Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the relative bioavailability of 100 mg nintedanib given as four capsules of 25 mg nintedanib compared with one capsule of 100 mg nintedanib.
Interventions
DRUGnintedanib 25 mg
soft gelatin capsule
DRUGnintedanib 100 mg
soft gelatin capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* 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 * Age of 18 to 55 years (inclusive) * Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive) * Signed and dated written informed consent prior to admission to the study, in accordance with Good Clinical Practice (GCP) and local legislation
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease assessed as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) * Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders * History of relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of the Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration. | Area under the concentration-time curve of the nintedanib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported. |
| Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration. | Maximum measured concentration of nintedanib in plasma (Cmax) is reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration. | Area under the concentration-time curve of nintedanib in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞) is reported. |
Countries
Germany
Participant flow
Recruitment details
This was a phase I trial to test the relative bioavailability of 100 milligram (mg) nintedanib (Ofev®) given as four capsules of 25 mg compared to one capsule of 100 mg following oral administration in healthy male subjects (an open-label, randomised, single-dose, two-period, two-sequence crossover study).
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.
Participants by arm
| Arm | Count |
|---|---|
| Nintedanib 1 X 100 mg (R) / Nintedanib 4 X 25 mg (T) On Day 1 of Period 1 participants were administered once 1 soft gelatin capsule of 100 milligram (mg) of nintedanib (reference treatment (R)) orally with 240 milliliter (mL) of water after breakfast.
On Day 1 of Period 2 participants were administered one single intake of 4 soft gelatin capsules of 25 mg of nintedanib (total administered dose = 100 mg) (test treatment (T)) orally with 240 mL of water after breakfast.
There was a washout period of at least 7 days between the treatments. | 10 |
| Nintedanib 4 X 25 mg (T) / Nintedanib 1 X 100 mg (R) On Day 1 of Period 1 participants were administered one single intake of 4 soft gelatin capsules of 25 milligram (mg) of nintedanib (total administered dose = 100 mg) (test treatment (T)) orally with 240 milliliter (mL) of water after breakfast.
On Day 1 of Period 2 participants were administered once 1 soft gelatin capsule of 100 mg of nintedanib (reference treatment (R)) orally with 240 mL of water after breakfast.
There was a washout period of at least 7 days between the treatments. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period 1 | Adverse Event | 1 | 0 |
| Washout Period 1 | Physician Decision | 0 | 1 |
Baseline characteristics
| Characteristic | Nintedanib 4 X 25 mg (T) / Nintedanib 1 X 100 mg (R) | Total | Nintedanib 1 X 100 mg (R) / Nintedanib 4 X 25 mg (T) |
|---|---|---|---|
| Age, Continuous | 32.4 Years STANDARD_DEVIATION 7.8 | 33.8 Years STANDARD_DEVIATION 8.9 | 35.2 Years STANDARD_DEVIATION 10.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 20 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 20 Participants | 10 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 10 / 19 | 5 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Area Under the Concentration-time Curve of the Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of the nintedanib in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) is reported.
Time frame: For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nintedanib 1 X 100 mg (R) | Area Under the Concentration-time Curve of the Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 150.65 hours (h) *nanogram(ng)/milliliter (mL) |
| Nintedanib 4 X 25 mg (T) | Area Under the Concentration-time Curve of the Nintedanib in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 148.34 hours (h) *nanogram(ng)/milliliter (mL) |
Comparison: The statistical model used for the analysis of this primary endpoint was an analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [90.87, 106.69]
Primary
Maximum Measured Concentration of Nintedanib in Plasma (Cmax)
Maximum measured concentration of nintedanib in plasma (Cmax) is reported.
Time frame: For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nintedanib 1 X 100 mg (R) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 15.23 nanogram (ng)/milliliter (mL) |
| Nintedanib 4 X 25 mg (T) | Maximum Measured Concentration of Nintedanib in Plasma (Cmax) | 15.27 nanogram (ng)/milliliter (mL) |
Comparison: The statistical model used for the analysis of this primary endpoint was an analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [85.05, 118.24]
Secondary
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-∞) is reported.
Time frame: For both arms: Within 3 hours (h) before and 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 24 h, 34 h, 48 h and 72h after nintedanib administration.
Population: Pharmacokinetic (PK) parameter analysis set (PKS): The PKS included all subjects in the TS who provided at least 1 PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Thus, a subject was included in the PKS, even if he contributed only 1 PK parameter value for 1 period to the statistical assessment.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Nintedanib 1 X 100 mg (R) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 157.55 hours * nanogram/milliliter |
| Nintedanib 4 X 25 mg (T) | Area Under the Concentration-time Curve of Nintedanib in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 155.85 hours * nanogram/milliliter |
Comparison: The statistical model used for the analysis of this primary endpoint was an analysis of variance (ANOVA) model on the logarithmic scale. This model included effects accounting for the following sources of variation: sequence, subjects within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed.90% CI: [91.35, 107.12]