Healthy
Conditions
Brief summary
The main objective of the study is investigate the effect of escalating doses of oral tyramine on systolic blood pressure (SBP) at baseline and following an oral treatment with BI 1467335 up to 39 days at a low or high dose once daily compared to placebo and phenelzine (Nardil®) as positive control.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tyramine Sensitivity Factor (TSF) | 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). | 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. |
Countries
Netherlands
Participant flow
Recruitment details
This was a a randomised, double-blind, placebo controlled clinical trial in healthy subjects to evaluate the effects of multiple oral doses of BI 1467335 and phenelzine as positive control on blood pressure response to oral tyramine. Trial was ended prematurely due to lockdown of the trial site by the Covid-19 pandemic.
Pre-assignment details
Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 13 |
| 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. | 14 |
| 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. | 16 |
| 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. | 10 |
| Total | 53 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Permanent discontinuation of the trial due to Covid-19 pandemic | 5 | 0 | 0 | 10 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo/Placebo + Tyramine | Total | 15 mg BI 1467335/15 mg BI 1467335 + Tyramine | 10 mg BI 1467335/10 mg BI 1467335 + Tyramine | Phenelzine/Phenelzine + Tyramine |
|---|---|---|---|---|---|
| Age, Continuous | 32.2 years STANDARD_DEVIATION 8.1 | 31.2 years STANDARD_DEVIATION 7.8 | 30.4 years STANDARD_DEVIATION 8.6 | 30.9 years STANDARD_DEVIATION 6.8 | 31.4 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 50 Participants | 9 Participants | 15 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 3 Participants | 1 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 3 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 3 Participants | 2 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 42 Participants | 7 Participants | 12 Participants | 11 Participants |
| Sex: Female, Male Female | 5 Participants | 21 Participants | 3 Participants | 7 Participants | 6 Participants |
| Sex: Female, Male Male | 8 Participants | 32 Participants | 7 Participants | 9 Participants | 8 Participants |
| Tyramine dose at baseline to reach TYR30 | 453.846 Milligramm (mg) STANDARD_DEVIATION 133.012 | 445.283 Milligramm (mg) STANDARD_DEVIATION 132.384 | 390.000 Milligramm (mg) STANDARD_DEVIATION 159.513 | 456.250 Milligramm (mg) STANDARD_DEVIATION 126.326 | 464.286 Milligramm (mg) STANDARD_DEVIATION 121.574 |
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 | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 53 | 0 / 13 | 0 / 14 | 0 / 16 | 0 / 10 | 0 / 9 | 0 / 14 | 0 / 15 | 0 / 6 |
| other Total, other adverse events | 39 / 53 | 9 / 13 | 11 / 14 | 8 / 16 | 7 / 10 | 8 / 9 | 14 / 14 | 10 / 15 | 5 / 6 |
| serious Total, serious adverse events | 0 / 53 | 0 / 13 | 0 / 14 | 0 / 16 | 0 / 10 | 0 / 9 | 0 / 14 | 1 / 15 | 0 / 6 |
Outcome results
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.
Time frame: 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).
Population: 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.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo/Placebo + Tyramine | Tyramine Sensitivity Factor (TSF) | 0.98 Ratio of tyramine dose | Standard Error 1.25 |
| Phenelzine/Phenelzine + Tyramine | Tyramine Sensitivity Factor (TSF) | 5.31 Ratio of tyramine dose | Standard Error 1.17 |
| 10 mg BI 1467335/10 mg BI 1467335 + Tyramine | Tyramine Sensitivity Factor (TSF) | 1.20 Ratio of tyramine dose | Standard Error 1.17 |
Comparison: The statistical model used for the analysis of the primary endpoint was an analysis of variance (ANOVA) model on the logarithmic scale for each treatment relative to placebo.~TSF was log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the fixed effects 'treatment'.90% CI: [340.57, 870.09]ANOVA
Comparison: The statistical model used for the analysis of the primary endpoint was an analysis of variance (ANOVA) model on the logarithmic scale for each treatment relative to placebo.~TSF was log-transformed (natural logarithm) prior to fitting the ANOVA model. The model included the fixed effects 'treatment'.90% CI: [77.09, 196.95]ANOVA