Solriamfetol for Excessive Sleepiness in Obstructive Sleep Apnea (TONES 3). A Randomized Controlled Trial

Abstract

Rationale: Primary treatment of obstructive sleep apnea can be accompanied by a persistence of excessive sleepiness despite adherence. Furthermore, effectiveness of sleep apnea treatment is limited by poor adherence. Currently available pharmacologic options for the treatment of sleepiness in this population are limited. Objectives: To evaluate the efficacy and safety of solriamfetol (JZP-110), a selective dopamine and norepinephrine reuptake inhibitor with robust wake-promoting effects, for the treatment of excessive sleepiness in participants with obstructive sleep apnea with current or prior sleep apnea treatment. Methods: This was a double-blind, randomized, placebo-controlled, parallel-group, 12-week trial comparing solriamfetol, 37.5, 75, 150, and 300 mg, with placebo. Measurements and Main Results: Of 476 randomized participants, 459 were included in the prespecified efficacy analyses. Coprimary endpoints (Maintenance of Wakefulness Test sleep latency and Epworth Sleepiness Scale score) were met at all solriamfetol doses (P < 0.05), with dose-dependent effects observed at Week 1 maintained over the study duration. All doses except 37.5 mg resulted in higher percentages of participants reporting improvement on Patient Global Impression of Change (key secondary endpoint; P < 0.05). Adverse events were reported in 47.9% of placebo- and 67.9% of solriamfetol-treated participants; five participants experienced serious adverse events (two [1.7%] placebo, three [0.8%] solriamfetol); none were deemed related to study drug. The most common adverse events with solriamfetol were headache (10.1%), nausea (7.9%), decreased appetite (7.6%), anxiety (7.0%), and nasopharyngitis (5.1%). Conclusions: Solriamfetol significantly increased wakefulness and reduced sleepiness in participants with obstructive sleep apnea and excessive sleepiness; most adverse events were mild or moderate in severity. Clinical trial registered with www.clinicaltrials.gov (NCT02348606) and www.eudract.ema.europa.eu (EudraCT 2014-005514-31).

Keywords: JZP-110; TONES 3; excessive sleepiness; obstructive sleep apnea; solriamfetol.

Figures

Figure 1.

Participant disposition (Consolidated Standards of Reporting Trials diagram). Fifteen participants in the randomized population did not have baseline or one or more postbaseline evaluations of Maintenance of Wakefulness Test sleep latency or Epworth Sleepiness Scale score, and two did not receive solriamfetol. These participants did not meet the prespecified criteria for inclusion in the modified intent-to-treat population.

Figure 2.

Change from baseline on the coprimary efficacy endpoints (modified intent-to-treat population). (A) Least squares (LS) mean change from baseline in Maintenance of Wakefulness Test sleep latency in minutes for all treatment groups and (B) LS mean change in Epworth Sleepiness Scale score for all treatment groups. *P < 0.05 and †P < 0.0001 versus placebo. ESS = Epworth Sleepiness Scale; MWT = Maintenance of Wakefulness Test.

Figure 3.

Change from baseline in sleep latency for each of the five individual trials in the Maintenance of Wakefulness Test (MWT) at Week 12 (modified intent-to-treat population). Individual MWT trials, each of 40-minute duration, were performed at 2-hour intervals beginning 2 hours after awakening and 1 hour after dosing at the approximate times postdose shown in parentheses. The result at trial 4 for 37.5 mg was of nominal significance based on the prespecified testing sequence. *P < 0.05 and †P < 0.0001 versus placebo.

Figure 4.

Percentage of participants (A) with Maintenance of Wakefulness Test sleep latency greater than or equal to 20 minutes and (B) with Epworth Sleepiness Scale (ESS) scores less than or equal to 10 among participants in the modified intent-to-treat population with missing data imputed using last-observation-carried-forward. Values at baseline include some participants with ESS scores of 10, because the inclusion criterion was an ESS score greater than or equal to 10. MWT = Maintenance of Wakefulness Test.

Figure 5.

Percentage of participants with improvement on the Global Impression of Change scales (modified intent-to-treat population): (A) Patient Global Impression of Change scale and (B) Clinical Global Impression of Change scale results. *P < 0.05 and †P < 0.0001 for difference between solriamfetol and placebo. CGI-C = Clinical Global Impression of Change scale; PGI-C = Patient Global Impression of Change scale.