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

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

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.

Study Overview

• Status: Completed
• Conditions: Osteoarthritis, Knee
• Intervention / Treatment: Drug: Traumeel® / Zeel® Injectable Solution; Drug: Placebo

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 Type: Interventional
• Enrollment (Actual): 287
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85050
      • Clinical Research Advantage - Arizona II
    • Tucson, Arizona, United States, 85712
      • Tucson Orthopaedic Institute
  • California
    • Dinuba, California, United States, 93618
      • Universal BioPharma Research Inc.
    • North Hollywood, California, United States, 91606
      • Providence Clinical Research
    • Santa Barbara, California, United States, 93108
      • Hans Richard Barthel, M.D., Inc.
    • Westlake Village, California, United States, 91361
      • Westlake Medical Research
  • Colorado
    • Denver, Colorado, United States, 80239
      • Radiant Research Inc. - Denver
  • Florida
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Miami, Florida, United States, 33155
      • AppleMed Research, Inc.
    • Pinellas Park, Florida, United States, 33781
      • Radiant Research Inc.
  • Idaho
    • Boise, Idaho, United States, 83713
      • Injury Care Medical Center
  • Indiana
    • Evansville, Indiana, United States, 47714
      • Global Scientific Innovations
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Sundance Clinical Research, LLC
  • New York
    • New York, New York, United States, 10016
      • Manhattan Medical Research
    • New York, New York, United States, 10022
      • Research Across America - NY
  • North Carolina
    • Cary, North Carolina, United States, 27518
      • PMG Cary Medical Research
    • Charlotte, North Carolina, United States, 28209
      • PMG Research of Charlotte
    • Charlotte, North Carolina, United States, 28204
      • New Hope Clinical Research
    • Raleigh, North Carolina, United States, 27609
      • PMG Research of Raleigh
    • Salisbury, North Carolina, United States, 28144
      • PMG Research of Salisbury
  • Ohio
    • Akron, Ohio, United States, 44311
      • Radiant Research Inc. - Akron
    • Cincinnati, Ohio, United States, 45246
      • Sterling Research Group, Ltd
    • Dayton, Ohio, United States, 45431
      • Clinical Inquest Center Ltd.
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73119
      • Hillcrest Clinical Research
  • Pennsylvania
    • Altoona, Pennsylvania, United States, 16602
      • Blair Orthopedic Associates, Inc.
  • Tennessee
    • Franklin, Tennessee, United States, 37064
      • Clinical Research Solutions
    • Knoxville, Tennessee, United States, 37912
      • PMG Research of Knoxville
    • Knoxville, Tennessee, United States, 37938
      • PMG Research of Knoxville
    • Smyrna, Tennessee, United States, 37167
      • Clinical Research Solutions
  • Utah
    • Salt Lake City, Utah, United States, 84123
      • Radiant Research Inc. - Salt Lake City

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Saline

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serious Adverse Events	Total number of patients affected.	Start of Lead-In period until individual study end, up to 16 weeks.
Each Adverse Event (AE)	Total number of patients affected.	Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119)
Incidence of Treatment Emergent Adverse Events (TEAEs)	Total number of patients affected.	during the treatment period and follow up period (Days 11 to 119)
Proportion of Patients Who Discontinued Due to an AE	Total number of patients affected.	All visits (Days 1 up to 119)

Collaborators and Investigators

• Sponsor: Biologische Heilmittel Heel GmbH
• Investigators: 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: Martin VanCleeff, MD, PMG Cary Medical Research; 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.

Publications and helpful links

General Publications

• 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;

Helpful Links

• Link to the above citation

Study record dates

Study Major Dates

• Study Start: June 1, 2013
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: June 14, 2013
• First Submitted That Met QC Criteria: June 26, 2013
• First Posted (Estimate): June 27, 2013

Study Record Updates

• Last Update Posted (Actual): April 2, 2018
• Last Update Submitted That Met QC Criteria: March 6, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Arthritis; Osteoarthritis; Osteoarthritis, Knee
• Other Study ID Numbers: C1301