Defining a Clinically Meaningful Within-Person Change Threshold for the Psychomotor Vigilance Test in Narcolepsy Type 1.

OBJECTIVES: To establish meaningful within-patient change (MWPC) thresholds for the Psychomotor Vigilance Test (PVT) and evaluate whether treatment with the orexin-2 receptor agonist oveporexton (TAK-861) achieved clinically meaningful improvements in attention in people with narcolepsy type 1 (NT1). METHODS: Attention was assessed as number of lapses (reaction times > 500 ms) on the PVT using data from 2 randomized placebo-controlled phase III trials, The First Light (N = 166) and The Radiant Light (N = 105). Anchor-based methods, supported by distribution-based methods, were used to derive MWPC estimates. Mean changes in square root-transformed PVT lapses (to account for data skewness) were calculated across anchor change categories, with weighted MWPC estimates derived across anchors. Estimates were confirmed with post-hoc receiver operating characteristic (ROC) curve analysis. The proportions of participants meeting MWPC criteria were compared between oveporexton and placebo arms, with odds ratios and 95% confidence intervals. RESULTS: Across both trials, participants reporting minimal, much, or very much improvement demonstrated progressively fewer PVT lapses. Anchor- and distribution-based analyses supported a reduction of ≥ - 2 PVT lapses, confirmed by ROC curves, as indicating a meaningful improvement in attention. Applying this threshold to unblinded samples, clinically meaningful improvement in attention at day 84 was reported in 66.9% of oveporexton-treated participants versus 25.7% of placebo-treated participants in The First Light and 57.6% versus 17.6% in The Radiant Light (both P ≤ 0.0001). CONCLUSIONS: Improvements in attention with oveporexton in people with NT1 were found to be clinically meaningful, with improvement of ≥ - 2 PVT lapses significantly more likely to occur with oveporexton versus placebo.