | Maximum Measured Concentration of R-BI 1015550 in Plasma (Cmax) | 404.46 nanomole/liter (nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [60.47, 114.71]
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [46.48, 101.41]
Secondary
Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of R-BI 1015550 (the pharmacologically active enantiomer, determined using the chiral bioanalytical assay) in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. Geometric least square mean (adjusted geometric mean) and adjusted geometric standard error were calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic (PK) endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale. The model was fitted separately for the two hepatic impaired groups.
Time frame: Within the 2 hours before and 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 6, 8, 10, 12, 14, 24, 36, 48, 72, 96, 120 and 144 hours after drug administration.
Population: The pharmacokinetic parameter analysis set (PKS) included all participants in the treated set who provided at least 1 primary or secondary PK endpoint and who were not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.~Thus, a participant was to be included in the PKS even if they contributed only 1 of the main PK parameter value to the statistical assessment. Descriptive and model-based analyses of PK parameters were based on the PKS.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 1015550 mild hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2964.46 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 moderate hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2866.58 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 normal hepatic function matched to mild hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2811.48 hour*nanomole/liter (h*nmol/L) |
| BI 1015550 normal hepatic function matched to moderate hepatic impairment | Area Under the Concentration-time Curve of R-BI 1015550 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 2186.53 hour*nanomole/liter (h*nmol/L) |
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [92.36, 120.38]
Comparison: Ratio of adjusted geometric means was calculated using an analysis of variance (ANOVA) model on the logarithmic scale. The pharmacokinetic endpoints were log-transformed (natural logarithm) prior to fitting the ANOVA model. This model included the effect 'degree of hepatic impairment' as a fixed effect and 'matched pair' as random effect. These quantities were then back-transformed to the original scale.90% CI: [89.96, 191.05]