| Eligibility |
Inclusion Criteria:
1. Signed and dated informed consent obtained before undergoing any
clinical-investigation-related procedure.
2. Male or female aged between 40 and 80 years.
3. Documented diagnosis of primary OA of the knee, based on the clinical and radiological
American College of Rheumatology (ACR) criteria for knee OA:
- Knee pain,
- X-ray osteophytes,
- at least one of the following: (a) age >50 years; (b) morning stiffness <30
minutes in duration; (c) crepitus on active motion.
4. Grade II-III according to the Kellgren and Lawrence classification (X-ray evidence at
enrolment or within the previous 12 months).
5. Knee OA symptoms for at least six months.
6. Failure to respond (i.e. did not respond sufficiently) to analgesics and/or regular
NSAIDs, or proven intolerance to regular use of NSAIDs or to weak opioids analgesics.
7. Presence of pain in the target knee, with a value =4 and =9 on the NRS, providing that
pain in the contralateral knee I less than 3 (see also Exclusion Criteria n. 3).
8. Ability and willingness to communicate, participate, and comply with the requirements
and scheduled procedures of the clinical investigation.
Exclusion Criteria:
(a) Medical history and Concomitant Diseases related criteria
1. Presence of isolated or predominantly symptomatic patellofemoral OA of the knee (i.e.
pain when climbing stairs or forcing the patient to extend his leg when sitting on a
low sit).
2. Presence of secondary osteoarthritis and/or other rheumatic diseases. In particular,
history or presence of the following diseases should be excluded: septic arthritis,
inflammatory joint disease, gout, recurrent episodes of pseudogout, Paget's disease of
bone, articular fracture, ochronosis, acromegaly, haemocromatosis, Wilson's disease,
primary osteochondromatosis.
3. Contralateral (i.e. non-target) knee pain >3 on the NRS
4. Any knee OA treatment for both knees (other than the clinical investigation
viscosupplementation of the target knee) anticipated within the next 6 months.
5. Presence of pain (any severity) in the ipsilateral and/or contralateral hip.
6. Presence of disease of the spine or other lower extremity joints of sufficient
severity to affect the clinical investigation assessments.
7. Anterior cruciate ligament repair, reconstruction or injury in the target knee within
the previous 3 years.
8. Cartilage repair/surgery in the target knee within the previous 3 years.
9. Any surgery in the lower limbs within the previous 12 months
10. Any planned surgery of the lower limbs during the clinical investigation period.
11. Significant articular deformities of the lower limbs, i.e. major dysplasia and
congenital abnormalities.
12. Presence of varus or valgus knee deformity = 8°.
13. History or presence of osteonecrosis in the lower limbs.
14. Presence of any significant injury of the ipsilateral limb within the previous 6
months.
15. Presence of joint effusion and/or infection at the target knee.
16. Presence of local skin abnormalities (e.g. infection or disease) at the target knee.
17. History or presence of knee joint infection secondary to previous intra-articular
injections, or increased predisposition to infections.
18. History or high risk of venous thromboembolism and/or venous or lymphatic stasis of
the limb of the target knee.
19. History of allergy or known hypersensitivity to hyaluronic acid, to any of the
components of the products under clinical investigation, or to paracetamol.
20. History of hypersensitivity to avian proteins.
21. Morbidly obese patients (BMI=35).
22. Severe concomitant disease at any organ or apparatus (including acute or chronic
infectious diseases) that may interfere with the free use and evaluation of the
affected knee for the 6 months course of the clinical investigation and/or malignancy
(with the exception of adequately treated or excised non metastatic basal cell or
squamous cell cancer of the skin or in situ uterine cervical cancer) active within the
previous 12 months.
23. History of drug, alcohol, or other substance abuse, or other factors limiting the
ability to cooperate during the clinical investigation.
24. Any other clinically relevant disease and condition that, in the opinion of the
principal investigators, may jeopardize the clinical investigation conduct according
to the CIP or performance or safety assessments or may compromise the patients' safety
or may place the patient at an undue risk by participating in the clinical
investigation.
(b) Previous or concomitant treatments
25. Patients requiring systemic analgesics (including opiates)/NSAIDs for the target knee,
or for indications other than OA pain at the target knee but likely to use these
medications for more than 5 consecutive days, or for more than 10 non-consecutive days
in one month, or unable to stop them during the 2 days preceding a clinic visit.
26. Patients requiring topical analgesics/NSAIDs for the target knee.
27. Patient requiring intra-articular corticosteroids into any joint or periarticular
structure in the lower limb, or systemic corticosteroids (oral or injected for any
indication).
28. Patients who underwent tidal lavage of the knee joint(s) during the three months prior
to randomization.
29. Viscosupplementation in the lower limbs within the previous 12 months.
30. Patients on SYSADOAs or a dietary supplement containing compounds considered specific
for OA (e.g. glucosamine, chondroitin sulphate, diacerein) if the dosage has not been
stable within the previous 3 months.
31. Patients on anticoagulant treatment other than direct oral anticoagulants (DOACS).
32. Non-pharmacological therapy for the lower extremities, unless stable for more than one
month (and not to be substantially altered during the clinical investigation).
Physical therapy is allowed.
33. Patients using assistive devices other than a cane (walking stick) or knee brace.
34. Concomitant participation in any clinical study/investigation or treatment with any
investigational drugs/treatments/devices within the previous 3 months or 5 of
half-lives (whichever is longer).
35. Contraindication to use of hyaluronic acid.
36. Contraindication to use of paracetamol. (c) Other
37. For women of childbearing potential, not surgically sterile or postmenopausal:
- Pregnancy (i.e. positive pregnancy test at screening) or breastfeeding;
- Failure to agree to practice a highly effective method of contraception for 3
months after the IA injection.
38. For sexually active men with a female partner of childbearing potential: failure to
use a reliable method of birth control for 3 months after the IA injection.
Randomization Criteria:
1. Pain value in the target knee =4 and =9 on the NRS.
2. Absence of joint effusion in the target knee.
3. Absence of local skin abnormalities (e.g. infection or disease) at the target knee.
4. No use of analgesics/NSAIDs during the 2 days preceding the Randomization Visit.
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