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

Osteoarthritis, Knee Clinical Trial

— MOZArT  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01887678
• Other study ID #: C1301
• Status: Completed
• Phase: Phase 3
• First received: June 14, 2013
• Last updated: March 6, 2018
• Start date: June 2013
• Est. completion date: January 2014

Study information

• Verified date: March 2018
• Source: Biologische Heilmittel Heel GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 287
• Est. completion date: January 2014
• Est. primary completion date: January 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 45 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Osteoarthritis
• Osteoarthritis, Knee

Intervention

Drug:
• 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 IA injection) on treatment days 1, 8 and 15.
• Placebo
Placebo is an injection of Saline

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Biologische Heilmittel Heel GmbH

Country where clinical trial is conducted

United States, 

References & Publications (1)

Lozada CJ, del Rio E, Reitberg DP, Smith RA, Kahn CB, Moskowitz RW. A double-blind, randomized, saline-controlled study of the efficacy and safety of co-administered intra-articular injections of Tr14 and Ze14 for treatment of painful osteoarthritis of th

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Serious Adverse Events	Total number of patients affected.	Start of Lead-In period until individual study end, up to 16 weeks.
Other	Each Adverse Event (AE)	Total number of patients affected.	Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119)
Other	Incidence of Treatment Emergent Adverse Events (TEAEs)	Total number of patients affected.	during the treatment period and follow up period (Days 11 to 119)
Other	Proportion of Patients Who Discontinued Due to an AE	Total number of patients affected.	All visits (Days 1 up to 119)
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.	from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
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.	from Baseline to post-Baseline visits except End of Study Visit (up to day 105)
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.	from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
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.	from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
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.	from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
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".	from Baseline (Day 1, predose)
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".	End of Study Visit (up to Day 119)
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".	Baseline (Day 1, predose)
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".	End of Study Visit (up to Day 119)
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'.	Baseline (Day 1, predose) to post-Baseline visits (up to day 119)
Secondary	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)
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.	Statistically derived
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.	Statistically derived
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.	Statistically derived
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.	Statistically derived

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