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

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.

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.

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.