Study to Evaluate Safety, Tolerability and Pharmacokinetics of Increasing Repeated Oral Doses of Ambroxol Lozenges in Healthy Male Volunteers

Study Overview
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Brief Summary
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The main objectives of the present study are to determine pharmacokinetics of ambroxol in healthy male volunteers following repeated administration of lozenges of 20 mg ambroxol for four days

Official Title
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A Double-blind (at Each Dose Level), Randomised, Placebo Controlled Phase I Study to Evaluate Safety, Tolerability and Pharmacokinetics of Increasing Repeated Oral Doses of Ambroxol Lozenges (Dosage: 20, 40, 80 mg Three Times Daily) Over 4 Days in Healthy Male Volunteers

Conditions
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Healthy

Intervention / Treatment
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* Drug: Ambroxol - in single rising doses
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs, 12-lead Electrocardiogram (ECG), clinical laboratory tests Age ≥21 and Age ≤50 year BMI ≥18.5 and BMI ≤29.9 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 vital signs 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 hours) 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 which might reasonably influence the results of the trial or that prolong the QT/QTc interval based on the knowledge at the time of protocol preparation within 10 days prior to administration or during the trial Participation in another trial with an investigational drug within two months prior to administration or during the trial Actual smoker Alcohol abuse (more than 40 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to administration or during the trial) Excessive physical activities (within one 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 trial site A marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 ms) A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalaemia, family history of Long QT Syndrome)

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: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ambroxol - in single rising doses<br> | Drug: Ambroxol - in single rising doses<br> <br> |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration of the analyte in plasma) |  | up to 24 hours after drug administration | 
| tmax (time from dosing to the maximum concentration of the analyte in plasma) |  | up to 24 hours after drug administration | 
| AUC0-24 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours) |  | up to 24 hours after drug administration | 
| Ae0-24 (amount of the analyte that is eliminated in urine from the time point 0 until time point 24) |  | up to 24 hours after drug administration | 
| CLR,0-24 (renal clearance of the analyte determined from the time point 0 until time point 24) using AUC0-24 and Ae0-24 |  | up to 24 hours after drug administration | 
| Cmax,ss (maximum concentration of the analyte in plasma at steady state) |  | up to 120 hours after first drug administration | 
| tmax,ss (time from last dosing to maximum concentration at steady state) |  | up to 120 hours after first drug administration | 
| Cmin,ss (minimum concentration of the analyte in plasma at steady state) |  | up to 120 hours after first drug administration | 
| AUC72-96,ss (area under the concentration-time curve of the analyte in plasma at steady state over a uniform 24 hour interval matching Day 1) |  | up to 96 hours after first drug administration | 
| Ae72-96,ss (amount of analyte that is eliminated in urine at steady state from the time point 72 to time point 96) |  | up to 96 hours after first drug administration | 
| CLR,72-96,ss (renal clearance of the analyte in plasma from the time point 72 until the time point 96 at steady state) using AUC72-96 and Ae72-96 |  | up to 96 hours after first drug administration | 
| λz,ss (terminal rate constant in plasma at steady state) |  | up to 120 hours after first drug administration | 
| t1/2,ss (terminal half-life of the analyte in plasma at steady state) |  | up to 120 hours after first drug administration | 
| RA (accumulation ratio) |  | up to 96 hours after first drug administration | 
| LI (linearity index) |  | up to 96 hours after first drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with adverse events |  | up to 36 days | 
| Number of patients with abnormal changes in laboratory parameters |  | up to 36 days | 
| Number of patients with clinically significant changes in vital signs (blood pressure [BP], pulse rate [PR]) |  | up to 36 days | 
| Number of patients with clinically significant changes in 12-lead electrocardiogram (ECG) |  | up to 36 days | 
| Assessment of tolerability on a 4-point scale |  | 10 days after last drug administration |