Novel biomarkers derived from the Maintenance of Wakefulness Test as predictors of sleepiness and response to treatment

Abstract

The Maintenance of Wakefulness Test (MWT) is a widely accepted objective test used to evaluate daytime somnolence and is commonly used in clinical studies evaluating novel therapeutics for excessive daytime sleepiness. In the latter, sleep onset latency (SOL) is typically the sole MWT endpoint. Here, we explored microsleeps, sleep probability measures derived from automated sleep scoring, and quantitative electroencephalography (qEEG) features as additional MWT biomarkers of daytime sleepiness, using data from a phase 1B trial of the selective orexin receptor 2 agonist danavorexton (TAK-925) in people with narcolepsy type 1 (NT1) or type 2 (NT2). Danavorexton treatment reduced the rate and duration of microsleeps during the MWT in NT1 (days 1 and 7; p ≤ .005) and microsleep rate in NT2 (days 1 and 7; p < .0001). The use of an EEG-sleep-staging - derived measure to determine the probability of wakefulness for each minute revealed a novel metric to track changes in daytime sleepiness, which were consistent with the θ/α ratio, a known biomarker of drowsiness. The slopes of line-fits to both the log-transformed sleepiness score or log-transformed θ/α ratio correlated well to (inverse) MWT SOL for NT1 (R = 0.93 and R = 0.83, respectively) and NT2 (R = 0.97 and R = 0.84, respectively), suggesting that individuals with narcolepsy have increased sleepiness immediately after lights-off. These analyses demonstrate that novel EEG-based biomarkers can augment SOL as predictors of sleepiness and its response to treatment and provide a novel framework for the analysis of wake EEG in hypersomnia disorders.

Keywords: MWT; TAK-925; danavorexton; excessive daytime sleepiness; hypnodensity; maintenance of wakefulness; narcolepsy; orexin; qEEG; sleep onset latency.

Graphical Abstract

Figure 1.

Maintenance of Wakefulness Test (MWT) sleep onset latency (SOL) and microsleep metrics by treatment group and day for participants with narcolepsy type 1 (NT1) (A, C, E) and narcolepsy type 2 (NT2; B, D, F). SOL (A, B) shows a clear treatment effect. A siesta effect was apparent at 02:00 pm in NT1 and NT2, also visible without treatment. Microsleep rate (C, D) decreases greatly during treatment, with microsleeps basically eliminated on day 1. Microsleep duration (E, F) is also reduced in the NT1 cohort. Cohort values: Bp, T1 placebo; B1, NT1 11 mg danavorexton; B2, NT1 44 mg danavorexton; Cp, NT2 placebo; C1, NT2 44 mg danavorexton; C2, NT2 112 mg danavorexton. One epoch, 30 seconds.

Figure 2.

Log-transformed sleepiness scores (A, B) and θ/α ratios (C, D) for an example participant with narcolepsy type 1 (cohort B1), for all 4 MWT sessions on the baseline visit day (A, C) and on treatment day 7 (B, D). Each line shows the response versus time during a single Maintenance of Wakefulness Test session. Note that treatment increases the time subjects remain awake, so the time duration on day 7 is much longer. Also, note the general consistency between sleepiness scores and θ/α ratio values.

Figure 3.

Changes in electroencephalogram-derived Maintenance of Wakefulness Test endpoints, by treatment group and day, for participants with narcolepsy type 1 (NT1) (A, C) and narcolepsy type 2 (NT2; B, D): (A, B) slopes of sleepiness scores and (C, D) θ/α ratios. Cohort values: Bp, NT1 placebo; B1, NT1 11 mg danavorexton; B2, NT1 44 mg danavorexton; Cp, NT2 placebo; C1, NT2 44 mg danavorexton; C2, NT2 112 mg danavorexton.

Figure 4.

Correlations between (A) sleepiness slope score and (B) microsleep rate with 1/(Maintenance of Wakefulness Test sleep onset latency [SOL]) for the narcolepsy type 1 (NT1) cohort. Each dot represents an individual participant/MWT session (note that analysis was limited to sessions in which the SOL was > 1 minute in order to improve the reliability of slope estimates). Cohort values: Bp, NT1 placebo; B1, NT1 11 mg danavorexton; B2, NT1 44 mg danavorexton. Regression lines are for visual guidance; correlations accounting for repeated measures within subjects are reported in Supplementary Tables S3 and S4.