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

Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Inhalative Doses (2 μg/5 μg, 10 μg/5 μg, and 40 μg/10 μg) of BI 1744 CL in Fixed Dose Combination With Tiotropium Bromide for 14 Days in Healthy Male Volunteers (Double-blind, Randomised, Placebo Controlled [at Each Dose Level] Study)

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: Single rising doses of BI 1744 CL, solution for oral inhalation; Drug: Tiotropium, fixed dose, solution for oral inhalation

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: BI 1744 CL in combination with Tiotropium	Drug: Single rising doses of BI 1744 CL, solution for oral inhalation; Drug: Tiotropium, fixed dose, solution for oral inhalation

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of subjects with clinically relevant findings in physical examination		Up to day 32
Number of subjects with clinically relevant findings in vital signs	blood pressure, pulse rate	Up to day 32
Number of subjects with clinically relevant findings in 12-lead ECG		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	Systemic metabolic parameters: cyclic adenosine mono phosphate (cAMP) and potassium	up to 318 hours after start of treatment
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

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: April 1, 2007
• Primary Completion (Actual): September 1, 2007

Study Registration Dates

• First Submitted: October 7, 2014
• First Submitted That Met QC Criteria: October 7, 2014
• First Posted (Estimate): October 9, 2014

Study Record Updates

• Last Update Posted (Estimate): October 9, 2014
• Last Update Submitted That Met QC Criteria: October 7, 2014
• Last Verified: October 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Parasympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Antagonists; Cholinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Pharmaceutical Solutions; Tiotropium Bromide; Olodaterol
• Other Study ID Numbers: 1237.2