Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the induction effect of multiple oral doses of BI 1015550 on the pharmacokinetics of nintedanib or pirfenidone.
Interventions
DRUGBI 1015550
BI 1015550
DRUGNintedanib
Soft capsules
DRUGPirfenidone
Film-coated tablets
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Patients cross over from test treatment (T) to reference treatment (R) (two periods, fixed sequence).
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests 2. Age of 18 to 55 years (inclusive) 3. Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) 4. Signed and dated written informed consent in accordance with International Council for Harmonisation-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 millimetre of mercury (mmHg), diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (bpm) 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders (including severe renal or hepatic impairment) 6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) 7. Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders 8. History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2) | Area under the concentration-time curve of pirfenidone in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
| Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2) | Area under the concentration-time curve of pirfenidone in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
| Maximum Measured Concentration of Pirfenidone in Plasma (Cmax) | At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2) | Maximum measured concentration of pirfenidone in plasma (Cmax). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
| Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2) | Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
| Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2) | Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
| Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2) | Maximum measured concentration of nintedanib in plasma (Cmax). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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. |
Countries
Germany
Participant flow
Recruitment details
This is an open-label, two-period, fixed-sequence crossover trial to investigate the effect of multiple oral doses of 18 mg nerandomilast on the pharmacokinetics of single oral doses of 100 mg nintedanib or 267 mg pirfenidone.
Pre-assignment details
14 participants who met the inclusion and none of the exclusion criteria were included in the study. All 14 participants were treated in period 1. One of the 14 participants was discontinued after period 1 due to an adverse event. 13 participants were treated in period 2 and 1 of these subjects discontinue participation due to on-treatment adverse events. All 14 subjects completed the planned trial assessments. Participants were free to withdraw from the clinical trial at any time.
Participants by arm
| Arm | Count |
|---|---|
| Reference Treatment/Test Treatment In the reference (R) treatment (period 1, two days of treatment), a single dose of 267 mg pirfenidone was administered on Day 1 and a single dose of 100 mg nintedanib on Day 2.
In the test (T) treatment (period 2, ten days of treatment), 18 mg nerandomilast were administered twice daily for 10 days (Day -6 to Day 4). A single dose of 267 mg pirfenidone was administered on Day 1 and a single dose of 100 mg nintedanib was administered on Day 2.
A washout period of at least 72 hours separated the last drug administration in the reference period from the first drug administration in the test period. | 14 |
| Total | 14 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Period 2 (Test treatment period) | Adverse Event | 1 |
| Washout period | Adverse Event | 1 |
Baseline characteristics
| Characteristic | Reference Treatment/Test Treatment |
|---|---|
| Age, Continuous | 36.3 Years STANDARD_DEVIATION 10.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 14 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 13 | 0 / 13 |
| other Total, other adverse events | 1 / 14 | 4 / 14 | 3 / 13 | 1 / 13 | 7 / 13 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 | 0 / 13 | 0 / 13 | 0 / 13 |
Outcome results
Primary
Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 145.03 hour * nanogram / milliliter (h*ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 157.82 hour * nanogram / milliliter (h*ng/mL) |
90% CI: [102.54, 115.49]
Primary
Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 137.88 hour * nanogram / milliliter (h*ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 149.43 hour * nanogram / milliliter (h*ng/mL) |
90% CI: [102.58, 114.49]
Primary
Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of pirfenidone in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 10146.47 hour * nanogram / milliliter (h*ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 10279.17 hour * nanogram / milliliter (h*ng/mL) |
90% CI: [93.6, 109.65]
Primary
Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of pirfenidone in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 9597.74 hour * nanogram / milliliter (h*ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Area Under the Concentration-time Curve of Pirfenidone in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 9786.78 hour * nanogram / milliliter (h*ng/mL) |
90% CI: [93.59, 111.1]
Primary
Maximum Measured Concentration of Nintedanib in Plasma (Cmax)
Maximum measured concentration of nintedanib in plasma (Cmax). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from pirfenidone administration (Period 1) and at 24, 24:30, 25, 25:30, 26, 27, 28, 30, 32, 34, 36, 48, 60,72, 96 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 16.18 nanogram / milliliter (ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 14.12 nanogram / milliliter (ng/mL) |
90% CI: [75.27, 101.11]
Primary
Maximum Measured Concentration of Pirfenidone in Plasma (Cmax)
Maximum measured concentration of pirfenidone in plasma (Cmax). Geometric least squares mean (adjusted geometric mean) and the standard error (actually 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.
Time frame: At 0, 0:30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from pirfenidone administration (Period 1) and at 0, 0.30, 1, 1:30, 2, 3, 4, 6, 8, 10, 12, 24 hours from nerandomilast and pirfenidone administration (Period 2)
Population: Pharmacokinetic parameter analysis set (PKS): This set included all subjects in the treated set (TS) who provided data for at least 1 primary 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 subject was to be included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.~Only participants with available data were included in the analysis.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Pirfenidone/Nintedanib alone (Reference) | Maximum Measured Concentration of Pirfenidone in Plasma (Cmax) | 2451.85 nanogram / milliliter (ng/mL) |
| Pirfenidone/Nintedanib in combination with Nerandomilast (Test) | Maximum Measured Concentration of Pirfenidone in Plasma (Cmax) | 2479.00 nanogram / milliliter (ng/mL) |
90% CI: [87.36, 117.02]