Mercuri 2018 (CHERISH).

Methods	Randomised sham‐procedure controlled, double‐blind trial. Randomisation 2:1 (nusinersen:sham procedure)
Participants	126 participants with SMA types II, aged 2–12 years Inclusion criteria: informed consent from parent or guardian and, if required, from participant medically diagnosed with SMA onset of clinical signs and symptoms consistent with SMA at > 6 months of age able to sit independently, but has never had the ability to walk independently HFMSE ≥ 10 and ≤ 54 at screening able to complete all study procedures, measurements and visits and parent or guardian and participant has adequately supportive psychosocial circumstances, in the opinion of the Investigator estimated life expectancy > 2 years from screening, in the opinion of the Investigator meets age‐appropriate institutional criteria for use of anaesthesia and sedation, if use is planned for study procedures satisfies study contraceptive requirements, if of reproductive age Exclusion criteria: respiratory insufficiency, defined by the need for invasive or non‐invasive ventilation for > 6 hours during a 24‐hour period, at screening requires a gastric feeding tube, via which the majority of feeds are given severe contractures or severe scoliosis evident on x‐ray hospitalisation for surgery (i.e. scoliosis surgery, other surgery), pulmonary event or nutritional support within 2 months of screening or planned during the duration of the study 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, including tumours, or abnormalities by magnetic resonance imaging or computerised tomography that would interfere with the lumbar puncture procedures or CSF circulation presence of an implanted shunt for the drainage of CSF or an implanted central nervous system catheter history of bacterial meningitis dosing with nusinersen in any previous clinical study prior injury or surgical procedure which impacts the participant's ability to perform any of the outcome measure testing required in the protocol and from which the participant has not fully recovered or achieved a stable baseline clinically significant abnormalities in haematology or clinical chemistry parameters or ECG at screening treatment with another investigational drug (e.g. oral albuterol or salbutamol, riluzole, carnitine, creatine, sodium phenylbutyrate, etc.), biological agent, or device within 1 month of screening or 5 half‐lives of study agent, whichever is longer. Treatment with valproate or hydroxyurea within 3 months of screening. Any history of gene therapy, antisense oligonucleotide therapy, or cell transplantation ongoing medical condition that would interfere with the study. Examples are medical disability that would interfere with the assessment of safety or compromise the ability of the participant to undergo study procedures
Interventions	Intrathecal injection with nusinersen 12 mg or sham procedure
Outcomes	Change in HFMSE, achievement of new motor milestones, change in Upper Limb Module Test, vital signs, weight changes, laboratory changes, ECG
Funding	Ionis Pharmaceuticals and Biogen Inc
Conflicts of interest	Investigators collected data, which were held and analysed by Biogen. The first manuscript was written by the authors and the senior industry author of Biogen, medical‐writing assistance was paid for by Biogen.
Notes	As of December 2016 the study was stopped and participants were transitioned to the open‐label SHINE study.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomly assigned by central and electronic procedure.
Allocation concealment (selection bias)	Low risk	Computer‐generated allocation.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study personnel who deliver the treatment were not involved in the assessments of participants. Key personnel for assessments and parents of participants were not present during procedure.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Study personnel who deliver the treatment were not involved in the assessments of participants. Key personnel for assessments and parents of participants were not present during procedure.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Trial stopped early for benefit on the basis of interim analyses. ITT and efficacy outcomes reported. Data imputed for ITT analyses. Supplementary data report sensitivity analyses. Quote: "Sensitivity analyses of the primary end point using final data were consistent with the results of the final analysis."
Selective reporting (reporting bias)	Low risk	Protocol available. There was clear evidence that reported results corresponded to all intended outcome measurements. Extensive data reporting in article and supplementary material.
Other bias	Unclear risk	Baseline differences with more severely affected children in the nusinersen‐treated group.