OBJECTIVES: Explore a newly defined composite measure of symptom progression for knee osteoarthritis (KOA) in a large, randomized study of a potential disease-modifying osteoarthritis drug (DMOAD). DESIGN: Using longitudinal KOA studies, a potential composite endpoint of time to symptom progression was defined as the first occurrence of worsening of Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain of ≥10 points with no improvement (≤9 point decrease) in WOMAC Function (0-100 scale). A post hoc analysis explored discrimination and association with structural outcomes in the sprifermin FORWARD trial through Years 3 and 5. All treatment arms of the intent-to-treat population were analyzed. RESULTS: Among the 549 FORWARD participants, 442 (80.5%) completed Year 3, and 378 (68.9%) completed Year 5. Sprifermin showed dose-dependent benefits in the time to symptom progression at Year 3 with hazard ratio (95% CI) for each sprifermin treatment arm vs placebo as follows: 100 μg every 6 months (Q6M), 0.51 (0.28, 0.93)
100 μg Q12M, 0.69 (0.40, 1.20)
30 μg Q6M, 0.89 (0.53, 1.50)
and 30 μg Q12M, 0.80 (0.47, 1.35). Similar findings were seen through Year 5 and for a subgroup based on modern clinical trial inclusion criteria. There were increased numbers of knee replacements in symptom progressors (n=8, 5.6%) vs non-progressors (n=7, 1.7%). CONCLUSIONS: The symptom progression endpoint discriminated between placebo and treatment responses in a post hoc analysis of a Phase 2 investigational DMOAD KOA trial. The endpoint requires validation and further exploration in DMOAD clinical trials. TRIAL NUMBER: NCT01919164.