A Comparison of the Analgesic Efficacy and Safety of Once Daily Tramadol HCl / Contramid® Tablets to Twice Daily Tramadol HCl (SR) for the Treatment of Osteoarthritis of the Knee

Study Overview
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Brief Summary
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A randomised, multi-centre, double-blind, double dummy, two arm parallel design study to compare the efficacy, safety, and clinical benefit of the test and reference product after treatment for 84 days in patients with osteoarthritis of the knee.

Official Title
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A Comparison of the Analgesic Efficacy and Safety of Once Daily Tramadol HCl / Contramid® Tablets to Twice Daily Tramadol HCl (SR) for the Treatment of Osteoarthritis of the Knee.

Conditions
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Osteoarthritis, Knee, Pain

Intervention / Treatment
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* Drug: Tramadol HCl Contramid® Once A Day
* Drug: Tramadol HCl Twice a day


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or Females between the ages of 40 and 75 with a diagnosis of Osteoarthritis (OA) of the knee consistent with the American College of Rheumatology (ACR) Clinical Classification Criteria for Arthritis of the Knee (Altman, R. et al., 1986): Knee pain at study enrolment, 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 1 year prior to entry into the study. ESR < 40 mm/h Western Ontario and McMaster University Osteoarthritis Index (WOMAC) Pain Subscales total score equal to or more than 150 mm at baseline. Oral and written language comprehension at a level sufficient to comply with the protocol and complete study-related materials. The Patient signed and dated the (IEC) approved, written, informed consent 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; heritable arthritic disorders; or collagen gene mutations. Obesity Class II [body mass index (BMI) equal to or more than 35 kg/m2] (NIH, 2000) Major illness that required hospitalisation during the 3 months before commencement of the screening period. Unwillingness to cease taking medication other than the study medication for arthritic pain, any other concomitant pain, or OA medications. Patients who had previously failed tramadol HCl therapy or those who discontinued tramadol HCl due to AEs. Patients who within the 3 weeks prior to study entry took the following medications: monoamine oxidase inhibitors; tricyclic antidepressants and other tricyclic compounds (e.g. cyclobenzaprine, promethazine); neuroleptics; selective serotonin reuptake inhibitors; or other drugs which reduce seizure threshold. Patients who took another investigational agent within the 30 days prior to study entry. Patients with a history of seizure disorder other than Infantile Febrile Seizures. Patients who were opioid dependent. Patients with bowel disease causing malabsorption. Patients who were pregnant or lactating or patients of child-bearing potential who were unwilling to utilise a medically approved method of contraception during participation in this clinical trial. Patients with significant liver disease, defined as active hepatitis or elevated liver enzymes >3 times the upper boundary of the normal range. Patients with 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, 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 HCl Contramid® Once A Day<br> | Drug: Tramadol HCl Contramid® Once A Day<br>* The patients orally self-administered the study medication: either 100, 200, 300 or 400 mg Tramadol HCl Contramid® Once A Day. Each patient was titrated to his or her optimum dose (up to a maximum of 400 mg) during the Titration Phase, which lasted between 4 and 12 days. The optimum dose was taken throughout the study.<br>|
| Active Comparator: 2 Tramadol HCl Twice a day (SR)<br> | Drug: Tramadol HCl Twice a day<br>* The patients orally self-administered the study medication: either 200, 300 or 400 mg Tramadol HCl Twice a day. Each patient was titrated to his or her optimum dose (up to a maximum of 400 mg) during the Titration Phase, which lasted between 4 and 12 days. The optimum dose was taken throughout the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Change From Baseline in WOMAC Pain Subscale Score at Week 12 | The WOMAC is a statistically validated, 24-item questionnaire assessing current OA symptoms and functional limitations. The Pain subscale score consists of 5 items each rated on a 100mm VAS scale (0mm=no pain to 100mm=extreme pain). In case of premature discontinuation, the last assessment was used to calculate the percentage of change. | Baseline to week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Arthritis Pain at the End of Dosing Interval (24-hour Efficacy) | Each day before morning dose, patients assessed arthritis pain in worst knee in a diary using a 5-point rating scale ranging from none to severe. A median score was estimated for each patient each week and re-categorized into different degrees of pain (rounding off to the closest integer). Results are of 12th week (day 78-84). | 12 weeks | 
| Percentage of Change From Baseline in WOMAC Stiffness Subscale Score at Week 12 | The WOMAC is a statistically validated, 24-item questionnaire assessing current OA symptoms and functional limitations. Stiffness subscale score consists of 2 items each rated on 100mm VAS scale (0mm=no stiffness to 100mm=extreme stiffness). In case of premature discontinuation, the last assessment was used to calculate the percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in WOMAC Physical Function Subscale Score at Week 12 | The WOMAC is a statistically validated, 24-item questionnaire assessing current OA symptoms and functional limitations. Physical Function subscale score consists of 17 items rated on a 100mm VAS scale (0mm=no difficulty to 100mm=extreme difficulty). In case of premature discontinuation, the last assessment was used to calculate percentage of change | Baseline to week 12 | 
| Percentage of Change From Baseline in WOMAC Total Score at Week 12 | The WOMAC is a statistically validated, 24-item questionnaire assessing current OA symptoms and functional limitations. Each item is rated on a 100mm VAS scale (0mm=no pain/stiffness/difficulty to 100mm=extreme no pain/stiffness/difficulty). In case of premature discontinuation, the last assessment was used to calculate percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in Current Pain at Week 12 | Pain Visual Analogue Scales: Current Pain. Patients indicated their current pain using a 100mm VAS scale ranging from 0=no pain to 100=extreme pain. The percentage of change in current pain was calculated from baseline to week 12. In case of premature discontinuation, the last assessment was used to calculate percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in Least Pain Within Last 24 Hours at Week 12 | Patients indicated their Least Pain Within Last 24 Hours using a 100mm VAS scale ranging from 0=no pain to 100=extreme pain. The percentage of change was calculated from baseline to week 12. In case of premature discontinuation, the last assessment was used to calculate percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in Worst Pain Within Last 24 Hours at Week 12 | Patients indicated their Worst Pain Within Last 24 Hours using a 100mm VAS scale ranging from 0=no pain to 100=extreme pain. The percentage of change was calculated from baseline to week 12. In case of premature discontinuation, the last assessment was used to calculate percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in Average Pain Within Last 24 Hours at Week 12 | Patients indicated their Average Pain Within Last 24 Hours using a 100mm VAS scale ranging from 0=no pain to 100=extreme pain. The percentage of change was calculated from baseline to week 12. In case of premature discontinuation, the last assessment was used to calculate percentage of change. | Baseline to week 12 | 
| Percentage of Change From Baseline in Walking Time for 15 Meters at Week 12 | The walking test is a measure of how many seconds it takes the patient to walk a distance of 15 meters. The change from baseline to week 12 was calculated. | Baseline to week 12 | 
| Patient Global Rating of Pain Relief at Week 12 | The Patient Global Rating of Pain is a Likert-scale that answers the question: How do you rate overall pain relief with the drug? with 4 possible answers that were dichotomized: very effective, effective, and somewhat effective were summarized to effective; not effective remained unchanged. | 12 Weeks | 
| Patient Global Assessment: Side Effects Interfering With Day to Day Activities at Week 12 | Patients were asked: How have any side effects you may have felt from the drug interfered with day-to-day activities? with 4 possible answers: Significantly, Somewhat, Minimally, Not at all. | 12 weeks | 
| Patient Global Assessment: Current Pain Relief Versus Pain Relief During Previous Tramadol Treatment at Week 12 | Patients who have previously taken tramadol HCl were asked to compare how they compare the current pain relief to the pain relief felt when previously taking tramadol, using a 4-point Likert-scale: Worse than before, Same as before, Somewhat better now, or Much better now. | 12 weeks | 
| Patient Global Assessment: Current Interfering Side Effects Versus Pain Relief During Previous Tramadol Treatment at Week 12 | Patients who have previously taken tramadol HCl were asked: Compared to when you were previously taking tramadol, how have any side effects you have felt during this study interfered with your day-to-day activities?. Possible answers were: Interfered much less now, Interfered somewhat less now, Same as before, Interfered more now. | 12 weeks | 
| Physician Overall Rating: Overall Assessment at Week 12 | The physician was asked to indicate his overall assessment of the formulation the patient was taking using a 4-point Likert-scale dichotomized for the analysis: Very Effective, Effective, and Somewhat Effective were summarized to Effective; Ineffective remained unchanged. | 12 weeks | 
| Physician Overall Rating: Effectiveness of Pain Control 24 Hours After the Most Recent Dose of Tramadol at Week 12 | The physician was asked to indicate the effectiveness of pain control 24 hours after the most recent dose of tramadol using a 4-point Likert-scale, dichotomized for the analysis: Very Effective, Effective, Somewhat Effective were summarized to Effective; Ineffective remained unchanged. | 12 weeks | 
| Patient Diary: Pain (Between Visit Means) at Week 12 | As part of the daily diary for the entire study, patients rated the arthritis pain in their worst knee using a five-point scale ranging from 1=none to 5=severe. Mean scores summarizing the entries of the preceding period were calculated. | 12 weeks | 
| Patient Diary: Stiffness (Between Visit Means) at Week 12 | As part of the daily diary for the entire study, patients rated the stiffness in their worst knee using a five-point scale ranging from 1=none to 5=severe. Mean scores summarizing the entries of the preceding period were calculated. | 12 weeks | 
| Patient Diary: Ability Getting Things Done (Between Visit Means) at Week 12 | As part of the daily diary for the entire study, patients rated their ability to get things done with their worst knee using a five-point scale ranging from: 1=No problem to 5=A lot of things didn't get done. Mean scores summarizing the entries of the preceding period were calculated. | 12 weeks | 
| Patient Diary: Difficulty With Walking (Between Visit Means) at Week 12 | As part of the daily diary for the entire study, patients rated their difficulty walking with their worst knee using a five-point scale ranging from 1=No problem to 5=Severe difficulty. Mean scores summarizing the entries of the preceding period were calculated. | 12 weeks | 
| Patient Diary: Difficulty With Stairs (Between Visit Means) at Week 12 | As part of the daily diary for the entire study, patients rated their difficulty with stairs with their worst knee using a five-point scale ranging from 1=No problem to 5=Severe difficulty. Mean scores summarizing the entries of the preceding period were calculated. | 12 weeks |