Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses of BI 1744 CL in Fixed Dose Combination With Tiotropium Bromide in Healthy Male Volunteers

Phase 1

Completed

• Conditions: Healthy
• Interventions: Drug: Single rising doses of BI 1744 CL, solution for oral inhalation; Drug: Placebo; Drug: Tiotropium, fixed dose, solution for oral inhalation

• Registration Number: NCT02259959
• Lead Sponsor: Boehringer Ingelheim

Brief Summary

To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of BI 1744 CL and Tiotropium Bromide when given as fixed dose combination

Detailed Description

Not available

Study Timeline

• Study Start: 2007-04
• Primary Completion: 2007-09
• Status Verified: 2014-10
• Study First Submitted: 2014-10-07
• Study First Submitted QC: 2014-10-07
• Last Update Submitted: 2014-10-07
• Study First Posted: 2014-10-09
• Last Update Posted: 2014-10-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 36

Inclusion Criteria

• Healthy male based upon a complete medical history, including physical examination, regarding vital signs (BP, PR), 12-lead ECG measurement, and clinical laboratory tests. There is no finding deviating from normal and of clinical relevance. There is no evidence of a clinically relevant concomitant disease
• Age ≥21 and ≤45 years
• BMI ≥18.5 and <30 kg/m2 (Body Mass Index)
• Signed and dated written informed consent prior to admission to the study in accordance with good clinical practice (GCP) and the local legislation

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Exclusion Criteria

• Any finding of the medical examination (including BP, PR, and ECG measurements) deviating from normal and of clinical relevance
• Evidence of a clinically relevant concomitant disease
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders
• History of relevant orthostatic hypotension, fainting spells or blackouts
• Chronic or relevant acute infections
• History of relevant allergy/hypersensitivity (including allergy to the drug or its excipients) as judged clinically relevant by the investigator
• Intake of drugs with a long half-life (>24 hours) within at least 1 month or less than 10 half-lives of the respective drug prior to randomization
• Use of drugs which might reasonably influence the results of the trial based on the knowledge at the time of protocol preparation within 10 days prior to randomisation
• Participation in another trial with an investigational drug within 2 months prior to randomisation
• Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
• Inability to refrain from smoking on trial days as judged by the investigator
• Alcohol abuse (more than 40 g alcohol a day)
• Drug abuse
• Blood donation (more than 100 mL blood within 4 weeks prior to randomisation or during the trial)
• Excessive physical activities within 1 week prior to randomisation or during the trial
• Any laboratory value outside the reference range that is of clinical relevance
• Inability to comply with dietary regimen of the study centre

The following exclusion criteria are specific for this study due to the known class side effect profile of ß2-mimetics:

• Asthma or history of pulmonary hyperreactivity
• Hyperthyrosis
• Allergic rhinitis in need of treatment
• Clinically relevant cardiac arrhythmia
• Paroxysmal tachycardia (>100 beats per minute)

The following exclusion criteria are specific for this study due to the known class side effect profile of Tiotropium:

• Hypersensitivity to tiotropium and/or related drugs of these classes
• History of narrow-angle glaucoma
• History of prostatic hyperplasia
• History of bladder-neck obstruction

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
BI 1744 CL in combination with Tiotropium	Single rising doses of BI 1744 CL, solution for oral inhalation	-
BI 1744 CL in combination with Tiotropium	Tiotropium, fixed dose, solution for oral inhalation	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Number of subjects with clinically relevant findings in physical examination	Up to day 32
Number of subjects with clinically relevant findings in vital signs	Up to day 32	blood pressure, pulse rate
Number of subjects with clinically relevant findings in 12-lead ECG	Up to day 32
Number of subjects with clinically relevant changes in airway resistance (Raw) measured by body plethysmography	Pre-dose, up to 408 hours after start of treatment
Number of subjects with adverse events	Up to day 32
Global assessment of tolerability by investigator on a 4-point scale	Up to day 32
Number of subjects with clinically relevant findings in laboratory tests	Up to day 32
Number of subjects witch clinically relevant changes in additional safety laboratory test parameters	up to 318 hours after start of treatment	Systemic metabolic parameters: cyclic adenosine mono phosphate (cAMP) and potassium

Secondary Outcome Measures

Name	Time	Method
Maximum concentration in plasma (Cmax)	up to 504 hours after start of treatment
Time from dosing to maximum concentration in plasma (tmax)	up to 504 hours after start of treatment
Area under the concentration-time curve in plasma (AUC)	up to 504 hours after start of treatment
Area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞)	up to 504 hours after start of treatment
Percentage of AUC 0-∞ that is obtained by extrapolation (%AUCtz-∞)	up to 504 hours after start of treatment
Terminal rate constant in plasma (λz)	up to 504 hours after start of treatment
Terminal half-life in plasma (t½)	up to 504 hours after start of treatment
Mean residence time in the body after inhalation (MRTih)	up to 504 hours after start of treatment
Apparent clearance after extravascular administration (CL/F)	up to 504 hours after start of treatment
Apparent volume of distribution during the terminal phase λz following an extravascular dose (Vz/F)	up to 504 hours after start of treatment
Amount eliminated in urine from the time point t1 to t2 (Aet1-t2)	up to 336 hours after start of treatment
Fraction excreted in urine from time point t1 to t2 (fet1-t2)	up to 336 hours after start of treatment
Renal clearance from the time point t1 until the time point t2 (CLR,t1-t2)	up to 504 hours after start of treatment
Minimum measured concentration in plasma at steady state over a uniform dosing interval τ (Cmin,ss)	up to 504 hours after start of treatment
Predose concentration of the analytes in plasma at steady state immediately before administration of the next dose (Cpre,ss)	Pre-dose every 24 hours
Time of last measurable concentration in plasma (tz)	up to 504 hours after start of treatment
Linearity index (LI)	up to 504 hours after start of treatment
Accumulation ratio based on Cmax (RA,Cmax)	up to 504 hours after start of treatment
Accumulation ratio based on AUCτ (RA,AUC)	up to 504 hours after start of treatment