Everolimus for the treatment of neuropsychological deficits in tuberous sclerosis complex: findings from the TRON multicentre randomised controlled trial

Background Mammalian target of rapamycin (mTOR) inhibitors are effective treatments for tumours and epilepsy in tuberous sclerosis complex (TSC). This study aimed to determine the effects of the mTOR inhibitor everolimus and a placebo on neuropsychological functioning in TSC. Methods Individuals with TSC aged 16–60 years and intelligence quotient >60 who scored ≤5th percentile in one or more of 10 memory or executive function variables from the Brain Injury Rehabilitation Trust Memory and Information Processing Battery, the Cambridge Neuropsychological Test Automated Battery and the Test of Everyday Attention were randomised 2:1 to 24 weeks everolimus or placebo and retested at baseline and 4, 12, 24 and 36 weeks. The primary outcome was the proportion of responders, defined as improvement by ≥1 SD in at least one variable. Results 38 participants were randomised, of whom 23 in the everolimus arm and 12 in the placebo arm completed all primary endpoint assessments and were included in outcome analyses. Effect sizes for individual neuropsychological variables were small to medium (Cohen’s d=0–0.465), but 20 of 23 (87%, 95% CI 67.9 to 95.5) in the everolimus arm and 9 of 12 (75%, 95% CI 46.8 to 91.1) in the placebo arm were responders. Adverse events were reported in 22/25 (88%) of those randomised to everolimus versus 8/13 (61.5%) for placebo. Discussion The large proportions of responders in both trial arms may reflect unexpectedly large familiarity, practice or placebo effects in TSC, psychometric issues with parallel test forms and how a response was defined. Our findings may inform the design of future trials of neuropsychological functioning in TSC and similar conditions. Trial registration number ISRCTN09739757 and NCT01954693 .