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

Phase 3

Completed

Conditions: Osteoarthritis, Knee

Interventions: Drug: Placebo
Drug: Traumeel® / Zeel® Injectable Solution

Registration Number: NCT01887678

Lead Sponsor: Biologische Heilmittel Heel GmbH

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 287

Inclusion Criteria

Not provided

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:
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)
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo injectable solution	Placebo	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)
Traumeel® / Zeel® Injectable Solution	Traumeel® / Zeel® Injectable Solution	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.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.
Physician Global Assessment (PhGA)	End of Study Visit (up to Day 119)	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'.
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.
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)
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.
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.
Patient Global Assessment (PGA)	End of Study Visit (up to Day 119)	Patients made an overall Global Assessment of the knee osteoarthritis with the assessment stages "Very good", "Good", "Fair", "Poor" and "Very poor".
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.
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.
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.

Trial Locations

Locations (28): AppleMed Research, Inc.
🇺🇸
Miami, Florida, United States
Sterling Research Group, Ltd
🇺🇸
Cincinnati, Ohio, United States
Radiant Research Inc. - Denver
🇺🇸
Denver, Colorado, United States
Injury Care Medical Center
🇺🇸
Boise, Idaho, United States
Clinical Research Advantage - Arizona II
🇺🇸
Phoenix, Arizona, United States
PMG Research of Knoxville
🇺🇸
Knoxville, Tennessee, United States
Riverside Clinical Research
🇺🇸
Edgewater, Florida, United States
Radiant Research Inc.
🇺🇸
Pinellas Park, Florida, United States
Tucson Orthopaedic Institute
🇺🇸
Tucson, Arizona, United States
Universal BioPharma Research Inc.
🇺🇸
Dinuba, California, United States
Providence Clinical Research
🇺🇸
North Hollywood, California, United States
Westlake Medical Research
🇺🇸
Westlake Village, California, United States
Hans Richard Barthel, M.D., Inc.
🇺🇸
Santa Barbara, California, United States
Global Scientific Innovations
🇺🇸
Evansville, Indiana, United States
Sundance Clinical Research, LLC
🇺🇸
Saint Louis, Missouri, United States
PMG Cary Medical Research
🇺🇸
Cary, North Carolina, United States
New Hope Clinical Research
🇺🇸
Charlotte, North Carolina, United States
PMG Research of Charlotte
🇺🇸
Charlotte, North Carolina, United States
Research Across America - NY
🇺🇸
New York, New York, United States
Manhattan Medical Research
🇺🇸
New York, New York, United States
PMG Research of Raleigh
🇺🇸
Raleigh, North Carolina, United States
PMG Research of Salisbury
🇺🇸
Salisbury, North Carolina, United States
Radiant Research Inc. - Akron
🇺🇸
Akron, Ohio, United States
Clinical Inquest Center Ltd.
🇺🇸
Dayton, Ohio, United States
Blair Orthopedic Associates, Inc.
🇺🇸
Altoona, Pennsylvania, United States
Hillcrest Clinical Research
🇺🇸
Oklahoma City, Oklahoma, United States
Clinical Research Solutions
🇺🇸
Smyrna, Tennessee, United States
Radiant Research Inc. - Salt Lake City
🇺🇸
Salt Lake City, Utah, United States