ORIGINAL ARTICLES ON THE IMPACT OF BLINDING ON CARTILAGE ANALYSIS IN DMOAD TRIALS

We are proud that two related original papers from the FORWARD study have now been fully published. These provide valuable information for further developing intra-articular sprifermin as a disease modifying osteoarthritis drug (DMOAD).

The first on: “Is detection of disease-modifying osteoarthritis drug treatment more effective when performing cartilage morphometry without blinding to MR image acquisition order?” has been published in Osteoarthritis Cartilage 2024 Oct;32(10):1346-1351 (https://pubmed.ncbi.nlm.nih.gov/38844160/) addresses the so far unanswered question, whether in osteoarthritis we should – as often done in other disease areas – analyze (MR) images unblinded rather than blinded to the relative temporal order of imaging acquisition, when trying to detect longitudinal change and treatment effects on articular structures. It has been theorized that a potential treatment effect may be discovered with greater sensitivity when employing unblinded analysis, but the potential drawback is a bias in estimating accurate rates of change over time, if of interest. Answering this question has taken so long because there were no trials with a structural treatment effect were available to test it.  

The second one: “Unbiased analysis of kneeartilage thickness change over three years after sprifermin vs. placebo treatment – A post hoc analysis from the phase2B FORWARD study” has been published in Osteoarthr Cartil Open 2024 Aug 23;6(4):100513: https://pubmed.ncbi.nlm.nih.gov/39286575/

Thanks to the OARSI Communications Committee members Jamie Collins and Shi Cong Tao for including this article into this month’s selection of the most relevant publications in the field (Oct 3rd, OARSI News).

FORWARD was the first randomized controlled trial evaluating post treatment benefits of a potential disease modifying osteoarthritis drug (DMOAD). The total observation time of this RCT was 5years (Y), 2Y during, and 3Y post treatment https://pubmed.ncbi.nlm.nih.gov/33962962/ In this post hoc study, we re-analyzed the previously published FORWARD MRI data, but with blinding the post-treatment cartilage thickness readings ((Y2 vs. Y5) to the temporal order of acquisition (blinded & unbiased analysis). This is relevant, because reading MRIs blinded vs. unblinded to acquisition order significantly affects the observed longitudinal rate of cartilage thickness change https://pubmed.ncbi.nlm.nih.gov/38844160/

Conducting an unbiased (blinded) cartilage analysis, we here find that cartilage thickness gained with 100μg sprifermin treatment up to Y2 is maintained up to Y5 compared with placebo. From this observation we infer that the cartilage accumulated during the anabolic treatment is structurally viable, mechanically competent, and sustainable, and able to withstand the mechanical environment similar to non-Sprifermin-treated osteoarthritic cartilage. Cartilage loss has been prospectively related to joint death (knee replacement) as the final clinical endpoint of knee OA. It is hence conceivable that maintenance of (anabolic) structural benefit is pivotal in achieving translation of structural benefit (i.e. increased cartilage thickness) to symptomatic improvement.

These findings strengthen the requirement to continue DMOAD trials beyond the actual treatment period, and to assess – in blinded and unbiased manner – to what extent structural treatment effect size is maintained post-treatment and eventually translates into clinical benefit.