A phase 2 trial has found memantine improved objective cognitive performance in patients with SLE, offering a potential treatment for one of the disease’s most troublesome neuropsychiatric manifestations.
Memantine has improved cognitive performance in patients with systemic lupus erythematosus and objectively confirmed neuropsychological dysfunction, according to results from the randomised ClearMEMory trial.
The 12-week, placebo-controlled phase 2 study found patients receiving the N-methyl-D-aspartate receptor antagonist had significantly greater improvement on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) than those receiving placebo.
Writing in Annals of the Rheumatic Diseases, the researchers said cognitive dysfunction represented a substantial unmet need in SLE and could persist despite immunomodulatory treatment.
“Neuropsychological complaints are among the most common manifestations of systemic lupus erythematosus (SLE), an autoimmune inflammatory disease affecting multiple organ systems and characterised by the presence of antinuclear antibodies and other autoantibodies,” they wrote.
“Up to 80% of patients with SLE have central nervous system involvement, a condition called neuropsychiatric SLE (NPSLE).
“Among patients with NPSLE, cognitive dysfunction commonly impacts quality of life. Learning, memory, and attention are the domains of cognition most frequently affected.”
Memantine is approved in the US for moderate-to-severe Alzheimer’s disease and was investigated because NMDAR dysfunction and autoantibodies targeting the receptor had been implicated in neuropsychiatric SLE.
The multicentre ClearMEMory study enrolled adults with physician-diagnosed SLE who had objective cognitive impairment, defined as an RBANS total score of 85 or lower.
Participants were randomised to memantine or placebo, with memantine titrated from 10mg daily to a maximum of 40mg daily over four weeks.
Of 131 patients who underwent baseline RBANS testing, 61 met the cognitive impairment threshold and 56 were randomised.
Related
The trial was stopped early because of low accrual, and 43 participants completed 12 weeks and were included in the primary analysis – 18 in the memantine group and 25 in the placebo group.
At 12 weeks, the median improvement in total RBANS score was eight points with memantine compared with five points with placebo. An adjusted analysis produced a mean between-group difference of 4.6 points (95% CI 0.7-8.6).
Two-thirds of memantine-treated participants achieved an improvement of at least eight RBANS points (the threshold considered clinically important) compared with 36% of placebo recipients. The resulting number needed to treat was 3.3, although its 95% confidence interval was wide at 1.7 to 53.
Immediate memory appeared to drive much of the difference, the researchers noted.
Median improvement in that domain was 18.5 points with memantine compared with seven points with placebo. Visuospatial/constructional ability and attention also favoured memantine numerically, but those differences were not statistically significant.
The apparent benefit did not extend to broader measures of lupus or psychological health. Changes in SLE disease activity, polysymptomatic distress, depression, and anxiety did not differ significantly between treatment groups.
Patients’ own assessments pointed in the same direction as the cognitive testing. However, the researchers said the difference was not statistically significant, with 61% of memantine recipients reporting an improvement in their overall health compared with 36% receiving placebo.
Tolerability could prove to be an issue at higher doses. Among all 26 patients randomised to memantine, only 42% reached a maximum tolerated dose of 40mg daily, compared with 70% of placebo recipients.
The researchers said dose limitation was largely attributable to mild or moderate adverse effects, particularly dizziness or light-headedness, but adverse event-related discontinuations did not differ between groups.
The findings contrasted with an earlier trial that failed to demonstrate significant cognitive improvement with memantine in SLE.
The researchers highlighted two important differences between the two trials – ClearMEMory required objective cognitive impairment for enrolment and used doses above the 20mg daily target of the previous study.
However, they noted that their small proof-of-concept study was terminated before reaching its planned enrolment, limiting its ability to assess secondary outcomes.
Primary outcome data were also available only for participants who completed 12 weeks of treatment, and the short follow-up meant the durability of any cognitive benefit remained unknown.
“We conclude that use of memantine up to 40mg/d is tolerated by many individuals with SLE and objective cognitive impairment, though adverse effects may require use of lower doses,” the researchers wrote.
“Treatment with memantine resulted in statistically and clinically meaningful improvement in neuropsychological function, specifically in cognition.
“This provides a proof of concept that memantine may be an effective therapeutic for cognitive manifestations of NPSLE. Larger trials are needed to confirm these results.”
