Unbiased analysis of knee cartilage thickness change over three years after sprifermin vs. placebo treatment - A post-hoc analysis from the phase 2B FORWARD study

Objective: Post-treatment cartilage morphometry in the FORWARD study was performed without blinding to MRI acquisition order, involving potential reader bias. Here we obtained unbiased estimates of cartilage change post-treatment, reading year (Y)2 and Y5 MRIs with blinding to time point. We studied whether post-treatment cartilage thickness change differed between sprifermin- and placebo-treated knees. Methods: FORWARD was a 5-year randomized control trial in 549 knee osteoarthritis patients. Here, Y2/Y5 images were analyzed with blinding to relative temporal order and treatment group. Cartilage change during Y2 -> Y5 was obtained in 337 participants: n = 57 treated with placebo intra-articular injections every 6 months (q6M); n = 69 with 30 mu g sprifermin every 12 months (q12 M), n = 67 with 30 mu g q6M, n = 73 with 100 mu g q12 M, and n = 71 with 100 mu g q6M between baseline (BL) and 18 M. Total femorotibial joint (TFTJ) cartilage thickness was the primary analytic focus. Results: TFTJ cartilage thickness change during Y2 -> Y5 was -26 mu m (SD64; 95%CI -32,-19) across the cohort; no statistically significant difference (p = 0.80) was observed between Sprifermin treated or placebo arms (one-way ANOVA). All groups lost cartilage, but the treatment-related difference in cartilage thickness in Sprifermin arms relative to placebo at Y2 was maintained until Y5. Annualized cartilage change in placebo participants was -8.2 mu m (SD21; 95%CI -14,-2.5) during Y2 -> Y5 vs. -5.4 mu m (SD27; 95%CI -13,1.8) during BL -> Y2; no significant difference was identified (t-test). Conclusion: FORWARD is the first study evaluating post-treatment benefits of a potential disease modifying osteoarthritis drug. Cartilage thickness gained with 100 mu g sprifermin at Y2 is maintained to Y5 and thus appears viable and sustainable. This is a post-hoc analysis of the FORWARD trial: ClinicalTrials.gov Identifier: NCT01919164.