Healthy
Conditions
Brief summary
To investigate the influence of fluvoxamine on the pharmacokinetics of BI 409306
Interventions
DRUGFluvoxamine
Fluvoxamine
DRUGBI 409306 - Powder for oral solution (PfOS)
BI 409306 - Powder for oral solution (PfOS)
DRUGBI 409306 - film coated tablet
BI 409306 - film coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female subjects according to the investigator's assessment, based on a complete medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests * Age of 18 to 50 years (incl.) * BMI of 18.5 to 29.9 kg/m2 (incl.) * Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation * Male or female subjects who meet any of the following criteria starting from screening until 30 days after trial completion regarding adequate contraception: * Non-hormonal intra-uterine device in combination with condom * Sexually abstinent * Surgically sterilised (including hysterectomy) * A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
* Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator * Repeated measurement of systolic blood pressure outside the range of 100 to 140 mmHg, diastolic blood pressure outside the range of 60 to 90 mmHg, or pulse rate outside the range of 50 to 85 bpm * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Any evidence of a concomitant disease judged as clinically relevant by the investigator * Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders * Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy and 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 * Chronic or relevant acute infections * History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) * Use of drugs within 30 days prior to administration of trial medication that might reasonably influence the results of the trial (incl. QT/QTc interval prolongation) * Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication * Current smoker or ex-smoker who quit smoking less than 30 days prior to screening * Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males) * Drug abuse or positive drug screening * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial * Inability to comply with dietary regimen of trial site * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other relevant ECG finding at screening * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * 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 * History of major bleeding events (e.g. gastric bleeding, intracranial haemorrhage) based on the investigator's judgement * Intake of drugs that may interfere with fluvoxamine such as monoamine oxidase inhibitors, and tizanidine. * Intake of hormonal contraception or ovary hormone replacement therapy in female subjects * Subjects with a medical history of suicidal behaviour * History of increased intraocular pressure * Positive pregnancy test, pregnancy or plans to become pregnant within 30 days after study completion * Lactation period
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | This outcome measured the area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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. |
| Maximum Measured Concentration of BI 409306 in Plasma (Cmax) | -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | This outcome measure presents the maximum measured concentration of BI 409306 in plasma in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration. | This outcome measure presents AUC0-infinity (area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity) in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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. |
Countries
Germany
Participant flow
Recruitment details
This trial was a randomised, open-label, two-treatment, two-sequence, two period crossover trial in healthy male and female subjects in order to compare the test treatment (T1) to the reference treatment (R1) in the pilot phase and the test treatment (T2) to the reference treatment (R2) in the main phase. Abbreviations used: R1 (Reference 1), R2 (Reference 2), T1 (Test 1), T2 (Test 2), SD (Standard Deviation).
Participants by arm
| Arm | Count |
|---|---|
| 3 mg BI 409306 (R1)/3 mg BI 409306 + 100 mg Fluvoxamine (T1) The subjects were administered 3 milligram (mg) BI 409306 Powder for Oral Solution (PfOS) single dose for one day in the pilot phase, taken as 6 mL of 0.5 mg/mL BI 409306 solved in 5 mg/mL (milliliter) tartaric acid orally with 240 mL of water after an overnight fast of at least 10h, followed by 3 mg BI 409306 PfOS single dose for one day together with 100 mg Fluvoxamine (Fevarin®) film-coated tablet once daily orally with 240 mL of water after an overnight fast of at least 10h.
Prior to the combined treatment, Fluvoxamine was given for 3 days: 50 mg twice daily on Day -3, followed by 100 mg bid on Day -2 and Day -1.
There was a washout of at least 3 days after administration of BI 409306 in R1. | 2 |
| 3 mg BI 409306 + 100 mg Fluvoxamine (T1)/3 mg BI 409306 (R1) The subjects were administered 3 mg BI 409306 PfOS single dose for one day in the pilot phase together with 100 mg Fluvoxamine (Fevarin®) film-coated tablet once daily orally with 240 mL of water after an overnight fast of at least 10h, followed by 3 mg BI 409306 PfOS single dose for one day orally with 240 mL of water after an overnight fast of at least 10h.
Prior to the combined treatment, Fluvoxamine was given for 3 days: 50 mg twice daily on Day -3, followed by 100 mg bid on Day -2 and Day -1.
There was a washout of at least 6 days after combined administration of BI 409306 and Fluvoxamine in T1. | 2 |
| 10 mg BI 409306 (R2)/10 mg BI 409306 + 100 mg Fluvoxamine (T2) The subjects were administered 10 mg BI 409306 film-coated tablet single dose for one day in the main phase orally with 240 mL of water after an overnight fast of at least 10h, followed by 10 mg BI 409306 film-coated tablet single dose for one day together with 100 mg Fluvoxamine (Fevarin®) film-coated tablet once daily orally with 240 mL of water after an overnight fast of at least 10h.
Prior to the combined treatment, Fluvoxamine was given for 3 days: 50 mg twice daily on Day -3, followed by 100 mg bid on Day -2 and Day -1.
There was a washout of at least 3 days after administration of BI 409306 in R2. | 7 |
| 10 mg BI 409306 + 100 mg Fluvoxamine (T2)/10 mg BI 409306 (R2) The subjects were administered 10 mg BI 409306 film-coated tablet single dose for one day in the main phase together with 100 mg Fluvoxamine (Fevarin®) film-coated tablet once daily orally with 240 mL of water after an overnight fast of at least 10h, followed by 10 mg BI 409306 single dose film-coated tablet for one day orally with 240 mL of water after an overnight fast of at least 10h.
Prior to the combined treatment, Fluvoxamine was given for 3 days: 50 mg twice daily on Day -3, followed by 100 mg bid on Day -2 and Day -1.
There was a washout of at least 6 days after combined administration of BI 409306 and Fluvoxamine in T2. | 7 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Wash-out | Adverse Event | 0 | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | 3 mg BI 409306 (R1)/3 mg BI 409306 + 100 mg Fluvoxamine (T1) | 3 mg BI 409306 + 100 mg Fluvoxamine (T1)/3 mg BI 409306 (R1) | 10 mg BI 409306 (R2)/10 mg BI 409306 + 100 mg Fluvoxamine (T2) | 10 mg BI 409306 + 100 mg Fluvoxamine (T2)/10 mg BI 409306 (R2) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 36.0 Years STANDARD_DEVIATION 5.7 | 41.0 Years STANDARD_DEVIATION 1.4 | 37.4 Years STANDARD_DEVIATION 10.6 | 36.9 Years STANDARD_DEVIATION 6.6 | 37.4 Years STANDARD_DEVIATION 7.7 |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 2 Participants | 3 Participants | 6 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 5 Participants | 4 Participants | 12 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 | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 4 | 3 / 4 | 1 / 4 | 0 / 13 | 10 / 14 | 3 / 14 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 4 | 0 / 13 | 0 / 14 | 0 / 14 |
Outcome results
Primary
Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
This outcome measured the area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz) in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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.
Time frame: -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: Pharmacokinetic (PK) analysis set (PKS) restricted to the main phase of the trial: Plasma and urine concentration data and parameters of a subject in the main phase of the trial were included in the statistical PK analyses if they were not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 10 mg BI 409306 + 100 mg Fluvoxamine (T2) | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 5441.83 nanomole (nmol)* hour (h)/Liter (L) |
| 10 mg BI 409306 (R2) | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 175.10 nanomole (nmol)* hour (h)/Liter (L) |
Comparison: The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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: [2332.9, 4140.1]
Primary
Maximum Measured Concentration of BI 409306 in Plasma (Cmax)
This outcome measure presents the maximum measured concentration of BI 409306 in plasma in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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.
Time frame: -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: Pharmacokinetic (PK) analysis set (PKS) restricted to the main phase of the trial: Plasma and urine concentration data and parameters of a subject in the main phase of the trial were included in the statistical PK analyses if they were not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 10 mg BI 409306 + 100 mg Fluvoxamine (T2) | Maximum Measured Concentration of BI 409306 in Plasma (Cmax) | 660.011 nmol/L |
| 10 mg BI 409306 (R2) | Maximum Measured Concentration of BI 409306 in Plasma (Cmax) | 100.153 nmol/L |
Comparison: The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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: [489.791, 886.676]
Secondary
Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity)
This outcome measure presents AUC0-infinity (area under the concentration-time curve of BI 409306 in plasma over the time interval from 0 extrapolated to infinity) in the main phase of the trial (10mg BI 409306 + 100 mg Fluvoxamine (T2) and 10 mg BI 409306 (R2)), as defined in the clinical trial protocol. The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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.
Time frame: -2:00h (hours: minutes) before drug administration and 0:20h, 0:30h, 0:45h, 1:00h, 1:30h, 2:00h, 2:30h, 3:00h, 4:00h, 6:00h, 8:00h, 10:00h, 12:00h, 24:00h, 34:00h, 48:00h and 72:00h after drug administration.
Population: Pharmacokinetic (PK) analysis set (PKS) restricted to the main phase of the trial: Plasma and urine concentration data and parameters of a subject in the main phase of the trial were included in the statistical PK analyses if they were not flagged for exclusion due to a protocol violation relevant to the evaluation of PK or due to PK non-evaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| 10 mg BI 409306 + 100 mg Fluvoxamine (T2) | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 5450.03 nmol*h/L |
| 10 mg BI 409306 (R2) | Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) | 175.61 nmol*h/L |
Comparison: The statistical model used for the analysis of the endpoint was an ANOVA (Analysis of Variance) model. 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: [2330.5, 4132.65]