Assessment of Efficacy of a Single Intra-articular Injection of HYALUBRIX 60 in Knee Osteoarthritis

Inclusion Criteria:

1. Voluntarily given informed consent to investigation participation in writingencompassing consent to data recording and verification procedures;

2. Male or female subjects aged ≥18 years and ≤70 years with active life-style;

3. BMI ≤40 kg/m2;

4. Patients affected by knee osteoarthritis, as defined by American College ofRheumatology (ACR) clinical and radiographic criteria for OA of the knee, andmeeting the following conditions:

• Kellgren-Lawrence Grade 2 to 3 severity OA of the target knee with presence ofosteophytes determined from X-rays of the knee obtained within 6 months fromthe screening visit; i.e. in the tibio-femoral compartment of the target kneewith at least 1 osteophyte and measurable joint space, as diagnosed by standardX-rays (anterior- posterior view [weight bearing extension or semi-flexion] andlateral). In the case that a patient has not a valid X-ray within 6 monthsprior to screening, the exam is to be performed during the screening period;

• Patients suffering from OA symptoms of the target knee for at least 3 monthsprior to the screening visit; Note: patients with bilateral OA of the knee willbe allowed as long as they can differentiate pain in the target knee, do notneed to use analgesics for treatment of their contralateral knee, and do notexpect to receive treatment of the contralateral knee during the investigation.In the case that both knees are eligible for the investigation based on painintensity, the knee with the greater pain VAS score on the WOMAC pain VAS A1subscale (walking on a flat surface) will be selected as the target knee;

5. Pain ≥50 mm on the WOMAC pain VAS A1 subscale (walking on a flat surface) in thetarget knee;

6. Patients having discontinued use of all systemic analgesic/non-steroidalanti-inflammatory drugs (NSAIDs) therapy for at least 7 days (24 hours forparacetamol) prior to the screening visit and agree not to resume them during theinvestigation. Note: paracetamol will be provided to patients as rescue medication.

7. If female of child-bearing potential, must have a negative urine pregnancy test atthe screening visit and use a reliable form of contraception for more than 1 monthprior to Screening and throughout the investigation. Note: to be considered femalesof non-child- bearing potential, females must be surgically sterile orpostmenopausal as documented in medical history for at least 1 year. Highlyeffective birth control methods include: combined hormonal contraception (containingestrogens and progestogen) associated with inhibition of ovulation (oral,intravaginal, transdermal); progestogen-only hormonal contraception associated withinhibition of ovulation (oral, injectable, implantable); intrauterine device (IUD);intrauterine hormone-releasing system (IUS); bilateral tubal occlusion; vasectomisedpartner; sexual abstinence.*

• Note: According to 4.1 paragraph "Birth control methods which may be consideredas highly effective" of the Clinical Trial Facilitation Group (CTFG)/Recommendations related to contraception and pregnancy testing inclinical trials.

Exclusion Criteria:

1. Radiographic assessment confirming abnormal patellofemoral tracking or articulationor abnormal/excessive patellar subluxation in lateral view;

2. Major injury to or disorder of the contralateral knee or other weight-bearing jointthat would interfere with the study assessments;

3. Secondary OA due to a prior or concomitant condition (e.g., septic arthritis,inflammatory joint disease, gout, articular fracture, major dysplasia, or congenitalabnormality, hemochromatosis, etc.);

4. Patients who have had arthroplasty at the target knee at any time;

5. Surgery in the target knee within the previous 12 months prior to Screening or anyplanned surgery throughout the duration of the investigation;

6. Surgery in the contralateral knee or other weight-bearing joint within the previous 12 months that would interfere with the study assessments;

7. Patients that are candidate for knee replacement within the next 12 months;

8. Patients having had diagnostic or surgical knee arthroscopy, or knee lavage in thetarget knee in the 6 months prior to the screening visit, or patients in which suchprocedures are planned during the study;

9. Patients with total joint replacement implants, unicondylar implants orpatellofemoral replacement implants in the study joint;

10. Ligament reconstruction of the target knee in the previous 3 years;

11. Inflammatory arthropathies such as rheumatoid arthritis, lupus, or psoriaticarthritis;

12. Patients with clinically relevant intra-articular effusion of the target knee;

13. Episode of gout or calcium pyrophosphate (pseudogout) diseases within 6 months priorto Screening;

14. Patients having received:

• Corticosteroids by systemic administration within 30 days prior to thescreening visit. Inhaled corticosteroids are permitted if the Subject has been on a stable regimenfor the past 1 month prior to Screening and remains on this regimen throughout thecourse of the investigation;

• Analgesic/NSAIDs by systemic administration within 7 days prior to thescreening visit;

• Intra-articular drugs within 12 weeks prior to the screening visit;

• Chondroitinsulphate, glucosamine, diacereine, bisphosphonates or matrixmetalloproteinase (MMP) inhibitors within 30 days prior to the screening visit;

• Viscosupplementation of the target knee within 6 months prior to the screeningvisit;

• Paracetamol in the 24 hours prior to the screening visit;

• Treatment with any other investigational product within 3 months prior to thescreening visit.

15. History of allergic reaction to an intra-articular Hyaluronic acid injection;

16. Known hypersensitivity (allergy) to gram positive bacterial proteins;

17. Inability to perform the Timed Up and Go (TUG) test;

18. X-ray findings of acute fractures, severe loss of bone density, avascular necrosisand/or severe deformity;

19. Axial deviation of the lower limbs greater than 20 degrees in valgus or varus onstanding X-ray, ligamentous laxity, or meniscal instability as per studyinvestigator(s);

20. Significant surgery of lower limbs (hip, ankle, foot) that may interfere with kneeassessments;

21. Patients with any musculoskeletal condition affecting the target knee that wouldimpair assessment of the effectiveness in the target knee (e.g. Paget's disease ofbone);

22. Patients with significant pain outside the target knee, including significant hip orback pain;

23. Chronic use of analgesia for pain (including pain in the other knee or any otherjoint) that may interfere with the evaluations of the test knee (such as possibleuse of rescue medication for these other conditions);

24. Known allergies to paracetamol and hyaluronan preparations;

25. Recurrent medical history of severe allergic or immune-mediated reactions;

26. Active infection or skin diseases in the area of the potential injection site orjoint;

27. Any dermatological disease overlying the study joint that would contraindicateinjections or aspirations;

28. Peripheral neuropathy that would be severe enough to interfere with the evaluationof the subject;

29. Psychological status (e.g., anxiety, depression, poor sleep quality, paincatastrophizing, etc.) that may interfere with functional assessment of the targetknee;

30. Vascular insufficiency of lower limbs that is severe enough to interfere with theevaluation of the subject;

31. Any concomitant disease(s) or condition(s) that may interfere with the free use andevaluation of the affected knee for the 12 months course of the investigation (cancer, other rheumatic diseases, gout, severe congenital defects, etc.);

32. Continued participation in an experimental drug/device study or any clinical trialwithin the previous 8 weeks prior to Screening. Subjects must have fully completedparticipation in an experimental drug/device study of any clinical trial at least 8weeks prior to screening;

33. Pregnancy, breastfeeding, planned conception, premenopausal women who have not hadtubal ligation, hysterectomy, or are unwilling or unable to utilize contraceptivemeasures (or contraception);

34. Prior history of any malignancy with the exception of basal cell carcinoma of theskin treated more than 2 years prior to Screening;

35. Significant bleeding diathesis;

36. Patients who are not able to comply with study procedures or who are likely to benoncompliant or uncooperative during the study according to the investigator'sopinion.