Safety, Tolerability and Pharmacokinetics of Multiple Rising Doses of Butylated Hydroxytoluene and BI 54903 XX Via Respimat® Soft MistTM Inhaler B in Healthy Male Volunteers

Study Overview
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Brief Summary
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The objective of the study was to investigate safety, tolerability and pharmacokinetics of butylated hydroxytoluene (BHT) (sub-study 1) administered via Respimat® Soft MistTM Inhaler B (SMI B); to assess safety, tolerability and pharmacokinetics of multiple rising doses of BI 54903 XX administered via Respimat® SMI B (main study), and to compare systemic exposure of single dose BI 54903 XX administered via Respimat® SMI B (sub-study 2) with single dose Alvesco® (ciclesonide) administered via HFA-134a propellant metered dose inhaler (MDI).

Official Title
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Safety, Tolerability and Pharmacokinetics of Multiple Rising Inhalative Doses of Butylated Hydroxytoluene Via Respimat Soft MistTM Inhaler B (Sub-study 1) and Safety, Tolerability and Pharmacokinetics of Multiple Rising Inhalative Doses of BI 54903 XX Via Respimat Soft MistTM Inhaler B as Randomised, Double-blind, Placebo-controlled Phase I Trial in Healthy Male Volunteers (Main Study) and Comparison of Systemic Exposure Following a Single Dose of BI 54903 XX Via Respimat Soft MistTM Inhaler B and of a Single Dose of Ciclesonide Via MDI (Randomised, Open-label, Two-way Crossover Sub-study 2)

Conditions
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Healthy

Intervention / Treatment
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* Drug: BHT low
* Drug: BHT medium
* Drug: BHT high
* Drug: BI 54903 XX low
* Drug: BI 54903 XX medium 1
* Drug: BI 54903 XX medium 2
* Drug: BI 54903 XX high
* Drug: Ciclesonide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males based upon a complete medical history, including the physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead Electrocardiogram (ECG) and clinical laboratory tests Age >= 21 and <= 50 years BMI >= 18.5 and <= 29.9 kg/m2 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) deviating from normal and of clinical relevance Any evidence of a clinically relevant concomitant disease Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders Surgery of the gastrointestinal tract (except appendectomy) 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 drug or its excipients) Intake of drugs with a long half-life (>24 h) within at least one month or less than 10 half-lives of the respective drug prior to administration or during the trial Use of drugs that could reasonably influence the results of the trial within 10 days prior to administration or during the trial (based on the knowledge at the time of protocol preparation) Participation in another trial with an investigational drug within 2 months prior to administration or during the trial Smoker (>10 cigarettes or >3 cigars or >3 pipes per day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g per day) Drug abuse Blood donation (>100 mL within 4 weeks prior to administration or during the trial) Excessive physical activities (within 1 week prior to administration or during the trial) Any laboratory value outside the reference range that is of clinical relevance Inability to comply with dietary regimen of the trial site Bacterial and viral infections of the lung, including active or latent tuberculosis

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Male

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: BHT low<br> | Drug: BHT low<br> <br> |
| Experimental: BHT medium<br> | Drug: BHT medium<br> <br> |
| Experimental: BHT high<br> | Drug: BHT high<br> <br> |
| Experimental: BI 54903 XX low<br> | Drug: BI 54903 XX low<br> <br> |
| Experimental: BI 54903 XX medium 1<br> | Drug: BI 54903 XX medium 1<br> <br> |
| Experimental: BI 54903 XX medium 2<br> | Drug: BI 54903 XX medium 2<br> <br> |
| Experimental: BI 54903 XX high<br> | Drug: BI 54903 XX high<br> <br> |
| Experimental: BI 54903 XX medium single dose<br> | Drug: BI 54903 XX medium 2<br> <br> |
| Active Comparator: Ciclesonide<br> | Drug: Ciclesonide<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | up to 21 days after last drug administration | 
| Number of patients with clinically significant findings in vitals signs |  | up to 21 days after last drug administration | 
| Number of patients with clinically significant findings in ECG |  | up to 21 days after last drug administration | 
| Number of patients with clinically significant findings in laboratory tests |  | up to 21 days after last drug administration | 
| Investigator assessed tolerability on a 4-point scale |  | up to 21 days after last drug administration | 
| Change in airway resistance (Raw) |  | baseline, after 80 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration in plasma) |  | up to 24 hours after last drug administration | 
| tmax (time from dosing to maximum measured concentration in plasma) |  | up to 24 hours after last drug administration | 
| AUCτ (area under the concentration-time curve in plasma over a uniform dosing interval τ) |  | up to 24 hours after last drug administration | 
| AUC0-inf (area under the concentration-time curve in plasma over the time interval from 0 extrapolated to infinity) |  | up to 24 hours after last drug administration | 
| AUCt1-t2 (area under the concentration-time curve in plasma over the time interval from time t1 to time t2) |  | up to 24 hours after last drug administration | 
| AUC0-tz (area under the concentration-time curve in plasma over the time interval from 0 to the last quantifiable concentration at tz) |  | up to 24 hours after last drug administration | 
| %AUCtz-∞ (the percentage of the AUC 0-∞ that is obtained by extrapolation) |  | up to 24 hours after last drug administration | 
| λz (terminal rate constant in plasma) |  | up to 24 hours after last drug administration | 
| t1/2 (terminal half-life in plasma) |  | up to 24 hours after last drug administration | 
| MRTih (mean residence time in the body after inhalation administration) |  | up to 24 hours after last drug administration | 
| CL/F (apparent clearance in plasma following inhalation administration) |  | up to 24 hours after last drug administration | 
| Vz/F (apparent volume of distribution during the terminal phase λz following inhalation administration) |  | up to 24 hours after last drug administration | 
| Aet1-t2 (amount that is eliminated in urine from the time point t1 to time point t2) |  | up to 24 hours after last drug administration | 
| fet1-t2 (fraction that is eliminated in urine from time point t1 to time point t2) |  | up to 24 hours after last drug administration | 
| CLR,t1-t2 (renal clearance from the time point t1 until the time point t2) |  | up to 24 hours after last drug administration | 
| Accumulation ratio based on Cmax (RA,Cmax) |  | up to 24 hours after last drug administration | 
| Accumulation ratio based on AUC (RA,AUC) |  | up to 24 hours after last drug administration | 
| Linearity index (LI) |  | up to 24 hours after last drug administration | 
| Metabolite-to-parent ratio for Cmax (RCmax,Met) |  | up to 24 hours after last drug administration | 
| Metabolite-to-parent ratio for AUC (AUCt1-t2,Met) |  | up to 24 hours after last drug administration |