Study to Investigate Safety With Special Emphasis on ECG Effects and Tolerability After Oral Doses of Dextromethorphan Hydrobromide Monohydrate in Healthy Male and Female Subjects

Study Overview
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Brief Summary
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The primary objective of the current study is to investigate the safety with special emphasis on ECG effects, and tolerability of dextromethorphan hydrobromide monohydrate (2mg/mL syrup) in healthy male and female subjects following oral administration of 30 mg q.i.d. and 90 mg q.i.d. for 2 days followed by a single morning dose (extensive metabolisers of CYP 2D6) and for 10 days followed by a single morning dose (poor metabolisers of CYP 2D6). Additionally pharmacokinetic properties of dextromethorphan and its main metabolites dextrorphan, 3-hydroxymorphinan, and 3-methoxymorphinan will be investigated

Official Title
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A Phase I Multiple Dose Trial to Investigate Safety With Special Emphasis on ECG Effects and Tolerability After Oral Doses of 30 mg q.i.d. and 90 mg q.i.d. Dextromethorphan Hydrobromide Monohydrate (2 mg/mL Syrup) in Healthy Male and Female Subjects for 2 Days Followed by a Morning Dose (Extensive Metabolisers of CYP 2D6) and for 10 Days Followed by a Morning Dose (Poor Metabolisers of CYP 2D6) (Randomised, Double-blind, Placebo-controlled Groups)

Conditions
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Healthy

Intervention / Treatment
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* Drug: Dextromethorphan syrup - low dose
* Drug: Dextromethorphan syrup - high dose
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females according to the following criteria: Based upon a complete medical history, including the physical examination, oral body temperature, vital signs (blood pressure, pulse rate), 12-lead Electrocardiogram (ECG), clinical laboratory tests Age ≥18 and Age ≤55 years BMI ≥18.5 and BMI ≤30 kg/m2 (Body Mass Index) Extensive or poor metabolisers for CYP 2D6 based on the results of a genotyping test 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 blood pressure, pulse rate 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 one month prior to first administration or during the trial Smoker (> 10 cigarettes or > 3 cigars or > 3 pipes/day) Inability to refrain from smoking on trial days Alcohol abuse (more than 60 g/day) Drug abuse Blood donation (more than 100 mL within four weeks prior to first administration or during the trial) Excessive physical activities (within one week prior to first 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 QTc interval of >450 ms; A history of additional risk factors for Torsades de points (e.g., heart failure, hypokalemia, family history of Long QT Syndrome) Exclusion criteria specific for this study: Use of drugs that inhibit or induce cytochrome P 450 enzymes, especially CYP2D6, within 30 days prior to first administration of the study medication or during the trial For female subjects: Pregnancy or planning to become pregnant within 2 months of study completion Positive pregnancy test No adequate contraception in woman of child bearing potential during the study, i.e., sterilisation, intrauterine device, injectables, oral contraceptive combined with a barrier method of contraception Lactation period

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

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: Dextromethorphan syrup - low dose<br> | Drug: Dextromethorphan syrup - low dose<br> <br> |
| Experimental: Dextromethorphan syrup - high dose<br> | Drug: Dextromethorphan syrup - high dose<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 |
| --- | --- | --- |
| Number of patients with abnormal findings in physical examination |  | up to day 20 | 
| Number of patients with clinically significant changes in vital signs (blood pressure and pulse rate) |  | up to day 20 | 
| Number of patients with clinically significant changes in 12-lead ECG (electrocardiogram) including QT interval and heart rate corrected QTcN, QTcF (Fridericia) and QTcB (Bazett) |  | up to day 20 | 
| Number of patients with abnormal changes in laboratory parameters |  | up to day 20 | 
| Assessment of tolerability by investigator on a 4-point scale |  | day 20 (end of trial examination) | 
| Number of patients with adverse events |  | up to 48 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax (maximum measured concentration of the analyte in plasma) after the first dose |  | within 5 hours after first drug administration | 
| tmax (time from dosing to the maximum concentration of the analyte in plasma) after the first dose |  | within 5 hours after first drug administration | 
| AUCt1-t2 (area under the concentration-time curve of the analyte in plasma from the time interval t1 to t2) after the first dose |  | within 5 hours after first drug administration | 
| AUC0-5 (area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 5 hours after administration) after the first dose |  | within 5 hours after first drug administration | 
| Cmax,N (maximum measured concentration of the analyte in plasma following the Nth dose) after the last dose |  | up to day 13 | 
| tmax,N (time from last dosing to the maximum concentration of the analyte in plasma following the Nth dose) after the last dose |  | up to day 13 | 
| AUCt1-t2,N (area under the concentration-time curve of the analyte in plasma from the time interval t1 to t2 following the Nth dose) after the last dose |  | up to day 13 | 
| AUC0-5,N (area under the concentration-time curve of the analyte in plasma over the time interval 0 to 5 hours following the Nth dose) after last dose |  | up to day 13 | 
| λz,N (terminal rate constant in plasma following the Nth dose) after the last dose |  | up to day 13 | 
| t1/2,N (terminal half-life of the analyte in plasma following the Nth dose) after the last dose |  | up to day 13 | 
| MRTpo,N (mean residence time of the analyte in the body after oral administration of the Nth dose) after the last dose |  | up to day 13 | 
| Cmax (maximum observed concentration of the analyte in plasma) after the second dose |  | Day 1 | 
| tmax (Time to Cmax of the analyte in plasma) after the second dose |  | Day 1 |