Kissel 2014.

Methods	Randomised, double‐blind, placebo‐controlled cross‐over trial
Participants	33 ambulatory adults with SMA type III Inclusion criteria: ambulatory adults with SMA 3 aged 18–60 years diagnosis of SMA must have been documented by the homozygous deletion of both SMN1 genes on standard genetic tests for the disorder. Patients must have been able to walk 30 feet without assistance (i.e. no sticks, walkers) interest in participating and the ability to meet the study requirements women of child‐bearing age were required to be on contraception or abstain while participating in the study Exclusion criteria: co‐existing medical conditions that precluded travel, testing or study medications participation in a treatment trial for SMA in the 3 months prior to this trial, or plan to enrol in any other treatment trial during this study requirement for any mechanical respiratory support > 12 hours per day inability to meet visit requirements or co‐operate reliably with functional testing mental or legal incapacitation from giving informed consent, or inability to read and understand written material including in the consent form abnormalities in baseline blood testing beyond established values use of medications or supplements which interfere with valproic acid metabolism, or are hypothesised to have a beneficial effect in SMA animal models or human neuromuscular disorders within 3 months of study enrolment, including riluzole, creatine, butyrate derivatives, growth hormone, anabolic steroids, albuterol, anticonvulsants or other histone deacetylase inhibitors
Interventions	Oral valproic acid 10–20 mg/kg/day (doses adequate to reach serum levels 50–100 mg/dL) divided over 2–3 doses or placebo orally Cross‐over of treatment after 6 months for a consecutive period of 6 months
Outcomes	Change in maximum voluntary isometric contraction testing for separate muscles (bilateral elbow flexors, elbow extensors, knee flexors, knee extensors and grip) and total muscle score, change in muscle strength measured by hand‐held dynamometer of elbow flexors/extensors and knee flexors/extensor, change in SMAFRS, change in CMAP of ulnar nerve, change in mRNA levels, change in SMN protein levels, change in pulmonary function (FVC, FEV1, MIP), change in muscle mass measured by DEXA, change in endurance assessed through 6‐minute walk test, change in function assessed in time to climb 4 standard stairs, change in mini‐SIP, adverse events
Funding	Quote: "Funded by Families of Spinal Muscular Atrophy and also by grants from the Center for Clinical and Translational Sciences, University of Utah (UL1RR025764), and the Center for Clinical and Translational Sciences, Ohio State University (UL1RR025755)." Abbott Pharmaceuticals provided valproic acid and placebo
Conflicts of interest	Authors reported receipt of grants and funding from Families of SMA and other non‐governmental, charitable, governmental, academic and pharmaceutical company sources. 2 authors report receipt of drugs from Abbott Pharmaceuticals for clinical trials in SMA.
Notes
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Randomly assigned. Unknown method. Since the trial was part of the previous Carni‐VAL‐I trial and most procedures were the same, one could suppose there was central randomisation by telephone; however, this was not exactly stated in the article or supplementary material.
Allocation concealment (selection bias)	Unclear risk	Randomly assigned. Unknown method. Since the trial was part of the previous Carni‐VAL‐I trial and most procedures were the same, one could suppose there was central randomisation by telephone; however, this was not exactly stated in the article or supplementary material.
Blinding of participants and personnel (performance bias) All outcomes	Unclear risk	Participants, physicians and investigators were blinded. 1 investigator was not blinded. Study compliance (tablet counts and valproic acid levels) were checked by unblinded investigator.
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	Participants, physicians and investigators were blinded. 1 investigator was not blinded. Study compliance (tablet counts and valproic acid levels) were checked by unblinded investigator.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	4 participants withdrew, but were included in ITT analysis.
Selective reporting (reporting bias)	Low risk	Incomplete data reported in article, but data available on request.
Other bias	High risk	Potential bias by design: cross‐over design implies risk of carryover effect. No report on a washout period between the 2 treatment periods.