Summary of findings 3. Oral hydroxyurea compared to placebo for children and adults with SMA types II and III.

Oral hydroxyurea compared to placebo for children and adults with SMA types II and III
Patient or population: children and adults with SMA types II and III Setting: outpatient clinic Intervention: oral hydroxyurea 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 hydroxyurea
Change in disability score assessed with: GMFM Scale: 0–264 Follow‐up: 18 months	The mean change in disability score was 2.02	MD 1.88 lower (3.89 lower to 0.13 higher)	—	57 (1 RCT)	⊕⊕⊝⊝ Lowa,b	Higher scores on the GMFM indicate better function.
Change in disability score assessed with: MHFMS Scale: 0–40 Follow‐up: 18 months	The mean change in disability score was 0.04	MD 0.02 lower (0.12 lower to 0.07 higher)	—	38 (1 RCT)	⊕⊕⊕⊝ Moderateb	Only performed in non‐ambulatory participants.
Change in muscle strength assessed with: MMT Scale: 16–80 Follow‐up: 18 months	The mean change in muscle strength was –0.03	MD 0.55 lower (2.65 lower to 1.55 higher)	—	57 (1 RCT)	⊕⊕⊕⊝ Moderateb	—
Acquiring the ability to stand or walk	Not measured
Change in quality of life	Not measured
Change in pulmonary function assessed with: FVC (in litres) Follow‐up: 18 months	The mean change in pulmonary function was –0.22 L	MD 0.01 L higher (0.25 lower to 0.26 higher)	—	57 (1 RCT)	⊕⊕⊝⊝ Lowb,c	—
Time from beginning of treatment until death or full‐time ventilation	1 participant died in the treatment group after 5 visits (after 8 months of treatment), due to respiratory complications.		—	57 (1 RCT)	⊕⊕⊕⊝ Moderateb	Also reported as the 1 serious adverse event.
Adverse events related to treatment Follow‐up: 18 months	All participants experienced adverse events. 129 events occurred in the 20 participants in the placebo group. 224 events occurred in the 37 participants in the hydroxyurea group.		—	57 (1 RCT)	⊕⊕⊕⊝ Moderated	Adverse events were systematically, prospectively collected using a questionnaire at every study visit. Adverse events: laboratory disturbances (e.g. neutropenia, thrombocytopenia, high transaminases), respiratory complaint, gastrointestinal complaints, rash, neurological symptoms, unspecified. 1 participant died in the treatment group due to respiratory complications.d
*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; 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 one level for imprecision. CIs were very wide.
 ^b Downgraded one level for imprecision because of small sample size (inadequate for optimal information size (OIS)). Cut‐off for OIS was the calculated sample size of the trial.
 ^c Downgraded one level for indirectness, because of discrepancy in results of respiratory failure (results in text and figures appeared different).
 ^d Downgraded one level for imprecision because the small sample size is unlikely to have captured uncommon adverse events.