. 2021 Oct 18;10(2):651–672. doi: 10.1007/s40120-021-00289-6

Table 4.

Currently available agents for the treatment of REDS due to OSA

Agent	Indication	MOA	Efficacy	Safety	CV effects
Modafinil/armodafinil	USA: improve wakefulness in adult patients with EDS in OSA, narcolepsy, or shift work disorder who are adherent to CPAP therapy (if it is the chosen treatment) [94, 95] EU: withdrawn because of risks of neuropsychiatric disorders and CV risks in patients with cardiac arrhythmias and uncontrolled hypertension [96]	• Armodafinil (active moiety) is the R-isomer of modafinil [95] • Binds to the dopamine transport protein [94, 95] • Increases dopamine in the extrasynaptic space [94, 95] • Increases dopamine tone [118] • Elevates norepinephrine in extrasynaptic spaces • Reduces GABA concentrations [118]	Meta-analysis (10 RCTs; n = 1466) [100] • ESS: improved by 2.2 units (95% CI 1.5–2.9) versus placebo • MWT: improved by 3 min (95% CI 2.1–3.8) versus placebo	• AEs vs. placebo: 0.54 per patient-year vs. 0.32 per patient-year (RR 1.7; 95% CI 1.3–2.2) [100] •No deaths [100]	• Increased SBP by 3 mmHg (95% CI 0.8–5.2) and DBP by 1.9 mmHg (95% CI 0.5–3.3) versus placebo [100] • Higher risk of stroke for patients with OSA and prior stroke versus no modafinil/armodafinil (HR 1.96; 95% CI 1.02–3.76) [119]
Solriamfetol	USA: improve wakefulness in adult patients with EDS associated with narcolepsy or OSA who are compliant with CPAP therapy [99, 101] EU: improve wakefulness and reduce EDS in adult patients associated with narcolepsy (with or without cataplexy) or OSA that has not been satisfactorily treated with initial OSA therapy (e.g., CPAP) [102]	Dual-acting dopamine and norepinephrine reuptake inhibitor [101, 120]	Phase 3 TONES 3 study (n = 459) [99] • ESS: significantly more patients receiving solriamfetol ≥ 75 mg achieved ESS ≤ 10 versus placebo (55.2–73.0% vs. 37.7%) • MWT: more patients receiving solriamfetol ≥ 75 mg reached MWT ≥ 20 min versus placebo (53.6–65.7% vs. 23.4%)	• Rates of AEs were higher with solriamfetol-versus placebo (67.9% vs 47.9%), were dose dependent, and mostly mild or moderate (94.6% vs. 93.0%) [99] • Most frequent AEs included headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, nasopharyngitis, and URTI [99, 121] • Discontinuations: 9.2% (psychiatric disorders 3.1%, nervous system disorders 2.0%, GI disorders 1.2%) [121]	• Small increases from baseline in SBP (mean 2.5 mmHg; 95% CI 0.4–4.6) and DBP (mean 1.5 mmHg; 95% CI 0.3–2.7) with solriamfetol 300 mg versus placebo (SBP, mean − 0.2 [95% CI − 1.7 to 1.4]; DBP, 0.0 [95% CI − 0.9 to 1.0]) [99] • Small increases in heart rate with solriamfetol 150 and 300 mg (2.2 and 2.9 bpm, respectively) versus placebo (0.1 bpm) [99]
Pitolisant	USA: treatment of EDS or cataplexy in adult patients with narcolepsy [106] EU: treatment of narcolepsy with or without cataplexy; treatment of EDS in adult patients with OSA [107, 108]	Selective histamine H₃ receptor antagonist and inverse agonist of presynaptic H₃ receptor [7, 98]	12-week RCT (n = 244) [98] • ESS: geometric mean reduction from baseline to week 12 was − 5.5 (95% CI − 6.2 to − 4.9) versus − 2.8 (95% CI − 4.3 to − 1.2) for placebo; p < 0.001 • Significantly improved the ability to maintain wakefulness in the OSleR test (p = 0.05) and the percentage of improved (very much, much, and minimally) patients according to the CGI-C versus placebo (p < 0.001) Phase 3 RCT (n = 268) [97] • ESS: significantly reduced versus placebo (− 6.3 vs. − 3.6; p < 0.001)	• TEAEs significantly higher with pitolisant versus placebo (47.0% vs. 32.8%) [98] • Most frequently reported TEAEs with pitolisant versus placebo: headache (14.8% vs. 11.5%), insomnia (9.3% vs. 3.3%) [98] • Similar frequencies of severe treatment-related TEAEs and treatment-related TEAEs (headache, insomnia, diarrhea) with pitolisant and placebo [98]	• Heart rate and blood pressure remained stable [98] • Post-dose QTcF > 450 ms and QTcF elongation ≥ 60 ms observed in several patients with pitolisant and placebo [97, 98]

Agent

Indication

MOA

Efficacy

Safety

CV effects

Modafinil/armodafinil

USA: improve wakefulness in adult patients with EDS in OSA, narcolepsy, or shift work disorder who are adherent to CPAP therapy (if it is the chosen treatment) [94, 95]

EU: withdrawn because of risks of neuropsychiatric disorders and CV risks in patients with cardiac arrhythmias and uncontrolled hypertension [96]

• Armodafinil (active moiety) is the R-isomer of modafinil [95]

• Binds to the dopamine transport protein [94, 95]

• Increases dopamine in the extrasynaptic space [94, 95]

• Increases dopamine tone [118]

• Elevates norepinephrine in extrasynaptic spaces

• Reduces GABA concentrations [118]

Meta-analysis (10 RCTs; n = 1466) [100]

• ESS: improved by 2.2 units (95% CI 1.5–2.9) versus placebo

• MWT: improved by 3 min (95% CI 2.1–3.8) versus placebo

• AEs vs. placebo: 0.54 per patient-year vs. 0.32 per patient-year (RR 1.7; 95% CI 1.3–2.2) [100]

•No deaths [100]

• Increased SBP by 3 mmHg (95% CI 0.8–5.2) and DBP by 1.9 mmHg (95% CI 0.5–3.3) versus placebo [100]

• Higher risk of stroke for patients with OSA and prior stroke versus no modafinil/armodafinil (HR 1.96; 95% CI 1.02–3.76) [119]

Solriamfetol

USA: improve wakefulness in adult patients with EDS associated with narcolepsy or OSA who are compliant with CPAP therapy [99, 101]

EU: improve wakefulness and reduce EDS in adult patients associated with narcolepsy (with or without cataplexy) or OSA that has not been satisfactorily treated with initial OSA therapy (e.g., CPAP) [102]

Dual-acting dopamine and norepinephrine reuptake inhibitor [101, 120]

Phase 3 TONES 3 study (n = 459) [99]

• ESS: significantly more patients receiving solriamfetol ≥ 75 mg achieved ESS ≤ 10 versus placebo (55.2–73.0% vs. 37.7%)

• MWT: more patients receiving solriamfetol ≥ 75 mg reached MWT ≥ 20 min versus placebo (53.6–65.7% vs. 23.4%)

• Rates of AEs were higher with solriamfetol-versus placebo (67.9% vs 47.9%), were dose dependent, and mostly mild or moderate (94.6% vs. 93.0%) [99]

• Most frequent AEs included headache, nausea, decreased appetite, insomnia, dry mouth, anxiety, nasopharyngitis, and URTI [99, 121]

• Discontinuations: 9.2% (psychiatric disorders 3.1%, nervous system disorders 2.0%, GI disorders 1.2%) [121]

• Small increases from baseline in SBP (mean 2.5 mmHg; 95% CI 0.4–4.6) and DBP (mean 1.5 mmHg; 95% CI 0.3–2.7) with solriamfetol 300 mg versus placebo (SBP, mean − 0.2 [95% CI − 1.7 to 1.4]; DBP, 0.0 [95% CI − 0.9 to 1.0]) [99]

• Small increases in heart rate with solriamfetol 150 and 300 mg (2.2 and 2.9 bpm, respectively) versus placebo (0.1 bpm) [99]

Pitolisant

USA: treatment of EDS or cataplexy in adult patients with narcolepsy [106]

EU: treatment of narcolepsy with or without cataplexy; treatment of EDS in adult patients with OSA [107, 108]

Selective histamine H₃ receptor antagonist and inverse agonist of presynaptic H₃ receptor [7, 98]

12-week RCT (n = 244) [98]

• ESS: geometric mean reduction from baseline to week 12 was − 5.5 (95% CI − 6.2 to − 4.9) versus − 2.8 (95% CI − 4.3 to − 1.2) for placebo; p < 0.001

• Significantly improved the ability to maintain wakefulness in the OSleR test (p = 0.05) and the percentage of improved (very much, much, and minimally) patients according to the CGI-C versus placebo (p < 0.001)

Phase 3 RCT (n = 268) [97]

• ESS: significantly reduced versus placebo (− 6.3 vs. − 3.6; p < 0.001)

• TEAEs significantly higher with pitolisant versus placebo (47.0% vs. 32.8%) [98]

• Most frequently reported TEAEs with pitolisant versus placebo: headache (14.8% vs. 11.5%), insomnia (9.3% vs. 3.3%) [98]

• Similar frequencies of severe treatment-related TEAEs and treatment-related TEAEs (headache, insomnia, diarrhea) with pitolisant and placebo [98]

• Heart rate and blood pressure remained stable [98]

• Post-dose QTcF > 450 ms and QTcF elongation ≥ 60 ms observed in several patients with pitolisant and placebo [97, 98]

AE adverse event, CGI-C Clinical Global Impressions–Clinicians, CI confidence interval, CPAP continuous positive airway pressure, CV cardiovascular, DBP diastolic blood pressure, EDS excessive daytime sleepiness, ESS Epworth Sleepiness Scale, GABA γ-aminobutyric acid, GI gastrointestinal, HR hazard ratio, MOA mechanism of action, MWT Maintenance of Wakefulness Test, OSA obstructive sleep apnea, OSleR Oxford Sleep Resistance Test, QTcF QT interval by Fredericia’s correction, RCT randomized controlled trial, REDS residual excessive daytime sleepiness, RR risk ratio, SBP systolic blood pressure, URTI upper respiratory tract infection