Observational study of spinal muscular atrophy type I and implications for clinical trials

Abstract

Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).

Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.

Results: Thirty-four of 54 eligible subjects with SMA-I (63%) enrolled and 50% of these completed at least 12 months of follow-up. The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months (interquartile range 8.1-22.0 months). Requirement for nutritional support preceded that for ventilation support. The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age (p=0.58). Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies. Baseline electrophysiologic measures indicated substantial motor neuron loss. By comparison, subjects with SMA-II who lost sitting ability (n=10) had higher motor function, motor unit number estimate and compound motor action potential, longer survival, and later age when feeding or ventilation support was required. The mean rate of decline in The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year (95% confidence interval 0.21-2.33, p=0.02).

Conclusions: Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint. These outcome data can be used for clinical trial design.

Figure 1. Time-to-event curves for SMA-I

Kaplan-Meier curves for SMA-I. (A) Probability of survival with advancing age by SMA-I subtype (type IB, n = 18; type IC, n = 16). (B) Probability of not reaching the combined endpoint of death or the need for a minimum of 16 hours/day of noninvasive ventilation support for a minimum of 14 continuous days, in the absence of an acute reversible illness or perioperatively, with advancing age by SMA-I subtype. (C) Probability of not reaching the combined endpoint with advancing age by SMN2 copy number (2 copies, n = 23; 3 copies, n = 9). SMA-I = spinal muscular atrophy type I.

Figure 2. CHOP INTEND motor function in SMA-I: Longitudinal data

The CHOP INTEND longitudinal data are represented for each subject with 2 or more assessments. Those subjects enrolled within 3 months of diagnosis (“recent”) are shown with a blue line and those enrolled more than 3 months after diagnosis (“chronic”) are shown with a red line. CHOP INTEND = The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders; SMA-I = spinal muscular atrophy type I.