Brief Report: A Phase IIb Trial of a Novel Extended‐Release Microsphere Formulation of Triamcinolone Acetonide for Intraarticular Injection in Knee Osteoarthritis

Abstract

Objective FX006 is a novel, microsphere‐based, extended‐release formulation of triamcinolone acetonide for intraarticular (IA) injection designed to maintain treatment concentration in the joint and provide prolonged analgesic benefits in patients with osteoarthritis (OA) of the knee. This study was undertaken to compare the analgesic benefits of 2 FX006 doses with saline placebo injection.MethodsIn this phase IIb study, participants with knee OA (Kellgren/Lawrence grade 2–3) and average daily pain (ADP) intensity ≥5 to ≤9 (on a 0–10 Numerical Rating Scale) were randomized (1:1:1) to receive single IA injections of FX006 32 mg (n = 104) or 16 mg (n = 102) or saline placebo (n = 100). The primary end point was the least squares mean (LSM) change from baseline to week 12 in weekly mean ADP intensity scores for FX006 32 mg versus saline placebo.ResultsThe primary end point was not met (LSM change at week 12 −3.1 with FX006 32 mg versus −2.5 with saline placebo; LSM difference [95% confidence interval] −0.58 [−1.22, 0.07]) (P = 0.08). However, improvements in ADP intensity were significantly greater with FX006 32 mg than saline placebo at weeks 1–11 and week 13. Improvements in ADP intensity were significantly greater with FX006 16 mg versus saline placebo at weeks 1–9. A dose‐response effect in duration of maximal analgesic effect was evident (13 weeks with 32 mg versus 9 weeks with 16 mg), with FX006 32 mg providing increased therapeutic benefit relative to FX006 16 mg. All treatments were well tolerated.ConclusionAlthough the primary end point was not met, our findings indicate a prolonged reduction in symptoms with FX006 with an evident dose response and a safety profile similar to saline placebo.

Synovial and systemic pharmacokinetics (PK) of triamcinolone acetonide (TA) following intra-articular (IA) injection of an extended-release microsphere-based formulation (FX006) or standard crystalline suspension in patients with knee osteoarthritis (OA)

“…The differences in SF TA concentrations observed in this studydGMs of 3590.0 and 290.6 pg/mL at Week 6 and Week 12, respectively, for FX006 and 7.7 pg/mL at Week 6 for TAcsdlikely constitute the basis for pharmacologic differentiation and provide a rational hypothesis for between-treatment efficacy differences observed in Phase 2/3 trials 37,39,47 39 . These effects are clinically important; post-hoc analyses demonstrated that the improvements in all WOMAC subscale scores afforded by FX006 exceeded the minimum clinically important improvement (MCII) thresholds utilized by the American Academy of Orthopedic Surgeons (AAOS) 39e42 .…”

“…These findings are consistent with those observed in larger Phase 2/3 clinical trials of FX006, in which a single IA FX006 injection demonstrated systemic and local safety profiles generally similar to placebo and TAcs, and no post-injection flares were observed. 37,39,47 Despite prolonged TA joint residence associated with microsphere delivery, index-knee related AEs were limited to two FX006treated patients (Grade-1 arthralgia, Grade-2 patellofemoral pain syndrome). This lack of adverse local effect is not unexpected given that the FX006 PLGA matrix degrades to oligomeric poly-acid units, then to lactic and glycolic acids 48 , followed by elimination as carbon dioxide and water.…”

Triamcinolone Acetonide Extended-Release: A Review in Osteoarthritis Pain of the Knee

“…The therapeutic efficacy of IA triamcinolone acetonide ER in patients with OA pain of the knee has been evaluated in three randomized, double-blind, multicentre studies, of which two were dose-ranging phase II ( n = 228) [ 26 ] or IIb ( n = 306) [ 27 ] trials and the other a phase III trial ( n = 484) [ 28 ]. This section focuses on the trials [ 27 , 28 ] that evaluated the dose (32 mg) and injection volume (5 mL) of triamcinolone acetonide ER that was approved in the USA for the management of OA pain of the knee [ 11 ].…”

The analgesic efficacy and safety of peri-articular injection versus intra-articular injection in one-stage bilateral total knee arthroplasty: a randomized controlled trial

“…It is well-known that exogenous IAI of hyaluronate is valid as a treatment for the symptoms of knee osteoarthritis [15]. IAI of the novel, microsphere-based, extended-release formation of triamcinolone acetonide leads to a prolonged reduction in symptoms of osteoarthritis [16]. Deducted from studies above, IAI of analgesic cocktail may also play a role in pain relief after TKA.…”