Evaluation of Safety and Tolerability of BI 894416 in Patients With Mild Asthma

Study Overview
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Brief Summary
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In both parts, the primary comparisons of interest are between the percentage of patients with drug-related adverse events at each dose and placebo during single and multiple dosing regimens. Based on these, the primary trial objective is to assess safety and tolerability of BI 894416 at each dose. Secondary measures of interest are the geometric means of BI 894416 plasma AUC0-∞ and Cmax after single dose in SRD part and AUC0-8 and Cmax after single dose as well as AUCτ,ss and Cmax,ss after 7 days multiple dosing in MRD part. The objective is to assess the pharmacokinetics of BI 894416 following single and multiple administration.

Official Title
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Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Rising Oral Doses and Multiple Rising Oral Doses of BI 894416 Versus Placebo in Male Patients With Asthma (Single-blind, Randomised, Placebo-controlled, Parallel Group Design).

Conditions
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Asthma

Intervention / Treatment
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* Drug: BI 894416
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial. Medication washout and medication restrictions according to protocol are allowed only after informed consent is obtained. Male patients aged at least 18 years but not more than 55 years at the time of informed consent. Men able to father a child must be ready and able to use highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the patient information. Pre-bronchodilator clinic measured FEV1 of ≥ 70% of predicted normal at the screening visit (Visit 1). Calculations will be based on Global Lung Function Initiative (GLI) formula A diagnosis of asthma, diagnosed by a physician. Patients should be non-smokers or ex-smokers who stopped smoking at least 12 weeks prior to screening and are expected to be able to not smoke for the duration of the study. Patients must be able to perform all trial related procedures including pulmonary function tests, nasal brushings. BMI of 18.5 to 32 kg/m2 (incl.) For MRD part: Patients are allowed to be on stable inhaled low dose corticosteroid (please refer to GINA guidelines) for at least 4 weeks prior to screening. Exclusion Criteria: Any finding in the medical examination (including BP, PR, echocardiography and echocardiography stress test or ECG and including the neurological examination) is deviating from normal and judged 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 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 (stress), 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 other than BI 894416 has been administered within 60 days or 5 half-lives (whichever is greater) prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug. In case of planned participation in the MRD part in this trial the previous participation in one dose group of the SRD part is allowed if BI 894416 has been administered more than 21 days prior to planned administration of BI 894416 in the MRD part. (Participation in an SRD dose group after the patient has participated in the MRD part is not allowed.) Alcohol abuse (consumption of more than 24 g per day) 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) 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) Patient unable or unwilling to comply with study requirements, or has a condition that would not allow safe participation in the study History of relevant neurological disorder affecting the peripheral or central nervous system (this includes, but is not limited to: stroke, epilepsy, inflammatory or atrophic diseases affecting the nervous system, cluster headache or any cancer of the nervous system) History of immunological disease except allergy not relevant to the trial (such as mild hayfever or dust mite allergy) and except asthma in childhood or adolescence History of cancer (other than successfully treated basal cell carcinoma) Use of any drug that could reasonably inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid) within 10 days prior to administration of trial medication, or planned use during the trial or within 7 days after last dose of trial medication. Further exclusion criteria apply.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: SRD part: Placebo<br>Single rising dose (SRD) part: Placebo film-coated tablet matching BI 894416 taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. | Drug: Placebo<br>* Placebo film-coated tablet matching BI 894416.<br>|
| Experimental: SRD part: 75 mg BI 894416<br>Single rising dose (SRD) part: 75 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>Drug: Placebo<br>* Placebo film-coated tablet matching BI 894416.<br>|
| Experimental: SRD part: 125 mg BI 894416<br>Single rising dose (SRD) part: 125 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|
| Experimental: SRD part: 170 mg BI 894416<br>Single rising dose (SRD) part: 170 milligram (mg) BI 894416 film-coated tablet taken once orally with 240 milliliter of water after an overnight fast of at least 10 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|
| Placebo Comparator: MRD part: Placebo<br>Multiple rising dose (MRD) part: Placebo film-coated tablet matching BI 894416 taken for 9 days orally with 240 milliliter of water. Administration of Placebo at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. | Drug: Placebo<br>* Placebo film-coated tablet matching BI 894416.<br>|
| Experimental: MRD part: 10 mg BI 894416<br>Multiple rising dose (MRD) part: 10 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|
| Experimental: MRD part: 25 mg BI 894416<br>Multiple rising dose (MRD) part: 25 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|
| Experimental: MRD part: 50 mg BI 894416<br>Multiple rising dose (MRD) part: 50 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|
| Experimental: MRD part: 60 mg BI 894416<br>Multiple rising dose (MRD) part: 60 milligram (mg) BI 894416 film-coated tablet taken for 9 days orally with 240 milliliter of water. Administration of BI 894416 at Day 1 and Day 9 once daily in the morning (q.d.) and at Day 2 to Day 8 three times daily at an interval of 8 hours (t.i.d.). Morning dose to be taken after an overnight fast of at least 10 hours, afternoon dose to be taken after fasting for 2 hours. | Drug: BI 894416<br>* BI 894416 film-coated tablet.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Patients With Treatment-emergent Adverse Events Related to BI 894416 | Percentage of patients with treatment-emergent adverse events (AEs) related to BI 894416. | From start of treatment till the end of trial, up to 30 days. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-∞ (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 Extrapolated to Infinity) of BI 894416 (SRD Part) | AUC0-∞ (area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity) of BI 894416 (single rising dose part). | 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following treatment. | 
| Cmax (Maximum Measured Concentration of the Analyte in Plasma) of BI 894416 (SRD Part) | Cmax (maximum measured concentration of the analyte in plasma) of BI 894416 (single rising dose part). | 3 hours before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 34, 48, 72 and 96 hours following treatment. | 
| AUC0-8 (Area Under the Concentration-time Curve of the Analyte in Plasma Over the Time Interval From 0 to 8 Hours) of BI 894416 After the First Dose (MRD Part) | AUC0-8 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 8 hours) of BI 894416 after the first dose (Multiple rising dose part). | 5 minutes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6 and 8 hours following first dose (day 1). | 
| Cmax (Maximum Measured Concentration of the Analyte in Plasma) of BI 894416 After the First Dose (MRD Part) | Cmax (maximum measured concentration of the analyte in plasma) of BI 894416 after the first dose (Multiple rising dose part). | 5 minutes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 23.92 hours following first dose (day 1). | 
| AUCtau,ss (Area Under the Concentration-time Curve of the Analyte in Plasma at Steady State) of BI 894416 After the Last Dose (MRD Part) | AUCtau,ss (area under the concentration-time curve of the analyte in plasma at steady state) of BI 894416 after the last dose (Multiple rising dose part). | 5 minutes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours following last dose (day 9). | 
| Cmax,ss (Maximum Measured Concentration of the Analyte in Plasma at Steady State) of BI 894416 After the Last Dose (MRD Part) | Cmax,ss (maximum measured concentration of the analyte in plasma at steady state) of BI 894416 after the last dose (Multiple rising dose part). | 5 minutes before and 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, 48, 72 and 96 hours following last dose (day 9). | 
| Difference From Baseline in Airway Resistance (RAW) After 7 Days of Treatment (MRD Part) | Difference in airway resistance (RAW) from baseline (measured on day 1) to day 9, after 7 days (day 2-8) of t.i.d. (three times daily) treatment. | Up to 9 days. |