Summary of findings 3. Antioxidant compared to placebo for multiple sclerosis (MS).

Antioxidant compared to placebo for multiple sclerosis
Patient or population: adults with multiple sclerosis, defined by established criteria Setting: multiple sclerosis clinics in France, Iran, Spain and USA Intervention: antioxidant (including coenzyme Q10, cranberry extract, inosine, lipoic acid, vitamin A) 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 antioxidant
Relapse (assessed as number of participants experiencing relapse) Follow‐up: 3 to 12 months	Adults with MS:		RR 0.98 (0.59 to 1.64)	345 (4 RCTs)	⊕⊕⊝⊝ Lowa	There may be little to no benefit of antioxidant versus placebo on relapses.
	17 per 100	17 per 100 (10 to 28)
Change in validated disability scale (assessed with EDSS ‐ scale: 0 to 10) Follow‐up: 3 to 24 months	Adults with MS:		‐	490 (6 RCTs)	⊕⊝⊝⊝ Very lowc	There may be little to no benefit of antioxidant versus placebo on progression, although evidence is very uncertain.
	Mean EDSS 3.0b	MD 0.19 lower (0.49 lower to 0.11 higher)
Global impression of deterioration (investigator defined global impression of deterioration) Follow‐up: 9 to 24 months	Adults with RRMS exposed to DMT (interferon beta):		RR 0.99 (0.50 to 1.93)	190 (2 RCTs)	⊕⊕⊝⊝ Lowd	There may be little to no benefit of antioxidant versus control on global impression deterioration.
	15 per 100	15 per 100 (8 to 29)
MRI activity (assessed as number of participants with gadolinium‐enhancing lesions) Follow‐up: 3 to 12 months	Adults with RRMS:		RR 0.67 (0.09 to 4.88)	131 (2 RCTs)	⊕⊝⊝⊝ Very lowe	There may be little to no benefit of antioxidant versus control on gadolinium‐enhancing lesions, although evidence is very uncertain.
	16 per 100	11 per 100 (1 to 77)
SAEs (assessed as number of participants experiencing a SAE) Follow‐up: 2 weeks to 1 year	Adults with MS:		RR 0.72 (0.17 to 3.08)	222 (3 RCTs)	⊕⊕⊝⊝ Lowf	There may be little to no difference in serious adverse events between antioxidant and placebo.
	4 per 100	3 per 100 (1 to 11)
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; DMT: disease‐modifying therapy; EDSS: Expanded Disability Status Scale; MD: mean difference: MS: multiple sclerosis; RCT: randomized control trial; RR: risk ratio; RRMS: relapsing remitting multiple sclerosis; SAE: serious adverse event
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.

^aDowngraded two levels for serious risk of bias (including high risk of attrition bias in 1 study and uncertain risk of attrition bias in 2 studies) and serious imprecision (small sample size in all studies).
^bMean EDSS does not include Bitarafan 2015, as absolute final EDSS was not provided after contacting author.
^cDowngraded three levels for very serious risk of bias (including high risk of attrition bias in 3 studies and uncertain risk of attrition bias in 3 studies) and serious inconsistency in EDSS between studies.
^dDowngraded two levels for serious risk of bias (including high risk of attrition bias in 1 study) and serious imprecision (small sample size in both studies).
^eDowngraded three levels for serious risk of bias (including high risk of attrition bias in 1 study and uncertain risk of attrition bias in 1 study), serious inconsistency in number of participants experiencing gadolinium‐enhancing lesions between studies, and serious imprecision (small sample size in both studies).
^fDowngraded two levels for serious risk of bias (including high risk of attrition bias in 1 study and high risk of reporting bias in 1 study) and serious imprecision (small sample size in all studies).