This study will be an open-label trial to determine the functional effects of bilateral IA injections of Zilretta into knee joints of 70 subjects with bilateral KL grade 2-4 symptomatic knee osteoarthritis (OA). Measurement and evaluation of outcomes at baseline, 6, 12 and 24 weeks will allow assessment of short and long-term effects, consistent with Osteoarthritis Research Society International (OARSI) and Outcome Measures in Rheumatology (OMERACT) recommendations.

The primary aim of the proposed study is to demonstrate the effect of IA injection of Zilretta on physical performance measures in adults with bilateral knee OA. The primary study endpoint will be the change in OARSI recommended physical performance tests (30-second chair standing test, 40m fast-paced walking test, stair ascent) 12 weeks after treatment.

The secondary outcome will be the change in Knee Injury and Osteoarthritis Outcome Score (KOOS-PS) patient-reported physical function short form.

The tertiary outcomes will be the change in KOOS-Quality of life subscale (QoL) and Numerical Rating Scale (NRS) for pain. All outcomes will be assessed at 6- and 24-week follow-up as well to define the course and trajectory of effects.

Specific Aim 1: To determine the extent to which intra-articular (IA) injection of Zilretta in patients with bilateral knee OA improves physical performance (OARSI recommended physical performance measures).

Primary Hypothesis 1: Bilateral knee intra-articular injection of Zilretta results in improved physical performance detectable at 6 weeks, 12 weeks (primary), and 24 weeks.

Specific Aim 2: To determine the extent to which IA injection of Zilretta in patients with bilateral knee OA improves physical function (KOOS-PF).

Hypothesis 2: Bilateral knee IA injection of Zilretta results in improved patient-reported physical function (KOOS-PS) at 6 weeks,12 weeks (primary), and 24 weeks.

Specific Aim 3: To determine the extent to which bilateral knee IA injection of Zilretta in patients with bilateral knee OA improves quality of life (KOOS-QoL).

Hypothesis 3: Intra-articular (IA) bilateral knee injection of Zilretta in patients with bilateral knee osteoarthritis results in improved quality of life (KOOS-QoL) detectable at 6 weeks, 12 weeks (primary), and 24 weeks.

Inclusion Criteria:

• Men and women age 30 years or older with symptomatic bilateral knee OA
• Symptomatic knee OA will be defined as the presence of a definite osteophyte or joint space narrowing (KL Grade ≥2) on posteroanterior (PA) fixed flexion knee radiographs in subjects limited by bilateral pain rated on a Numerical Rating Scale as ≥ 4/10 on more than half of the days over the past month. Radiographic change must be visible at standard image size, irrespective of capability to detect more subtle changes through digital enhancement.
• Bilateral knee symptoms for ≥ 3 months prior to screening
• Has undergone at least one prior conservative osteoarthritis treatment (e.g. Physical therapy, analgesics)
• Body Mass Index ≤ 41 kg/m2
• Ambulatory
• Willing and able to comply with the study procedures and visit schedules and ability to follow verbal and written instructions.
• Willingness to abstain from the use of protocol-restricted medications during the study after signing informed consent and also willing to abstain from use of all analgesics other than acetaminophen 1 week prior to beginning of treatment.

Exclusion Criteria:

• Current consumption of more than 14 alcoholic drinks per week
• Clinical signs and symptoms of active knee infection or crystal disease of either knee within 1 month of screening
• Diagnosed with rheumatoid arthritis, Reiter's syndrome, psoriatic arthritis, gout, ankylosing spondylitis, or arthritis secondary to other inflammatory diseases; HIV, viral hepatitis; chondrocalcinosis, Paget's disease, or villonodular synovitis
• Diagnosed with leukemia, known presence of metastatic malignant cells, or ongoing or planned chemotherapeutic treatment.
• A gout attack in the past 2 years.
• Diseases of the spine, hip or other lower extremity joints judged by the investigator to be contributing to the pain in either knee (i.e. sciatica, nerve pain, hip OA). Note: Patients with hip replacement in either hip may be enrolled provided there is sufficient pain relief after hip replacement that analgesics are not required.
• Untreated symptomatic injury of either knee (e.g., acute traumatic injury, anterior cruciate ligament injury, clinically symptomatic meniscus injury characterized by a mechanical issue such as locking or catching).
• Uncontrolled diabetes (HbA1c >7.2)
• Women who report pregnancy or childbearing potential and not using acceptable contraceptive measures (oral contraceptive, long acting reversible contraceptive therapy) (due to the potential for change in body mass and distribution to alter knee symptoms over the period of follow-up).
• Presence of surgical hardware or other foreign body intended to treat arthritis or cartilage-related pathology in either knee.
• Arthroscopy or open surgery of either knee within 6 months of screening.
• Planned/anticipated surgery of either knee during the study period.
• Use of systemic immunosuppressant within 6 weeks of screening.
• Oral corticosteroids (investigational or marketed) within 2 weeks of screening (unless on chronic stable dose for >3 months).
• IA corticosteroid (investigational or marketed) in either knee within 3 months of screening.
• IV or IM (Intramuscular) Corticosteroid injection (investigational or marketed) within 3 months of screening.
• Any other IA drug/biologic use within 6 months of screening or 5 half-lives (whichever is longer) (e.g., hyaluronic acid, platelet-rich plasma (PRP) injection, stem cells, prolotherapy and amniotic fluid injection).
• Any documented clinically significant degree of cognitive impairment or other condition, finding, or psychiatric illness at screening which, in the opinion of the investigator, could compromise subject safety.
• Any condition other than OA of the knee which, in the opinion of the investigator, affects the ability to ambulate to a sufficient degree to interfere with the assessment of the safety and treatment effects of the study injection.
• Participated in any interventional drug or device trial within 30 days prior to screening or concurrent participation in another research study that could complicate interpretation of the study findings.

24 Weeks