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

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ClinicalTrials.gov Identifier: NCT01887678
Recruitment Status : Completed
First Posted : June 27, 2013
Results First Posted : March 20, 2015
Last Update Posted : April 2, 2018
Sponsor:
Information provided by (Responsible Party):
Biologische Heilmittel Heel GmbH

Study Description
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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.

Condition or disease Intervention/treatment Phase
Osteoarthritis, Knee Drug: Traumeel® / Zeel® Injectable Solution Drug: Placebo Phase 3

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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 287 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Study Start Date : June 2013
Actual Primary Completion Date : January 2014
Actual Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoarthritis

Arms and Interventions
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Arm Intervention/treatment
Experimental: 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.
 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.
Other Names:
  • Traumeel
  • Zeel
Placebo Comparator: Placebo injectable solution
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
Placebo is an injection of Saline
Other Name: Saline


Outcome Measures
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Primary Outcome Measures :
  1. Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS [ Time Frame: 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 :
  1. Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS [ Time Frame: 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.

  2. Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS [ Time Frame: 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.

  3. Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS [ Time Frame: 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.

  4. Total WOMAC Score (All Subscales) Recorded on 100 mm VAS [ Time Frame: 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.

  5. Patient Global Assessment (PGA) [ Time Frame: 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".

  6. Patient Global Assessment (PGA) [ Time Frame: 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".

  7. Physician Global Assessment (PhGA) [ Time Frame: 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".

  8. Physician Global Assessment (PhGA) [ Time Frame: 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".

  9. Pain Immediately Following the 50-foot Walk (100 mm VAS) [ Time Frame: 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'.

  10. Time to Walking (50-foot Walk Test) [ Time Frame: Baseline (Day 1, predose) to post-Baseline visits (up to day 119) ]
    Changes in time to walk 50 feet (seconds)

  11. Time to 50% Pain Relief (Study Population Measure Statistically Derived) [ Time Frame: 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.

  12. Patients Achieving 100% Pain Relief [ Time Frame: 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.

  13. 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 Frame: 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.

  14. 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 Frame: 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.


Other Outcome Measures:
  1. Serious Adverse Events [ Time Frame: Start of Lead-In period until individual study end, up to 16 weeks. ]
    Total number of patients affected.

  2. Each Adverse Event (AE) [ Time Frame: Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119) ]
    Total number of patients affected.

  3. Incidence of Treatment Emergent Adverse Events (TEAEs) [ Time Frame: during the treatment period and follow up period (Days 11 to 119) ]
    Total number of patients affected.

  4. Proportion of Patients Who Discontinued Due to an AE [ Time Frame: All visits (Days 1 up to 119) ]
    Total number of patients affected.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   45 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01887678


Locations
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Sponsors and Collaborators
Biologische Heilmittel Heel GmbH
Investigators
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Principal Investigator: Nebojsa Skrepnik, MD Tucson Orthopaedic Institute
Principal Investigator: Royal Anspach, MD Clinical Research Advantage - Arizona II
Principal Investigator: Hans Barthel, MD Hans Richard Barthel, M.D., Inc.
Principal Investigator: Shariar Cohen-Gadol, MD Westlake Medical Research
Principal Investigator: David Bolshoun, MD Radiant Research Inc. - Denver
Principal Investigator: Linda Murray, DO Radiant Research Inc
Principal Investigator: Susan Hole, DO Riverside Clinical Research
Principal Investigator: Agustin Latorre, MD AppleMed Research, Inc.
Principal Investigator: Richard Radnovich, DO Injury Care Medical Center
Principal Investigator: Moges Sisay, MD Global Scientific Innovations
Principal Investigator: Larkin T Wadsworth, MD Sundance Clinical Research, LLC
Principal Investigator: Kurian Abraham, MD New Hope Clinical Research
Principal Investigator: Rakesh Patel, MD PMG Research of Salisbury
Principal Investigator: George Raad, MD PMG Research of Charlotte
Principal Investigator: Martin VanCleeff, MD PMG Cary Medical Research
Principal Investigator: John Rubino, MD PMG Research of Raleigh
Principal Investigator: Howard R Adelglass, MD Research Across America - NY
Principal Investigator: Louis Re, MD Manhattan Medical Research
Principal Investigator: Daniel Whitmer, MD Clinical Inquest Center Ltd.
Principal Investigator: Jeffrey Klein, MD Radiant Research Inc. - Akron
Principal Investigator: Rakesh Davit, MD Sterling Research Group, Ltd.
Principal Investigator: Glenn Smith, DO Hillcrest Clinical Research
Principal Investigator: Shawn Saylor, DO Blair Orthopedic Associates, Inc
Principal Investigator: Alex Slandzicki, MD Clinical Research Solutions
Principal Investigator: Sadia Dar, MD Clinical Research Solutions
Principal Investigator: Rickey Manning, MD PMG Research of Knoxville
Principal Investigator: Paul Wakefield, MD PMG Research of Knoxville
Principal Investigator: Michael R Adams, MD Radiant Research Inc. - Salt Lake City
Principal Investigator: Teresa Sligh, MD Providence Clinical Research
Principal Investigator: David. Cardona, MD Universal BioPharma Research Inc.
More Information
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Additional Information:

Publications of Results:
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 the knee: The MOZArT trial. Eur J Integr Med 2017;13:54-63. DOI: 10.1016/j.eujim.2017.07.005;

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Responsible Party: Biologische Heilmittel Heel GmbH
ClinicalTrials.gov Identifier: NCT01887678    
Other Study ID Numbers: C1301
First Posted: June 27, 2013    Key Record Dates
Results First Posted: March 20, 2015
Last Update Posted: April 2, 2018
Last Verified: March 2018
Additional relevant MeSH terms:
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Osteoarthritis
Osteoarthritis, Knee
Arthritis
 Joint Diseases
Musculoskeletal Diseases
Rheumatic Diseases