Table 3.

Summary of RCTs for other treatments

Authors (year)	N	Primary cognitive outcomes	Cognition as the primary endpoint?	Main findings	Effect sizes for positive measures	AAN classification	Comments
Recombinant human erythropoietin (EPO)
Schreiber et al. (2017) [82]	50 progressive MS patients (comparator = placebo)	TMT Part B	No	No significant differences between groups after 24 weeks	NA	Class II	Met the class I criteria but downgraded because cognition was not the sole primary outcome
Ehrenreich et al. (2007) [95]	Eight chronic progressive MS patients who previously did not respond to DMTs: 5 in the high-dose group (48,000 IU) and three in the low-dose group (8000 IU)	Study-specific neuropsychological battery	Primary endpoint not specified	The high-dose group significantly improved on 7 of 13 measures after 24 weeks of treatment; the low-dose group did not improve over 12 weeks of treatment	From the table in the electronic supplementary material, at 12 weeks, treatment effect (high-dose vs. low-dose): Cohen’s d = − 0.063 to 2.012 (mean = 0.82)	Class IV	Open-label; authors did not directly compare the high-dose and low-dose groups after 12 weeks of treatment (last time point when data were available for both groups); no inclusion of baseline comparison between the groups
Simvastatin
Chan et al. (2017) [83]	140 SPMS patients not treated with DMTs (comparator = placebo)	Study-specific neuropsychological battery	No	Significant improvement after 24 months of treatment compared with placebo on one screening measure of 15 total measures	Insufficient data	Class II	MS-STAT trial; study did not specify the primary outcomes
Atorvastatin
Lanzillo et al. (2016) [84]	154 RRMS patients (comparator = placebo)	BRNB	No	No significant treatment effect after 24 months	NA	Class II	Large dropout rate; only 63% of the original randomized patients were analyzed for cognitive data
Estrogen
De Giglio et al. (2017) [85]	142 female RRMS patients (comparators: IFN β-1a with 20 μg estrogen, IFN β-1a with 40 μg estrogen, or IFN β-1a)	BRNB: proportion of people with at least two test scores that were 1 SD below the mean	No	At month 24, the high-dose estrogen group had significantly fewer patients with cognitive impairment than the IFN-only group, and lower risk of developing cognitive impairment	Odds ratio for the high-dose estrogen group’s reduced risk of cognitive impairment = 0.27a	Class II	Did not specify the primary outcomes

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, DMTs disease-modifying therapies, IFN interferon, MS multiple sclerosis, NA not available, RCT randomized controlled trial, RRMS relapsing-remitting multiple sclerosis, SD standard deviation, SPMS secondary-progressive multiple sclerosis, TMT Trail-Making Test

^aEffect sizes provided by the study authors