BACKGROUND: Minimal clinically important differences (MCIDs) and responder definitions are important to measure to support inferences regarding changes in spinal muscular atrophy (SMA), particularly the impact of therapies and evidence to support coverage decisions in the U.S. Currently there exists no definition for MCID or responder for patients with infantile-onset SMA. OBJECTIVE: To calculate thresholds of meaningful change on the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Infant Neurological Examination (HINE) motor milestones in patients treated for infantileonset SMA. METHODS: Data from ENDEAR, a phase 3 randomized, double-blind, multicenter, sham-procedure-controlled clinical trial were analyzed. Distribution- and anchor-based methods, latent growth modeling, cumulative distribution functions, and receiver operating characteristic curve analyses were applied to determine MCIDs and responder definitions. RESULTS: Provisional MCIDs (group change) for the CHOP INTEND ranged from 3.4 to 4.0 points on the 0 to 64 CHOP INTEND scale and 0.4 to 0.7 points on the 0 to 23 HINE scale (without grasp). Responder definitions (individual change) were much larger than the MCIDs, reflecting actual change experienced by patients treated with nusinersen. For example, those in the nusinersen group showed a very large improvement in total HINE milestones score, (5.5 points, on average) versus no change (-0.4 points) for sham group. Thus, the calculated MCID values represent conservative levels of group (treatment arm) change in motor skills and motor milestones that are clinically meaningful, whereas the responder definitions reflect change at the individual patient level. The results of the responder analyses indicated that the majority of patients in the nusinersen group attained this higher threshold compared with those in the sham arm. CONCLUSIONS: This is the first study to estimate MCIDs for the CHOP INTEND and HINE in patients treated for infantile-onset SMA. These values can help clinicians evaluate how well patients are responding to treatment and provide rationale for payer decisions about coverage for treatment. Future research evaluating MCID among subgroups (by age or disease duration) of infantile-onset SMA is warranted. SPONSORSHIP: Biogen.
Minimal clinically important differences in motor function in patients with infantile-onset spinal muscular atrophy
Results from the Phase 3 ENDEAR trial
Stull, Jr., D. E., Williams, V. S., Houghton, K. F., Williams, N., & Teynor, M. (2019). Minimal clinically important differences in motor function in patients with infantile-onset spinal muscular atrophy: Results from the Phase 3 ENDEAR trial. Journal of managed care & specialty pharmacy, 25(3-a Suppl), S55. https://doi.org/10.18553/jmcp.2019.25.3-a.s1