A Dose Ranging Escalation Study of Tramadol Hydrochloride in Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety and tolerability profile of tramadol hydrochloride (HCl) given as oral doses every 6 hours, within the range of dosages supported by currently available toxicology and clinical data (200 mg to 600 mg per day).

Detailed Description
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This is a randomized (study drug assigned by chance), sequential-cohort (time lagged), double-blind (neither the participant or the study doctor will know the name of the assigned treatment), parallel-group, placebo-controlled, 3-arm (participants will be assigned to 1 of 3 treatment groups), single-center, Phase 1 study of multiple ascending doses of tramadol HCl in healthy adult volunteers. Thirty participants (15 men and 15 women) will be sequentially assigned to 1 of 3 treatment groups of 10 subjects each (5 men and 5 women). Participants in each treatment group will receive a total of 9 oral doses (one every 6 hours) of tramadol HCl or placebo, in the ratio of 4:1. The study includes a screening phase and a double-blind treatment phase. The treatment phase will consist of 3 treatment periods separated by a 5-day safety review period before the next ascending dose of study drug is administered to the next group. Participants in each group will be confined to the study center for a total of 5 days, the total duration of each subject's participation will be up to 33 days, including the screening phase. The total duration of the study (completion of all 3 treatment cohorts) will be up-to-approximately 2 months.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Dose Escalation Study to Assess the Safety, Tolerability, and Pharmacokinetics Following Multiple Ascending Doses of Tramadol Hydrochloride in Healthy Male and Female Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: Tramadol HCl, 50 mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: body mass index between 18 and 30 kg/m², inclusive body weight not less than 50 kg have a normal electroencephalogram under basic and stimulated conditions have a 12-lead ECG that is consistent with normal cardiac conduction and function have not used any tobacco products (eg, cigarettes, cigars, chewing tobacco, gum, or patch) for at least 6 months before first study drug administration Exclusion Criteria: any personal or family history of epileptic seizures or convulsions have suffered from head trauma with loss of consciousness -have suffered from central nervous system infection have suffered from loss of consciousness of unknown origin drowning or sudden infant death syndrome in a first degree relative

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: Tramadol HCl 200 mg daily or placebo<br>Participants will receive one capsule of Tramadol hydrochloride (HCl) every 6 hours. Participants assigned to placebo will receive matching placebo capsules. A total of 9 doses will be administered. | Drug: Tramadol HCl, 50 mg<br>* 50-mg overencapsulated tablet for oral administration<br>Drug: Placebo<br>* Size-matching capsules containing an appropriate inactive excipient<br>|
| Experimental: 2: Tramadol HCl 400 mg daily or placebo<br>Participants will recieve two capsules of Tramadol HCl every 6 hours. Participants assigned to placebo will receive matching placebo capsules. A total of 9 doses will be administered. | Drug: Tramadol HCl, 50 mg<br>* 50-mg overencapsulated tablet for oral administration<br>Drug: Placebo<br>* Size-matching capsules containing an appropriate inactive excipient<br>|
| Experimental: 3: Tramadol HCl 600 mg daily or placebo<br>Participants will receive three capsules of Tramadol HCl every 6 hours. Participants assigned to placebo will receive matching placebo capsules. A total of 9 doses will be administered. | Drug: Tramadol HCl, 50 mg<br>* 50-mg overencapsulated tablet for oral administration<br>Drug: Placebo<br>* Size-matching capsules containing an appropriate inactive excipient<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in vital signs and other parameters as a measure of safety and tolerability of tramadol | Changes in clinical laboratory results, vital signs, psycopharmacologic status (Richmond Agitation-Sedation Scale (RASS), and physical examination. | Baseline, Days 1 through 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in time-matched electrocardiogram (ECG) measurements | ECG will detect abnormal changes from baseline in cardiac depolarization/repolarization. | Baseline, Day 1, Day 3 and Day 4 | 
| Change from baseline in pharmacokinetic parameters of tramadol and M1 metabolite | Determination of concentrations of tramadol and M1 metabolite pharmacokinetic parameters in venous plasma. | Baseline, up to 72 hours after the 1st dose | 
| Incidence and type of adverse events |  | Baseline, till the end of study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy, Pain, Tramadol hydrochloride, Tramadol HCl, Analgesic, QT prolongation, RWJ-26898-002