Study of Two Tramadol Contramid® OAD 300 mg Controlled-Release Tablets From Two Different Manufacturing Sites Following a 300 mg Dose in Healthy Subjects Under Fasting and Fed Conditions

Study Overview
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Brief Summary
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The objective of this study is to compare the rate and extent of absorption of two Tramadol Contramid® OAD 300 mg controlled-release tablets from two different manufacturing sites, administered as 1 x 300 mg controlled-release tablet under fasting conditions. The effect of food on the to-be-marketed formulation was also assessed.

Conditions
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Healthy

Intervention / Treatment
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* Drug: Tramadol hydrochloride
* Drug: Tramadol HCl
* Drug: Tramadol HCl


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, non-smoker, ≥18 and ≤55 years of age. Capable of consent. Body Mass Index (BMI) ≥19.0 and <30.0 kg/m2. Exclusion Criteria: Clinically significant illness or surgery within 4 weeks prior to dosing. Any clinically significant abnormality or abnormal laboratory test results found during medical screening. Any reason which, in the opinion of the Medical Sub-Investigator, would prevent the subject from participating in the study. Positive test for hepatitis B, hepatitis C, or HIV at screening. Electrocardiogram (ECG) abnormalities (clinically significant) or vital sign abnormalities (systolic blood pressure lower than 90 or over 140 mmHg, diastolic blood pressure lower than 50 or over 90 mmHg, or heart rate less than 50 or over 100 beats per minute [bpm]) at screening. History of significant alcohol abuse or drug abuse within one year prior to the screening visit. Regular use of alcohol within six months prior to the screening visit (more than fourteen units of alcohol per week [1 Unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol]). Use of soft drugs (such as marijuana) within 3 months prior to the screening visit or hard drugs (such as cocaine, phencyclidine [PCP] and crack) within 1 year prior to the screening visit or positive urine drug screen at screening. History of allergic reactions to tramadol or other related drugs. Use of any drugs known to induce or inhibit hepatic drug metabolism (examples of inducers: barbiturates, carbamazepine, phenytoin, glucocorticoids, omeprazole; examples of inhibitors: antidepressants (Selective serotonin reuptake inhibitors [SSRIs]), cimetidine, diltiazem, macrolides, imidazoles, neuroleptics, verapamil, fluoroquinolones, antihistamines) within 30 days prior to administration of the study medication. Use of an investigational drug or participation in an investigational study within 30 days prior to dosing. Clinically significant history or presence of any gastrointestinal pathology (e.g. chronic diarrhea, inflammatory bowel diseases), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), liver or kidney disease, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of the drug. Any clinically significant history or presence of neurological, endocrinal, cardiovascular, pulmonary, hematologic, immunologic, psychiatric, or metabolic disease. Use of prescription medication within 14 days prior to administration of study medication or over-the-counter products (including natural food supplements, vitamins, garlic as a supplement) within 7 days prior to administration of study medication, except for topical products without systemic absorption and hormonal contraceptives. Difficulty to swallow study medication. Use of any tobacco products in the 3 months preceding drug administration. Any food allergy, intolerance, restriction or special diet that, in the opinion of the Medical Sub-Investigator, could contraindicate the subject's participation in this study. A depot injection or an implant of any drug (other than hormonal contraceptives) within 3 months prior to administration of study medication. Donation of plasma (500 mL) within 7 days prior to drug administration. Donation or loss of whole blood (excluding the volume of blood that will be drawn during the screening procedures of this study) prior to administration of the study medication as follows: 50 mL to 499 mL of whole blood within 30 days, more than 499 mL of whole blood within 56 days prior to drug administration. Consumption of food or beverages containing grapefruit (e.g. fresh, canned, or frozen) within 7 days prior to administration of the study medication. History or presence of substance addiction. History of anaphylactoid reactions to codeine and other opioids. History of respiratory depression. History of increased intracranial pressure or head injury. History or presence of asthma, chronic obstructive pulmonary disease or other pulmonary condition that may predispose to hypoventilation. Opioid consumption in the 3 months preceding drug administration or history of drug dependence to any opioids. Positive urine pregnancy test at screening. Breast-feeding subject. Female subjects of childbearing potential having unprotected sexual intercourse with any non-sterile male partner (i.e. male who has not been sterilized by vasectomy for at least 6 months) within 14 days prior to study drug administration. Acceptable methods of contraception are: intra-uterine contraceptive device (placed at least 4 weeks prior to study drug administration; condom or diaphragm + spermicide; hormonal contraceptives (starting at least 4 weeks prior to study drug administration).

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

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1: Tramadol HCl (Confab Laboratories) fasting<br> | Drug: Tramadol hydrochloride<br>* 1x300mg Tramadol Hydrochloride (HCl) tablet (Confab Laboratories), fasting condition. Taken for one treatment period only, then subjects switched treatment at each period as per randomization schedule. Results are presented per treatment group overall.<br>|
| Experimental: 2: Tramadol HCl (Confab Laboratories) fed<br> | Drug: Tramadol HCl<br>* 1x300mg Tramadol Hydrochloride (HCl) tablet (Confab Laboratories), fed condition. Taken for one treatment period only, then subjects switched treatment at each period as per randomization schedule. Results are presented per treatment group overall.<br>|
| Experimental: 3: Tramadol HCl (Trillium Healthcare) fasting<br> | Drug: Tramadol HCl<br>* 1x300mg Tramadol Hydrochloride (HCl) tablet (Trillium Healthcare) fasting condition. Taken for one treatment period only, then subjects switched treatment at each period as per randomization schedule. Results are presented per treatment group overall.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC(0-t) | Area under the plasma concentration (AUC) versus time curve to the last measurable concentration. | 48 hours | 
| AUC(0-∞) | The area under the plasma concentration (AUC) curve was estimated by extrapolating to infinity AUC0-t. The extrapolation to infinity was done by regression with the last log-transformed data to estimate the terminal area by means of the line that maximized R'2 (coefficient of determination). The units are ng.h/mL. h=hours | 48 hours | 
| Cmax | Maximum plasma concentration (Cmax) | 48 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tmax | Time to maximum plasma concentration (Tmax) | 48 hours | 
| t1/2 | Apparent terminal elimination half-life (t1/2) | 48 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy Subjects