Clinical Impact of Pitolisant on Excessive Daytime Sleepiness and Cataplexy in Adults With Narcolepsy: An Analysis of Randomized Placebo-Controlled Trials

Gerard J Meskill, Craig W Davis, Donna Zarycranski, Markiyan Doliba, Jean-Charles Schwartz, Jeffrey M Dayno, Gerard J Meskill, Craig W Davis, Donna Zarycranski, Markiyan Doliba, Jean-Charles Schwartz, Jeffrey M Dayno

Abstract

Background: Pitolisant, a selective histamine 3 receptor antagonist/inverse agonist, is indicated for the treatment of excessive daytime sleepiness or cataplexy in adults with narcolepsy. The efficacy and safety of pitolisant have been demonstrated in randomized placebo-controlled trials. When evaluating the results of randomized placebo-controlled trials, the clinical impact of a treatment can be assessed using effect size metrics that include Cohen's d (the standardized mean difference of an effect) and number needed to treat (NNT; number of patients that need to be treated to achieve a specific outcome for one person).

Objective: The objective of this study was to evaluate the clinical impact of pitolisant for the reduction in excessive daytime sleepiness or cataplexy in adults with narcolepsy.

Methods: This post hoc analysis incorporated data from two 7-week or 8-week randomized placebo-controlled trials (HARMONY 1, HARMONY CTP). Study medication was individually titrated, with a maximum possible pitolisant dose of 35.6 mg/day. Efficacy was assessed using the Epworth Sleepiness Scale (ESS) and weekly rate of cataplexy (HARMONY CTP only). Cohen's d was derived from the least-squares mean difference between treatment groups (pitolisant vs placebo), and NNTs were calculated from response rates. Treatment response was defined for excessive daytime sleepiness in two ways: (a) reduction in ESS score ≥ 3 or final ESS score ≤ 10 and (b) final ESS score ≤ 10. Treatment response was defined for cataplexy as a ≥ 25%, ≥ 50%, or ≥ 75% reduction in weekly rate of cataplexy.

Results: The analysis population included 61 patients in HARMONY 1 (pitolisant, n = 31; placebo, n = 30) and 105 patients in HARMONY CTP (pitolisant, n = 54; placebo, n = 51). For pitolisant vs placebo, Cohen's d effect size values were 0.61 (HARMONY 1) and 0.86 (HARMONY CTP) based on changes in ESS scores, and 0.86 (HARMONY CTP) based on changes in weekly rate of cataplexy. NNTs for pitolisant were 3-5 for the treatment of excessive daytime sleepiness and 3-4 for the treatment of cataplexy.

Conclusions: The results of this analysis demonstrate the robust efficacy of pitolisant for the reduction in both excessive daytime sleepiness and cataplexy. These large effect sizes and low NNTs provide further evidence supporting the strength of the clinical response to pitolisant in the treatment of adults with narcolepsy.

Clinical trial registration: ClinicalTrials.gov identifiers: NCT01067222 (February 2010), NCT01800045 (February 2013).

Conflict of interest statement

GJM reports serving on advisory boards and on the speakers’ bureau for Harmony Biosciences and Jazz Pharmaceuticals. CWD, DZ, MD, and JMD are employees of Harmony Biosciences. JCS is a co-founder of Bioprojet Pharma.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Effect size, assessed using Cohen’s d, for pitolisant in the treatment of excessive daytime sleepiness in HARMONY 1 and HARMONY CTP. End of treatment defined as the mean of the last two assessments (last observation carried forward). ESS Epworth Sleepiness Scale, LS least-squares
Fig. 2
Fig. 2
Effect size, assessed using Cohen’s d, for pitolisant in the treatment of cataplexy (HARMONY CTP). End of treatment defined as the stable dose period (last observation carried forward). LS least-squares, WRC weekly rate of cataplexy
Fig. 3
Fig. 3
Number needed to treat (NNT) for pitolisant in the treatment of excessive daytime sleepiness in HARMONY 1 and HARMONY CTP for treatment response defined in two ways: a Epworth Sleepiness Scale score reduction ≥ 3 or final Epworth Sleepiness Scale score ≤ 10 and b final Epworth Sleepiness Scale score ≤ 10
Fig. 4
Fig. 4
Number needed to treat (NNT) for pitolisant in the treatment of cataplexy (HARMONY CTP) for treatment response defined as a ≥ 25%, ≥ 50%, and ≥ 75% reduction in the weekly rate of cataplexy (WRC)

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Source: PubMed

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