Study of Intra-articular Injections vs Placebo in Patients With Pain From Osteoarthritis of the Knee

Study Overview
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Brief Summary
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The aim of this study is to evaluate the effectiveness and safety of a combined Traumeel® / Zeel® injection against placebo (saline) in patients with moderate-to-severe pain associated with osteoarthritis of the knee.

Detailed Description
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The primary objective is to demonstrate the superiority of Traumeel® and Zeel® co-administered intra-articular (IA) injections vs placebo IA injections on the change in knee pain in patients with moderate to severe knee pain associated with osteoarthritis. The secondary objectives are to evaluate reduction of pain and stiffness and change in physical function. Safety is evaluated by the incidence of treatment emergent adverse events during the treatment period and follow up period for all randomized patients.

Official Title
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Multi-center Double-blind Randomized Controlled Trial to Evaluate Effectiveness and Safety of Co-administered Traumeel® / Zeel® Intra-articular Injections vs Placebo in Patients With Moderate-to-Severe Pain With Osteoarthritis of the Knee

Conditions
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Osteoarthritis, Knee

Intervention / Treatment
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* Drug: Traumeel® / Zeel® Injectable Solution
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (Screening Visit 1): Osteoarthritis (OA) of the knee by American College of Rheumatology criteria Men or women between 45-80 years of age. Have documented diagnosis of primary OA of the target knee based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment of the target knee confirmed by standard post-anterior weightbearing X-ray of the knee in full extension taken </= 6 months prior to Visit 1. Currently taking an Nonsteroidal anti-inflammatory drug (NSAID), or acetaminophen on a regular basis (4-7 days/ week) over last 2 weeks prior to Visit 1 and has experienced amelioration of pain on these medications. Must have a 50-foot walk test pain score of less than 40 mm on a 100 mm VAS in the target knee at screening Pain in the non-target (contralateral) knee must not be greater than 30 mm on a 100 mm VAS on 50-foot walk test, and the target knee must be more symptomatic. Willingness to stop all OA treatments. Fully informed of the risks of entering the study and willing to provide written consent to enter the study. Able to understand and be willing to comply with all study requirements, particularly the weekly injection regimen for administration of study drug. Primary complaint is pain immediately following an unassisted 50-foot walk. They must show: moderate to severe pain score in the target knee as demonstrated by 40 - 90 mm recorded on a 100 mm VAS, and 20 mm increase in pain from their screening visit pain score (a flare) pain in the non-target (contralateral) knee must </= 30 mm on a 100 mm VAS Exclusion Criteria: Known hypersensitivity or allergy to any of the components of Traumeel or Zeel Known hypersensitivity or allergy to acetaminophen. Has body mass index (BMI) >38 kg/m2. Avoidance of, or aversion to, nonprescription medications. Clinical symptoms of meniscal instability or significant valgus/ varus that requires corrective osteotomy Any major injury or surgery to the target knee in the prior 12 months. One or a combination of the following co-morbidities: other inflammatory arthropathies, gout or pseudogout within previous 6 months avascular necrosis severe bone or joint deformity in target knee osteonecrosis of either knee fibromyalgia pes anserine bursitis lumbar radiculopathy with referred pain to either knee neurogenic or vascular claudication significant anterior knee pain due to diagnosed isolated patella-femoral syndrome in the target knee target knee joint infection or skin disorder/infection to the area surrounding the knee within previous 6 months current treatment or treatment of cancer within the previous 2 years (excluding basal cell or squamous cell carcinoma of the skin) Participated in any experimental drug or device study within the prior one (1) month and/or IA injections six (6) months. Referred pain from other joints Significantly debilitating concurrent infection(s) Significant ligamentous instability Any prior viscosupplementation therapy (in target knee) within 6 months prior to Screening Systemic or IA injection of corticosteroids in any joint within 3 months of enrollment Therapy with oral hyaluronic acid products, and/or oral pharmaceutical products containing glucosamine and/or chondroitin sulphate and/or diacerein Therapy with opioids within the last 90 days including intra-dermal delivery systems (patches) Therapy with autologous stem cells Therapy with coumarins such as warfarin, Coumadin; heparin and derivative substances including low molecular weight heparin, synthetic pentasaccharide inhibitors of factor Xa such as fondaparinux and idraparinux; direct factor Xa inhibitors such as rivaroxaban and apixaban; direct thrombin inhibitors such as hirudin, lepirudin, bivalirudin, argatroban and dabigatran. Concomitant inflammatory or other rheumatologic, neurological or cardiovascular diseases which could affect the evaluation of knee pain Ongoing litigation for workers compensation for musculoskeletal injuries or disorders Use of alcohol of more than 4 drinks per day Clinically important axial deviation (varus, valgus) greater than 15 degrees Concomitant severe OA of the hip or other joints, which might interfere with the assessments required by the study Painful knee conditions other than OA (e.g., Paget's disease) Hemiparesis of lower limbs Significant planned surgery to lower limbs, which might interfere with the patient's ability to comply with study requirements Presence of serious gastrointestinal, renal, hepatic, pulmonary, cardiovascular, neurological disease that might interfere with the outcome of the study or the patient's ability to comply with study requirements Presence of infections and/or skin diseases in the area of the injection site such as psoriasis Females who are pregnant or breast-feeding or not using recognized effective contraceptive measures. Females of childbearing potential (including those less than one year post-menopausal) must agree to maintain reliable birth control throughout the study. Clinically significant abnormal laboratory values. Patients who are likely to be non-compliant or uncooperative during the study.

Ages Eligible for Study
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Minimum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Traumeel® / Zeel® Injectable Solution<br>Injection volume is 4.2 mL for active study medication (2.0 mL Zeel plus 2.2 mL Traumeel in one intra articular (IA) injection) on treatment days 1, 8 and 15. | Drug: Traumeel® / Zeel® Injectable Solution<br>* Injection volume is 4.2 mL for active study medication (2.0 mL Zeel plus 2.2 mL Traumeel in one IA injection) on treatment days 1, 8 and 15.<br>* Other names: Zeel;|
| Placebo Comparator: Placebo injectable solution<br>Injection volume of placebo is 4.2 mL as well (taken from the 10.0 mL vial by unblinded staff member, rest to be kept for drug accountability) | Drug: Placebo<br>* Placebo is an injection of Saline<br>* Other names: Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS | Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess pain, scores from WOMAC Section A, items 1 to 5 are averaged to yield the Pain Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. A two-sided test of equality of the study drug (Traumeel®-Zeel®) and Placebo at level 0.05 was computed using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and the corresponding Baseline value of the primary efficacy variable as a covariate. The test decision was based on the (two-sided) p-value for the corresponding test of no treatment difference. | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS | Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess stiffness, scores from WOMAC Section B, items 6 to 7 are averaged to yield the Stiffness Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in stiffness score were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate. | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 
| Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS | Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess physical function, scores from WOMAC Section C, items 8 to 24 are averaged to yield the Physical Function Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in Physical Function subscore were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate. | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 
| Total WOMAC Score (All Subscales) Recorded on 100 mm VAS | Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. A total WOMAC score was computed by averaging all 24 possible responses. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in total WOMAC score were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate. | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 
| Patient Global Assessment (PGA) | Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. | from Baseline (Day 1, predose) | 
| Patient Global Assessment (PGA) | Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. | End of Study Visit (up to Day 119) | 
| Physician Global Assessment (PhGA) | Study Physicians made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. | Baseline (Day 1, predose) | 
| Physician Global Assessment (PhGA) | Study Physicians made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. | End of Study Visit (up to Day 119) | 
| Pain Immediately Following the 50-foot Walk (100 mm VAS) | Changes of the target (treated) knee pain following a 50 feet walk self-assessed by the patients on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. | Baseline (Day 1, predose) to post-Baseline visits (up to day 119) | 
| Time to Walking (50-foot Walk Test) | Changes in time to walk 50 feet (seconds) | Baseline (Day 1, predose) to post-Baseline visits (up to day 119) | 
| Time to 50% Pain Relief (Study Population Measure Statistically Derived) | Changes of the target (treated) knee pain following a 50 feet walk self-assessed by the patients on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. The time to 50% pain relief were statistical exercises and were analyzed for each individual patient from their self-assessment. | Statistically derived | 
| Patients Achieving 100% Pain Relief | Changes of the target (treated) knee pain following a 50 feet walk self-assessed by the patients on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. The time to 100% pain relief were statistical exercises and were analyzed for each individual patient from their self-assessment, however, the prevalence of 100% pain relief did not support an estimate for the median time. The number of patients who reached 100% pain relief is reported and the log rank test for difference in time to 100% pain relief was calculated for each injection. | Statistically derived | 
| Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use | Time to and use of rescue medication (acetaminophen up to 3000 mg per day for breakthrough pain) as reported by the patients. Patients who used any rescue medication during the study. | Statistically derived | 
| Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken. | Time to and use of rescue medication (acetaminophen up to 3000 mg per day for breakthrough pain) (study population measure statistically derived). Total number of tablets taken as reported by patient. | Statistically derived | 
| Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Changes of the target (treated) knee were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index version 3.1 (WOMAC OA) whereby patients self-assessed 24 parameters on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) where 0 corresponded to 'None' and 100 to 'Extreme'. To assess pain, scores from WOMAC Section A, items 1 to 5 are averaged to yield the Pain Subscale total score. At Study Days 1, 8 and 15 where injections were administered, this was to be done before injection. Changes in pain subscore were analyzed by using an analysis of covariance (ANCOVA) model with treatment group as qualitative factor and Baseline value as a covariate. | from Baseline to post-Baseline visits except End of Study Visit (up to day 105) |