Influence of Fluvoxamine on the Pharmacokinetics of BI 409306

• Fluvoxamine (Drug), also known as Fevarin®: Fluvoxamine
• BI 409306 - Powder for oral solution (PfOS) (Drug): BI 409306 - Powder for oral solution (PfOS)
• BI 409306 - film coated tablet (Drug): BI 409306 - film coated tablet

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 18 Years to 50 Years, accepts healthy volunteers

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

Participant flow

Outcome results

• 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) (Primary), Geometric least squares mean, nanomole (nmol)* hour (h)/Liter (L): 10 mg BI 409306 + 100 mg Fluvoxamine (T2) 5441.83 +/- NA; 10 mg BI 409306 (R2) 175.10 +/- NA
• Maximum Measured Concentration of BI 409306 in Plasma (Cmax) (Primary), Geometric least squares mean, nmol/L: 10 mg BI 409306 + 100 mg Fluvoxamine (T2) 660.011 +/- NA; 10 mg BI 409306 (R2) 100.153 +/- NA
• Area Under the Concentration-time Curve of BI 409306 in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC 0-infinity) (Secondary), Geometric least squares mean, nmol*h/L: 10 mg BI 409306 + 100 mg Fluvoxamine (T2) 5450.03 +/- NA; 10 mg BI 409306 (R2) 175.61 +/- NA

Adverse events

Time frame: From first drug administration until 4 days after last drug, up to 8.71 weeks.

Other adverse events by term

• Boehringer Ingelheim, Study chair, Boehringer Ingelheim

NIH grants: 2016