BI 443651 Multiple Rising Dose in Healthy Volunteers Followed by a Cross-over in CF Subjects

Study Overview
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Brief Summary
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The objective of this study is to investigate the safety, tolerability, and pharmacokinetics of BI 443651 in male and female healthy volunteers and subjects with Cystic Fibrosis (CF).

Official Title
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A Phase Ib, Multicentre, Double Blind, Randomized, Two-part Study, First Part Multiple Rising Dose and Second Part Two-way Cross-over, to Assess Safety, Tolerability, Efficacy and Pharmacokinetics of BI 443651 Compared to Placebo Via Respimat® in Healthy Volunteers and CF Subjects.

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: BI 443651
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Healthy volunteers: Signed informed consent Healthy male or female subjects - Women of childbearing potential (WOCBP) should only be dosed after a confirmed menstrual period and/or with a progesterone level at Day -5 to Day -3 that demonstrates a dip from baseline, indicating a menstrual bleed prior to dosing. Age of 18 to 55 years (incl.) Body mass index (BMI) of 18.5 to 32.0 kg/m2 (incl.) Forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) of equal or greater than 80% of predicted normal, at screening and prior to randomisation Cystic Fibrosis (Cross over part): Signed informed consent Males or females with a documented diagnosis of cystic fibrosis Women of childbearing potential (WOCBP) should only be dosed after a confirmed menstrual period and/or with a progesterone level at Day -5 to Day -3, that demonstrates a dip from baseline, indicating a menstrual bleed prior to dosing. For CF subjects of child bearing potential this must confirmed prior to second treatment period. Age 18 to 55 years (each inclusive) BMI of 18 to 32.0 kg/m2 (incl.) Pre-bronchodilator FEV1 >/= to 70% of predicted normal at screening and prior to randomisation Clinical stability as defined by no evidence of acute upper or lower respiratory tract infection; no pulmonary exacerbation requiring use of i.v. / oral / inhaled antibiotics, or oral corticosteroids; no change in pulmonary disease therapy; if on cycling antibiotics, these must be initiated within 2 weeks prior to randomisation; no acute (serious or non-serious) illness not related to cystic fibrosis; no infection with an organism associated with more rapid decline in pulmonary function (eg, Burkholderia cenocepacia, B dolosa, or Mycobacterium abscessus). Able to perform technically acceptable pulmonary functions test (PFTs) Further inclusion criteria apply. Exclusion criteria: Any evidence of a concomitant disease judged as clinically relevant by the investigator including gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological, dermatologic, hematologic, neurological and psychiatric, oncological, coagulation or hormonal disorders as determined by medical history, examination, and clinical investigations at screening that may, in the opinion of the investigator, result in any of the following: Put the subject at risk because of participation in the study. Influence the results of the study. Cast doubt on the subject's ability to participate in the study. Chronic or relevant acute infections. History of relevant orthostatic hypotension, fainting spells, or blackouts History of myocardial infarction; history of acute coronary syndrome History of and/or active life-threatening cardiac arrhythmia, as assessed by the investigator Major surgery (major according to the investigator's assessment) History of chronic kidney disease (estimate glomerular filtration rate (EGFR) <59 mls/min including corrections as per ethnicity) History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients) Unsuitable veins for venipuncture (for instance, veins which are difficult to locate, access or puncture, veins with a tendency to rupture during or after puncture) as assessed by the investigator Any finding in the medical examination (including blood pressure (BP), pulse rate (PR) or electrocardiogram (ECG) is deviating from normal and judged as clinically relevant by the investigator Any laboratory value outside the reference range that the investigator considers to be of clinical relevance, specifically volunteers with serum potassium > upper limit of normal should be excluded; Safety laboratory screening and Day -7 to Day -3, evaluation can be repeated twice during screening. For healthy volunteers, repeated measurement (i.e. > 2 measurements) of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg. Volunteers will be excluded with a pulse rate outside the range of 45 to 90 bpm. A marked baseline prolongation of mean QT/QTcF interval (such as QTcF 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 or prior to randomisation A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome). Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTcF interval Intake of drugs with a long half-life (more than 24hrs) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication unless this is allowed medications. CF subjects treated with non-permitted concomitant medication. Specifically medications causing changes in serum potassium are restricted Current or previous participation in another interventional trial, including where an investigational drug has been or will be administered within 60 days or 5 half-lives (whichever is longer) prior to screening For healthy volunteers and CF subjects: current smokers or ex-smokers of less than 12 months and/or with a pack year history of more than 5 years 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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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BI 443651<br> | Drug: BI 443651<br>* twice daily<br>|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Treatment-emergent Adverse Events (TEAE) Over the Treatment Period in Part 1 and Part 2 | Percentage of participants with treatment-emergent adverse events (TEAE) over the treatment period in Part 1 and Part 2. For Part 1: From the first dose of study medication up to 30 days after the day of last intake of study medication, up to 44 days. For Part 2: From the first dose of study medication up to 30 days after the day of last intake of study medication, up to 51 days. | Up to 44 days (for Part 1) or 51 days (for Part 2) (Please check the measure description for detailed timeframe) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Measured Concentration of the BI 443651 in Plasma After the Administration of the First Dose (Cmax) on Day 1 and Over the Time Interval From 0 to 12 h After the 13th Dose (Cmax,13) on Day 7, in Part 1 | Maximum measured concentration of the BI 443651 in plasma after the administration of the first dose (Cmax) on day 1 and over the time interval from 0 to 12 h after the 13th dose (Cmax,13) on day 7, in Part 1. Pharmacokinetic samples were collected at 00:15 hours:minutes (h:m) pre-dose and at 00:15, 00:30, 00:45, 1:00, 2:00, 4:00, 6:00, 8:00 and 11:45 h:m after first drug administration on day 1 (for Cmax) and after last drug administration on day 7 (for Cmax,13). | Day 1 and Day 7 (Please check the measure description for detailed timeframe) | 
| Area Under the Concentration-time Curve of the BI 443651 in Plasma Over the Time Interval From 0 to 12 Hours After the Administration of the First Dose (AUC0-12) on Day 1 and After the 13th Dose (AUC0-12,13) on Day 7 in Part 1 | Area under the concentration-time curve of the BI 443651 in plasma over the time interval from 0 to 12 hours (h) after the administration of the first dose (AUC0-12) on day 1 and after the 13th dose (AUC0-12,13) on day 7 in Part 1. Pharmacokinetic samples were collected at 00:15 h:m pre-dose and at 00:15, 00:30, 00:45, 1:00, 2:00, 4:00, 6:00, 8:00 and 11:45 h:m after first drug administration on day 1 (for AUC0-12) and after last drug administration on day 7 (for AUC0-12,13). | Day 1 and Day 7 (Please check the measure description for detailed timeframe) |