BACKGROUND: Histaminergic neurons are crucial to maintain wakefulness, but their 
role in cataplexy is unknown. We assessed the safety and efficacy of pitolisant, 
a histamine H3 receptor inverse agonist, for treatment of cataplexy in patients 
with narcolepsy.
METHODS: For this randomised, double-blind, placebo-controlled trial we 
recruited patients with narcolepsy from 16 sleep centres in nine countries 
(Bulgaria, Czech Republic, Hungary, Macedonia, Poland, Russia, Serbia, Turkey, 
and Ukraine). Patients were eligible if they were aged 18 years or older, 
diagnosed with narcolepsy with cataplexy according to version two of the 
International Classification of Sleep Disorders criteria, experienced at least 
three cataplexies per week, and had excessive daytime sleepiness (defined as an 
Epworth Sleepiness Scale score ≥12). We used a computer-generated sequence via 
an interactive web response system to randomly assign patients to receive either 
pitolisant or placebo once per day (1:1 ratio). Randomisation was done in blocks 
of four. Participants and investigators were masked to treatment allocation. 
Treatment lasted for 7 weeks: 3 weeks of flexible dosing decided by 
investigators according to efficacy and tolerance (5 mg, 10 mg, or 20 mg oral 
pitolisant), followed by 4 weeks of stable dosing (5 mg, 10 mg, 20 mg, or 40 
mg). The primary endpoint was the change in the average number of cataplexy 
attacks per week as recorded in patient diaries (weekly cataplexy rate [WCR]) 
between the 2 weeks of baseline and the 4 weeks of stable dosing period. 
Analysis was by intention to treat. This trial is registered with 
ClinicalTrials.gov, number NCT01800045.
FINDINGS: The trial was done between April 19, 2013, and Jan 28, 2015. We 
screened 117 patients, 106 of whom were randomly assigned to treatment (54 to 
pitolisant and 52 to placebo) and, after dropout, 54 patients from the 
pitolisant group and 51 from the placebo group were included in the 
intention-to-treat analysis. The WCR during the stable dosing period compared 
with baseline was decreased by 75% (WCRfinal=2·27; WCRbaseline=9·15; 
WCRfinal/baseline=0·25) in patients who received pitolisant and 38% 
(WCRfinal=4·52; WCRbaseline=7·31; WCRfinal/baseline=0·62) in patients who 
received placebo (rate ratio 0·512; 95% CI 0·43-0·60, p<0·0001). 
Treatment-related adverse events were significantly more common in the 
pitolisant group than in the placebo group (15 [28%] of 54 vs 6 [12%] of 51; 
p=0·048). There were no serious adverse events, but one case of severe nausea in 
the pitolisant group. The most frequent adverse events in the pitolisant group 
(headache, irritability, anxiety, and nausea) were mild or moderate except one 
case of severe nausea. No withdrawal syndrome was detected following pitolisant 
treatment; one case was detected in the placebo group.
INTERPRETATION: Pitolisant was well tolerated and efficacious in reducing 
cataplexy. If confirmed in long-term studies, pitolisant might constitute a 
useful first-line therapy for cataplexy in patients with narcolepsy, for whom 
there are currently few therapeutic options.
FUNDING: Bioprojet, France.