0635 Modafinil vs Amphetamine-dextroamphetamine for Idiopathic Hypersomnia & Narcolepsy Type 2: A Non-inferiority Trial

Abstract Introduction Despite recent introduction of several FDA-approved treatments for narcolepsy, clinical management of narcolepsy type 2 (NT2) and idiopathic hypersomnia (IH) still relies heavily on treatment with modafinil and amphetamines. While modafinil has a strong recommendation for use in these disorders by the American Academy of Sleep Medicine, clinical trial evidence regarding efficacy of amphetamines is scarce. Methods We performed a 12-week, randomized, fully-blinded, non-inferiority trial to determine if amphetamine-dextroamphetamine was non-inferior to modafinil in people with IH and NT2. Eligible participants were randomized 1:1 to modafinil (starting 100 mg once daily, titrating as tolerated to maximum 200 mg twice daily) or amphetamine-dextroamphetamine (starting 10 mg once daily, titrating as tolerated to maximum 20 mg twice daily). The primary outcome was Epworth change from baseline. Secondary outcomes included Patient Global Impression of Change (PGI-C, for overall severity, sleepiness, sleep inertia, cognitive symptoms), the Hypersomnia Severity Index (HSI), and the Sleep Inertia Questionnaire (SIQ). Outcomes were collected at baseline, weeks 4, 8, and 12, with last observation carried forward in the case of missing responses or dropouts. Results 44 participants were randomized and took at least one dose of medication (75% with IH, 84% women, mean age 35.4 +/- 8.9). Although change in Epworth scores was similar between the two medications (5.0 +/- 2.7 points improved for modafinil group, 4.4 +/- 4.7 for amphetamine-dextroamphetamine), non-inferiority of amphetamine-dextroamphetamine was not demonstrated. However, amphetamine-dextroamphetamine was shown to be non-inferior to modafinil for several secondary outcomes, including PGI-C for cognitive symptoms and sleep inertia, change in HSI, and change in SIQ. Participants experiencing at least one adverse event was similar between groups (77.3% for each medication); dropouts due to adverse events were numerically but not statistically higher in the modafinil group (32% for modafinil, 9% for amphetamine-dextroamphetamine, p=0.13). Conclusion Amphetamine-dextroamphetamine is non-inferior to modafinil across a variety of disease measures included as secondary outcomes, but may not be non-inferior for sleepiness as measured by the Epworth. Depending on patient symptoms, this study provides evidence in support of amphetamine-dextroamphetamine. Support (if any) American Academy of Sleep Medicine Foundation, National Institutes of Health (UL1TR002378, NS111280)