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

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)

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

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: Dextromethorphan syrup - low dose; Drug: Dextromethorphan syrup - high dose

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 53 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo
Experimental: Dextromethorphan syrup - low dose	Drug: Dextromethorphan syrup - low dose
Experimental: Dextromethorphan syrup - high dose	Drug: Dextromethorphan syrup - high dose

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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	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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: June 1, 2009
• Primary Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: July 15, 2014
• First Submitted That Met QC Criteria: July 15, 2014
• First Posted (Estimate): July 16, 2014

Study Record Updates

• Last Update Posted (Estimate): July 16, 2014
• Last Update Submitted That Met QC Criteria: July 15, 2014
• Last Verified: July 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Respiratory System Agents; Antitussive Agents; Dextromethorphan
• Other Study ID Numbers: 1134.3