Influence of Fluvoxamine on the Pharmacokinetics of BI 40... | NCT02853136

NCT02853136

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

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Document Section

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Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2016-000752-10	EudraCT Number

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
3 mg BI 409306 [R1]/3 mg BI 409306 + 100 mg Fluvoxamine [T1]	Experimental	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.	Drug: Fluvoxamine Drug: BI 409306 - Powder for oral solution (PfOS)
3 mg BI 409306 + 100 mg Fluvoxamine [T1]/3 mg BI 409306 [R1]	Experimental	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.	Drug: Fluvoxamine Drug: BI 409306 - Powder for oral solution (PfOS)
10 mg BI 409306 [R2]/10 mg BI 409306 + 100 mg Fluvoxamine [T2]	Experimental	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.

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Fluvoxamine	Drug	Fluvoxamine	10 mg BI 409306 + 100 mg Fluvoxamine [T2]/10 mg BI 409306 [R2] 10 mg BI 409306 [R2]/10 mg BI 409306 + 100 mg Fluvoxamine [T2]

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	-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.
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.	-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.

Secondary Outcomes

Measure	Description	Time Frame
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.

Eligibility Module

Eligibility Criteria

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

Name	Affiliation	Role
Boehringer Ingelheim	Boehringer Ingelheim	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Humanpharmakologisches Zentrum Biberach		Biberach		88397	Germany

Label	URL
Related Info	View source

IPD Sharing Statement Module

Arm/Group Information

ID	Title	Description
FG000	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.
FG001	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.
FG002	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.
FG003	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.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	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.

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type	Title	Description	Population Description	Reporting Status	Anticipated Posting Date	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Time Frame	Units Analyzed	Denominator Units Selected	Arm/Group Information	Denominators	Classes	Analyses
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.	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.	Posted		Geometric Least Squares Mean	Standard Error	nanomole (nmol)* hour (h)/Liter (L)		-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.

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	3 mg BI 409306 (R1)	The subjects were administered 3 mg BI 409306 PfOS orally with 240 mL of water after an overnight fast of at least 10h. The Adverse Event (AE) assignment period for this treatment lasted from the time of the administration of the single dose of BI 409306 until the end of the Residual Effect Period (REP) (24h).

ID	Term
D016666	Fluvoxamine
D012996	Solutions
C000630656	BI 409306

ID	Term
D010091	Oximes
D006898	Hydroxylamines
D000588	Amines
D009930	Organic Chemicals
D004364