Introduction
Excessive daytime sleepiness (EDS) and cataplexy (intermittent partial or complete muscle paralysis) are the most frequently recognized symptoms of narcolepsy, with hallucinations upon falling asleep or awakening, sleep paralysis, and disrupted nighttime sleep completing the pentad of symptoms associated with this disease [
1,
2]. While onset of narcolepsy generally occurs in childhood or early adulthood [
3,
4], it has consistently been reported that there can be a delay of 10–15 years between symptom onset and confirmed diagnosis, with the lack of recognition by physicians the primary reason for this delay [
5]. This failure to recognize the signs and symptoms of narcolepsy not only contributes to reported misdiagnosis [
6,
7], but also delays appropriate treatment, thereby prolonging the adverse psychosocial impact of the disease [
5].
In addition to the disease-related physical impairment and the recognized economic burden of narcolepsy resulting from the direct costs of higher healthcare resource utilization and indirect costs associated with unemployment and lost productivity [
8‐
10], there is a substantial humanistic burden. Patients with narcolepsy not only tend to have a greater prevalence of comorbidities and higher odds of mortality than those without narcolepsy [
11‐
13], but health-related quality of life (HRQoL) has been shown to be reduced across countries and cultures [
14‐
23]. In particular, studies using the 36-item Short Form Health Status Survey (SF-36) to assess HRQoL in patients with narcolepsy have reported lower scores in most SF-36 domains compared to the general population as well as to those experiencing obstructive sleep apnea, Parkinson’s disease, and epilepsy [
14‐
16,
18‐
24].
Because there is no cure for narcolepsy, treatment occurs over the lifetime of the patient, with EDS and cataplexy the main targets of most current therapies [
25,
26]. Sodium oxybate (SXB) is the sodium salt of gamma hydroxybutyrate, an endogenous metabolite of gamma-aminobutyric acid; SXB is approved for the treatment of cataplexy and EDS in narcolepsy [
27]. Randomized controlled trials have demonstrated the efficacy of SXB for reducing EDS and the frequency of cataplexy attacks in patients with narcolepsy [
28‐
30]. Improvements in functional outcomes, assessed using the Functional Outcomes of Sleep Questionnaire (FOSQ) [
31], have also been suggested [
32]. However, no studies to date have reported on the effects of SXB on HRQoL using a standard assessment measure such as the SF-36.
Objective
The purpose of this analysis is to provide data on the effect of SXB on HRQoL collected during an 8-week randomized controlled trial.
Methods
Design and Patients
This analysis of HRQoL in patients with narcolepsy treated with SXB is based on data obtained during an 8-week phase 3 randomized placebo-controlled trial. Details of the study design and methods were published previously [
29]. Patients ≥16 years of age with a diagnosis of narcolepsy with cataplexy, based on clinical history, an overnight polysomnogram, and multiple sleep latency test, were randomized to 8 weeks of treatment with placebo or with SXB in doses of 4.5, 6, or 9 g, administered as two equally divided nightly doses; the second dose was taken 2.5–4 h after the first dose. For patients receiving 6 and 9-g doses of SXB, the doses were titrated in weekly 1.5-g increments. The use of stable doses of stimulants for the treatment of EDS was allowed.
Medical Outcomes Survey 36-Item Short Form
To assess changes in HRQoL associated with treatment, the Medical Outcomes Survey SF-36 [
33,
34] was administered during the study as an exploratory efficacy endpoint. The SF-36 is a widely used generic instrument for evaluating HRQoL, consisting of eight subscales evaluating specific health status domains and two summary scales, a Physical Component Summary (PCS) and a Mental Component Summary (MCS). The domain subscales include Physical Functioning (ability to perform physical activity); Role–Physical, which assesses the impact of physical function on daily roles (work, daily activities); Bodily Pain (presence of pain and its impact on limiting activities); General Health (GH; overall health status); Vitality (energy and tiredness); Social Functioning (ability to perform social activities); Role–Emotional (impact of emotional problems on participation in life activities such as work and other daily activities); and Mental Health (general mood, i.e., anxiety, depression). The PCS is derived from positively weighting the domains of Physical Functioning, Role–Physical, Bodily Pain, and GH, while the MCS weights the domains of Vitality, Social Functioning, Role–Emotional, and Mental Health. Scores on the SF-36 range from 0 to 100, with higher scores indicating better health status. Normative values for the US population have been published [
35], and a change of five points is generally accepted as the minimum clinically important difference (MCID) [
36].
Statistical Analyses
The SF-36 was administered at baseline and at weeks 4 and 8, with efficacy measured as change from baseline at the end of double-blind treatment (week 8) using a last-observation-carried-forward analysis on the intent-to-treat population. Scores were transformed to norm-based scoring using 1998 SF-36 US population norms [
37].
Within-group change from baseline was evaluated using a paired
t test, and differences in the change from baseline between groups were evaluated using an analysis of variance model with adjustment for treatment and site. Pairwise comparisons versus placebo were performed if the overall
p was less than 0.05. Effect sizes (ES) versus placebo were estimated based on the difference between the mean change from baseline in the active treatment group and the mean change in the placebo group divided by the pooled standard deviation (SD) of the active and placebo treatment groups (Cohen’s
d); ES of 0.20 are generally considered small, 0.50 are moderate, and 0.80 are large [
38].
Statistical analyses were performed using SAS version 9 software (SAS Institute, Inc., Cary, NC, USA).
Compliance with Ethics Guidelines
All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for inclusion in the study (ClinicalTrials.gov identifier NCT00049803).
Conclusions
SXB appears to improve QoL measures in a dose-dependent manner, with the largest impact at the 9-g/night dose, which had a significant effect on the Vitality, GH, and Physical and Social Functioning domains of the SF-36. Studies of longer duration may be needed to more fully evaluate the effects of SXB on HRQoL in patients with narcolepsy, and the results reported here also highlight the need for a narcolepsy-specific measure of HRQoL.
Acknowledgments
Funding support for this research was provided by Orphan Medical, Inc., and Jazz Pharmaceuticals. Sponsorship for article processing charges was provided by Jazz Pharmaceuticals. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published. Under the direction of the authors, E. Jay Bienen, Ph.D., of The Curry Rockefeller Group, LLC (CRG), provided editorial assistance for this publication. Editorial assistance in formatting, proofreading, copy editing, and fact checking was also provided by CRG. Jazz Pharmaceuticals provided funding to CRG for all editorial support of this manuscript. Each author has certified that they have made substantial contributions to all aspects of this manuscript, including conception and planning, analysis and interpretation of data, and drafting and critical revision. All authors have read and approved the submitted version. As corresponding author, Richard Bogan will act as the overall guarantor.
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