Clinical trial NCT01887678: Study of Intra-articular Injections vs Placebo in Patients With Pain From Osteoarthritis of the Knee
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Osteoarthritis, Knee
Lead sponsor: Biologische Heilmittel Heel GmbH
Sponsor class: INDUSTRY
First posted: 2013-06-27
Enrollment: 287
Sex: ALL
Minimum age (years): 45
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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.

Primary outcomes:
measure: Change in Knee Pain as Measured by the WOMAC Osteoarthritis (OA) Index Pain Subscale (Section A, Items #1-5) Measured by 100 mm VAS
timeFrame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
Secondary outcomes:
measure: Pain Subscore (WOMAC Section A, Items #1-5) Measured by 100 mm VAS
timeFrame: from Baseline to post-Baseline visits except End of Study Visit (up to day 105)
measure: Stiffness Subscore (WOMAC Section B, Items #6-7) Measured by 100 mm VAS
timeFrame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
measure: Physical Function Bubscore (WOMAC Section C, Items #8-24) Recorded on 100 mm VAS
timeFrame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
measure: Total WOMAC Score (All Subscales) Recorded on 100 mm VAS
timeFrame: from Baseline (Day 1, predose) to End of Study Visit (up to Day 119)
measure: Patient Global Assessment (PGA)
timeFrame: from Baseline (Day 1, predose)
measure: Patient Global Assessment (PGA)
timeFrame: End of Study Visit (up to Day 119)
measure: Physician Global Assessment (PhGA)
timeFrame: Baseline (Day 1, predose)
measure: Physician Global Assessment (PhGA)
timeFrame: End of Study Visit (up to Day 119)
measure: Pain Immediately Following the 50-foot Walk (100 mm VAS)
timeFrame: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)
measure: Time to Walking (50-foot Walk Test)
timeFrame: Baseline (Day 1, predose) to post-Baseline visits (up to day 119)
measure: Time to 50% Pain Relief (Study Population Measure Statistically Derived)
timeFrame: Statistically derived
measure: Patients Achieving 100% Pain Relief
timeFrame: Statistically derived
measure: Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived) - Patients Use
timeFrame: Statistically derived
measure: Time to and Use of Rescue Medication (Acetaminophen up to 3000 mg Per Day for Breakthrough Pain) (Study Population Measure Statistically Derived). Tablets Taken.
timeFrame: Statistically derived
Other outcomes:
measure: Serious Adverse Events
timeFrame: Start of Lead-In period until individual study end, up to 16 weeks.
measure: Each Adverse Event (AE)
timeFrame: Starting at Visit 2/ Start of Lead-In period (Day 7 up to day 119)
measure: Incidence of Treatment Emergent Adverse Events (TEAEs)
timeFrame: during the treatment period and follow up period (Days 11 to 119)
measure: Proportion of Patients Who Discontinued Due to an AE
timeFrame: All visits (Days 1 up to 119)
Locations:
city: Phoenix
country: United States
facility: Clinical Research Advantage - Arizona II
state: Arizona
city: Tucson
country: United States
facility: Tucson Orthopaedic Institute
state: Arizona
city: Dinuba
country: United States
facility: Universal BioPharma Research Inc.
state: California
city: North Hollywood
country: United States
facility: Providence Clinical Research
state: California
city: Santa Barbara
country: United States
facility: Hans Richard Barthel, M.D., Inc.
state: California
city: Westlake Village
country: United States
facility: Westlake Medical Research
state: California
city: Denver
country: United States
facility: Radiant Research Inc. - Denver
state: Colorado
city: Edgewater
country: United States
facility: Riverside Clinical Research
state: Florida
city: Miami
country: United States
facility: AppleMed Research, Inc.
state: Florida
city: Pinellas Park
country: United States
facility: Radiant Research Inc.
state: Florida
city: Boise
country: United States
facility: Injury Care Medical Center
state: Idaho
city: Evansville
country: United States
facility: Global Scientific Innovations
state: Indiana
city: Saint Louis
country: United States
facility: Sundance Clinical Research, LLC
state: Missouri
city: New York
country: United States
facility: Manhattan Medical Research
state: New York
city: New York
country: United States
facility: Research Across America - NY
state: New York
city: Cary
country: United States
facility: PMG Cary Medical Research
state: North Carolina
city: Charlotte
country: United States
facility: New Hope Clinical Research
state: North Carolina
city: Charlotte
country: United States
facility: PMG Research of Charlotte
state: North Carolina
city: Raleigh
country: United States
facility: PMG Research of Raleigh
state: North Carolina
city: Salisbury
country: United States
facility: PMG Research of Salisbury
state: North Carolina
city: Akron
country: United States
facility: Radiant Research Inc. - Akron
state: Ohio
city: Cincinnati
country: United States
facility: Sterling Research Group, Ltd
state: Ohio
city: Dayton
country: United States
facility: Clinical Inquest Center Ltd.
state: Ohio
city: Oklahoma City
country: United States
facility: Hillcrest Clinical Research
state: Oklahoma
city: Altoona
country: United States
facility: Blair Orthopedic Associates, Inc.
state: Pennsylvania
city: Franklin
country: United States
facility: Clinical Research Solutions
state: Tennessee
city: Knoxville
country: United States
facility: PMG Research of Knoxville
state: Tennessee
city: Knoxville
country: United States
facility: PMG Research of Knoxville
state: Tennessee
city: Smyrna
country: United States
facility: Clinical Research Solutions
state: Tennessee
city: Salt Lake City
country: United States
facility: Radiant Research Inc. - Salt Lake City
state: Utah
Study officials:
affiliation: Tucson Orthopaedic Institute
name: Nebojsa Skrepnik, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Advantage - Arizona II
name: Royal Anspach, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hans Richard Barthel, M.D., Inc.
name: Hans Barthel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Westlake Medical Research
name: Shariar Cohen-Gadol, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radiant Research Inc. - Denver
name: David Bolshoun, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radiant Research Inc
name: Linda Murray, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Riverside Clinical Research
name: Susan Hole, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: AppleMed Research, Inc.
name: Agustin Latorre, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Injury Care Medical Center
name: Richard Radnovich, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Global Scientific Innovations
name: Moges Sisay, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sundance Clinical Research, LLC
name: Larkin T Wadsworth, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: New Hope Clinical Research
name: Kurian Abraham, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Salisbury
name: Rakesh Patel, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Charlotte
name: George Raad, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Cary Medical Research
name: Martin VanCleeff, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Raleigh
name: John Rubino, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Research Across America - NY
name: Howard R Adelglass, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Manhattan Medical Research
name: Louis Re, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Inquest Center Ltd.
name: Daniel Whitmer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radiant Research Inc. - Akron
name: Jeffrey Klein, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sterling Research Group, Ltd.
name: Rakesh Davit, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hillcrest Clinical Research
name: Glenn Smith, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Blair Orthopedic Associates, Inc
name: Shawn Saylor, DO
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Solutions
name: Alex Slandzicki, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Research Solutions
name: Sadia Dar, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Knoxville
name: Rickey Manning, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: PMG Research of Knoxville
name: Paul Wakefield, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Radiant Research Inc. - Salt Lake City
name: Michael R Adams, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Providence Clinical Research
name: Teresa Sligh, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Universal BioPharma Research Inc.
name: David. Cardona, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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;