Pitolisant Leads to Improvement in Narcolepsy Symptoms Among Children

The use of pitolisant among children aged 6 years and older can lead to clinically meaningful improvements in narcolepsy symptoms.

Treatment with pitolisant, a selective histamine H3 receptor inverse agonist, is associated with improvement in narcolepsy symptoms among children aged 6 years and older, according to the findings of a phase 3 trial published in The Lancet Neurology.

Pitolisant has been approved for the treatment of excessive daytime sleepiness in adults with narcolepsy, with or without cataplexy, by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The agent was recently approved by the EMA on January 26, 2023 to treat adolescents and children aged 6 years and older with narcolepsy, with or without cataplexy. Prior to this, only 2 agents — sodium oxybate and low-sodium oxybate — were approved by the FDA for the treatment of excessive daytime sleepiness and cataplexy in children with narcolepsy, with only sodium oxybate having been approved by the EMA.

Researchers sought to evaluate the efficacy and safety of pitolisant in children with narcolepsy with or without cataplexy. The current phase 3 multisite study (ClinicalTrials.gov Identifier: NCT02611687) was conducted in patients between ages 6 and 17 with narcolepsy, with or without cataplexy, from 11 sleep centers in 5 different countries (Finland, France, Italy, the Netherlands, and Russia).

The study involved a 4-week screening period, which included a 2-week baseline phase, followed by an 8-week, double-blind phase (pitolisant or placebo in escalating doses; up to 40 mg per day for participants who weighed more than 40 kg) and a 1-week single-blinded washout period. There were 8 face-to-face visits planned. For at least 2 weeks prior to enrollment, all study participants needed to have a Pediatric Daytime Sleepiness Scale (PDSS) score of ≥15 and not have taken any psychostimulants.

Altogether, our results on self-reported sleepiness and cataplexy via the UNS support the efficacy of pitolisant in paediatric patients with narcolepsy.

The primary efficacy outcome was a change in Ullanlinna Narcolepsy Scale (UNS). The UNS is an 11-item scale that measures the frequency and intensity of narcolepsy symptoms, with scores ranging from 0 to 44. Higher scores are indicative of more severe symptoms.

Secondary endpoints included the following:

  • Changes in excessive daytime sleepiness, as measured by the PDSS
  • UNS cataplexy subscore
  • Average number of cataplexy episodes per week
  • Changes in wakefulness according to the Maintenance of Wakefulness Test

Among 115 individuals screened, a total of 110 patients (mean age, 12.9 years; 55% boys; 82% with cataplexy) were enrolled, with 107 individuals completing the 8-week double-blind period. Participants were randomly assigned in a 2:1 ratio, with 72 treated with pitolisant and 38 with placebo. Following the withdrawal of 3 individuals, 70 remained in the pitolisant arm and 37 in the placebo arm.

In the full analysis set, the researchers found that the mean adjusted difference in total UNS score from baseline to end of the double-blind phase was –6.3 in the pitolisant treatment group vs –2.6 in the placebo treatment group (least squares mean difference, –3.7; 95% CI, –6.4 to –1.0; P =.007).

Regarding patients with treatment-emergent adverse events (TEAEs), 31% of participants in the pitolisant arm vs 34% of those in the placebo arm reported experiencing ≥1 TEAE. The most frequently occurring TEAEs, which were reported in ≥5% of participants in either group, included headache and insomnia.

Researchers noted that “Altogether, our results on self-reported sleepiness and cataplexy via the UNS support the efficacy of pitolisant in paediatric patients with narcolepsy.”

Several limitations of the analysis should be noted. Due to the short study duration, the issue of potential tolerance to pitolisant treatment was not addressed. Further, since anticataplectic agents (ie, sodium oxybate) at a stable dose were permitted for ≥4 weeks, this might have been linked to an underestimation of the effects of pitolisant on the frequency of cataplexy, sleep quality, and excessive daytime sleepiness.

“[I]n children with narcolepsy aged 6 years or older, pitolisant 5 mg to 40 mg a day showed significant efficacy in reducing excessive daytime sleepiness and cataplexy,” the researchers stated. “The safety profile was consistent with that observed in adults and adverse events were generally mild, suggesting good benefit-risk profile in children and adolescents with narcolepsy,” they concluded.

Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Dauvilliers Y, Lecendreux M, Lammers GJ, et al. Safety and efficacy of pitolisant in children aged 6 years or older with narcolepsy with or without cataplexy: a double-blind, randomised, placebo-controlled trial. Lancet Neurol. 2023;22(4):303-311. doi:10.1016/S1474-4422(23)00036-4