Determine if memantine improves objective neuropsychological function in individuals with systemic lupus erythematosus (SLE).

ClearMEMory (NCT03527472) was a phase II, multi-site, randomized, double-blind, placebo-controlled trial.  Potential participants meeting pre-screening criteria were screened for objective dysfunction using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).  Individuals scoring one age-adjusted standard deviation below population norms were eligible for the study and randomized to memantine or placebo stratified by NMDA receptor antibodies.  Participants underwent a weekly dose escalation to identify the maximum tolerated dose 10-40 mg/d.  The primary outcome was change in RBANS from baseline to endpoint (week 12).  Other measures included RBANS subscales and measures of lupus disease activity, fibromyalgia, depression/anxiety, and global impression of change (PGIC).

Of 257 prescreened and 131 screened, 56 were randomized to either memantine (n=26) or placebo (n=30).  Failure to meet the eligibility threshold on the RBANS (≤85 out of 100) accounted for 96% of screen failures.  Premature discontinuations after randomization due to AE were the same (5 per group), but fewer in the memantine group tolerated maximum dose (42% vs 70%).  We observed significantly greater improvement of RBANS total score in memantine (baseline:75.3) compared to placebo (baseline:77.1) groups (+10.4 vs +4.2, p= 0.032).  Responders were higher in the memantine than placebo groups (+8: 67% vs 36%, NNT=3.3; +5 MCID: 78% vs 56%, NNT=4.6).  The RBANS immediate memory subscale was also improved (P=0.023).  More participants taking memantine were improved or much improved on PGIC.  There were no significant differences in other outcome measures.

In SLE, treatment with memantine meaningfully improved objective neuropsychological performance without significant effects on other domains.