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

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) 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 hal