A Four-Arm Study Comparing the Analgesic Efficacy and Safety of Tramadol Once a Day 100, 200 and 300 mg Versus Placebo for the Treatment of Pain Due to Osteoarthritis of the Knee

Study Overview
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Brief Summary
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The purpose of this study is to compare the analgesic efficacy and safety of Tramadol Once a Day 100, 200, 300 mg and Placebo

Conditions
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Pain, Osteoarthritis, Knee

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: Males or Females between the ages of 40-75 with a diagnosis of moderate to severe osteoarthritis of the knee, consistent with the American College of Rheumatology (ACR) Clinical Classification Criteria for Arthritis 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. C-reactive protein (CRP) < 8 ug/ml (if available at local lab) or erythrocyte sedimentation rate (ESR) < 40 mm/hr Total WOMAC (Western Ontario and McMaster University Osteoarthritis Index) Pain Subscale Score of > 150 mm at Baseline corresponding with moderate to severe Osteoarthritis. Oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials. Research Ethics Board (REB) approval of the written Informed Consent Form in Spanish or English which was signed and dated by the patient and Investigator, prior to study participation. Exclusion Criteria: Known rheumatoid arthritis or any other rheumatoid disease. Secondary arthritis i.e. any of the following: septic arthritis; inflammatory joint disease; gout; pseudogout; Paget's disease; joint fracture; acromegaly; fibromyalgia; Wilson's disease; ochronosis; haemochromatosis; osteochondromatosis; or collagen gene mutations. Evidence of effusion greater than 15 cubic centimetre (cc) upon physical examination of the joint at Baseline (Visit 1). Body Mass Index (BMI) ≥ 38. Major illness, requiring hospitalization during the 3 months before commencement of the screening period. The patient was unwilling to stop taking pain medication (for arthritis or other types of pain) or was unwilling to stop taking other medications for the treatment of osteoarthritis (OA). Previous failure or discontinuation (due to adverse events) of tramadol hydrochloride (HCl) therapy. 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; or any other drug that reduces seizure threshold. Treatment with another investigational agent within the last 30 days. A history of seizure disorder other than Infantile Febrile Seizures. Previous or current opioid dependency. Bowel disease causing malabsorption. Pregnancy or lactating or childbearing potential and unwilling to utilize a medically approved method of contraception during participation in this clinical trial. Significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range. Significant renal disease, defined as creatinine clearance <30 mL/min as estimated by the method of Levey et al., 1999. Current substance abuse or dependence, other than nicotine. Allergy or adverse reaction to tramadol or any structurally similar drugs e.g. opiates. Any other condition, that, in the opinion of the Investigators, would have adversely affected the patient's ability to complete the study or its measures.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 75 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 100mg<br> | Drug: Tramadol Once A Day<br>* One Tramadol Once A Day tablet at randomized dose daily.<br>|
| Experimental: 2: Tramadol Once A Day 200mg<br> | Drug: Tramadol Once A Day<br>* One Tramadol Once A Day tablet at randomized dose daily.<br>|
| Experimental: 3: Tramadol Once A Day 300mg<br> | Drug: Tramadol Once A Day<br>* One Tramadol Once A Day tablet at randomized dose daily.<br>|
| Experimental: 4: Placebo<br> | Drug: Placebo<br>* One Placebo tablet daily.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Global Rating of Pain for the Study Period (12 Weeks) | 3-item Likert-scale: How do you rate overall pain relief with the drug? with 3 possible answers: very effective, effective, or ineffective. The average of ratings at visits 2-5 was calculated as median, rounded up to the closest integer. | 12 weeks | 
| Percentage Difference Between WOMAC Pain Subscale Score From Baseline to the End of the Study (Week 12) | Percentage of difference in WOMAC Pain Subscale score between baseline and week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Pain Subscale results from the sum of 5 questions. | Baseline to week 12 | 
| Percentage Difference Between WOMAC Physical Function Subscale Score From Baseline to the End of the Study (Week 12) | Percentage of difference in WOMAC Physical Function Subscale score between baseline and week 12. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Physical Function subscale results from the sum of 17 questions. | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Difference in WOMAC Pain Subscale Score From Baseline to Intervening Visits (Visits 2-4) | Percentage of difference in WOMAC Pain Subscale score between baseline and intervening visits 2-4. The WOMAC scale is a 24-item questionnaire divided in 3 subscales, using a 100mm visual analog scale ranging from no pain (0mm) to extreme pain (100mm). The WOMAC Pain Subscale results from the sum of 5 questions. | Week 0, week 3, week 6 | 
| Percentage Difference in WOMAC Physical Function Subscale Score From Baseline to Intervening Visits (Visits 2-4) | Percentage of difference in WOMAC Physical Function Subscale score between baseline and intervening visits 2-4. The WOMAC scale is a 24-item questionnaire divided in 3 subscales. The WOMAC Physical Function Subscale comprises 17 questions each rated on a 100mm visual analog scale (VAS) ranging from no pain (0mm) to extreme pain (100mm). | Week 0, week 3, week 6 | 
| Multiple Dose Effect Using 24-hour VAS Pain Questionnaire | Patients rated their knee pain by marking a 100mm Visual Analogue Scale, ranging from no pain (0mm) to extreme pain (100mm). | 12 weeks | 
| Investigator Global Rating of Pain Relief | The Investigator Global Rating of Pain is a 3-item Likert-scale to answer the following question: How do you rate this patient's overall pain relief with the drug? with 3 possible answers: very effective, effective, or ineffective. | 12 weeks | 
| Percentage of Participants Who Dropped Out From Trial by Dropout Reason | Reasons for withdrawal from the trial were collected and the percentage of participants who dropped out from trial were calculated by dropout reason | 12 weeks |