Summary of findings 9. Oral valproic acid plus acetyl‐L‐carnitine compared to placebo for non‐ambulatory children with SMA types II and III.

Oral valproic acid + acetyl‐L‐carnitine compared to placebo for non‐ambulatory children with SMA types II and III
Patient or population: non‐ambulatory children with SMA types II and III Setting: outpatient clinic Intervention: oral valproic acid + acetyl‐L‐carnitine Comparison: placebo
Outcomes	Anticipated absolute effects* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
	Risk with placebo	Risk with oral valproic acid + acetyl‐L‐carnitine
Change in disability score assessed with: MHFMS Scale: 0–40 Follow‐up: 6 months	The mean change in disability score was 0.18	MD 0.64 higher (1.1 lower to 2.38 higher)	—	61 (1 RCT)	⊕⊕⊕⊝ Moderatea	Higher scores on the MHFMS indicate better function.
Change in muscle strength assessed with: myometry with myometer (in kg) Follow‐up: 6 months	The mean change in muscle strength was –0.25 kg	MD 1.43 kg higher (0.69 lower to 3.56 higher)	—	16 (1 RCT)	⊕⊕⊝⊝ Lowb	Only performed in participants aged > 5 years.
Acquiring the ability to stand or walk	Not measured
Change in quality of life assessed with: PedsQL Scale: 0–100 Follow‐up: 6 months	The mean change in quality of life was 0.3	MD 2.2 lower (9.27 lower to 4.87 higher)	—	54 (1 RCT)	⊕⊝⊝⊝ Very lowa,c,d	Higher scores on the PedsQL indicate better quality of life. Only 54 participants completed PedsQL at follow‐up. Characteristics of this subset are unknown.
Change in pulmonary function assessed with: FVC (in % predicted) Follow‐up: 6 months	No numerical data available for analysis		—	24 (1 RCT)	⊕⊕⊝⊝ Lowb,e	Only performed in participants aged > 5 years.
Time from beginning of treatment until death or full‐time ventilation Follow‐up: 6 months	0 deaths or no need for full‐time ventilation		—	61 (1 RCT)	⊕⊕⊕⊝ Moderatea	—
Adverse events related to treatment Follow‐up: 12 months	581 per 1000	755 per 1000 (534 to 1000)	RR 1.32 (0.92 to 1.89)	61 (1 RCT)	⊕⊕⊕⊝ Moderatef	18/31 participants in the placebo group had ≥ 1 adverse events. 23/30 participants in the valproic acid + acetyl‐L‐carnitine group had ≥ 1 adverse events. Adverse events were systematically, prospectively collected at every study visit.
*The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; FVC: forced vital capacity; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; SMA: spinal muscular atrophy.
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

^a Downgraded for imprecision because the small sample size.
 ^b Downgraded two levels because of very small sample size, inadequately for optimal information size (OIS). Cut off for OIS was the calculated sample size of the trial.
 ^c Downgraded one level due to risk of bias. Only a subset of participants completed PedsQL at follow‐up.
 ^d Downgraded one level due to inconsistency. Only a subset of participants completed follow‐up.
 ^e Downgraded one level due to risk of bias. Data on pulmonary function was not available.
 ^f Downgraded for imprecision because the small sample size is unlikely to have captured uncommon adverse events.