Randomized Controlled Trial of Solriamfetol for Excessive Daytime Sleepiness in OSA: An Analysis of Subgroups Adherent or Nonadherent to OSA Treatment

Paula K Schweitzer, Geert Mayer, Russell Rosenberg, Atul Malhotra, Gary K Zammit, Mark Gotfried, Patricia Chandler, Michelle Baladi, Kingman P Strohl, Paula K Schweitzer, Geert Mayer, Russell Rosenberg, Atul Malhotra, Gary K Zammit, Mark Gotfried, Patricia Chandler, Michelle Baladi, Kingman P Strohl

Abstract

Background: Solriamfetol, a dopamine-norepinephrine reuptake inhibitor, is approved in the United States to improve wakefulness in adults with excessive daytime sleepiness (EDS) associated with OSA (37.5-150 mg/d).

Research question: Does solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?

Study design and methods: Participants were randomized to 12 weeks of placebo or solriamfetol 37.5, 75, 150, or 300 mg/d (stratified by primary OSA therapy adherence). Coprimary end points were week 12 change from baseline in 40-min Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) in the modified intention-to-treat population. Primary OSA therapy use (hours per night, % nights) and safety were evaluated.

Results: At baseline, 324 participants (70.6%) adhered to OSA therapy (positive airway pressure use ≥ 4 h/night on ≥ 70% nights, surgical intervention, or oral appliance use on ≥ 70% nights) and 135 participants (29.4%) did not adhere. Least squares (LS) mean differences from placebo in MWT sleep latency (minutes) in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were 4.8 (95% CI, 0.6-9.0), 8.4 (95% CI, 4.3-12.5), 10.2 (95% CI, 6.8-13.6), and 12.5 (95% CI, 9.0-15.9) and among nonadherent participants were 3.7 (95% CI, -2.0 to 9.4), 9.9 (95% CI, 4.4-15.4), 11.9 (95% CI, 7.5-16.3), and 13.5 (95% CI, 8.8-18.3). On ESS, LS mean differences from placebo in the 37.5-, 75-, 150-, and 300-mg/d groups among adherent participants were -2.4 (95% CI, -4.2 to -0.5), -1.3 (95% CI, -3.1 to 0.5), -4.2 (95% CI, -5.7 to -2.7), and -4.7 (95% CI, -6.1 to -3.2) and among nonadherent participants were -0.7 (95% CI, -3.5 to 2.1), -2.6 (95% CI, -5.4 to 0.1), -5.0 (95% CI, -7.2 to -2.9), and -4.6 (95% CI, -7.0 to -2.3). Common adverse events included headache, nausea, anxiety, decreased appetite, nasopharyngitis, and diarrhea. No clinically meaningful changes were seen in primary OSA therapy use with solriamfetol.

Interpretation: Solriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.

Trial registry: ClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu.

Keywords: JZP-110; obstructive sleep apnea syndromes; sleep apnea.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Flow chart showing participant disposition (Consolidated Standards of Reporting Trials Diagram). Fifteen participants in the randomized population did not have baseline or ≥ 1 postbaseline evaluation of Maintenance of Wakefulness Test sleep latency or Epworth Sleepiness Scale scores, and two participants did not receive solriamfetol. These participants did not meet the prespecified criteria for inclusion in the modified intention-to-treat population.
Figure 2
Figure 2
Bar graph showing the difference from placebo in change in Maintenance of Wakefulness Test score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 3

Bar graph showing the difference…

Figure 3

Bar graph showing the difference from placebo in change in Epworth Sleepiness Scale…

Figure 3
Bar graph showing the difference from placebo in change in Epworth Sleepiness Scale score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 4

Bar graph showing the difference…

Figure 4

Bar graph showing the difference from placebo in the percentage of participants with…

Figure 4
Bar graph showing the difference from placebo in the percentage of participants with improvement on the PGI-C scale at week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 5

Bar graph showing the difference…

Figure 5

Bar graph showing the difference from placebo in change in Functional Outcomes of…

Figure 5
Bar graph showing the difference from placebo in change in Functional Outcomes of Sleep Questionnaire short version total score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 
Similar articles
References
    1. Bjorvatn B., Lehmann S., Gulati S., Aurlien H., Pallesen S., Saxvig I.W. Prevalence of excessive sleepiness is higher whereas insomnia is lower with greater severity of obstructive sleep apnea. Sleep. Breath. 2015;19(4):1387–1393. - PubMed
    1. Peppard P.E., Young T., Barnet J.H., Palta M., Hagen E.W., Hla K.M. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–1014. - PMC - PubMed
    1. Antic N.A., Catcheside P., Buchan C. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111–119. - PMC - PubMed
    1. Patil S.P., Ayappa I.A., Caples S.M., Kimoff R.J., Patel S.R., Harrod C.G. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2019;15(2):335–343. - PMC - PubMed
    1. Weaver T.E., Maislin G., Dinges D.F. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. - PMC - PubMed
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Figure 3
Figure 3
Bar graph showing the difference from placebo in change in Epworth Sleepiness Scale score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 4

Bar graph showing the difference…

Figure 4

Bar graph showing the difference from placebo in the percentage of participants with…

Figure 4
Bar graph showing the difference from placebo in the percentage of participants with improvement on the PGI-C scale at week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 5

Bar graph showing the difference…

Figure 5

Bar graph showing the difference from placebo in change in Functional Outcomes of…

Figure 5
Bar graph showing the difference from placebo in change in Functional Outcomes of Sleep Questionnaire short version total score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 
Similar articles
References
    1. Bjorvatn B., Lehmann S., Gulati S., Aurlien H., Pallesen S., Saxvig I.W. Prevalence of excessive sleepiness is higher whereas insomnia is lower with greater severity of obstructive sleep apnea. Sleep. Breath. 2015;19(4):1387–1393. - PubMed
    1. Peppard P.E., Young T., Barnet J.H., Palta M., Hagen E.W., Hla K.M. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–1014. - PMC - PubMed
    1. Antic N.A., Catcheside P., Buchan C. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111–119. - PMC - PubMed
    1. Patil S.P., Ayappa I.A., Caples S.M., Kimoff R.J., Patel S.R., Harrod C.G. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2019;15(2):335–343. - PMC - PubMed
    1. Weaver T.E., Maislin G., Dinges D.F. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. - PMC - PubMed
Show all 39 references
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Figure 4
Figure 4
Bar graph showing the difference from placebo in the percentage of participants with improvement on the PGI-C scale at week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

Figure 5

Bar graph showing the difference…

Figure 5

Bar graph showing the difference from placebo in change in Functional Outcomes of…

Figure 5
Bar graph showing the difference from placebo in change in Functional Outcomes of Sleep Questionnaire short version total score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 
Similar articles
References
    1. Bjorvatn B., Lehmann S., Gulati S., Aurlien H., Pallesen S., Saxvig I.W. Prevalence of excessive sleepiness is higher whereas insomnia is lower with greater severity of obstructive sleep apnea. Sleep. Breath. 2015;19(4):1387–1393. - PubMed
    1. Peppard P.E., Young T., Barnet J.H., Palta M., Hagen E.W., Hla K.M. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–1014. - PMC - PubMed
    1. Antic N.A., Catcheside P., Buchan C. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111–119. - PMC - PubMed
    1. Patil S.P., Ayappa I.A., Caples S.M., Kimoff R.J., Patel S.R., Harrod C.G. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2019;15(2):335–343. - PMC - PubMed
    1. Weaver T.E., Maislin G., Dinges D.F. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719. - PMC - PubMed
Show all 39 references
Publication types
MeSH terms
Associated data
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Figure 5
Figure 5
Bar graph showing the difference from placebo in change in Functional Outcomes of Sleep Questionnaire short version total score from baseline to week 12 in adherent and nonadherent subgroups (modified intention-to-treat population). ∗P 

References

    1. Bjorvatn B., Lehmann S., Gulati S., Aurlien H., Pallesen S., Saxvig I.W. Prevalence of excessive sleepiness is higher whereas insomnia is lower with greater severity of obstructive sleep apnea. Sleep. Breath. 2015;19(4):1387–1393.
    1. Peppard P.E., Young T., Barnet J.H., Palta M., Hagen E.W., Hla K.M. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol. 2013;177(9):1006–1014.
    1. Antic N.A., Catcheside P., Buchan C. The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA. Sleep. 2011;34(1):111–119.
    1. Patil S.P., Ayappa I.A., Caples S.M., Kimoff R.J., Patel S.R., Harrod C.G. Treatment of adult obstructive sleep apnea with positive airway pressure: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2019;15(2):335–343.
    1. Weaver T.E., Maislin G., Dinges D.F. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep. 2007;30(6):711–719.
    1. Gasa M., Tamisier R., Launois S.H. Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure. J Sleep Res. 2013;22(4):389–397.
    1. Pepin J.L., Viot-Blanc V., Escourrou P. Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study. Eur Respir J. 2009;33(5):1062–1067.
    1. Black J. Sleepiness and residual sleepiness in adults with obstructive sleep apnea. Respir Physiol Neurobiol. 2003;136(2-3):211–220.
    1. Veasey S.C., Davis C.W., Fenik P. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep-wake brain regions. Sleep. 2004;27(2):194–201.
    1. Zhu Y., Fenik P., Zhan G. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci. 2007;27(37):10060–10071.
    1. Zhang J., Weaver T.E., Zhong Z. White matter structural differences in OSA patients experiencing residual daytime sleepiness with high CPAP use: a non-Gaussian diffusion MRI study. Sleep Med. 2019;53:51–59.
    1. Rotenberg B.W., Murariu D., Pang K.P. Trends in CPAP adherence over twenty years of data collection: a flattened curve. J Otolaryngol Head Neck Surg. 2016;45(1):43.
    1. Lindberg E., Carter N., Gislason T., Janson C. Role of snoring and daytime sleepiness in occupational accidents. Am J Respir Crit Care Med. 2001;164(11):2031–2035.
    1. Sateia M.J. Neuropsychological impairment and quality of life in obstructive sleep apnea. Clin Chest Med. 2003;24(2):249–259.
    1. Stepnowsky C., Sarmiento K.F., Bujanover S., Villa K.F., Li V.W., Flores N.M. Comorbidities, health-related quality of life, and work productivity among people with obstructive sleep apnea with excessive sleepiness: findings from the 2016 US National Health and Wellness Survey. J Clin Sleep Med. 2019;15(2):235–243.
    1. Tregear S., Reston J., Schoelles K., Phillips B. Obstructive sleep apnea and risk of motor vehicle crash: systematic review and meta-analysis. J Clin Sleep Med. 2009;5(6):573–581.
    1. Young T., Peppard P.E., Gottlieb D.J. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med. 2002;165(9):1217–1239.
    1. Avellar A.B., Carvalho L.B., Prado G.F., Prado L.B. Pharmacotherapy for residual excessive sleepiness and cognition in CPAP-treated patients with obstructive sleep apnea syndrome: a systematic review and meta-analysis. Sleep Med Rev. 2016;30:97–107.
    1. Sukhal S., Khalid M., Tulaimat A. Effect of wakefulness-promoting agents on sleepiness in patients with sleep apnea treated with CPAP: a meta-analysis. J Clin Sleep Med. 2015;11(10):1179–1186.
    1. Baladi M.G., Forster M.J., Gatch M.B. Characterization of the neurochemical and behavioral effects of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor. J Pharmacol Exp Ther. 2018;366(2):367–376.
    1. Jazz Pharmaceuticals . Jazz Pharmaceuticals, Inc.; Palo Alto, CA: 2019. Inc. Sunosi™ (Solriamfetol) Tablets Prescribing Information.
    1. Committee for Human Medicinal Products. Summary of positive opinion for Sunosi. 2019. European Medicines Agency website.
    1. Schweitzer P.K., Rosenberg R., Zammit G.K. Solriamfetol for excessive sleepiness in obstructive sleep apnea (TONES 3): a randomized controlled trial. Am J Respir Crit Care Med. 2019;199(11):1421–1431.
    1. Pack A.I., Black J.E., Schwartz J.R., Matheson J.K. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med. 2001;164(9):1675–1681.
    1. Roth T., White D., Schmidt-Nowara W. Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week, multicenter, double-blind, randomized, placebo-controlled study in nCPAP-adherent adults. Clin Ther. 2006;28(5):689–706.
    1. Weaver T.E., Grunstein R.R. Adherence to continuous positive airway pressure therapy: the challenge to effective treatment. Proc Am Thorac Soc. 2008;5(2):173–178.
    1. American Academy of Sleep Medicine . 3rd ed. American Academy of Sleep Medicine; Darien, IL: 2014. International Classification of Sleep Disorders.
    1. Johns M.W. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep. 1991;14(6):540–545.
    1. Doghramji K., Mitler M.M., Sangal R.B. A normative study of the maintenance of wakefulness test (MWT) Electroencephalogr Clin Neurophysiol. 1997;103(5):554–562.
    1. Kribbs N.B., Pack A.I., Kline L.R. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis. 1993;147(4):887–895.
    1. Guy W. U.S. Department of Health, Education and Welfare; Rockville, MD: 1976. ECDEU Assessment Manual for Psychopharmacology. Revised.
    1. Chasens E.R., Ratcliffe S.J., Weaver T.E. Development of the FOSQ-10: a short version of the Functional Outcomes of Sleep Questionnaire. Sleep. 2009;32(7):915–919.
    1. Johns M., Hocking B. Daytime sleepiness and sleep habits of Australian workers. Sleep. 1997;20(10):844–849.
    1. Lammers G.J., Bogan R., Schweitzer P.K. Thresholds for clinically meaningful changes on the Epworth sleepiness scale and maintenance of wakefulness test sleep latency [abstract] Sleep Med. 2019;64(suppl 1):S210.
    1. Weaver T.E., Crosby R.D., Bron M., Menno D., Mathias S.D. Using multiple anchor-based and distribution-based estimates to determine the minimal important difference (MID) for the FOSQ-10 [abstract 0612] Sleep. 2018;41(suppl 1):A227.
    1. Chapman J.L., Vakulin A., Hedner J., Yee B.J., Marshall N.S. Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis. Eur Respir J. 2016;47(5):1420–1428.
    1. Kuan Y.C., Wu D., Huang K.W. Effects of modafinil and armodafinil in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. Clin Ther. 2016;38(4):874–888.
    1. Bakker J.P., Weaver T.E., Parthasarathy S., Aloia M.S. Adherence to CPAP: what should we be aiming for, and how can we get there? Chest. 2019;155(6):1272–1287.
    1. Lopez-Lopez L., Torres-Sanchez I., Cabrera-Martos I., Ortiz-Rubio A., Granados-Santiago M., Valenza M.C. Nursing interventions improve continuous positive airway pressure adherence in obstructive sleep apnea with excessive daytime sleepiness: a systematic review. Rehabil Nurs. 2020;45(3):140–146.

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