Clinical Pharmacology Study to Evaluate the Total Systemic Exposure and the Lung Availability of CHF 5993 in Healthy Volunteers

Inclusion criteria

• Subject's written informed consent obtained prior to any study related procedure.
• Ability to understand the study procedures, the risks involved, and ability to be trained to use the pMDI device correctly with AIM™ (Aerosol Inhalation Monitor) Vitalograph®.
• Ability to generate sufficient PIF (at least 40 L/min) using the In-Check device simulating NEXThaler® device.
• Male and female Caucasian subjects aged 18 to 55 years inclusive.
• Body mass index (BMI) within the range of 18 to 30 kg/m2 inclusive.
• Non-smokers or ex-smokers who smoked < 5 pack years (pack-years = the number of cigarette packs per day, times the number of years) and stopped smoking > 1 year prior to screening.
• Good physical and mental status, determined on the basis of the medical history and a general clinical examination, at screening and before randomization.
• Lung function measurements within normal limits (Normal values: FEV1/FVC is > 0.70 and FEV1 > 80% predicted).
• Female subject of non-childbearing potential (WONCBP) defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile) and female subjects of childbearing potential (WOCBP) fulfilling one of the following criteria:

• WOCBP with fertile male partners: they and/or their partner of childbearing potential must be willing to use a double barrier contraceptive method including one highly effective birth control method and one acceptable birth control method (male or female condom with or without spermicide and/or cap, diaphragm or sponge with spermicide), from the signature of the informed consent and until 3 months after follow-up visit;
• WOCBP with non-fertile male partners: contraception is not required in this case.

Exclusion criteria

• Blood donation (equal or more than 450 ml) or blood loss, less than 8 weeks prior screening or prior randomization.
• Abnormal haemoglobin level defined as < 10.5 g/dl
• For females only: pregnant and lactating female subjects, confirmed by a positive serum test at screening and/or urine test before randomization.
• Positive HIV1 or HIV2 serology.
• Positive results from the Hepatitis serology which indicates acute or chronic Hepatitis B or Hepatitis C.
• Unsuitable veins for repeated venipuncture.
• Documented history of alcohol abuse within 12 months prior to screening.
• Documented history of drug abuse within 12 months prior to screening, or positive urine drug test performed at screening and/or before randomization.
• Subjects who have a positive urine test for cotinine at screening and/or before randomization.
• Clinically relevant abnormal laboratory values, suggesting an unknown disease and requiring further clinical investigation.
• Clinically relevant and uncontrolled respiratory, cardiac, hepatic, renal, gastrointestinal, endocrine, metabolic, neurologic, or psychiatric disorder that may interfere with successful completion of this protocol.
• Subjects with medical diagnosis of narrow-angle glaucoma, prostatic hypertrophy or bladder neck obstruction that in the opinion of the investigator would prevent use of anticholinergic.
• Subjects with history of asthma, including childhood asthma.
• Known intolerance/ hypersensitivity to any of the excipients contained in any of the formulations used in the trial.
• Abnormal 12-lead digitized Electrocardiogram (12-lead ECG) parameter (i.e.: QRS > 120 msec and/or PR > 220 msec and/or HR < 40 bpm and/or HR > 110 bpm and/or QTcF > 450 ms for males or QTcF > 470 ms for female, considering the average from triplicate) or 12-lead ECG evaluated as abnormal clinical significant by the investigator, at screening.
• Abnormal Blood Pressure (i.e.: Diastolic Blood Pressure > 90 mmHg and/or Systolic Blood Pressure > 140 mmHg, considering the average from triplicate) at screening.
• Participation in another clinical trial where investigation drug was received less than 8 weeks prior to screening.
• Subject taking any drug treatment, including prescribed or OTC medicines as well as vitamins, homeopathic remedies etc, in the 14 days before the screening, with the exception of :

• Occasional paracetamol (maximum 2 g per day with a maximum of 10 g per 14 days for mild non-excluding conditions);
• Hormonal contraceptives;
• Hormonal replacement treatment for post-menopausal women.
• Subject taking enzyme-inducing drugs, enzyme-inhibiting drugs, biologic drugs or any drug known to have a well-defined potential for hepatotoxicity (e.g. isoniazide, nimesulide, ketoconazole) in the 3 months before screening.
• Heavy caffeine drinker (> 5 caffeinated beverages e.g., coffee, tea, cola per day).
• Subject who has had a lower respiratory tract infection within 4 weeks prior to screening or prior randomization.