A Two-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol HCl Once-a-Day Versus Placebo for the Treatment of Pain Due to Osteoarthritis

Study Overview
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Brief Summary
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The purpose of this study is to compare the analgesic efficacy, safety and clinical benefit of Tramadol OAD tablets versus Placebo.

Conditions
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Pain, Osteoarthritis

Intervention / Treatment
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* Drug: Tramadol Once a day
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria for Open-Label phase: Males or females Must be between the ages of 40-80 Must meet the American College of Rheumatology (ACR) Clinical Classification Criteria for Osteoarthritis of the Knee: Current knee pain Less than 30 minutes of morning stiffness with or without crepitus on active motion Confirmation either by arthroscopy or radiologist's report (X-rays showing osteophytes, joint space narrowing or subchondral bone sclerosis {eburnation}) within five years prior to entry into the study Must have a history of exposure to treatment (for pain due to osteoarthritis (OA) of the knee) with Non-steroidal anti-inflammatory drugs (NSAIDs), COX II inhibitors or tramadol. Must be taking one of the above medications on a regular basis in the 30 days prior to Visit 2 (S0). Must meet the following criteria for severity of pain at Visit 2 (Day S0): Have a score of ≥ 4 on the 11-point Numerical Rating Scale (PI-NRS; range: 0-10) Have a total increase of ≥ 2 points on the 11-point Numerical Rating Scale (range: 0-10) compared to the rating at Visit 1 (Day SX) Must have a erythrocyte sedimentation rate (ESR) < 40 mm/hr Must have oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials Must have signed and dated an approved written Informed Consent form in French, Spanish, English or Romanian, which has also been signed and dated by the Investigator (unless otherwise required by the ethics committee), prior to study participation Exclusion Criteria for Open-Label phase: Has known rheumatoid arthritis or any other rheumatic disease Has secondary arthritis i.e. any of the following: septic arthritis; inflammatory joint disease; gout; pseudogout; Paget's disease; target joint fracture; acromegaly; fibromyalgia; Wilson's disease; Ochronosis; Haemochromatosis; Osteochondromatosis; heritable arthritic disorders; or collagen gene mutations Has a history of bursitis of the knee (target knee) Has a history of pain in the ipsilateral hip (target knee) Has had a meniscal tear in the target knee within the last 12 months Has had cartilage reconstruction procedure in the target knee Has had a therapeutic arthroscopy procedure in the target knee within the last 12 months Has a Body Mass Index (BMI) greater than 37 Has had a major illness, requiring hospitalisation during the 3 months before commencement of the screening period Is unwilling to stop taking pain medication other than the study medication (for arthritis or other types of pain) or is unwilling to stop taking other medications for the treatment of OA Has previously failed treatment with tramadol or discontinued treatment with tramadol due to adverse events Has been taking other opioids (e.g. codeine, oxycodone, hydromorphone, etc.) for treatment of OA or other chronic conditions Has received Corticosteroid Injections in the target knee within the last 3 months or Viscous injections in the target knee within the last 6 months Has had treatment within the last 3 weeks with any of the following medications: monoamine oxidase inhibitors; tricyclic antidepressants and other tricyclic compounds (e.g. cyclobenzaprine, promethazine); neuroleptics; selective serotonin reuptake inhibitors; serotonin-norepinephrine reuptake inhibitors or any other drug that reduces seizure threshold Has had treatment with another investigational agent within the last 30 days Has a history of seizure disorder other than Infantile Febrile Seizures Has a previous or current opioid dependency Has a bowel disease causing malabsorption Is pregnant, lactating or of childbearing potential and is unwilling to utilise a medically approved method of contraception during participation in this clinical trial Has significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range Has significant renal disease (defined as creatinine clearance <30 mL/min Has a history of current or past substance abuse or dependence, other than nicotine Has a known and documented allergy to tramadol or any structurally similar drugs (e.g. opiates) Has a known and documented allergy to acetaminophen or any structurally similar drugs Has any other condition that, in the opinion of the Investigators, would adversely affect the patient's ability to complete the study or its measures. Inclusion criteria for the double-blinded phase: Patients must continue to meet the open-label eligibility criteria and Must have a score of ≥ 4 on the Numerical Rating Scale (NRS) with a total increase of ≥ 2 points on the NRS compared to Visit 3(Day R14) and Must not have taken any of the prohibited medications during the Open-label Phase. Exclusion criteria for the double-blinded phase: Patient Request Adverse Events that contraindicate further administration of the study medication Any other situation where in the opinion of the Investigator continued participation in the study would not be in the patient's best interest.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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 Once A Day<br> | Drug: Tramadol Once a day<br> <br> |
| Placebo Comparator: 2 Placebo<br> | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Intensity Score as Measured by the 11-point Pain Intensity-Numerical Rating Scale Score at the End of the Study (Week 12 or Time of Discontinuation) | The Pain Intensity Score is an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain. The mean score at the end of the study (week 12 or time of discontinuation) was calculated. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain Intensity Score (11-point PINRS) After 6 Weeks of Maintenance Treatment | The Pain Intensity Score is an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain | 6 weeks | 
| Pain Intensity Score Stratified by Dose, at the End of the Study (Week 12 or Time of Discontinuation) | Pain Intensity Score (an 11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain) was stratified by final dose level, at week 12 or time of discontinuation. The final optimum dose level based upon efficacy and tolerability was kept for the entire study. The mean score was calculated. | 12 weeks | 
| WOMAC Pain Subscale Score at the End of the Study (Week 12 or Time of Discontinuation) | Mean WOMAC Pain Subscale score at week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 5-point Likert-scale ranging from no difficulty to extreme difficulty (0-none; 1-slight; 2-moderate; 3-severe; 4-extreme). The WOMAC pain subscale results from the sum of 5 pain questions. The maximum total score is 20. | 12 weeks | 
| WOMAC Physical Function Subscale Score at the End of the Study (Week 12 or Time of Discontinuation) | Mean WOMAC Physical Function Subscale score at week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 5-point Likert-scale ranging from no difficulty to extreme difficulty (0-none; 1-slight; 2-moderate; 3-severe; 4-extreme). The WOMAC Physical Function subscale results from the sum of 17 physical function questions and the maximum possible score is 68. | 12 weeks | 
| Patient Global Impression of Change at the End of the Study (Week 12 or Time of Discontinuation) | This assessment of overall status integrates the effect of the treatment on pain, side effects, and the patient's expectation of pain relief. It is made using a 7-point categorical scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse) | 12 weeks | 
| Physician Global Impression of Change at the End of the Study (Week 12 or Time of Discontinuation) | This assessment of overall impression of study drug is made using a 7-point categorical scale (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse) | week 12 | 
| Time to Response | Response was defined as a decrease of ≥1 point in an 11-point PINRS (11-point pain intensity numerical rating scale ranging from 0: no pain to 10: worst possible pain) from baseline to the last visit. The time to response was estimated using Kaplan-Meier analysis and a 95% CI for the median time was calculated. | 12 weeks | 
| Discontinuation Due to Lack of Efficacy | The number of patients who discontinued due to lack of efficacy was reported. | 12 weeks | 
| Discontinuation Due to Adverse Events | The number of patients who discontinued due to adverse events (AEs). An AE is defined as any untoward medical event that occurs during the course of a clinical investigation in which a patient is administered a pharmaceutical or other therapeutic product. Its occurrence does not necessarily imply a causal relationship with the treatment. | 12 weeks |