(262) - Assay sensitivity of average daily pain (ADP) and western ontario and mcmaster osteoarthritis index A-pain (WOMAC-A) in a phase 3 trial of intra-articular FX006 for osteoarthritis knee pain

Abstract

Average daily pain (ADP) and the disease-specific WOMAC-A pain index are commonly used to assess analgesic effect of osteoarthritis pain treatments. In a Phase 3 study (NCT02357459), analgesic response to FX006, a triamcinolone acetonide extended-release formulation, was evaluated vs active comparator (TA crystalline suspension; TAcs), and saline-placebo using ADP and the WOMAC-A. Patients with knee osteoarthritis (age ≥40 years; Kellgren-Lawrence grade 2/3) received a single intra-articular injection of FX006 32 mg (n = 161), TAcs 40 mg (n = 161), or saline-placebo (n = 162). ADP, the primary efficacy variable, was assessed daily (0–10 numerical rating scale [NRS]); WOMAC-A, a secondary efficacy variable, was assessed every 4 weeks (wk) with a 5-point Likert scale. At Wk12, FX006 demonstrated significant improvement over saline-placebo (P < .0001; primary endpoint) but not TAcs (P > .05) with ADP, but over both saline-placebo and TAcs with WOMAC-A (P < .05). We evaluated the assay sensitivity of the 2 instruments for discriminating treatment differences. Standardized Effect Size (SES) was reduced for ADP vs WOMAC-A (Wk4: FX006, .21 vs .81; TAcs, .19 vs .50). Lower ADP SES may have related to study eligibility specifying baseline ADP scores (≥5–≤9). WOMAC-A had no baseline pre-specification, and baseline ADP correlated poorly with normalized baseline WOMAC-A (r = .402). In this trial, ADP was sensitive for discerning differences between active treatments and saline-placebo but not between 2 active treatments (FX006 vs TAcs). WOMAC-A was more sensitive and able to discern differences between active treatments. The analysis of assay sensitivity suggests that trial and instrument characteristics, including an enriched population using baseline ADP; scale differences (ADP: 0–10 NRS; WOMAC-A: 0–4 Likert); response frequency (daily vs Q4wk); and response variability (standard deviation of ADP vs WOMAC-A scores), must be considered when evaluating the magnitude of analgesic benefit observed between active therapies and defining the primary end-point in future trials. Supported by Flexion Therapeutics.