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

Am J Respir Crit Care Med. 2019 Jun 1;199(11):1421-1431. doi: 10.1164/rccm.201806-1100OC.


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 (NCT02348606) and (EudraCT 2014-005514-31).

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

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carbamates / therapeutic use*
  • Disorders of Excessive Somnolence / drug therapy*
  • Disorders of Excessive Somnolence / etiology*
  • Dopamine Uptake Inhibitors / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Norepinephrine Plasma Membrane Transport Proteins / drug effects*
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / therapeutic use
  • Sleep Apnea, Obstructive / complications*


  • Carbamates
  • Dopamine Uptake Inhibitors
  • Norepinephrine Plasma Membrane Transport Proteins
  • SLC6A2 protein, human
  • Phenylalanine
  • solriamfetol

Associated data

  • EudraCT/2014-005514-31