Study to Investigate the Mechanism of Action of an Oral Enzyme Treatment With Bromelain, Trypsin and Rutoside Versus Placebo in Subjects With OsTeoarthritis (WobeSmart)

Inclusion Criteria:

1. Male or female ≥ 40 years of age and with BMI ≤ 35 kg/m2;

2. Uni- or bilateral femorotibial knee OA :

   1. Responding to clinical and radiological criteria of American College of Rheumatology (ACR);
   2. Symptomatic for more than 6 months in the index knee;
   3. Radiological Kellgren & Lawrence (K&L) grade II-III in standing x-rays from less than 12 months.
3. Mild-to-Moderate mean knee pain score at rest or at walking over the last 24 hours on the index knee evaluated on VAS (0-100) ≥ 40 at baseline;
4. Able to follow the instructions of the study;
5. Having signed an informed consent.

Exclusion Criteria:

Related to knee:

1. Recent macro-trauma of the knee responsible of the symptomatic knee left to the Investigator's discretion;
2. Concurrent articular disease interfering with the evaluation of pain left to the Investigator's discretion;
3. Prosthesis in the target knee;

4. Knee swelling requiring corticosteroids local injection.

   Related to treatments:

5. Analgesics to manage knee pain 24 hours before inclusion visit;
6. Corticosteroids injection in the target knee in the last 3 months;
7. Hyaluronan injection in the target knee in the last 6 months;
8. Arthroscopy in the last 6 months;
9. Oral corticotherapy ≥ 5mg/day (in Prednisolone equivalent) in the last 3 months;
10. Symptomatic slow-acting drugs for osteoarthritis (SYSADOA) or dietary supplement, i.e., curcuma extract, chondroitin, glucosamine, diacerein or avocado-soya unsaponifiables in the last 3 months;
11. An anticipated need for any forbidden treatments during the trial;

12. Contraindications to the product :

    1. severe hepatic and renal impairment
    2. congenital or acquired coagulation disorders, e.g. haemophilia
    3. severe liver and/or kidney damage
    4. hereditary galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
13. Hypersensitivity or allergy to the product components, and pineapple;
14. Treatments based on strontium ranelate, bisphosphonates, selective estrogen-receptor modulator (SERM) and parathormone (PTH) in the last 12 months;
15. Treatment based on zoledronate in the last 2 years;
16. Treatment based on denosumab in the last 6 months;

17. Treatment with anticoagulants and/or anti-platelet agents

    Related to associated diseases:

18. Any severe, uncontrolled and limiting disease left to the Investigator's discretion;
19. Patient with widespread pain/depression (e.g. fibromyalgia);
20. Lower or upper extremity surgery or fracture in the last 6 months;
21. Anticipated need for any surgical or other invasive procedure during the trial including prosthesis in the target knee;

22. Severe alteration of mobility enabling functional evaluation.

    Related to subjects

23. Close collaborators to the investigational team, the study coordinator (ARTIALIS) or to the Sponsor;
24. Currently participating or having participated in another therapeutic clinical trial in the three previous months;
25. Having made a blood donation in the past month;
26. Under guardianship or judicial protection;
27. Pregnancy, breastfeeding, planned conception, or premenopausal women without effective contraception (tablet, patch, ring, diaphragm, implant and intrauterine device, tubal ligation or hysterectomy);
28. Counter-indication to an MRI examination.