Healthy
Conditions
Brief summary
The main objective of this trial is to investigate the pharmacodynamic effects of a single dose of BI 1358894 on CCK-4- induced anxiogenic/ panic-like symptoms using the PSS in preselected CCK-4 sensitive healthy volunteers.
Interventions
DRUGBI 1358894
Film-coated tablet
DRUGPlacebo
Film-coated tablet
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy male 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 tests * Age of 18 to 55 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 * Willingness to comply with contraception requirements. Subjects who are sexually active must use adequate contraception with their female partner throughout the study and until one month after the last administration of trial medication. Adequate methods are: * Sexual abstinence or * A vasectomy performed at least 1 year prior to screening (with medical assessment of the surgical success) or * Surgical sterilisation (including bilateral tubal occlusion, hysterectomy or bilateral oophorectomy) of the subject's female partner or * Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with FSH above 40 U/L and estradiol below 30 ng/L is confirmatory) or * The use of condoms, if the female partner uses an adequate contraception method in addition, e.g., intrauterine device (IUD), hormonal contraception (e.g. implants, injectables, combined oral or vaginal contraceptives) that started at least 2 months prior to first drug administration, or barrier method (e.g. diaphragm with spermicide)
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 50 to 90 bpm * C-Reactive Protein \>ULN, erythrocyte sedimentation rate (ESR) ≥15 millimeters/h, liver or kidney parameter above ULN, * 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 * 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, CCK-4 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 5 cigarettes or 3 cigars or 3 pipes per day) * Inability to refrain from smoking on specified trial days * Average intake of more than 21 units of alcohol per week (1 unit of alcohol equals approximately 250 mL of beer, 100 mL of wine, or 35 mL of spirits) * 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) or any other relevant Electrocardiogram (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 * Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour) * Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active suicidal thought, active suicidal thought with method, active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent) * Insufficient response to the CCK-4 challenge in Screening Visit 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Change From Baseline in Panic Symptom Scale (PSS) Sum Intensity Score | Within 3 hours (h) prior trial medication administration and 4h, 4h 45 minutes (min), 5h 5min, 5h 10min, 5h 20min, 5h 30min and 192h thereafter. | The last value before administration of the CCK-4 challenge in each period was considered the corresponding period baseline measurement. The PSS sum intensity score mean value of the two period baseline values was considered as the subject baseline. The PSS is a patient reported outcome measurement from which the following factors where derived: physical symptoms of fear and the perception of alertness, anxiety, fear, and pain. The subjects were asked to rate each of 18 characteristic questions on a scale from 0 (absent) to 4 (very strong). The sum of the scale over all items constituted the PSS sum intensity score, ranging from 0 to 72. A higher score implies a stronger panic symptom. |
Countries
Netherlands
Participant flow
Recruitment details
A double-blind, randomized, two-way cross-over, single-dose, placebo-controlled trial to investigate the effects of BI 1358894 on cholecystokinin tetrapeptide (CCK-4) induced panic symptoms in healthy male subjects.
Pre-assignment details
All participants were screened for eligibility to participate in the trial. Participants attended specialist sites which would then ensure that all participants met all inclusion and non of the exclusion criteria. Participants were not to be entered to trial treatment in any of the specific entry criteria were not met.
Participants by arm
| Arm | Count |
|---|---|
| 100 mg BI 1358894 (T) / Placebo (R) 4 film-coated tablets of 25 milligram (mg) of BI 1358894 were administered as a single oral dose with 240 milliliter (mL) of water after a standard high-fat meal as test treatment (T), followed by a washout period of at least 17 days, followed by 4 placebo film-coated tablets, administered as a single oral dose with 240 mL of water after a standard high-fat meal, as reference treatment (R). Treatments were administered 5 hours (h) prior to the provoking agent cholecystokinin tetrapeptide (CCK-4). CCK-4 was administered in 2 single doses of 50 microgram (μg) intravenous via bolus injection. | 10 |
| Placebo (R) / 100 mg BI 1358894 (T) 4 film-coated tablets of matching placebo were administered as a single oral dose with 240 milliliter (mL) of water after a standard high-fat meal as reference treatment (R), followed by a washout period of at least 17 days, followed by 4 film-coated tablets of 25 mg of BI 1358894, administered as a single oral dose with 240 mL of water after a standard high-fat meal, as test treatment (T). Treatments were administered 5 h prior to the provoking agent CCK-4. CCK-4 was administered in 2 single doses of 50 μg intravenous via bolus injection. | 10 |
| Total | 20 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout Period | Protocol Violation | 1 | 1 |
Baseline characteristics
| Characteristic | Placebo (R) / 100 mg BI 1358894 (T) | Total | 100 mg BI 1358894 (T) / Placebo (R) |
|---|---|---|---|
| Age, Continuous | 27.0 Years STANDARD_DEVIATION 9.5 | 26.7 Years STANDARD_DEVIATION 9.5 | 26.3 Years STANDARD_DEVIATION 10 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 19 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 9 Participants | 16 Participants | 7 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 10 Participants | 20 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 19 |
| other Total, other adverse events | 14 / 19 | 10 / 19 |
| serious Total, serious adverse events | 0 / 19 | 0 / 19 |
Outcome results
Primary
Maximum Change From Baseline in Panic Symptom Scale (PSS) Sum Intensity Score
The last value before administration of the CCK-4 challenge in each period was considered the corresponding period baseline measurement. The PSS sum intensity score mean value of the two period baseline values was considered as the subject baseline. The PSS is a patient reported outcome measurement from which the following factors where derived: physical symptoms of fear and the perception of alertness, anxiety, fear, and pain. The subjects were asked to rate each of 18 characteristic questions on a scale from 0 (absent) to 4 (very strong). The sum of the scale over all items constituted the PSS sum intensity score, ranging from 0 to 72. A higher score implies a stronger panic symptom.
Time frame: Within 3 hours (h) prior trial medication administration and 4h, 4h 45 minutes (min), 5h 5min, 5h 10min, 5h 20min, 5h 30min and 192h thereafter.
Population: Pharmacodynamic set (PDS): All participants in the treated set (TS) who provided at least one primary pharmacodynamic parameter that was not excluded (due to protocol deviation or due to non-evaluability).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| 100 mg BI 1358894 (T) | Maximum Change From Baseline in Panic Symptom Scale (PSS) Sum Intensity Score | 22.639 Score on a scale | Standard Error 2.88 |
| Placebo (R) | Maximum Change From Baseline in Panic Symptom Scale (PSS) Sum Intensity Score | 29.944 Score on a scale | Standard Error 2.884 |
Comparison: Mixed effects model including effects for 'treatment', 'period' and 'subject' as well as covariates 'period baseline' and 'subject baseline'.90% CI: [-10.949, -3.661]
Comparison: Mixed effects model including effects for 'treatment', 'period' and 'subject' as well as covariates 'period baseline' and 'subject baseline'.