A Study to Test How Well Healthy Men and Women Tolerate Different Doses of BI 706321

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: BI 703621
Drug: Placebo
Drug: Midazolam

Registration Number: NCT04241458

Lead Sponsor: Boehringer Ingelheim

Brief Summary: The main objectives of this trial are to investigate safety, tolerability and pharmacokinetics (PK) of BI 706321 in healthy male and female subjects following oral administration of multiple rising doses for 14 days.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 39

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), temperature), 12-lead electrocardiogram (ECG), and clinical laboratory tests
Age of 18 to 55 years (inclusive, at screening)
Body mass index (BMI) of 18.5 to 29.9 kg/m2 (inclusive, at screening)
Signed and dated written informed consent prior to admission to the study, in accordance with GCP and local legislation

Exclusion Criteria

Any finding in the medical examination (including BP, PR, temperature or 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 45 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
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 30 days (or 5 half-lives (whichever longer)) of planned administration of investigational drug in the current trial, or concurrent participation in another clinical trial in which investigational drug is administered
Smoker of more than 10 cigarettes or 3 cigars or 3 pipes per day
Inability to refrain from smoking while in-house stay
Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for males), and unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior to the trial medication administration and until Day 7 post trial medication administration.
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
ALT (alanine transaminase), AST (aspartate transaminase), or creatinine exceed upper limit of normal range at screening, confirmed by a repeat test
hemoglobin (Hb), platelets and neutrophils below lower limit of normal range at screening, confirmed by a repeat test
Positive result for human immunoinsufficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infection at screening.
History of tuberculosis (TB) or positive finding in interferon-gamma release assay (IGRA).

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

Not surgically sterilised or not postmenopausal, defined as at least 1 year of spontaneous amenorrhea without an alternative medical cause (in questionable cases a blood sample with simultaneous levels of FSH above 30 U/L and estradiol below 20 ng/L is confirmatory)
Positive pregnancy test
Lactation

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

Male subjects with women of childbearing potential (WOCBP) partner who are unwilling to use male contraception (condom or sexual abstinence) from time point of administration of trial medication until 30 days thereafter. Sperm donation is not allowed from the time point of drug administration until 30 days thereafter.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
2 mg BI 706321	BI 703621	Subjects were orally administered a single daily dose of 2 x 1 capsule of 1 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h).
10 mg BI 706321+ 75 ug midazolam	Midazolam	Subjects were orally administered a single daily dose of 2 capsules of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h).
5 mg BI 706321	BI 703621	Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h).
8 mg BI 706321 + 75 ug midazolam	BI 703621	Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) and 3 capsules of 1 mg of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h).
8 mg BI 706321 + 75 ug midazolam	Midazolam	Subjects were orally administered a single daily dose of 1 capsule of 5 milligrams (mg) and 3 capsules of 1 mg of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h).
10 mg BI 706321+ 75 ug midazolam	BI 703621	Subjects were orally administered a single daily dose of 2 capsules of 5 milligrams (mg) of BI 706321 on Day 1 and from Day 6 to 19. Subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 mL of water after an overnight fast of at least 10 hours (h).
Placebo	Placebo	Subjects were orally administered a single daily dose of matching placebo to BI 706321 capsules on Day 1 and from Day 6 to 19. Three out of the seven subjects were also orally administered a single daily dose of 1.5 millilitres (mL) (75 micrograms) of Midazolam solution on Day -1 and Day 19. The trial medication was administered with about 240 millilitres (mL) of water after an overnight fast of at least 10 hours (h).

Primary Outcome Measures

Name	Time	Method
Number of Subjects With Drug-related Adverse Events	From first administration of study drug until 8 days after the last dosing, up to 27 days.	Number of subjects with drug-related adverse events is presented.

Secondary Outcome Measures

Name	Time	Method
Area Under the Concentration-time Curve of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (AUCτ,ss)	From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h, 456h after dosing on Day 1.	Area under the concentration-time curve of BI 706321 in plasma at steady state over a uniform dosing interval τ (AUCτ,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Maximum Measured Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmax,ss)	From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.	Maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Minimum Concentration of BI 706321 in Plasma at Steady State Over a Uniform Dosing Interval τ (Cmin,ss)	From 432.5 hours (h) and 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.	Minimum concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmin,ss) is presented with a dosing interval τ of 24 hours. Pharmacokinetics parameters were determined after the last dose.
Accumulation Ratio Based on Cmax,ss (RA,Cmax)	Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.	Accumulation ratio (RA) based on maximum measured concentration of BI 706321 in plasma at steady state over a uniform dosing interval τ (Cmax,ss), (RA,Cmax) is presented. RA,cmax = Cmax,ss \[nmol/L\]/ Cmax,1 \[nmol/l\], and the unit of measure is hence unitless.
Accumulation Ratio Based on AUC0-τ (RA,AUC)	Within 3 hours (h) prior to drug administration on Day 1 and 0.5h, 1h, 2h, 3h, 4h, 5h, 6h, 8h, 10h, 12h, 24h and 432.5h, 433h, 434h, 435h, 436h, 437h, 438h, 440h, 442h, 444h, 446h and 456h after dosing on Day 1.	Accumulation ratio (RA) based on area under the concentration-time curve of BI 706321 in plasma after repeated doses over the time interval from τ (AUC0-τ), (RA,AUC) is presented with a dosing interval τ of 24 hours. RA, AUC= AUC tau, ss \[h\nmol/L\]/ AUC tau,1 \[h\nmol/L\]; hence the unit of measure is unitless.