Randomized Controlled Trial of Solriamfetol for Excessive Daytime Sleepiness in OSA

Abstract

BackgroundSolriamfetol, 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 QuestionDoes solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use?Study Design and MethodsParticipants 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.ResultsAt 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.InterpretationSolriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol.Trial RegistryClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu 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). Does solriamfetol have differential effects on EDS based on adherence to primary OSA therapy and does solriamfetol affect primary OSA therapy use? 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. 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. Solriamfetol improved EDS in OSA regardless of primary OSA therapy adherence. Primary OSA therapy use was unaffected with solriamfetol. ClinicalTrials.gov; No.: NCT02348606; URL: www.clinicaltrials.gov; EU Clinical Trials Register; No.: EudraCT2014-005514-31; URL: www.clinicaltrialsregister.eu Excessive daytime sleepiness (EDS) is common among individuals with OSA.1Bjorvatn 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: 1387-1393Crossref Scopus (40) Google Scholar,2Peppard 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: 1006-1014Crossref PubMed Scopus (2500) Google Scholar Positive airway pressure (PAP) or other airway therapies (eg, oral appliances, surgical procedures) are treatments for the underlying airway obstruction in OSA and subsequently reduce EDS in many patients.3Antic N.A. Catcheside P. Buchan C. et al.The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA.Sleep. 2011; 34: 111-119Crossref PubMed Scopus (309) Google Scholar, 4Patil 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: 335-343Crossref PubMed Scopus (192) Google Scholar, 5Weaver T.E. Maislin G. Dinges D.F. et al.Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning.Sleep. 2007; 30: 711-719Crossref PubMed Scopus (652) Google Scholar However, despite adherence to these therapies and control of other factors that may contribute to pathologic sleepiness, EDS persists in some individuals. Specifically, residual EDS is reported by an estimated 9% to 22% of CPAP-treated patients in population-based studies.6Gasa M. Tamisier R. Launois S.H. et al.Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.J Sleep Res. 2013; 22: 389-397Crossref PubMed Scopus (93) Google Scholar,7Pepin J.L. Viot-Blanc V. Escourrou P. et al.Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study.Eur Respir J. 2009; 33: 1062-1067Crossref PubMed Scopus (114) Google Scholar In addition, other studies have shown that a substantial percentage of patients who use CPAP treatment for ≥ 7 h/night do not achieve normal responses on standard measures of sleepiness and functional outcomes.3Antic N.A. Catcheside P. Buchan C. et al.The effect of CPAP in normalizing daytime sleepiness, quality of life, and neurocognitive function in patients with moderate to severe OSA.Sleep. 2011; 34: 111-119Crossref PubMed Scopus (309) Google T.E. Maislin G. Dinges D.F. et al.Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning.Sleep. 2007; 30: 711-719Crossref PubMed Scopus (652) Google Scholar patients with OSA may may have EDS and not of pathologic T.E. Maislin G. Dinges D.F. et al.Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning.Sleep. 2007; 30: 711-719Crossref PubMed Scopus (652) Google Scholar or in contribute to EDS in OSA and to a despite OSA J. Sleepiness and residual sleepiness in adults with obstructive sleep PubMed Scopus Google Scholar of sleep apnea to from and of sleep P. et in with to PubMed Scopus Google P. G. et of in a sleep apnea 2007; PubMed Scopus Google Scholar whereas studies in differences in treated OSA patients with residual sleepiness with J. T.E. et differences in OSA patients residual daytime sleepiness with CPAP a Med. 2019; PubMed Scopus Google Scholar adherence or or other primary OSA treatment is in and the treatment in CPAP adherence of a PubMed Scopus Google Scholar of of EDS in and quality of life, for and treatment of EDS is and some patients who despite to other of pathologic sleepiness may from these are not a for primary OSA T. C. of and daytime sleepiness in J Respir Med. PubMed Scopus Google Scholar, and quality of in obstructive sleep Med. PubMed Scopus Google Scholar, C. S. quality of life, and among with obstructive sleep apnea with excessive from the and Clin Sleep Med. 2019; 15: PubMed Scopus Google Scholar, S. J. B. sleep apnea and of systematic and Clin Sleep Med. 2009; PubMed Scopus Google Scholar, T. P.E. of obstructive sleep a J Respir Med. PubMed Scopus Google Scholar studies of for treatment of residual sleepiness in CPAP-treated patients have not shown clinically in CPAP for residual excessive sleepiness and in CPAP-treated patients with obstructive sleep apnea a systematic and 30: PubMed Scopus Google S. M. of on sleepiness in patients with sleep apnea treated with a Clin Sleep Med. 2015; PubMed Scopus Google Scholar the effect of on adherence to primary OSA therapy is an to the of or treated Solriamfetol, a dopamine-norepinephrine reuptake et of the and effects of solriamfetol a and reuptake PubMed Scopus Google Scholar is approved by the and to improve wakefulness in adults with EDS associated with OSA (37.5-150 or a positive from the for for was for the for of positive for Scholar Solriamfetol effects in a in patients with OSA in a R. et for excessive sleepiness in obstructive sleep apnea a randomized J Respir Med. 2019; PubMed Scopus Google Scholar of that included patients who were CPAP a of therapy for daytime sleepiness in obstructive sleep J Respir Med. 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Treatment of EDS is an of OSA EDS is associated with quality of life, and a for and may in a substantial of patients despite treatment of the underlying airway M. Tamisier R. Launois S.H. et al.Residual sleepiness in sleep apnea patients treated by continuous positive airway pressure.J Sleep Res. 2013; 22: 389-397Crossref PubMed Scopus (93) Google Scholar,7Pepin J.L. Viot-Blanc V. Escourrou P. et al.Prevalence of residual excessive sleepiness in CPAP-treated sleep apnoea patients: the French multicentre study.Eur Respir J. 2009; 33: 1062-1067Crossref PubMed Scopus (114) Google T. C. of and daytime sleepiness in J Respir Med. PubMed Scopus Google Scholar, and quality of in obstructive sleep Med. PubMed Scopus Google Scholar, C. S. quality of life, and among with obstructive sleep apnea with excessive from the and Clin Sleep Med. 2019; 15: PubMed Scopus Google Scholar, S. J. B. sleep apnea and of systematic and Clin Sleep Med. 2009; PubMed Scopus Google Scholar, T. 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