Table 1.

Summary of RCTs for disease-modifying therapies

Authors (year)	N	Primary cognitive outcomes	Cognition as the primary endpoint?	Main findings	Effect sizes for positive measures	AAN classification	Comments
IFNs β-1a and 1b
Mokhber et al. (2014) [15]	63 RRMS patients (comparators = IFNs β-1a and 1b)	BRNB	Yes	IFN β-1a (Avonex and Rebif) groups significantly improved on more measures (six and five of eight, respectively) than the IFN β-1b (Betaferon) group (one of eight) after 1 year	Compared with Betaferon, Cohen’s d = 0.04–0.25 for Avonex and 0.02–0.36 for Rebif (mean = 0.16)	Class II	More than two primary endpoints
IFN β-1a
Cohen et al. (2002) [17]	436 SPMS patients (comparator = placebo)	PASAT	No	Trend of improvement after 2 years of treatment relative to the placebo group	Cohen’s d = 0.20	Class II	IMPACT trial; met class I criteria but downgraded because cognition was not the sole primary endpoint
IFN β-1b
Montalban et al. (2009) [21]	73 primary or transitional progressive MS patients (comparator = placebo)	BRNB	No	No significant differences between groups after 2 years of treatment	NA	Class II	Unclear if allocation was concealed
Penner et al. (2012) [22]	439 originally CIS patients (comparator = placebo)	PASAT	No	RCT phase: Significant improvement after 2 years of treatment relative to the placebo group Open-label phase: At year 5 (3 years after the double-blind phase ended), the early treatment group (previously in the treatment group) had a higher score increase than the delayed treatment group (previously in the placebo group)	Cohen’s d = 0.23 at year 2 Cohen’s d = 0.32 at year 5	Class II	BENEFIT trial; secondary analysis of a previous study that did not a priori define cognitive endpoints
Glatiramer acetate
Weinstein et al. (1999) [26]	248 RRMS patients (comparator = placebo)	BRNB	No	No significant treatment effect after 24 months	NA	Class II	Secondary analysis of previous study that did not a priori define cognitive endpoints; current study did not specify primary endpoints
Fingolimod
Kappos et al. (2016) [45]	1556 RRMS patients (subset of original trials: lower-dose vs. placebo groups)—first 6 months of data (comparator = placebo)	PASAT	No	Significant improvement after 6 months of treatment relative to the placebo group	Cohen’s d = 0.13	Class II	FREEDOMS and FREEDOMS II trials; secondary analysis of a previous study that did not a priori define cognitive endpoints
Comi et al. (2017) [46]	157 RRMS patients with ≥ 1 test of BRNB of scores <10th percentile (comparator = IFN β-1b)	BRNB and D-KEFS Sorting Test	Primary endpoint not specified	No significant differences between groups after 18 months of treatment	NA	Class III	Open-label, rater-blinded GOLDEN trial; authors noted an imbalance in baseline characteristics and dropout pattern may have favored the comparator group
Daclizumab β
Benedict et al. (2018) [47]	1841 RRMS patients (comparator = IFN β-1a)	SDMT	No	Significant improvement but negligible treatment effect relative to the IFN group after 96 and 144 weeks	Cohen’s d = 0.11 at week 96; week 144 data were omitted because they were only 33% of the originally randomized sample	Class II	DECIDE trial; secondary analysis of RCT that did not a priori define cognitive endpoints; drug discontinued by drug companies due to reports of encephalitis in Europe

Effect sizes were only calculated for studies with positive findings; some effect sizes could not be calculated due to insufficient data provided in the papers. The total number of cognitive measures was determined by what the authors presented in their Results sections; multiple scores from a cognitive test count as multiple measures (e.g. immediate recall, delayed recall, and recognition of a memory test)

AAN American Academy of Neurology, BRNB Brief Repeatable Neuropsychological Battery, CIS clinically isolated syndrome, D-KEFS Delis–Kaplan Executive Function System, IFN interferon, MS multiple sclerosis, NA not available, PASAT Paced Auditory Serial Addition Test, RCT randomized controlled trial, RRMS relapsing-remitting multiple sclerosis, SDMT Symbol Digit Modalities Test, SPMS secondary-progressive multiple sclerosis