Osteoarthritis, Knee
Conditions
Brief summary
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
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.
Interventions
DRUGTraumeel® / Zeel® Injectable Solution
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.
DRUGPlacebo
Placebo is an injection of Saline
Sponsors
Biologische Heilmittel Heel GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
(Screening Visit 1): 1. Osteoarthritis (OA) of the knee by American College of Rheumatology criteria 2. Men or women between 45-80 years of age. 3. 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. 4. 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. 5. 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 6. 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. 7. Willingness to stop all OA treatments. 8. Fully informed of the risks of entering the study and willing to provide written consent to enter the study. 9. Able to understand and be willing to comply with all study requirements, particularly the weekly injection regimen for administration of study drug. 10. Primary complaint is pain immediately following an unassisted 50-foot walk. They must show: 1. moderate to severe pain score in the target knee as demonstrated by 40 - 90 mm recorded on a 100 mm VAS, and 2. 20 mm increase in pain from their screening visit pain score (a flare) 3. pain in the non-target (contralateral) knee must \</= 30 mm on a 100 mm VAS
Exclusion criteria
1. Known hypersensitivity or allergy to any of the components of Traumeel or Zeel 2. Known hypersensitivity or allergy to acetaminophen. 3. Has body mass index (BMI) \>38 kg/m2. 4. Avoidance of, or aversion to, nonprescription medications. 5. Clinical symptoms of meniscal instability or significant valgus/ varus that requires corrective osteotomy 6. Any major injury or surgery to the target knee in the prior 12 months. 7. One or a combination of the following co-morbidities: 1. other inflammatory arthropathies, gout or pseudogout within previous 6 months 2. avascular necrosis 3. severe bone or joint deformity in target knee 4. osteonecrosis of either knee 5. fibromyalgia 6. pes anserine bursitis 7. lumbar radiculopathy with referred pain to either knee 8. neurogenic or vascular claudication 9. significant anterior knee pain due to diagnosed isolated patella-femoral syndrome in the target knee 10. target knee joint infection or skin disorder/infection to the area surrounding the knee within previous 6 months 11. current treatment or treatment of cancer within the previous 2 years (excluding basal cell or squamous cell carcinoma of the skin) 8. Participated in any experimental drug or device study within the prior one (1) month and/or IA injections six (6) months. 9. Referred pain from other joints 10. Significantly debilitating concurrent infection(s) 11. Significant ligamentous instability 12. Any prior viscosupplementation therapy (in target knee) within 6 months prior to Screening 13. Systemic or IA injection of corticosteroids in any joint within 3 months of enrollment 14. Therapy with oral hyaluronic acid products, and/or oral pharmaceutical products containing glucosamine and/or chondroitin sulphate and/or diacerein 15. Therapy with opioids within the last 90 days including intra-dermal delivery systems (patches) 16. Therapy with autologous stem cells 17. 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. 18. Concomitant inflammatory or other rheumatologic, neurological or cardiovascular diseases which could affect the evaluation of knee pain 19. Ongoing litigation for workers compensation for musculoskeletal injuries or disorders 20. Use of alcohol of more than 4 drinks per day 21. Clinically important axial deviation (varus, valgus) greater than 15 degrees 22. Concomitant severe OA of the hip or other joints, which might interfere with the assessments required by the study 23. Painful knee conditions other than OA (e.g., Paget's disease) 24. Hemiparesis of lower limbs 25. Significant planned surgery to lower limbs, which might interfere with the patient's ability to comply with study requirements 26. 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 27. Presence of infections and/or skin diseases in the area of the injection site such as psoriasis 28. 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. 29. Clinically significant abnormal laboratory values. 30. Patients who are likely to be non-compliant or uncooperative during the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken. | Statistically derived | 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. |
| Time to Walking (50-foot Walk Test) | Baseline (Day 1, predose) to post-Baseline visits (up to day 119) | Changes in time to walk 50 feet (seconds) |
| Time to 50% Pain Relief (Study Population Measure Statistically Derived) | 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. |
| Patients Achieving 100% Pain Relief | 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 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. |
| Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use | Statistically derived | 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. |
| Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | from Baseline to post-Baseline visits except End of Study Visit (up to day 105) | 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. |
| Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 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. |
| Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 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. |
| Total WOMAC Score (All Subscales) Recorded on 100 mm VAS | from Baseline (Day 1, predose) to End of Study Visit (up to Day 119) | 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. |
| Patient Global Assessment (PGA) | from Baseline (Day 1, predose) | Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. |
| Physician Global Assessment (PhGA) | Baseline (Day 1, predose) | Study Physicians made an overall Global Assessment of the knee osteoarthritis with the assessment stages Very good, Good, Fair, Poor and Very poor. |
| Pain Immediately Following the 50-foot Walk (100 mm VAS) | Baseline (Day 1, predose) to post-Baseline visits (up to day 119) | 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'. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Each Adverse Event (AE) | Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119) | Total number of patients affected. |
| Incidence of Treatment Emergent Adverse Events (TEAEs) | during the treatment period and follow up period (Days 11 to 119) | Total number of patients affected. |
| Proportion of Patients Who Discontinued Due to an AE | All visits (Days 1 up to 119) | Total number of patients affected. |
| Serious Adverse Events | Start of Lead-In period until individual study end, up to 16 weeks. | Total number of patients affected. |
Countries
United States
Participant flow
Recruitment details
A total of 28 investigational sites in the United States (US) entered at least one patient into the study database, 24 sites randomized at least one patient, 4 sites had Lead-In screening failures only.
Pre-assignment details
In total, 287 patients were enrolled into the study, 55 of them were Lead-In screening failures and therefore were not included.
Participants by arm
| Arm | Count |
|---|---|
| Co-administered Traumeel® and Zeel® Patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a Traumeel/Zeel injection solution administered once weekly into the target knee on Study Days 1, 8 and 15. | 119 |
| Placebo Injectable Solution At baseline, patients with documented diagnosis of primary osteoarthritis of the based on clinical and radiographic criteria (Kellgren-Lawrence Numerical Grading System of Grade 2-3) in the tibial-femoral compartment with an age of between 45 to 80 years and the ability to understand the explanations and instructions given by the study physician got a placebo injection solution administered once weekly into the target knee on Study Days 1, 8 and 15. | 113 |
| Total | 232 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 6 |
| Overall Study | Deterioration of clinical condition | 0 | 4 |
| Overall Study | Exceeded rescue medication dosage | 4 | 5 |
| Overall Study | Lack of Efficacy | 1 | 2 |
| Overall Study | Lost to Follow-up | 4 | 2 |
| Overall Study | Non-compliance | 0 | 3 |
| Overall Study | Specified | 1 | 2 |
| Overall Study | Withdrawal of consent | 3 | 4 |
Baseline characteristics
| Characteristic | Co-administered Traumeel® and Zeel® | Placebo Injectable Solution | Total |
|---|---|---|---|
| Age, Continuous | 60.7 years STANDARD_DEVIATION 9.11 | 59.7 years STANDARD_DEVIATION 8.68 | 60.2 years STANDARD_DEVIATION 8.9 |
| Region of Enrollment United States | 119 participants | 113 participants | 232 participants |
| Sex: Female, Male Female | 43 Participants | 46 Participants | 89 Participants |
| Sex: Female, Male Male | 76 Participants | 67 Participants | 143 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 64 / 119 | 43 / 113 |
| serious Total, serious adverse events | 2 / 119 | 1 / 113 |
Outcome results
Primary
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.
Time frame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS | -32.0 units on a scale | Standard Deviation 26.88 |
| Placebo Injectable Solution | Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS | -25.5 units on a scale | Standard Deviation 24.08 |
p-value: 0.038395% CI: [-12.4, -0.35]ANCOVA
Secondary
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'.
Time frame: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 8±1 | -26.5 units on a scale | Standard Deviation 22.39 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 15±1 | -37.4 units on a scale | Standard Deviation 23.8 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 29±3 | -38.1 units on a scale | Standard Deviation 25.37 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 43±3 | -42.3 units on a scale | Standard Deviation 25.13 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 57±3 | -43.0 units on a scale | Standard Deviation 25.04 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 71±3 | -42.6 units on a scale | Standard Deviation 25.31 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 85±3 | -41.3 units on a scale | Standard Deviation 27.29 |
| Co-administered Traumeel® and Zeel® | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 119±3 | -42.3 units on a scale | Standard Deviation 26.33 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 119±3 | -36.7 units on a scale | Standard Deviation 24.53 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 8±1 | -21.1 units on a scale | Standard Deviation 22.09 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 57±3 | -33.6 units on a scale | Standard Deviation 25.32 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 15±1 | -26.5 units on a scale | Standard Deviation 21.97 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 85±3 | -35.0 units on a scale | Standard Deviation 24.38 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 29±3 | -30.7 units on a scale | Standard Deviation 24.14 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 71±3 | -35.1 units on a scale | Standard Deviation 23.69 |
| Placebo Injectable Solution | Pain Immediately Following the 50-foot Walk (100 mm VAS) | Day 43±3 | -32.9 units on a scale | Standard Deviation 24.45 |
Comparison: Day 8±1p-value: 0.112895% CI: [-11.12, 1.18]ANCOVA
Comparison: Day 15±1p-value: 0.001395% CI: [-16.85, -4.13]ANCOVA
Comparison: Day 29±3p-value: 0.047295% CI: [-13.69, -0.09]ANCOVA
Comparison: Day 43±3p-value: 0.010995% CI: [-15.6, -2.05]ANCOVA
Comparison: Day 57±3p-value: 0.012395% CI: [-15.8, -1.95]ANCOVA
Comparison: Day 71±3p-value: 0.042595% CI: [-13.52, -0.23]ANCOVA
Comparison: Day 85±3p-value: 0.119995% CI: [-12.47, 1.45]ANCOVA
Comparison: Day 119±3p-value: 0.157595% CI: [-11.86, 1.93]ANCOVA
Secondary
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.
Time frame: from Baseline to post-Baseline visits except End of Study Visit (up to day 105)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 43±3 | -26.8 units on a scale | Standard Deviation 26.12 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 57±3 | -30.4 units on a scale | Standard Deviation 26.69 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 15±1 | -24.4 units on a scale | Standard Deviation 24.31 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 71±3 | -31.0 units on a scale | Standard Deviation 26.23 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 29±3 | -29.7 units on a scale | Standard Deviation 26.65 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 85±3 | -31.1 units on a scale | Standard Deviation 26.63 |
| Co-administered Traumeel® and Zeel® | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 8±1 | -15.8 units on a scale | Standard Deviation 18.65 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 85±3 | 24.7 units on a scale | Standard Deviation 24.57 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 8±1 | -13.6 units on a scale | Standard Deviation 19.11 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 15±1 | -18.5 units on a scale | Standard Deviation 20.02 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 43±3 | -21.5 units on a scale | Standard Deviation 21.62 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 29±3 | -22.4 units on a scale | Standard Deviation 22.33 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 57±3 | -22.7 units on a scale | Standard Deviation 23.37 |
| Placebo Injectable Solution | Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS | Day 71±3 | -23.3 units on a scale | Standard Deviation 24.38 |
Comparison: Day 8±1p-value: 0.371595% CI: [-6.89, 2.58]ANCOVA
Comparison: Day 15±1p-value: 0.029395% CI: [-11.15, -0.6]ANCOVA
Comparison: Day 29±3p-value: 0.068695% CI: [-10.88, 0.4]ANCOVA
Comparison: Day 43±3p-value: 0.01595% CI: [-13.08, -1.42]ANCOVA
Comparison: Day 57±3p-value: 0.013495% CI: [-13.54, -1.58]ANCOVA
Comparison: Day 71±3p-value: 0.012195% CI: [-13.52, -1.68]Least Squares
Comparison: Day 85±3p-value: 0.037695% CI: [-12.28, -0.37]ANCOVA
Secondary
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.
Time frame: from Baseline (Day 1, predose)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Very Good | 1 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Good | 6 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Fair | 62 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Poor | 39 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Very Poor | 8 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Missing | 1 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Very Poor | 2 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Very Good | 0 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Poor | 43 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Good | 7 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Missing | 0 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Fair | 59 participants |
Secondary
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.
Time frame: End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Very Good | 30 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Good | 49 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Fair | 31 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Poor | 6 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Very Poor | 1 participants |
| Co-administered Traumeel® and Zeel® | Patient Global Assessment (PGA) | Missing | 0 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Very Poor | 1 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Very Good | 22 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Poor | 11 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Good | 39 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Missing | 0 participants |
| Placebo Injectable Solution | Patient Global Assessment (PGA) | Fair | 38 participants |
Secondary
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.
Time frame: Statistically derived
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Patients Achieving 100% Pain Relief | After 1st Injection | 26 participants |
| Co-administered Traumeel® and Zeel® | Patients Achieving 100% Pain Relief | After 2nd Injection | 25 participants |
| Co-administered Traumeel® and Zeel® | Patients Achieving 100% Pain Relief | After 3rd Injection | 26 participants |
| Placebo Injectable Solution | Patients Achieving 100% Pain Relief | After 1st Injection | 12 participants |
| Placebo Injectable Solution | Patients Achieving 100% Pain Relief | After 2nd Injection | 12 participants |
| Placebo Injectable Solution | Patients Achieving 100% Pain Relief | After 3rd Injection | 11 participants |
Comparison: After third injection of study drugp-value: 0.0172Log Rank
Comparison: After first injection of study drugp-value: 0.0264Log Rank
Comparison: After second injection of study drugp-value: 0.0346Log Rank
Secondary
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.
Time frame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS | -31.1 units on a scale | Standard Deviation 27.38 |
| Placebo Injectable Solution | Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS | -26.9 units on a scale | Standard Deviation 24.4 |
p-value: 0.171595% CI: [-10.33, 1.85]ANCOVA
Secondary
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.
Time frame: Baseline (Day 1, predose)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Very Good | 0 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Good | 7 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Fair | 73 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Poor | 34 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Very Poor | 3 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Missing | 0 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Very Poor | 0 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Very Good | 0 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Poor | 27 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Good | 7 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Missing | 0 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Fair | 77 participants |
Secondary
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.
Time frame: End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Missing | 0 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Good | 51 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Very Poor | 0 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Fair | 34 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Very Good | 28 participants |
| Co-administered Traumeel® and Zeel® | Physician Global Assessment (PhGA) | Poor | 4 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Very Good | 20 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Very Poor | 2 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Missing | 0 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Poor | 4 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Good | 38 participants |
| Placebo Injectable Solution | Physician Global Assessment (PhGA) | Fair | 47 participants |
Secondary
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.
Time frame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS | -34.1 units on a scale | Standard Deviation 28.16 |
| Placebo Injectable Solution | Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS | -28.2 units on a scale | Standard Deviation 25.73 |
p-value: 0.137395% CI: [-11.05, 1.53]ANCOVA
Secondary
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.
Time frame: Statistically derived
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 1st Injection | 15 days |
| Co-administered Traumeel® and Zeel® | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 2nd Injection | 22 days |
| Co-administered Traumeel® and Zeel® | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 3rd Injection | 29 days |
| Placebo Injectable Solution | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 1st Injection | 22 days |
| Placebo Injectable Solution | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 2nd Injection | 34 days |
| Placebo Injectable Solution | Time to 50% Pain Relief (Study Population Measure Statistically Derived) | After 3rd Injection | 50 days |
Comparison: After first injection of study drugp-value: 0.2164Log Rank
Comparison: After second injection of study drugp-value: 0.1651Log Rank
Comparison: After third injection of study drugp-value: 0.222Log Rank
Secondary
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.
Time frame: Statistically derived
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Co-administered Traumeel® and Zeel® | Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use | 82 participants |
| Placebo Injectable Solution | Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use | 72 participants |
Secondary
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.
Time frame: Statistically derived
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken. | 49.0 Tablets | Standard Deviation 64.64 |
| Placebo Injectable Solution | Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken. | 55.8 Tablets | Standard Deviation 59.71 |
Secondary
Time to Walking (50-foot Walk Test)
Changes in time to walk 50 feet (seconds)
Time frame: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 8±1 | -2.8 seconds | Standard Deviation 7.38 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 15±1 | -3.0 seconds | Standard Deviation 7.25 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 29±3 | -3.7 seconds | Standard Deviation 8.28 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 43±3 | -4.4 seconds | Standard Deviation 9.23 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 57±3 | -4.1 seconds | Standard Deviation 8.24 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 71±3 | -4.6 seconds | Standard Deviation 9.59 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 85±3 | -4.6 seconds | Standard Deviation 9.84 |
| Co-administered Traumeel® and Zeel® | Time to Walking (50-foot Walk Test) | Day 119±3 | -4.8 seconds | Standard Deviation 9.66 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 119±3 | -4.6 seconds | Standard Deviation 10.24 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 8±1 | -2.5 seconds | Standard Deviation 5.91 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 57±3 | -3.7 seconds | Standard Deviation 9.02 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 15±1 | -2.7 seconds | Standard Deviation 6.9 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 85±3 | -4.9 seconds | Standard Deviation 10.26 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 29±3 | -3.5 seconds | Standard Deviation 7.94 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 71±3 | -4.3 seconds | Standard Deviation 9.63 |
| Placebo Injectable Solution | Time to Walking (50-foot Walk Test) | Day 43±3 | -3.9 seconds | Standard Deviation 8.05 |
Comparison: Day 8±1p-value: 0.634695% CI: [-1.45, 0.89]ANCOVA
Comparison: Day 15±1p-value: 0.645895% CI: [-1.49, 0.92]ANCOVA
Comparison: Day 29±3p-value: 0.758195% CI: [-1.35, 0.99]ANCOVA
Comparison: Day 43±3p-value: 0.33595% CI: [-1.48, 0.51]ANCOVA
Comparison: Day 57±3p-value: 0.441995% CI: [-1.44, 0.63]ANCOVA
Comparison: Day 71±3p-value: 0.44695% CI: [-1.32, 0.58]ANCOVA
Comparison: Day 85±3p-value: 0.655295% CI: [-0.84, 1.33]ANCOVA
Comparison: Day 119±3p-value: 0.744395% CI: [-1.33, 0.95]ANCOVA
Secondary
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.
Time frame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 to Placebo and all were included in the Safety Set. Two patients in each group could not be evaluated for primary efficacy. 117 patients in Traumeel/Zeel and 111 patients in Placebo formed the Full Analysis - efficacy. For missing values, Last-observation carried forward (LOCF) was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Total WOMAC Score (All Subscales) Recorded on 100 mm VAS | -31.5 units on a scale | Standard Deviation 26.94 |
| Placebo Injectable Solution | Total WOMAC Score (All Subscales) Recorded on 100 mm VAS | -26.7 units on a scale | Standard Deviation 24.14 |
p-value: 0.121195% CI: [-10.82, 1.27]ANCOVA
Other Pre-specified
Each Adverse Event (AE)
Total number of patients affected.
Time frame: Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. 8 patients without any injection (not randomized) reported 12 adverse events
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Co-administered Traumeel® and Zeel® | Each Adverse Event (AE) | 64 participants |
| Placebo Injectable Solution | Each Adverse Event (AE) | 43 participants |
Other Pre-specified
Incidence of Treatment Emergent Adverse Events (TEAEs)
Total number of patients affected.
Time frame: during the treatment period and follow up period (Days 11 to 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. MedDRA Version 16.0 terminology. Adverse events during treatment (treatment-emergent) in 5% or more of total study patients
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Injury, poisoning and procedural complications | 6 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Total Number of Patients affected | 64 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Musculoskeletal and connective tissue disorders | 26 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Infections and infestations | 12 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Nervous system disorders | 14 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | Skin and subcutaneous tissue disorders | 14 participants |
| Co-administered Traumeel® and Zeel® | Incidence of Treatment Emergent Adverse Events (TEAEs) | General disorders and administration site conditio | 11 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Injury, poisoning and procedural complications | 6 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Nervous system disorders | 8 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Total Number of Patients affected | 43 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | General disorders and administration site conditio | 8 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Musculoskeletal and connective tissue disorders | 14 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Skin and subcutaneous tissue disorders | 9 participants |
| Placebo Injectable Solution | Incidence of Treatment Emergent Adverse Events (TEAEs) | Infections and infestations | 10 participants |
Other Pre-specified
Proportion of Patients Who Discontinued Due to an AE
Total number of patients affected.
Time frame: All visits (Days 1 up to 119)
Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. Medical Dictionary for Regulatory Activities (MedDRA) Version 16.0 terminology.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Haemarthrosis | 1 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Total number of patients affected | 3 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Injection site joint pain | 1 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Injection site vesicles | 1 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Muscle tightness | 0 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Pain in extremity | 0 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Nephrolithiasis | 0 participants |
| Co-administered Traumeel® and Zeel® | Proportion of Patients Who Discontinued Due to an AE | Rash maculopapular | 0 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Rash maculopapular | 1 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Muscle tightness | 1 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Total number of patients affected | 4 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Nephrolithiasis | 1 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Injection site joint pain | 1 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Pain in extremity | 1 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Injection site vesicles | 0 participants |
| Placebo Injectable Solution | Proportion of Patients Who Discontinued Due to an AE | Haemarthrosis | 0 participants |
Other Pre-specified
Serious Adverse Events
Total number of patients affected.
Time frame: Start of Lead-In period until individual study end, up to 16 weeks.
Population: 119 patients were randomized to Traumeel/Zeel and 113 patients to Placebo and all randomized patients were included in the Safety Set. MedDRA Version 16.0 terminology
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Co-administered Traumeel® and Zeel® | Serious Adverse Events | Haematemesis | 1 participants |
| Co-administered Traumeel® and Zeel® | Serious Adverse Events | Total number of patients affected | 2 participants |
| Co-administered Traumeel® and Zeel® | Serious Adverse Events | Transient ischemic attack | 0 participants |
| Co-administered Traumeel® and Zeel® | Serious Adverse Events | Bradycardia and Hyperglycaemia | 1 participants |
| Placebo Injectable Solution | Serious Adverse Events | Transient ischemic attack | 1 participants |
| Placebo Injectable Solution | Serious Adverse Events | Total number of patients affected | 1 participants |
| Placebo Injectable Solution | Serious Adverse Events | Haematemesis | 0 participants |
| Placebo Injectable Solution | Serious Adverse Events | Bradycardia and Hyperglycaemia | 0 participants |