Trial Oversight

The CHERISH trial protocol (available with the full text of this article at NEJM.org) was approved by the independent review board or ethics committee at each participating site and was conducted according to the provisions of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The parents or legal guardians of eligible children provided written informed consent before participation; the children provided assent as appropriate, on the basis of institutional guidelines and the child’s age. In collaboration with the sponsors (Biogen and Ionis Pharmaceuticals), an independent data and safety monitoring board reviewed safety data at quarterly intervals, including the results of the prespecified interim analysis.

The trial was designed by employees of the sponsors in collaboration with clinicians who had experience in the treatment of SMA. Investigators collected the data, which were held and analyzed by Biogen. The authors had access to the complete data set after unblinding, participated in data analysis and interpretation and in manuscript development, and vouch for the accuracy and completeness of the data. The principal investigators vouch for the fidelity of the study to the protocol and protocol amendments. The first draft of the manuscript was written by the first author and the senior industry author from Biogen; medical-writing assistance was paid for by Biogen. The sponsors reviewed the manuscript and provided feedback to the authors, who had full editorial control and approved the final manuscript for submission.

Patients

Key eligibility criteria were genetic documentation of 5q SMA (a homozygous deletion, mutation, or compound heterozygote in SMN1) with symptom onset after 6 months of age, as well as the presence of the following features at screening: an age of 2 to 12 years, the ability to sit independently, no history of the ability to walk independently (defined as the ability to walk ≥15 ft unaided), and a Hammersmith Functional Motor Scale–Expanded (HFMSE) score of 10 to 54. HFMSE scores range from 0 to 66, with higher scores indicating better motor function.18,19 Children were not eligible for inclusion in the trial if they had a severe contracture (i.e., any contracture that could interfere with assessment of the HFMSE score, according to the investigator), evidence of severe scoliosis on radiography (i.e., spine curvature with a Cobb angle of >40 degrees), respiratory insufficiency (i.e., receipt of invasive or noninvasive ventilation for >6 hours during a 24-hour period), or a gastric tube placed to provide adequate nutrition (see the Supplementary Appendix, available at NEJM.org).

Trial Design and Treatment

The trial was conducted at 24 sites in 10 countries and was designed to have a screening period of 4 weeks, a treatment period of 9 months, and a follow-up period of 6 months. To ensure balance across the trial groups, the children were stratified according to age at screening (<6 years vs. ≥6 years) and then were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group). Randomization was performed with the use of an interactive Web response system. Nusinersen was administered or the sham procedure was performed by dedicated personnel who were aware of the group assignments; the child’s parents and key trial personnel who performed assessments were unaware of the group assignments until trial completion and were not present for the procedure. Participants were sedated to avoid any awareness of the procedure. Treatments that were considered to be necessary to manage adverse events or provide supportive care were permitted, in accordance with standard-of-care guidelines.20

Trial Procedures and End Points

Nusinersen was administered intrathecally on days 1, 29, and 85, and a maintenance dose was administered on day 274. The sham procedure was performed on the same days; it consisted of a small needle prick to the lower back, which was covered with a bandage to simulate the appearance of a lumbar puncture. Children were observed at the trial site for at least 24 hours after the first procedure was performed and for at least 6 hours after each procedure thereafter.

The primary end point was the least-squares mean change from baseline in the total HFMSE score at month 15. Trained clinical evaluators21 assessed the HFMSE score twice during the screening period and at 3, 6, 9, 12, and 15 months. The HFMSE is a 33-item measure of motor function that is specifically validated for use in patients with SMA to assess activities related to daily living.2,18,19,21,22 Each of the 33 activities is scored on a scale ranging from 0 (no response) to 2 (full response), and total HFMSE scores range from 0 to 66 points, with an increase in total score indicating an improvement in motor function.19 A change in the HFMSE score of at least 3 points is considered to be clinically meaningful.23

The trial had six secondary end points, including the percentage of children who had an increase from baseline to month 15 in the HFMSE score of at least 3 points, the percentage of children who achieved at least one new World Health Organization (WHO) motor milestone (out of a total of six milestones),24 and the change from baseline in the Revised Upper Limb Module (RULM) score (which ranges from 0 to 37, with higher scores indicating better function).25 Safety was evaluated throughout the trial (see the Supplementary Appendix).

Statistical Analysis

We estimated that a sample size of 117 children would give the trial at least 90% power to detect a mean (±SD) difference of 3±4.4 points between trial groups in the change from baseline in the HFMSE score, at a two-sided alpha level of 0.05. To control the overall type I error rate at 0.05 across the interim and final analyses for the primary and secondary end points, a hierarchical strategy with independent alpha spending functions for primary and secondary end points was applied26 (see the Supplementary Appendix). Because the P value for the primary end point was significant in the interim analysis, this end point was not formally tested for significance in the final analysis. All secondary efficacy end points were assessed in the final analysis.

The prespecified interim analysis of the primary end point was performed in the intention-to-treat population, which included patients who were randomly assigned to a group and underwent at least one assigned procedure (Fig. S1 in the Supplementary Appendix); this analysis was conducted when all the children had been enrolled for at least 6 months and at least 39 children had completed their 15-month assessment. Because some children would not have completed the 15-month assessment by the time of the interim analysis, the analysis was performed with the use of a multiple-imputation method to account for missing data on HFMSE scores obtained after baseline. Least-squares mean values are reported. In the final analysis, the least-squares mean changes in the total HFMSE score, the number of WHO motor milestones achieved per child, and the RULM score and least-squares mean differences in change between groups were based on an analysis of covariance, with group assignment as a fixed effect and with adjustment for each child’s age at screening and the value at baseline.