Effects of a Single Intra-Articular Injection of a Microsphere Formulation of Triamcinolone Acetonide on Knee Osteoarthritis Pain

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.

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 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 . Specifically, FX006 effects achieved the AAOS definition of 'clinically significant' at Weeks 4 and 8 and 'possibly clinically significant' at Week 12 for all WOMAC subscale scores 39,40 . Conversely, TAcs never achieved the AAOS definition of 'clinically significant' at any time point for any WOMAC subscale 39,40 .…”

“…Specifically, FX006 effects achieved the AAOS definition of 'clinically significant' at Weeks 4 and 8 and 'possibly clinically significant' at Week 12 for all WOMAC subscale scores 39,40 . Conversely, TAcs never achieved the AAOS definition of 'clinically significant' at any time point for any WOMAC subscale 39,40 . These results represent the first time an injectable OA therapy has surpassed the AAOS-defined threshold for 'clinical significance,' and are likely attributable to sustained TA occupancy of the corticosteroid receptor afforded by the prolonged IA residency of TA associated with FX006 relative to TAcs reported herein.…”

Efficacy and safety of intra-articular injection of tropomyosin receptor kinase A inhibitor in painful knee osteoarthritis: a randomized, double-blind and placebo-controlled study

“…Despite the fact that standard IA steroids can reliably reduce pain only for 1e3 weeks 12 , it is still the only IA injection therapeutics recommended by treatment guidelines 9,10 , and its chronic use may be associated with cartilage damage 41 . More recently, a novel, microsphere-based, extended-release steroid formulation showed a prolonged pain relief for 12 weeks following a single IA injection in study participants with painful knee OA 42 and it is currently indicated for single use. So, there is an urgent need for effective and safe alternative IA injection treatments to fill in the chronic journey of OA patients.…”

Dolor en la Artrosis de Rodilla

“…[16][17][18] Por otra parte, las causas de dolor sinovial ocurren como consecuencia de la irritación de las terminaciones nerviosas sensoriales dentro de la capa sinovial, que cubre los osteofitos y la propia inflamación del tejido sinovial por prostaglandinas, leucotrienos y citocinas, que estimulan los nociceptores, además de la distención articular y el edema. [19][20][21] El dolor de la artrosis de rodilla también es de origen muscular, a través de la inestabilidad articular típica de esos enfermos, aumenta el estrés sobre la articulación y por ende la activación de los nociceptores.…”