SAFETY AND SYSTEMIC EXPOSURE OF TRIAMCINOLONE ACETONIDE FOLLOWING INTRA-ARTICULAR INJECTION OF TRIAMCINOLONE ACETONIDE EXTENDED-RELEASE OR STANDARD TRIAMCINOLONE IN PATIENTS WITH HIP OSTEOARTHRITIS

Purpose: The hip joint is the second most common site of osteoarthritis (OA), a debilitating disease associated with pain and functional limitations. Hip OA symptoms and progression are linked to the presence of pro-inflammatory mediators and inflammation in synovial tissues. Intra-articular corticosteroids (IACS) have anti-inflammatory effects and are recommended by the Osteoarthritis Research Society International (OARSI) and American Academy of Orthopaedic Surgeons (AAOS) guidelines for the treatment of hip OA. Results from prior studies have demonstrated that IACS provide relief from hip OA pain for up to 8 weeks post-injection . Triamcinolone acetonide extended-release (TA-ER; formerly FX006) is a microsphere-based formulation of triamcinolone acetonide (TA). TA-ER has demonstrated efficacy and safety through 16 weeks post-injection in patients with knee OA and is approved by the United States Food and Drug Administration for the treatment of knee OA pain. Phase 2 pharmacokinetic (PK) studies in patients with knee OA confirmed the extended-release profile of TA-ER, as single or bilateral IA injection showed a gradual increase in plasma TA that plateaued through Hour 24, followed by slow elimination from the systemic circulation. Peak systemic TA concentration was markedly lower following IA injection of TA-ER compared to standard TA crystalline suspension (TAcs). As an initial evaluation in patients with hip OA, we examined the safety and systemic TA exposure following IA injection of TA-ER or TAcs. Methods: This Phase 2, randomized, open-label study (NCT03382262) included patients (≥40 years, BMI ≤40 kg/m2) meeting the ACR clinical/radiographic criteria for hip OA, with symptoms consistent of hip OA for ≥6 months prior to screening and pain in the index joint for >15 days over the last month. Patients were randomized (1:1) to a single IA injection of TA-ER (32 mg) or TAcs (40 mg) and were evaluated for 12 weeks following injection. IA injection was performed using ultrasound guidance. Safety was evaluated based on adverse events (AEs), physical exams, index hip assessments, vital signs, and laboratory evaluations. Blood samples for PK were collected at baseline (within 1 hour prior to injection), at Hours 1-6, 8, 10, and 12 postinjection, and on Days 2, 3, 5, 8, 15, 22, 29, 57, and 85. Plasma TA concentrations were assayed with a validated LC-MS/MS method. Results: Thirty patients with hip OA (TA-ER, n=15; TAcs, n=15) were enrolled/randomized and treated. All treated patients were included in safety analyses. The PK population (TA-ER, n=11; TAcs, n=14) included all patients from the safety population who received a full dose of study drug, completed PK sampling, and had sufficient plasma concentration for PK analysis. Baseline demographic characteristics and OA history were well balanced across the TA-ER and TAcs treatment groups for most parameters. Participants had a mean age of 59.1 (range: 46-73) and 90% were overweight or obese. There were slightly more males in the TAcs group (10/15) than in the TA-ER group (7/15). AE profiles were similar, and both treatments were well tolerated. AEs were reported in 4/15 (TA-ER) and 7/15 (TAcs) patients. There were no serious AEs or AEs leading to treatment discontinuation across treatment groups. No study drug related AEs occurred in the TA-ER group. Index-hip AEs occurred in 1/15 (TA-ER) and 3/15 (TAcs) patients. TA-ER plasma concentrations peaked at median 5.0 hours with a geometric mean (GM) (95% CI) Cmax of 890.4 (415.86-1906.63) pg/mL, whereas TAcs peaked at median 4.0 hours with a GM (95% CI) Cmax of 5549.4 (3085.98-9979.20) pg/mL (Table 1 and Figure 1). Conclusions: In patients with hip OA, a single 32 mg IA injection of TA-ER was generally safe and well tolerated, adding to the established body of evidence in patients with knee OA. The PK profile of TA-ER injected into the hip was consistent with that of single- and bilateral-knee injections, showing some systemic absorption and a plateau in plasma TA concentration through Hour 24, followed by gradual systemic elimination. TA-ER injection into the hip resulted in lower peak plasma levels and reduced systemic exposure relative to TAcs, a pattern similarly observed in knee OA. These findings support initiation of a Phase 3 study to assess the safety and efficacy of TA-ER in patients with hip OA pain.View Large Image Figure ViewerDownload Hi-res image Download (PPT)