Summary of findings for the main comparison. Oral creatine compared to placebo for children with SMA types II and III.

Oral creatine compared to placebo for children with SMA types II and III
Patient or population: children with SMA types II and III Setting: outpatient clinic Intervention: oral creatine 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 creatine
Change in disability score assessed with: GMFM Scale: 0–264 Follow‐up: 9 months	The median change in disability score was –1	Median change 1 higher (1 lower to 2 higher)	—	40 (1 RCT)	⊕⊕⊕⊝ Moderatea	—
Change in total muscle strength (total muscle strength) assessed with: quantitative muscle testing (in pounds) Follow‐up: 9 months	The mean change in total muscle strength was 2.42 pounds	MD 1.25 pounds lower (10.1 lower to 7.6 higher)	—	22 (1 RCT)	⊕⊕⊝⊝ Lowb,c	Only participants aged ≥ 5 years.
Acquiring the ability to stand or walk	Not measured
Change in quality of life assessed with: Parent Questionnaire for the PedsQL Neuromuscular Module Scale: 0–100 Follow‐up: 9 months	The median change in quality of life was 2	Median change 7 lower (11 lower to 3 higher)	—	38 (1 RCT)	⊕⊕⊝⊝ Lowa,b	Higher scores on the PedsQL indicate better quality of life.
Change in pulmonary function assessed with: FVC (in % predicted) Follow‐up: 9 months	The mean change in pulmonary function was –0.83 % predicted	MD 0.56 % predicted higher (10.8 lower to 11.9 higher)	—	23 (1 RCT)	⊕⊕⊝⊝ Lowb,c	Only participants aged ≥ 5 years.
Time from beginning of treatment until death or full‐time ventilation	1 death occurred in the placebo group in 28 participants (36 per 1000)	0 deaths occurred in the treatment group among 27 participants (0 per 1000)	—	40 (1 RCT)	⊕⊕⊕⊝ Moderatea	—
Adverse events related to treatment	571 per 1000	480 per 1000 (291 to 800)	0.84 (0.51 to 1.4)	40 (1 RCT)	⊕⊕⊝⊝ Lowd,e	There were 43 events in 16/28 participants in placebo group and 55 events in 13/27 participants treated with creatine. Adverse events were systematically, prospectively collected at every study visit. Adverse events included mainly respiratory infections.
*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; GMFM: Gross Motor Function Measure; MD: mean difference; MHFMS: Modified Hammersmith Functional Motor Scale; MMT: Manual Muscle Testing; PedsQL: Pediatric Quality of Life Inventory; RCT: randomised controlled trial; RR: risk ratio; 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 one level for imprecision because of the small sample size.
 ^b Downgraded one level due to inconsistency. Unknown cohort representation (outcome reported for 22 of the randomised participants).
 ^c Downgraded one level because of imprecision. Small sample size, inadequately for optimal information size (OIS). Cut off for OIS was the calculated sample size of the trial.
 ^d Downgraded one level for risk of bias. No information on type of adverse events included.
 ^e Downgraded one level for imprecision because the small sample size is unlikely to have captured uncommon adverse events.