A Study to Assess Safety and Tolerability of PCRX-201 in Subjects With Painful Osteoarthritis of the Knee

The study will consist of two parts, Part A and Part B, which will use PCRX-201 from two different manufacturing processes. A total of 135 eligible subjects, with painful OA of the index knee will be enrolled. Subjects will be randomly assigned to a treatment dose group, stratified by Kellgren-Lawrence (K-L) Grade, in both parts of the study. Enrollment of subjects with K-L Grade 4 will be capped at 4 subjects per dose group in Part A and 8 subjects per dose group in Part B.

Enrollment of subjects with K-L Grade 2 or 3 will include a minimum of 4 subjects per Grade per dose group in Part A and a minimum of 8 subjects per Grade per dose group in Part B. This study does not require an equal number of subjects between K-L Grade 2 and 3. All eligible subjects will be pretreated with the same dose of methylprednisolone acetate (40 mg) on Day 1 immediately before treatment with PCRX-201 or placebo.

Part A will enroll approximately 45 subjects into 3 dose groups (15 subjects in each treatment group, stratified by K-L Grade as noted above).

Part B will enroll approximately 90 subjects into 3 groups (30 subjects in each treatment group, stratified by K-L Grade as noted above). Enrollment in Part B is dependent upon the availability of study drug developed with manufacturing process 2.

Inclusion criteria

• Subjects must be willing and able to comply with the study procedures and visit schedule and able to follow verbal and written instructions.
• Subjects must be male or female and 45 to 80 years old, inclusive, at Screening.
• Subjects must exhibit symptoms associated with osteoarthritis of the index knee for ≥12 months before Screening (subject self-reporting is acceptable).
• Subjects must have index knee pain for >15 days over the last month before Screening (subject self-reporting is acceptable).
• Subjects must have failed 2 or more therapies: Restricted physical activity as per Osteoarthritis Research Society International (OARSI) core level recommendation, ie, "structured land-based exercise" (this may include physical therapy), and failure of an additional type of conservative therapy for OA of the index knee, eg, nonselective NSAIDs or COX-2 inhibitors, in the past 12 months.
• Subjects must have a body mass index (BMI) ≤40 kg/m2 at Screening.
• Subjects must have an index knee examination indicating the index knee and the intended injection site area are free of any signs of local or joint infection at Baseline.
• Subjects must have an index knee Average Daily Knee Pain (NRS) between ≥5.0 and ≤9.0 at Screening and Baseline.
• Sexually active subjects of child-bearing potential (SOCBP) and their partners must agree to use effective birth control while in the study
• Subjects must have active synovitis in the index knee as determined by ultrasound Doppler.
• Subjects must exhibit American College of Rheumatology Criteria (clinical and radiological) for osteoarthritis as follows:

• Knee pain
• At least 1 of the following:

i. Age >50 years ii. Morning stiffness <30 minutes iii. Crepitus on knee motion c. Osteophytes

• Subjects must have K-L Grade 2, 3, or 4 in the index knee based on X-rays performed during Screening and confirmed by trained radiographers at a central facility before enrollment
• Subjects need to show the presence of moderate or severe synovitis based on 11-point synovitis score using contrast-enhanced MRI

Exclusion criteria

• Subjects have any current or prior diagnosis of autoimmune connective tissue disorders, secondary OA conditions, benign synovial tumors, gout/pseudogout, reactive arthritis, RA, psoriatic arthritis, ankylosing spondylitis, or arthritis associated with inflammatory bowel disease.
• Subjects have any active systemic or local infection, including infection of the index knee
• Subjects are unable to undergo MRI with contrast MRI
• Subjects with X-ray or MRI exclusionary events
• Subjects have an unstable index knee joint (eg, torn anterior cruciate ligament) within 12 months of Screening
• Subjects have used any approved or investigational IA drug/biologic in index knee within 6 months of Screening (eg, hyaluronic acid, platelet rich plasma, stem cells, prolotherapy, and amniotic fluid injection)
• Subjects are receiving or have received any gene therapy treatment (eg, IL-1Ra) in the past 3 years
• Subjects have used IA steroids ≤3 months before screening

Other protocol-defined criteria apply