Healthy
Conditions
Brief summary
To establish the bioequivalence of 1 soft gelatine capsule containing 200 mg nintedanib compared to 2 soft gelatine capsules containing 100 mg nintedanib
Interventions
DRUGNintedanib
1 soft gelatine capsule, single dose, oral
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male subjects according to the investigators assessment, based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests. 2. Age of 18 to 50 years (incl.) 3. Body weight of at least 70 kg 4. BMI of 21 to 31 kg/m2 (incl.) 5. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation 6. Male subjects, who are willing to use a medically acceptable method of contraception during the first 3 months after administration of nintedanib. Acceptable methods of contraception for use by male volunteers include sexual abstinence, a vasectomy performed at least 1 year prior to dosing and barrier contraception (condom). Subjects, who are not vasectomised or sexually abstinent have to ensure that an additional acceptable method of contraception will be used by his female partner such as IUD (intrauterine device), surgical sterilisation (including hysterectomy), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first nintedanib administration, or barrier method (e.g. diaphragm with spermicide).
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator 2. 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 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease judged as clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 6. Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and 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 9. Chronic or relevant acute infections 10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) 11. Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication 12. Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial 13. Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication 14. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day) 15. Inability to refrain from smoking on specified trial days 16. Alcohol abuse (consumption of more than 30 g per day for males) 17. Drug abuse or positive drug screening 18. Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial 19. Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial 20. Inability to comply with dietary regimen of trial site 21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-tz | -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference treatment 1 (R1) and Reference treatment 2 (R2) separately. |
| Cmax | -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | Maximum measured concentration of the analyte in plasma (Cmax). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC0-inf | -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately. |
Countries
Germany
Participant flow
Pre-assignment details
The trial was randomised and open-label with a 3-way crossover design (2 administrations of reference treatment and 1 administration of test treatment in all subjects). In this study 70 subjects were entered and treated.
Participants by arm
| Arm | Count |
|---|---|
| Nin 2x100 mg(R1) / Nin 2x100 mg(R2) / Nin 1x200 mg(T) Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) and Period 2 (Reference treatment (R2)) with nintedanib (nin) soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water, followed in Period 3 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days. | 23 |
| Nin 2x100 mg(R1) / Nin 1x200 mg(T) / Nin 2x100 mg(R2) Subjects were treated with single oral dose, started in Period 1 (Reference treatment (R1)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water, followed in Period 2 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water and in Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days. | 23 |
| Nin 1x200 mg(T) / Nin 2x100 mg(R1) / Nin 2x100 mg(R2) Subjects were treated with single oral dose, started in Period 1 (Test treatment (T)) with nintedanib soft gelatine capsule, 200 mg (1x200mg) with about 240 mL of water, followed in Period 2 (Reference treatment (R1)) and Period 3 (Reference treatment (R2)) with nintedanib soft gelatine capsule, 200 mg (2x100 mg) with about 240 mL of water. Treatment periods were separated by a wash-out phase of at least 12 days. | 24 |
| Total | 70 |
Baseline characteristics
| Characteristic | Nin 2x100 mg(R1) / Nin 2x100 mg(R2) / Nin 1x200 mg(T) | Nin 2x100 mg(R1) / Nin 1x200 mg(T) / Nin 2x100 mg(R2) | Nin 1x200 mg(T) / Nin 2x100 mg(R1) / Nin 2x100 mg(R2) | Total |
|---|---|---|---|---|
| Age, Continuous | 34.0 Years STANDARD_DEVIATION 10.3 | 36.6 Years STANDARD_DEVIATION 9.5 | 31.6 Years STANDARD_DEVIATION 7.2 | 34.0 Years STANDARD_DEVIATION 9.2 |
| Gender Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Gender Male | 23 Participants | 23 Participants | 24 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 24 / 70 | 29 / 70 |
| serious Total, serious adverse events | 0 / 70 | 0 / 70 |
Outcome results
Primary
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference treatment 1 (R1) and Reference treatment 2 (R2) separately.
Time frame: -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: Pharmacokinetic Set (PKS) : This analysis set included all treated subjects who provided at least 1 observation for at least 1 primary endpoint, and who had no important protocol violations impacting statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib, Test Treatment (T) | AUC0-tz | 300 ng*h/mL | Geometric Coefficient of Variation 38.8 |
| Nintedanib, Reference Treatment (R1) | AUC0-tz | 310 ng*h/mL | Geometric Coefficient of Variation 37.6 |
| Nintedanib, Reference Treatment (R2) | AUC0-tz | 306 ng*h/mL | Geometric Coefficient of Variation 36.2 |
Comparison: An Analysis of variance (ANOVA) model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixedp-value: <0.000190% CI: [94.545, 100.502]ANOVA
Primary
Cmax
Maximum measured concentration of the analyte in plasma (Cmax). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.
Time frame: -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib, Test Treatment (T) | Cmax | 39.3 ng/mL | Geometric Coefficient of Variation 56 |
| Nintedanib, Reference Treatment (R1) | Cmax | 41.1 ng/mL | Geometric Coefficient of Variation 43.4 |
| Nintedanib, Reference Treatment (R2) | Cmax | 39.8 ng/mL | Geometric Coefficient of Variation 46.3 |
Comparison: An ANOVA model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixed.p-value: <0.000190% CI: [90.948, 103.463]ANOVA
Secondary
AUC0-inf
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-inf). The unadjusted geometric mean (gMean) and geometric coefficient variation (gCV) was calculated for Test treatment (T), Reference 1 treatment (R1) and Reference 2 treatment (R2) separately.
Time frame: -1:00 hour(h) before drug administration and 0:30h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 3:30h, 4:00h, 4:30h, 5:00h, 5:30h, 6:00h, 7:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Nintedanib, Test Treatment (T) | AUC0-inf | 311 ng*h/mL | Geometric Coefficient of Variation 38.8 |
| Nintedanib, Reference Treatment (R1) | AUC0-inf | 322 ng*h/mL | Geometric Coefficient of Variation 37.7 |
| Nintedanib, Reference Treatment (R2) | AUC0-inf | 319 ng*h/mL | Geometric Coefficient of Variation 36.4 |
Comparison: An ANOVA model was used on the logarithmic scale in order to compare the Test treatment vs. the Reference treatment (without differentiation between R1 and R2). This model included effects for 'sequence', 'subjects within sequences', 'period' and 'treatment'. For the two 1-sided t-test procedure, the effect 'subjects within sequences' was considered to be random, whereas the other effects were considered to be fixedp-value: <0.000190% CI: [94.223, 100.166]ANOVA