Finkel 2017 (ENDEAR).

Methods	Phase III, randomised, double‐blind, sham procedure‐controlled study Randomisation 2:1
Participants	121 participants with infantile‐onset SMA < 7 months (210 days) of age at time of inclusion, with genetically confirmed deletion or mutation of SMN1 and 2 copies of SMN2. Inclusion criteria Genetic documentation of 5q SMA homozygous gene deletion or mutation SMN2 copy number = 2 Onset of clinical signs and symptoms consistent with SMA at ≤ 6 months (180 days) of age Males and females ≤ 6 months (180 days) of age at screening or ≤ 8 months (240 days) of age at screening with time from symptom onset within 120 days of age at screening At study entry, adequate nutrition and hydration (with or without gastrostomy) Body weight ≥ 5th percentile for age Gestational age of 37 to 42 weeks and gestational body weight ≥ 2.5 kg Reside within approximately 9 hours ground travel distance from a participating study centre for the duration of the study. Residence > 2 hours ground travel distance from a study centre, must obtain clearance from the site investigator and the study medical monitor Able to complete all study procedures, measurements, and visits, and parent or guardian and child have adequately supportive psychosocial circumstances Exclusion criteria Hypoaxemia (O2 saturation awake < 96% or O2 saturation asleep < 96%, without ventilation support) Signs or symptoms of SMA present at birth or within the first week after birth Presence of an untreated or inadequately treated active infection requiring systemic antiviral or antimicrobial therapy at any time during the screening period History of brain or spinal cord disease that would interfere with the lumbar puncture procedures, CSF circulation, or safety assessments Presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter Clinically significant abnormalities in haematology or clinical chemistry parameters at screening Treatment with an investigational drug given for the treatment of SMA (e.g. albuterol/salbutamol, riluzole, carnitine, sodium phenylbutyrate, valproate, hydroxyurea, etc), biological agent, or device within 30 days prior to enrolment or anytime during the study Any history of gene therapy or cell transplantation
Interventions	Intrathecal injection by lumbar puncture of nusinersen scaled equivalent 12 mg dose versus sham procedure with placebo Participants received loading doses on day 1, 15, 29, and 64, followed by maintenance doses on day 183 and 302 (i.e. every 4 months) Prespecified interim analysis 78 infants: 51 nusinersen, 27 sham procedure Time‐to‐event analysis 121 infants: 80 nusinersen, 41 sham procedure Final analysis 110 participants: 73 nusinersen, 37 sham procedure
Outcomes	Primary Time to death or permanent ventilation Percentage of motor milestone responders* on the HINE Secondary % CHOP INTEND responders** Summary of time to death at given time points based on the Kaplan‐Meier product limit method Percentage of compound muscular action potential responders Percentage of participants not requiring permanent ventilation Number of participants experiencing adverse events, serious adverse events and discontinuations due to adverse events Number of participants with adverse events corresponding to changes on tests (haematology, blood chemistry, ECG, vital signs, urinalysis) *"A response on the HINE‐2 was defined as improvement in at least one category (i.e. an increase in the score for head control, rolling, sitting, crawling, standing, or walking of ≥1 point, an increase in the score for kicking of ≥ 2 points, or achievement of the maximal score for kicking) and more categories with improvement than categories with worsening (i.e. a decrease in the score for head control, rolling, sitting, crawling, standing, or walking of ≥ 1 point or a decrease in the score for kicking of ≥ 2 points." The lowest possible score for the HINE is 0 (zero), and the highest possible score is 28. **"A participant was considered a CHOP INTEND responder if the change from baseline in CHOP INTEND total score is ≥ 4 points based on assessment at the end of trial visit at day 183, day 302, or day 394 study visits." Total CHOP INTEND scores range from 0 to 64, with higher scores indicating better movement functioning.
Funding	"Supported by Biogen and Ionis Pharmaceuticals"
Conflicts of interest	"The sponsors, Biogen and Ionis Pharmaceuticals, designed the trial in collaboration with clinicians who had experience in the treatment of spinal muscular atrophy. An independent data and safety monitoring board provided trial oversight in collaboration with the sponsors. Investigators collected the data, which was analyzed by the sponsors. All the authors contributed to data interpretation and manuscript development, approved the manuscript for submission, and vouch for the accuracy and completeness of the reported data. All the principal investigators agreed to follow the protocol and protocol amendments (available with the full text of this article at NEJM.org). The first draft of the manuscript was written by the first author and the senior industry author (penultimate author); medical writing assistance was paid for by Biogen. The sponsors reviewed the manuscript and provided feedback to the authors, who had full editorial control."
Notes	Study stopped after predefined interim analysis and participants transitioned to the open‐label SHINE study (SHINE 2015)
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned by central and electronic procedure. Within each randomisation, subjects were also stratified for disease duration (participant's age at screening ‐ age at symptom onset): ≤ 12 weeks versus > 12 weeks
Allocation concealment (selection bias)	Low risk	Computer‐generated allocation. Permutated block randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study personnel who delivered the treatment were not involved in the assessments of participants. Key personnel for assessments and parents of participants were not present during the procedure.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study personnel who delivered the treatment were not involved in the assessments of participants. Key personnel for assessments and parents of participants were not present during the procedure.
Incomplete outcome data (attrition bias) All outcomes	Low risk	149 infants screened, 27 excluded following screening (reasons reported) 122 infants randomised, 1 infant (nusinersen group) withdrawn before treatment 78 infants in interim analysis (43 infants were "without at least day 183 assessment at data cut‐off date for interim analysis") 110 participants in final analysis (11 infants were "without at least day 183 assessment at data cut‐off date for final analysis") 121 infants in safety analysis Comment: adequate, stopped early for efficacy
Selective reporting (reporting bias)	Low risk	A protocol exists; changes to outcome measurement related to interim analyses were documented. Motor milestone response became the primary outcome and analysed as response rates rather than change from baseline, with rationale: "Change informed by Phase 2 data that suggest that a functional response could provide early evidence of efficacy and thus allow for an earlier interim analysis" CHOP‐Intend analysed as a responder analysis rather than change from baseline, with reason: "to assess the magnitude of response in individual subjects while accounting for the potential influence of different survival rates in treated and sham subjects" Comment: there is clear evidence (through examination of the trial protocol) that reported results correspond to all intended outcome measurements in the revised protocol.
Other bias	Unclear risk	Baseline characteristics were slightly different concerning age at time of onset and diagnosis, respiratory complications and the presence of respiratory and bulbar problems. Children in the nusinersen‐treated group had an earlier onset and were more severely affected by respiratory and bulbar problems. These baseline differences seem not to have affected the final results.