Lamotrigine for cognitive deficits associated with neurofibromatosis type 1: A phase II randomized placebo-controlled trial.

The trial stopped at 31 participants, fewer than the 46 the power calculation called the bare minimum and about half the 60 originally planned, so it may have been too small to detect a real effect. The authors argue the differences between groups were so small that more participants would not have changed the conclusion. Only one centre recruited. The intended sites in Belgium and Spain never opened, because of COVID-19 restrictions and logistical problems that followed. The placebo group had more adolescents in special education and more with a diagnosis of autism spectrum disorder than the lamotrigine group, although the authors argue this would if anything have made a treatment effect easier to see. Eleven of the 30 analysed participants were taking methylphenidate, which can improve attention. The authors acknowledge this may have lifted scores in both groups and partly masked any effect of lamotrigine. Participants were 12 to 17 years old. Cognition is still developing at that age, so an effect in younger children cannot be ruled out; the authors give ethical and practical reasons for choosing this age group. Treatment lasted 26 weeks, short compared with other trials that used IQ as an outcome. The authors say a longer course was not justified given the risk of side effects. The analysis included everyone who had a 26-week outcome measure rather than everyone who was randomised. One participant on placebo stopped medication because of side effects and did not complete the 26-week visit, so 30 of the 31 randomised adolescents were analysed. The sustained attention result was one of seven secondary outcomes and the analysis did not adjust for multiple testing.

The trial was paid for by Dutch non-profit funders (Let's Beat NF, ZonMw, and the Sophia Children's Hospital Fund), and Teva Pharmaceuticals supplied the study drug. Authors declared advisory board roles with Jazz Pharmaceuticals and Alexion, consulting fees from Alexion and Springworks Therapeutics, and local investigator funding from Roche and Alexion for research they state is unrelated to this topic.

Do not read the trend on the sustained attention task, p = 0.07, as evidence that lamotrigine sharpens attention. It was one of seven secondary outcomes, the analysis was not corrected for multiple testing, and the authors themselves said they would not call it a true treatment effect.