The present study is designed to test the hypothesis that Intra-Articular Hyaluronic Acid (IAHA) is superior to placebo in slowing structural progression and on long term symptomatic effect in primary knee Osteoarthritis (OA) patients.

The investigators will perform a multicenter double-blind, randomized, placebo-controlled, parallel group trial.

The target population will be patients with the diagnosis of knee osteoarthritis who are followed at two Portuguese hospitals (Centro Hospitalar de Lisboa Norte - Hospital Santa Maria, Centro Hospitalar de Lisboa Ocidental - Hospital Egas Moniz).

All patients selected will be included in the intention-to-treat group. Then, using blocked randomization method they will be assigned to receive either IAHA, or placebo (saline solution). At both hospitals the study will consist of four injections of IAHA, 6 months apart, plus a 6 month period after the injection, resulting in a total follow-up period of 24 months. Before each new cycle a follow-up consultation will be performed in order to assess pain and function (KOOS), quality of life (SF-36), adverse events and consumption of acetaminophen and NSAIDS regarding the week before evaluation. X-rays will be performed in the beginning of follow-up, one year after that and 6 months after the last cycle of IAHA or placebo injections (24 months).

Ultrasound evaluation will be performed at the target knee in same time points as X-rays by two rheumatologists trained in musculoskeletal ultrasound examination. Additionally, the investigators will assess potential biochemical biomarkers of knee OA structural progression and response to treatment. Measurements will be performed in both serum and urine and, If possible, synovial fluid aspiration will be performed and together with blood and urine samples stored at the Biobanco-IMM Instituto de Medicina Molecular for analysis. Biologic samples collection will be performed at baseline and repeated at the 4th, 12th, 24th, 36th weeks, and then every 6 months.

Inclusion Criteria:

• Symptomatic knee OA as defined by the ACR clinical and radiographic criteria
• Kellgren-Lawrence grade of II or III on prior x-rays (taken within 6 months of the screen visit) or screen X-ray
• A minimum medial and/or lateral JSW of the target knee of 2 mm
• Knee pain of 40 mm or greater on a 100 mm visual analogue scale (VAS) at any time during the week before inclusion
• Oral corticosteroids (≤10 mg/day prednisolone or equivalent), NSAIDs, and acetaminophen are permitted if the dose had been stable for at least one month prior to baseline

Exclusion Criteria:

• Body mass index greater than 40 kg/m2
• Varus or valgus deformity of the knee > 15 degrees (assessed by goniometry)
• History of trauma, surgery or planned surgery to the study joint (including arthroscopy surgery), joint inflammatory diseases, septic arthritis and/or microcrystalline arthropathies
• Coagulation/platelet disorders
• Active malignancy, active systemic infection, or any contraindication to MRI
• Potent analgesics including opiates, oral corticosteroid therapy within one month prior to enrolment into the study other than stable doses of ≤ 10 mg daily prednisolone or equivalent
• Knee administration of intra-articular steroids in the previous 3 months or HA injections during the past year