Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial

25  Download (0)

Full text

(1)

Archive University of Zurich Main Library Strickhofstrasse 39 CH-8057 Zurich www.zora.uzh.ch Year: 2018

Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial

Büchele, Fabian ; Hackius, Marc ; Schreglmann, Sebastian R ; Omlor, Wolfgang ; Werth, Esther ; Maric, Angelina ; Imbach, Lukas L ; Hägele-Link, Stefan ; Waldvogel, Daniel ; Baumann, Christian R

DOI: https://doi.org/10.1001/jamaneurol.2017.3171

Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-141748

Journal Article Accepted Version

Originally published at:

Büchele, Fabian; Hackius, Marc; Schreglmann, Sebastian R; Omlor, Wolfgang; Werth, Esther; Maric, An-gelina; Imbach, Lukas L; Hägele-Link, Stefan; Waldvogel, Daniel; Baumann, Christian R (2018). Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial. JAMA Neurology, 75(1):114.

(2)

Important Instructions for Approving Your Edited Manuscript

 This PDF document contains your edited manuscript (text and tables).  Please respond to my queries within 24 hours.

 Do not generate a new electronic version of your manuscript.

 If you have Adobe Reader (http://www.adobe.com/products/reader.html) or Adobe Acrobat, you may indicate your changes in the file, but you must use Adobe’s Comment tool. Do not make any changes directly in the file using strikethroughs and underscores. Upload the annotated PDF file to The JAMA Network production system using the encrypted link sent to you in the email.

 If you are unable to use Adobe, indicate clearly all changes by page number and line number. Please include the entire sentence, with your changes clearly marked (in bold, italics, or underline).

 Please verify that the email address we are displaying is accurate and is the one you wish to use for correspondence.

 Please answer all questions and review the manuscript thoroughly.

 If your manuscript contains tables, they will be more readable when they have been formatted; review them for content only, not for bad word breaks or the shapes of the cells.

 If your manuscript has figures, they are being formatted and will be sent to you separately and/or included in the proof that we will send to you for final review.

 The information in your manuscript is confidential. You should not distribute copies of the edited manuscript to anyone, except coauthors, without our approval. The news media should not release any information about your article until the date of publication. Please contact me if you need to confirm your publication date.

 If you have questions or need help coordinating news releases or media attention, contact JAMA Network Media Relations at mediarelations@jamanetwork.org or 312-464-5262.

 Please verify and confirm that all Conflict of Interest disclosure information for you and all coauthors is accurate, complete, up-to-date, and reported accurately and in its entirety.

 Our policy requires that all authors disclose all potential conflicts of interest, including specific financial interests and relationships and affiliations (other than those listed in the author affiliations) as listed are disclosed. Definitions and terms of such disclosures can be found at the journal’s Instructions for Authors. Authors should err on the side of full disclosure and should contact the editorial office if they have questions or concerns.

 Please be sure that any funding/support information is complete and accurate, including the role of the sponsor.

 You may order author reprints or eprints online at www.ama-authorreprints.com. I hope you will be pleased with our editing and the published version of your manuscript. Sincerely yours,

Donna J. Thordsen Copy Editor thoredit@gmail.com

(3)

1

Sodium Oxybate for Excessive Daytime

2

Sleepiness and Sleep Disturbance in Parkinson

3

Disease

4

A Randomized Clinical Trial 5 Fabian Büchele, MD1 6 Marc Hackius, MD1 7 Sebastian R. Schreglmann, MD1 8 Wolfgang Omlor, MD1 9 Esther Werth, PhD1 10 Angelina Maric, PhD1 11 Lukas L. Imbach, MD1 12 Stefan Hägele-Link, MD2 13 Daniel Waldvogel, MD1 14 Christian R. Baumann, MD1 15 1

Department of Neurology, University Hospital Zurich, Frauenklinikstrasse

16

26, 8091 Zürich, Switzerland 17

(4)

2

Department of Neurology, Kantonsspital St Gallen, Rorschacher Strasse 95,

1

9007 St Gallen, Switzerland 2

Question: Is sodium oxybate superior to placebo in improving 3

electrophysiological measures of daytime sleepiness and sleep disturbance in 4

Parkinson disease? 5

Findings: In this double-blind, placebo-controlled crossover trial with

6

including 12 patients with Parkinson disease, sodium oxybate, as compared 7

to with placebo, significantly improved sleepiness and disturbed nighttime 8

sleep both subjectively and objectively. However, it induced de novo 9

obstructive sleep apnea in two 2 patients and parasomnia in one1 patient. 10

Meaning: The study provides class I evidence for the efficacy of sodium 11

oxybate for sleep-wake disturbances in patients with Parkinson 12

patientsdisease, but stringent monitoring is necessary and larger follow-up 13

trials with longer treatment durations are warranted for validation. 14

Importance: Sleep-wake disorders are a common and debilitating non

-15

motor manifestation of Parkinson disease (PD), but treatment options are 16

scarce. 17

Objective: To determine whether nocturnal administration of

«DT1:

18

sodium oxybate (SO

»

), a first-line treatment in narcolepsy, is effective and 19

Comment [DT1]: Drug

names are not abbreviated in JAMA Network journals; revised from here with no further tracking

(5)

safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in 1

patients with PD. 2

Design, Setting, and Participants: Randomized, double-blind, placebo-3

controlled, crossover phase 2a study carried out between January 9, 2015, 4

and February 24, 2017. In a Monocenter single-center study in the sleep 5

laboratory at the University Hospital Zurich, Zurich, Switzerland, we

6

screened 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] 7

score >10) were screened in the sleep laboratory. 5 Five patients were 8

excluded due to the polysomnographic diagnosis of sleep apnea and 1 9

patient withdrew consent. Thus, 12 patients were randomized to a treatment 10

sequence (sodium oxybate followed by /placebo or placebo followed by 11

/sodium oxybate, ratio 1:1) and, after dropout of one 1 patient due to an 12

unrelated adverse event during the washout period, 11 patients completed 13

the study. Two patients developed obstructive sleep apnea under during 14

sodium oxybate treatment (one 1 was the dropout) and were excluded from 15

the per-protocol analysis (n = 10) but included in the intention-to-treat 16

analysis (n = 12). 17

Interventions: Nocturnal sodium oxybate and placebo taken at bedtime and 18

2.5 to -4.0 hours later with an individually titrated dose between 3.0 and -9.0 19

(6)

g/night for a duration of 6 weeks with a 2- to 4-week washout period 1

interposed. 2

Main Outcomes and Measures: Primary outcome measure was change of 3

objective EDS score as electrophysiologically measured by mean sleep 4

latency in the Multiple Sleep Latency Test. Secondary outcome measures 5

included change of subjective EDS (Epworth Sleepiness ScaleESS), sleep 6

quality (Parkinson Disease Sleep Scale–2) and objective parameters

7

variables of nighttime sleep (polysomnography). 8

Results: Among 12 patients in the intention-to-treat population («DT2: 10 9

malesmen, 2 femaleswomen

»

; mean [SD] age, 62 [11.1] years; , mean

10

disease duration [SD]disease duration, 8.4 [4.6] years), sodium oxybate 11

substantially improved EDS as measured objectively (mean sleep latency, 12

+2.9minutes; 95% confidence interval [CI, 2.1 to 3.8minutes; P = .002) and 13

subjectively (ESS score, −4.2points Epworth score; 95% CI, −5.3 to −3.0 14

points; P = .001). Thereby, 8 (67%)of patients exhibited an 15

electrophysiologically-defined positive treatment response. Moreover, 16

sodium oxybate significantly enhanced subjective sleep quality and 17

objectively measured slow-wave sleep duration (+72.7minutes; 95% CI, 18

55.7 to 89.7minutes; P < .001). Differences were more pronounced in the 19

(7)

per-protocol analysis. Sodium oxybate was generally well tolerated under 1

dose adjustments (no treatment-related dropouts), but induced de novo 2

obstructive sleep apnea in 2 patients and parasomnia in one1 patient, as 3

detected by polysomnography, all of whom did not benefit from sodium 4

oxybate treatment. 5

Conclusions and Relevance: This study provides class I evidence for the 6

efficacy of SOsodium oxybate in treating EDS and nocturnal sleep 7

disturbance in patients with PD. Special monitoring with follow-up 8

polysomnography is necessary to rule out treatment-related complications 9

and larger follow-up trials with longer treatment durations are warranted for 10

validation. 11

Trial Registration: clinicaltrials.gov Identifier: NCT02111122. 12

Introduction 13

Excessive daytime sleepiness (EDS) and disturbed nighttime sleep are 14

common and debilitating nonmotor symptoms of Parkinson disease (PD),1,2 15

but treatment options are scarce.3 Therefore, a previous open-label trial has 16

introduced sodium oxybate, a potent central nervous system depressor4 and 17

first-line treatment in narcolepsy type 1,5 for sleep-wake disorders in patients 18

with PD patients.6While Although it demonstrateding improvement, the 19

(8)

open-label study’s significance is limited given the lack of a control group 1

and objective outcome measures for sleepiness. To close this gap, the 2

present trial examinedsthe efficacy and safety of sodium oxybate for EDS 3

and disturbed nighttime sleep in a double-blind, placebo-controlled 4

electrophysiological study. 5

Methods 6

This crossover, phase 2a trial was carried out at the University

7

Hospital Zurich between 01/09/2015, and 02/24/2017. It was approved by

8

the local ethics committee/Swissmedic and registered with clinicaltrials.gov

9

(NCT02111122). All participants gave written informed consent.

10

We enrolled patients with PD patients (Hoehn-Yahr stage II/III) with 11

EDS (Epworth Sleepiness Scale,[ESS] >10 points) and stable with 12

dopaminergic medication. Exclusion criteria included:use of sleep-inducing 13

substances,; sleep apnea, (SA); significant cognitive impairment («DT3:

14

MoCA

»<22

points), moderate to severe depression («DT4: HADS 15

»questionnaire), and significant concomitant diseases.

16

This crossover, phase 2a trial was carried out at University Hospital 17

Zurich, Zurich, Switzerland, between January 9, 2015, and February 24, 18

Comment [DT3]: expand

abbreviation and provide reference

Comment [DT4]: expand

abbreviation and provide reference

(9)

2017. It was approved by the

«DT5:

local ethics committee/Swissmedic

»

; 1

the protocol is available in Supplement 1. All participants gave written 2

informed consent.

«DT6:

X

»

3

Eligible patients were screened with baseline polysomnography to 4

rule out sleep apnea(apnea-hypopnea index (AHI)>«DT7: 15/h») and

5

subsequently randomized to one 1 of two 2 treatment sequences (sodium 6

oxybate followed by /placebo or placebo followed by /sodium oxybate, 1:1 7

ratio). Both medications (provided by

«DT8:

UCB, Switzerland

»

) were 8

taken daily as drinkable solutions at bedtime and 2.5 to 4.0 hours later 9

(standard regimen in narcolepsy) for a duration of 6 weeks with a 2- to 4-10

week washout period before crossover (Figure 1). In weekly alternating 11

telephone calls and clinical visits, the dosage was titrated between 3.0 and

-12

9.0 g/night according to efficacy and /tolerability (maximum change,of 1.5 13

g/week). Outcome measures were evaluated in the sleep laboratory at 14

baseline and after 6 weeks on of therapy and differences were calculated 15

both for sodium oxybate and placebo. Treatment effects were analyzed by 16

comparing these differences, using a linear mixed model, as described(see

17

below). 18

Comment [DT5]: is

Swissmedic the name of the local ethics commitee? If not, provide the name of that committee.

Comment [DT6]: Did

participants receive financial compensation?

Comment [DT7]: 15

episodes per hours?

Comment [DT8]: Moved to

(10)

Primary efficacy endpoint was treatment effect on mean sleep latency 1

(MSL),in with the Multiple Sleep Latency Test (MSLT) objectively 2

quantifying EDS.7 Secondary endpoints included change of subjective EDS 3

(assessed by ESS), sleep quality (PDSS-2, questions 1-3), objective sleep 4

parameters (in 7-hour nighttime polysomnography7,8), OFFoff-medication 5

motor symptoms («DT9: UPDRS-III»), and quality of life («DT10: 6

PDQ-39»). Positive treatment response was assumed when MSL increased 7

by more than >50% or when ESS was normalized (≤10 points on the EDS). 8

Safety was assessed by monitoring adverse events (AEs) as well as, routine 9

laboratory and polysomnographic parametersmeasures. 10

Statistical Analysis

11

Statistical analysis (using R, version 0.999375-42)9,10) was primarily 12

by intention-to-treat and secondarily by per protocol. For efficacy analysis, a 13

linear mixed model was applied with treatment as a fixed factor (subjects

14

participants and treatment sequence as random factors). For evaluating 15

carryover and period effects, we used time and sequence as fixed factors. 16

«DT11:

P-values »were obtained by likelihood ratio tests11 and 17

significance was accepted at P < .05. We furthermore performed Pearson 18

correlation to relate changes of sleep and EDS and multivariate logistic 19

Comment [DT9]: Expand

abbreviation and provide reference

Comment [DT10]: Expand

abbreviation and provide reference

Comment [DT11]: 1-tailed

(11)

regression analysis to identify predictors estimators of treatment responseds

1

(independent variables: baseline values for age, Hoehn-Yahr stage, disease 2

duration, UPDRS-III, ESS, MSL, and levodopa equivalent dose). 3

Calculation of sample size was based on previous open-label study results6 4

and yielded 12 samples. 5

Results 6

We screened 18 patients in the sleep laboratory, five 5 of whom were 7

excluded due to the polysomnographic diagnosis of sleep apnea,SA and one

8

1 patient withdrew consent (Figure 1). Thus, 12 patients were randomized 9

(10 males/men and 2 femaleswomen;, mean [SD] age, [standard deviation]

10

62 [11.1] years;, disease duration, 8.4 [4.6] years),see (eTable 1 in the

11

Supplement 2) and, after dropout of one 1 patient due to an unrelated 12

adverse event (AE) during washout, 11 patients completed the study. Two 13

patients developed «DT12: new-onsetde novo »sleep apnea on during 14

sodium oxybate treatment (1 was the patient who dropped -out) and were 15

excluded for the per-protocol analysis (n = 10) but included in the intention-16

to-treat analysis (n = 12). Mean baseline measures of EDS were 3.3 (3.0) 17

minutes in MSLT and 14.3 (2.3) points in ESS. Final doses of study 18

Comment [DT12]: revised

(12)

medication were 4.8g (1.5g) for sodium oxybate and «DT13: 8.7g (0.6 1

g) »for placebo. No carryover or period effect was detected. 2

In the efficacy analysis as intention-to-treat, sodium oxybate 3

improved EDS both objectively (+2.9 minutes

«DT14:

on MSLT

»; 95%

4

CI, 2.1 to 3.8 minutes; P = .002) (Figure 2A) and subjectively (−4.2 points 5

on ESS; 95% CI, −5.3 to −3.0 points; P = .001) (Figure 2B), which was 6

even more pronounced in the per-protocol analysis (+3.5 minuteson MSLT, 7

P < .001; −5.2 points on ESS, P < .001); raw data are available in eTable 2 8

in the Supplement 2). Responder rate was 67%, as in eight 8 patients the 9

«DT15: MSL

T score »increased clinically significantly by more than 10

>50% on during sodium oxybate treatment (placebo: 1 patient), while in 6 11

(50%) patientsthe ESS score normalized (placebo: none). None of the 12

clinical baseline parameters variables predicted treatment response in a 13

multivariate logistic regression analysis. 14

Sodium oxybate enhanced subjective sleep quality (−2.0 points on 15

PDSS-2; 95% CI, −2.8 to −1.2 points; P = .0216),(Figure 2C) and slow-16

wave sleep duration (+72.7 minutes of stage N3 sleep; 95% CI, 55.7 to 89.7; 17

P < .001)= .0002,(Figure 2D), mainly at the expense of superficial stage N1 18

sleep. Accordingly, slow-wave energy, a marker of deep sleep accumulation, 19

Comment [DT13]: what

measurable substance was contained in placebo?

Comment [DT14]: addition

of "Test" correct?

Comment [DT15]: edit

correct? if not, this sounds like the length to sleep increased

(13)

increased significantly (+9.9 mV2 • s; 95% CI, 7.3 to 12.5 mV2 • s; P < .001) 1

with 2 major increments in time-locked response to the intake of the first and 2

second doses of sodium oxybate (Figure 2E). Otherwise, no significant 3

changes were found regarding other parameters variables of nighttime sleep, 4

fatigue, motor symptoms, or quality of life (eTable 2 in the Supplement 2). 5

In the per-protocol analysis, improvements in objective EDS and nocturnal 6

slow-wave sleep correlated significantly (Pearson r = 0.8; P = .006) (Figure 7

2F). 8

The safety profile of sodium oxybate seemed benign (Table). 9

Although every patient (100%) experienced AEs on while receiving sodium 10

oxybate, the latter effects were mainly of mild (not interfering with daily 11

activities; 75% of AEs) or maximally moderate intensity (mild to -moderate 12

interference, 25% of AEs),intensity and largely «DT16: faded resolved 13

»after dose adjustment (58% of AEs

, in 67% of patients). Thus, only 4 14

patients (33%) remained affected at study termination and none dropped out 15

due to an sodium oxybate–-related AE. These individuals also displayed 16

sleep abnormalities in polysomnography on while receiving sodium oxybate 17

treatment (2 with sleep apnea, 1 with NREM non–rapid eye movement

18

parasomnia, 1 with increased periodic limb movements that were, already 19

(14)

present during placebo treatment) and were non-responders regarding EDS 1

or sleep troubles. No significant increase of the mean apnea-hypopnea index 2

or sign of abuse or /dependency was noted. 3

Discussion 4

The present study provides class I evidence for the efficacy of sodium 5

oxybate in treating sleep-wake disturbances in PD. This finding is based on 6

the extensive, electrophysiologically proven treatment effect whichthat, to 7

our knowledge, is unmatched by any other intervention reported so far.3,12,13 8

Under the premise of stringent monitoring (including regular clinical and 9

polysomnographic follow-up), the safety profile seems benign as no sodium 10

oxybate–related AE led to study discontinuation; however, , but further 11

studies with longer treatment durations and larger sample sizes are 12

warranted. 13

Intriguingly,

«DT17:

tThere »was a reciprocal relationship

14

association between nighttime sleep and EDS, as sodium oxybate–related 15

improvements of sleep and EDS correlated significantly, whereas sodium 16

oxybate–induced sleep disturbances predicted insufficient treatment 17

response and side effectsAEs. 18

Comment [DT17]: Paragrap

hs must contain more than 1 sentence. Please revise

(15)

Limitations

1

«TG18: The main limitation of the present study is the limited

2

number of participants. »

«TG19:

However, in accordance with the 3

initial calculation of sample size, the strong therapy effect did not warrant 4

higher numbers. »Moreover, our efficacy and safety results correspond with 5

evidence from large narcolepsy trials14,15 and the study by Ondo et al,6 with 6

few exceptions. For instance, we found no effect on fatigue, which may be 7

related to differences in study population (eg, lower baseline fatigue level), 8

placebo-controlled study design, or lower final sodium oxybate dosage. 9

Conclusions 10

«DT20:

In

»

summary, sSodium oxybate may be a powerful novel 11

treatment option for sleep-wake disturbances in PD, but stringent monitoring 12

is necessary (as already established in many countries for sodium oxybate in 13

narcolepsy through regulatory restrictions6,14) and larger follow-up trials 14

with longer treatment durations are warranted for validation. 15

Article Information 16

Accepted for Publication: August 6, 2017. 17

Comment [TG18]: Au:

please expand on why number of participants is a limitation in randomized clinical trials.

Comment [TG19]: Au:

please rephrase this and the following “Limitations” sentences. They assert that the limitation is not a limitation at all, which will pose a problem with executive reviewers

Comment [DT20]: As

above, revise so this is more than 1 sentence

(16)

Corresponding Author: Fabian Büchele, MD, Department of Neurology, 1

University Hospital Zurich, «DT21: University of Zurich», 2

Frauenklinikstrasse 26, 8091 Zürich, Switzerland (fabian.buechele@usz.ch). 3

Author Contributions: Drs Büchele and Baumann had full access to all the 4

data in the study and take responsibility for the integrity of the data and the 5

accuracy of the data analysis. 6

Study concept and design: Buechele, Schreglmann, Maric, Waldvogel, 7

Baumann. 8

Acquisition, analysis, or interpretation of data: Buechele, Hackius, 9

Schreglmann, Omlor, Werth, Imbach, Hägele-Link, Waldvogel, Baumann. 10

Drafting of the manuscript: Buechele, Imbach. 11

Critical revision of the manuscript for important intellectual content: All 12

authors. 13

Statistical analysis: Imbach. 14

Obtained funding: Baumann. 15

Administrative, technical, or material support: Hackius, Maric, Waldvogel, 16

Baumann. 17

Study supervision: Baumann. 18

Conflict of Interest Disclosures: Dr Büchele received speaker honoraria 19

from Hoffmann-La Roche Pharma. Dr Schreglmann received grants from 20

Comment [DT21]: This is

not stated on the byline page; include there or delete here

(17)

the Swiss National Science Foundation, Swiss Neurological Society, the 1

European Academy of Neurology, and the EMDO foundation, Zurich. Dr 2

Werth received grant from the Swiss National Science Foundation. Dr 3

Hägele-Link received speaker honoraria from GE Healthcare, Zambon 4

Pharma, Teva Pharma, and an unrestricted gGrant from AbbVie Pharma. Dr

5

Werth received grant from the Swiss National Science Foundation. Dr 6

Baumann received grants from Swiss National Science Foundation, HSM-2 7

Grant Canton of Zurich, UCB Pharma, and AbbVie Pharma, and speaker 8

honoraria from Hoffmann-La Roche Pharma, UCB Pharma, and Teva 9

Pharma. «DT23: All other authors report

«DT22:

nNo other conflicts 10

of interest

»

were reported

».

11

Funding/Support: This study was funded by UCB Pharma and by the 12

Clinical Research Priority Program Sleep and Health of the University of 13

Zurich. 14

Role of the Funder/Sponsor: The funding sources had no role in the design 15

and conduct of the study; collection, management, analysis or interpretation 16

of the data; preparation, review, or approval of the manuscript; and decision 17

to submit the manuscript for publication. 18

Comment [DT22]: Any

updates needed?

Comment [DT23]: Update

(18)

Additional Contributions: Sodium oxybate and placebo were provided by 1

UCB Pharma.

«DT24: We »thank Judith Meier, Janina Leemann

, and 2

Zdenka Herzeg for excellent technical support in the sleep laboratory; Zita 3

Jerg and Manuela Steinauer for outstanding administrative support; and 4

Michael Sommerauer for helping with data acquisition. 5

References 6

1. Pandey S, Bajaj BK, Wadhwa A, Anand KS. Impact of 7

sleep quality on the quality of life of patients with 8

Parkinson’s disease: a questionnaire based study. Clin 9

Neurol Neurosurg. 2016;148:29-34. Medline:27372436

10

2. Ozdilek B, Gunal DI. Motor and non-motor symptoms in 11

Turkish patients with Parkinson’s disease affecting 12

family caregiver burden and quality of life. J 13

Neuropsychiatry Clin Neurosci. 2012;24(4):478-483.

14

Medline:23224455 15

3. Chahine LM, Amara AW, Videnovic A. A systematic review 16

of the literature on disorders of sleep and wakefulness 17

in Parkinson’s disease from 2005 to 2015. Sleep Med 18

Rev. 2017;35:33-50. Medline:27863901

19

Comment [DT24]: For all

named contributors, provide: 1. academic degrees

2. affiliations

3. whether they received

financial compensation for these services

(19)

<eref>4. Busardò FP, Kyriakou C, Napoletano S, Marinelli E, 1

Zaami S. Clinical applications of sodium oxybate 2

(GHB): from narcolepsy to alcohol withdrawal 3

syndrome. Eur Rev. 2015;19(23):4654-4663.European

4

Review. http://www.europeanreview.org/article/9952.

5

Published December 9, 2015. Accessed February 22,

6

2017.</eref>

7

5. Scammell TE. The neurobiology, diagnosis, and treatment 8

of narcolepsy. Ann Neurol. 2003;53(2):154-166. 9

Medline:12557281 10

6. Ondo WG, Perkins T, Swick T, et al. Sodium oxybate for 11

excessive daytime sleepiness in Parkinson disease: an 12

open-label polysomnographic study. Arch Neurol. 13

2008;65(10):1337-1340. Medline:18852348

14

7. Baumann CR, Werth E, Stocker R, Ludwig S, Bassetti CL. 15

Sleep-wake disturbances 6 months after traumatic 16

brain injury: a prospective study. Brain. 2007;130(Pt 17

7):1873-1883. Medline:17584779

(20)

8. Berry RB, Brooks R, Gamaldo CE, et al, eds. The AASM 1

Scoring Manual for the Scoring of Sleep and Associated

2

Events: Rules, Terminology and Technical

3

Specifications, Version 2. Darien, IL: American

4

Academy of Sleep Medicine; 2015. 5

9. R Development Core Team. R: A language and 6

environment for statistical computing. Vienna, Austria:

7

The R Foundation for Statistical Computing; 2008. 8

10. Bates D, Maechler M, Bolker B. lme4: Linear mixed-9

effects models using S4 classes; R package version 10

0.999375-42.. 2012. http://cran.R-11

project.org/package=lme4. Accessed «DT25: month 12

day, year

»

.R package version 0.999375-42.

13

11. Pinheiro JC, Bates DM. Mixed-Effects Models in S and S-14

PLUS. New York, NY: Springer; 2000.

15

12. Baumann-Vogel H, Imbach LL, Sürücü O, et al. The 16

impact of subthalamic deep brain stimulation on sleep-17

wake behavior: a prospective electrophysiological study 18

(21)

in 50 Parkinson patients. Sleep. 2017;40(5). 1

Medline:28369624 2

13. Videnovic A, Klerman EB, Wang W, Marconi A, Kuhta T, 3

Zee PC. Timed light therapy for sleep and daytime 4

sleepiness associated with Parkinson disease: a 5

randomized clinical trial. JAMA Neurol. 6

2017;74(4):411-418. 7

14. Wang YG, Swick TJ, Carter LP, Thorpy MJ, Benowitz NL. 8

Safety overview of postmarketing and clinical 9

experience of sodium oxybate (Xyrem): abuse, misuse, 10

dependence, and diversion. J Clin Sleep Med. 11

2009;5(4):365-371. Medline:19968016

12

15. Alshaikh MK, Tricco AC, Tashkandi M, Mamdani M, 13

Straus SE, BaHammam AS. Sodium oxybate for 14

narcolepsy with cataplexy: systematic review and 15

meta-analysis. J Clin Sleep Med. 2012;8(4):451-458. 16

Medline:22893778 17

Figure 1. CONSORT Flow Diagram and Study Design. 18

(22)

Abbreviations: SO, sodium oxybate; AE indicates adverse event; 1

SAS, sleep apnea syndrome.;AE, adverse event

2

Figure 2. Effect of Placebo vs Sodium Oxybate on Excessive Daytime 3

Sleepiness and Nighttime Sleep 4

A, Objective excessive daytime sleepiness (measured by changes of 5

mean sleep latency in MSLT (the Multiple Sleep Latency Test 6

(MSLT);(baseline vs treatment). B, Subjective excessive daytime 7

sleepiness (measured by changes in the Epworth Sleepiness Scale 8

of (ESS) (Epworth sleepiness scale). C, Objective nighttime sleep (as 9

measured by changes of in durations of different sleep stages in

10

noted on polysomnography (PSG) (polysomnography). D, Subjective 11

nighttime sleep (as measured by the Parkinson Disease Sleep 12

Scale–2 (PDSS-2), questions 1-3, regarding general sleep quality 13

and / disturbances with initiation and/ maintenance of aining sleep). 14

E, Cumulative slow-wave energy, plotted longitudinally over the 15

course of the polysomnography PSG night.The (x-axis shows:

16

percentiles of individual sleep time; arrows indicate mean time points 17

of sodium oxybate and/ placebo intake,(ie, at lights off and 2.5-4.0 18

hours later). Panel F, shows the cCorrelation between change of 19

slow-wave sleep duration and change of objective excessive daytime 20

(23)

sleepiness (measured by mean sleep latency) under during sodium 1

oxybate treatment. Red dots indicate those 2 patients that who 2

developed a sleep apnea syndrome under during sodium oxybate 3

treatment and that were excluded in from the per-protocol analysis. 4

Data are presented as means;, error bars indicate SD standard

5

deviation (exception: standard error of the meanSE for panel C for 6

better overview).REM indicates rapid eye movement. 7

Table. Safety Analysis

a

8

Adverse Events No. (%)

Sodium Oxybate (n = 12) Placebo (n = 12) Patients Affected Adverse Events Patients Adverse Events

Any adverse event 12 (100) 28 (100) 5 (42) 10 (100) Adverse events unrelated to

study medication

3 (25) 4 (14) 3 (25) 5 (50) Adverse events potentially

related to study medication

12 (100) 24 (86) 3 (25) 5 (50) Of mMild intensity 8 (67) 18 (75) 3 (100) 5 (100) Of mModerate intensity 4 (33) 6 (25) 0 (0 0 (0)

Of sSevere intensity 0 (0) 0 (0) 0 (0 0 (0)

With iImprovement after dose adjustment or/

spontaneously

12 (100) 14 (58) 3 (25) 4 (80)

Mild dizziness and asthenia 6 (50) 6 (43) 1 (8) 1 (25)

Mild nausea 2 (17) 2 (14) 0 0

Mild deterioration of PD motor symptoms

1 (8) 1 (7) 0 0

Mild thoracic discomfort 1 (8) 1 (7) 1 (8) 1 (25) Short episode with dyspnea

at night

1 (8) 1 (7) 0 0

Mild leg cramps 1 (8) 1 (7) 0 0

Nocturesis (once) 1 (8) 1 (7) 0 0

(24)

Mild dry mouth 0 0 1 (8) 1 (25)

Mild headache 0 0 1 (8) 1 (25)

Without improvement after dose adjustment

4 (33) 10 (42) 1 (8) 1 (20) Obstructive sleep apnea

syndromeb(PSG)

2 (17) 2 (20) 0 0

NREM parasomniab(PSG) 1 (8) 1 (10) 0 0

Increased periodic limb movementbs (PSG)

1 (8) 1 (100)

Moderate weight loss 1 (8) 1 (10) 0 0

Moderate nervousness 1 (8) 1 (10) 0 0

Moderate dizziness 2 (17) 2 (20) 0 0

Moderate deterioration of motor symptoms

2 (17) 2 (20) 0 0

Mild lack of drive 1 (8) 1 (10) 0 0

Abbreviations: NREM, non–rapid eye movement; PD, Parkinson disease. 1

a

Data are in number of patients with an adverse event (percentage within 2

study population) and total number of adverse events (percentage of all 3

adverse events in the respective category). No severe adverse events were 4

reported and no patients dropped out due to treatment-related adverse events. 5

Abbreviations: PD, Parkinson Disease; PSG, polysomnography; NREM, non

6

rapid eye movement.

7 b Determined on polysomnography. 8 9 10

«TG26: Supplement 1. Protocol»

11

Supplement 2. eTable. Baseline Characteristics and Final Dosages of Study 12

Medications 13

eTable 2. Effect of Sodium Oxybate and Placebo on Daytime Vigilance, 14

Nighttime Sleep, Parkinson Disease Symptoms 15

16

Comment [TG26]: Au:

please supply an English language version of trial protocol

(25)

Figure

Updating...

References

Related subjects :