A Study in Healthy People to Test How Combining BI 146733... | NCT03979820

NCT03979820

Protocol Section

Identification Module

Results Section

Participant Flow Module

Annotation Section

No data available

No data is available for this block.

Document Section

Large Document Module

Derived Section

Miscellaneous Info Module

ID	Type	Description	Link
2018-003965-32	EudraCT Number

Status Module

Label	Type	Intervention Names
10 mg BI 1467335/10 mg BI 1467335 + Tyramine	Experimental	Drug: BI 1467335 Drug: Tyramine
15 mg BI 1467335/15 mg BI 1467335 + Tyramine	Experimental	Drug: BI 1467335 Drug: Tyramine
Phenelzine/Phenelzine + Tyramine	Active Comparator	Drug: Phenelzine sulfate Drug: Tyramine
Placebo/Placebo + Tyramine	Placebo Comparator	Drug: Placebo Drug: Tyramine

Name	Type	Description	Arm Group Labels	Other Names
BI 1467335	Drug	Film-coated tablet	10 mg BI 1467335/10 mg BI 1467335 + Tyramine 15 mg BI 1467335/15 mg BI 1467335 + Tyramine

Measure	Description	Time Frame
Tyramine Sensitivity Factor (TSF)	TSF was defined as ratio of the tyramine dose causing an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30) at baseline and at steady state of BI 1467335, placebo or phenelzine. Geometric Mean is the Geometric Least Squares Mean and is extracted from the ANOVA model that includes all treatments. Standard error is the geometric standard error of the mean (gSE) and is extracted from the ANOVA model that includes all treatments.	At baseline (Day -11 up to Day-2) and at steady state (Day 29 up to Day 39 for the "Placebo/Placebo + Tyramine" and "10 mg BI 1467335/10 mg BI 1467335 + Tyramine" arms, Day 8 up to Day 19 for the "Phenelzine/ Phenelzine + Tyramine" arm).

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Healthy male or female 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
Age of 18 to 45 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
Male subjects, or female subjects who meet any of the following criteria before the first administration of trial medication until 30 days after trial completion:
- Use of adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral or vaginal contraceptives, intrauterine device (in case of oral contraceptives start of contraception at least 30 days before administration of trial medication)
- Sexually abstinent
- A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
- Surgically sterilised (including hysterectomy)
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with levels of FSH above 33,4 U/L and estradiol below 71,6 pmol/L is confirmatory) Alternatively, true abstinence is acceptable when it is in line with the subject's preferred and usual lifestyle. If a subject is usually not sexually active but becomes active, with their partner, they must comply with the contraceptive requirements detailed above.

Exclusion Criteria:

Any finding in the medical examination (including Blood pressure (BP), Pulse rate (PR) or Electrocardiogram (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 assessed as clinically relevant by the investigator
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
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 of planned administration of trial medication that might reasonably influence the results of the trial (including drugs that cause QT/QTc interval prolongation)
Intake of an investigational drug in another clinical trial within 60 days of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered
Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
Inability to refrain from smoking on specified trial days
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 of planned administration of trial medication or intended blood donation during the trial
Intention to perform excessive physical activities within one week prior to the administration of trial medication or during the trial
Inability to comply with the dietary regimen of the 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 Torsade de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)
Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the subject is not considered able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
Use of monoamine oxidase (MAO) inhibitors within 90 days before tyramine dosing
Use of fluoxetine within 5 weeks before tyramine dosing
Use of over-the-counter sympathomimetic or grapefruit products within 7 days before tyramine dosing
Subject has a known intolerability to tyramine-containing foods
At screening, no increase of systolic blood pressure > 30 mmHg during tyramine challenge at the highest tested dose of 700 mg tyramine

Female subjects will not be allowed to participate, if any of the following apply:

Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after study completion
Lactation

Facility	Status	City	State	ZIP	Country	Contacts
PRA Health Sciences Onderzoekscentrum Martini		Groningen		9728 NZ	Netherlands

Label	URL
Related Info	View source

Arm/Group Information

ID	Title	Description
FG000	Placebo/Placebo + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of placebo matching BI 1467335. During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 2 or 3 film-coated tablets of 5 mg of placebo matching BI 1467335 were administered once daily (daily dosage: 10 or 15 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with placebo matching BI 1467335 was to be stopped as soon as the individual participant had attained TYR30 on treatment.
FG001	Phenelzine/Phenelzine + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 8 to Day 19) following multiple doses of phenelzine sulfate (Nardil®). During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. Additionally an intermediate tyramine dose of 150 mg once daily was administered. 1 film-coated tablet of 15 mg of phenelzine sulfate was administered twice daily (daily dosage: 30 mg) from Day 1 to Day 18 and once daily (daily dosage: 15 mg) on Day 19 orally with 240 ml of water. Treatment with phenelzine sulfate was stopped as soon as the individual participant attained TYR30 on treatment.
FG002	10 mg BI 1467335/10 mg BI 1467335 + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of BI 1467335. During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 2 film-coated tablets of 5 mg of BI 1467335 were administered once daily (daily dosage: 10 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with BI 1467335 was stopped as soon as the individual participant attained TYR30 on treatment.
FG003	15 mg BI 1467335/15 mg BI 1467335 + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of BI 1467335. Participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 3 film-coated tablets of 5 mg of BI 1467335 were administered once daily (daily dosage: 15 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with BI 1467335 was to be stopped as soon as the individual participant attained TYR30 on treatment.

Baseline Characteristics Module

Arm/Group Information

ID	Title	Description
BG000	Placebo/Placebo + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of placebo matching BI 1467335. During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 2 or 3 film-coated tablets of 5 mg of placebo matching BI 1467335 were administered once daily (daily dosage: 10 or 15 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with placebo matching BI 1467335 was to be stopped as soon as the individual participant had attained TYR30 on treatment.

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	Tyramine Sensitivity Factor (TSF)	TSF was defined as ratio of the tyramine dose causing an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30) at baseline and at steady state of BI 1467335, placebo or phenelzine. Geometric Mean is the Geometric Least Squares Mean and is extracted from the ANOVA model that includes all treatments. Standard error is the geometric standard error of the mean (gSE) and is extracted from the ANOVA model that includes all treatments.	Per protocol analysis set (PPS): This analysis set included all participants in the TS who provided at least one endpoint that was defined as primary and was not excluded due to a protocol violation relevant. Descriptive and model-based analyses of the primary endpoint were based on the PPS. Participants of the arms "15 mg BI 1467335/15 mg BI 1467335 + Tyramine" and "Placebo/Placebo + Tyramine" who could not complete the tyramine steady state challenge were excluded from the analysis.	Posted		Geometric Least Squares Mean	Standard Error	Ratio of tyramine dose		At baseline (Day -11 up to Day-2) and at steady state (Day 29 up to Day 39 for the "Placebo/Placebo + Tyramine" and "10 mg BI 1467335/10 mg BI 1467335 + Tyramine" arms, Day 8 up to Day 19 for the "Phenelzine/ Phenelzine + Tyramine" arm).

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	Tyramine Screening	As part of the screening procedure, participants were challenged (tyramine screening/baseline challenge) from Day -11 up to Day -2 with escalating oral doses of tyramine. Planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, 700 mg given once daily orally with 240 ml of water. In each individual participant, the tyramine dose escalation was stopped when SBP increased ≥30 mmHg in at least 3 consecutive measurements (TYR30). Participants who did not attain the predefined systolic BP target elevation within 4 h after 700 mg tyramine were not to be included in the trial.

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Troponin increased	Investigations	MedDRA 23.0	Systematic Assessment

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Nausea	Gastrointestinal disorders	MedDRA 23.0	Systematic Assessment

Title	Organization	Phone	Extension	Email
Boehringer Ingelheim, Call Center	Boehringer Ingelheim	1-800-243-0127		clintriage.rdg@boehringer-ingelheim.com

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Feb 13, 2020	Apr 20, 2021	Prot_000.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Jul 16, 2020	Apr 1, 2021	SAP_001.pdf

ID	Term
D010624	Phenelzine
D014439	Tyramine

ID	Term
D006834	Hydrazines
D009930	Organic Chemicals
D015306	Biogenic Monoamines
D001679	Biogenic Amines

ID	Title	Description
OG000	Placebo/Placebo + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of placebo matching BI 1467335. During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 2 or 3 film-coated tablets of 5 mg of placebo matching BI 1467335 were administered once daily (daily dosage: 10 or 15 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with placebo matching BI 1467335 was to be stopped as soon as the individual participant had attained TYR30 on treatment.
OG001	Phenelzine/Phenelzine + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 8 to Day 19) following multiple doses of phenelzine sulfate (Nardil®). During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. Additionally an intermediate tyramine dose of 150 mg once daily was administered. 1 film-coated tablet of 15 mg of phenelzine sulfate was administered twice daily (daily dosage: 30 mg) from Day 1 to Day 18 and once daily (daily dosage: 15 mg) on Day 19 orally with 240 ml of water. Treatment with phenelzine sulfate was stopped as soon as the individual participant attained TYR30 on treatment.
OG002	10 mg BI 1467335/10 mg BI 1467335 + Tyramine	Tyramine was administered during the screening process (tyramine screening/baseline challenge, Day -11 to Day -2) and at steady state (tyramine steady state challenge, Day 29 up to Day 39) following multiple doses of BI 1467335. During tyramine baseline challenge and tyramine steady state challenge participants received escalating tyramine doses until tyramine dose caused an increase of systolic blood pressure (SBP) ≥ 30 millimetre of mercury (mmHg) for at least 3 consecutive measurements (TYR30). During the tyramine baseline challenge the planned tyramine doses were 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 milligram (mg) once daily orally with 240 milliliter (ml) of water. During the tyramine steady state challenge the planned tyramine doses were 5, 10, 25, 50, 100, 200, 300, 400, 500, 600, and 700 mg once daily orally with 240 ml of water. 2 film-coated tablets of 5 mg of BI 1467335 were administered once daily (daily dosage: 10 mg) orally with 240 ml of water from Day 1 up to Day 39. Treatment with BI 1467335 was stopped as soon as the individual participant attained TYR30 on treatment.