AbstractObjectiveTo evaluate the impact of solriamfetol, a dopamine and norepinephrine reuptake inhibitor, on on‐the‐road driving performance in participants with narcolepsy.MethodsIn this randomised, double‐blind, placebo‐controlled, crossover study, driving performance during a 1 h on‐road driving test was assessed at 2 and 6 h post‐dose following 7 days of treatment with solriamfetol (150 mg/day for 3 days, followed by 300 mg/day for 4 days) or placebo. The primary endpoint was standard deviation of lateral position (SDLP) at 2 h post‐dose.ResultsThe study included 24 participants (54% male; mean age, 40 years); 22 had evaluable SDLP data. At 2 h post‐dose, median SDLP was significantly lower (improved) with solriamfetol compared with placebo (19.08 vs. 20.46 cm [median difference, −1.9 cm], p = 0.002). Four participants on solriamfetol and 7 on placebo had incomplete driving tests. At 6 h post‐dose, median SDLP was not statistically significantly different with solriamfetol compared with placebo (19.59 vs. 19.78 cm [median difference, −1.1 cm], p = 0.125). Three participants on solriamfetol and 10 on placebo had incomplete driving tests. Common adverse events (≥5%) included headache, decreased appetite, and somnolence.ConclusionsSolriamfetol 300 mg/day improved on‐the‐road driving performance, at 2 h post‐administration in participants with narcolepsy.