Effects of a Single Intra-Articular Injection of a Microsphere Formulation of Triamcinolone Acetonide on Knee Osteoarthritis Pain: A Double-Blinded, Randomized, Placebo-Controlled, Multinational Study

Abstract

Background: Intra-articular corticosteroids relieve osteoarthritis pain, but rapid systemic absorption limits efficacy. FX006, a novel, microsphere-based, extended-release triamcinolone acetonide (TA) formulation, prolongs TA joint residence and reduces systemic exposure compared with standard TA crystalline suspension (TAcs). We assessed symptomatic benefits and safety of FX006 compared with saline-solution placebo and TAcs.

Methods: In this Phase-3, multicenter, double-blinded, 24-week study, adults ≥40 years of age with knee osteoarthritis (Kellgren-Lawrence grade 2 or 3) and average-daily-pain (ADP)-intensity scores of ≥5 and ≤9 (0 to 10 numeric rating scale) were centrally randomized (1:1:1) to a single intra-articular injection of FX006 (32 mg), saline-solution placebo, or TAcs (40 mg). The primary end point was change from baseline to week 12 in weekly mean ADP-intensity scores for FX006 compared with saline-solution placebo. Secondary end points were area-under-effect (AUE) curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with saline-solution placebo, AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, change in weekly mean ADP-intensity scores from baseline to week 12 for FX006 compared with TAcs, and AUE curves of the change in weekly mean ADP-intensity scores from baseline to week 24 for FX006 compared with saline-solution placebo. Exploratory end points included week-12 changes in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score Quality of Life (KOOS-QOL) subscale scores for FX006 compared with saline-solution placebo and TAcs. Adverse events were elicited at each inpatient visit.

Results: The primary end point was met. Among 484 treated patients (n = 161 for FX006, n = 162 for saline-solution placebo, and n = 161 for TAcs), FX006 provided significant week-12 improvement in ADP intensity compared with that observed for saline-solution placebo (least-squares mean change from baseline: -3.12 versus -2.14; p < 0.0001) indicating ∼50% improvement. FX006 afforded improvements over saline-solution placebo for all secondary and exploratory end points (p < 0.05). Improvements in osteoarthritis pain were not significant for FX006 compared with TAcs using the ADP-based secondary measures. Exploratory analyses of WOMAC-A, B, and C and KOOS-QOL subscales favored FX006 (p ≤ 0.05). Adverse events were generally mild, occurring at similar frequencies across treatments.

Conclusions: FX006 provided significant, clinically meaningful pain reduction compared with saline-solution placebo at week 12 (primary end point).

Level of evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Figures

Fig. 1

Figs. 1-A and 1-B FX006, an intra-articular extended-release formulation of triamcinolone acetonide (TA). Fig. 1-A Raman image of microsphere cross-sections. Within each microsphere, small crystals of TA (red) are embedded in a poly(lactic-co-glycolic acid) matrix (green). Fig. 1-B Scanning electron microscopy (SEM) image of a microsphere collected in the initial phase of release. Small channels approximately 500 nm in diameter appear on the smooth, largely intact surface of the microsphere.

Fig. 2

FX006 Phase-3 study in knee osteoarthritis: patient disposition through week 24. TAcs = triamcinolone acetonide crystalline suspension, and placebo = saline-solution placebo.

Fig. 3

Figs. 3-A through 3-F Least-squares (LS) mean change from baseline (BL) (and standard error [SE]) for the efficacy end points of weekly mean average daily pain (ADP)-intensity scores (0 to 10 on numeric rating scale) at week 12, the primary end point (n = 484) (Fig. 3-A); Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-A (pain), WOMAC-B (stiffness), and WOMAC-C (physical function) subscale scores (n = 484) (Figs. 3-B, 3-C, and 3-D); Knee Injury and Osteoarthritis Outcome Score-Quality of Life (KOOS-QOL) subscale score (n = 414) (Fig. 3-E); and rescue medication (med) use (mean number of daily rescue medication [500-mg] tablets per week; n = 484) over time in the full analysis set (Fig. 3-F). Primary and exploratory secondary end-point analyses employed an analysis of covariance with model parameters for treatment and covariates of baseline pain-intensity score and study site. TAcs = triamcinolone acetonide crystalline suspension, and placebo = saline-solution placebo.