Efficacy, Safety and Tolerability of Low Sodium Oxybate for Nocturnal Cluster Headache Attacks

Overview

The goal of this clinical trial is to evaluate the efficacy of low sodium oxybate (LXB) (brand name Xywav) in the treatment of (nocturnal) cluster headache attacks in subjects with chronic cluster headache. It is an 16 week, randomized, double-blind, placebo- controlled, bi-center trial. LXB will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. The main trial endpoint is the change from baseline in average weekly frequency of nocturnal cluster headache attacks over 4-week fixed stable dose of treatment period.

The exact aetiology of cluster headache remains unknown and fundamental questions are still unanswered. However, the tendency of cluster headache attacks to occur during sleep suggests a pivotal role of the hypothalamus, a brain structure that regulates essential body functions such as sleep and the biological clock. Low sodium oxybate (LXB) is a naturally occurring neurotransmitter and a psychoactive substance that deepens sleep by increasing slow wave sleep and reducing Rapid eye movement (REM) sleep. The chemical name of oxybate is gamma-hydroxybutyrate (GHB). The mechanism of action of LXB is still unknown. It is hypothesized that the therapeutic effects are mediated through GABA-B actions during sleep at noradrenergic and dopaminergic neurons, as well as at thalamocortical neurons. We hypothesize that cluster headache attacks occur in relation to specific characteristics and time-points of the sleep microstructure and expect that a sleep-deepening treatment with LXB will reduce nocturnal attack-frequency and thereby improve sleep and quality of life. The main objective of this study is to evaluate the efficacy and safety of LXB in the treatment of nocturnal cluster headache attacks in subjects with chronic cluster headache. The main trial endpoint is the change from baseline in average weekly frequency of nocturnal cluster headache attacks over 4-week fixed stable dose of treatment period. Nocturnal attacks are defined as occurring after sleep onset during the night until morning awakening between 22:00 and 08:00. Secondary endpoints include change from baseline in weekly frequency of cluster headache attacks in a 24-hr period (both nocturnal and day-time attacks) over 4-week fixed stable dose of treatment period. Additionally, the i) percentage of participants with a ≥50% reduction from baseline in the weekly number of nocturnal cluster headache attacks, ii) percentage of participants with a ≥50% reduction from baseline in the weekly number of cluster headache attacks in a 24-hr period (both nocturnal and day-time attacks) and iii) cluster headache attack pain intensity will be assessed over the 4-week fixed stable dose of treatment period, iv) Mean change in weekly number of times an abortive medication was taken v) number of patients with improvement in Patient Global Impressions Scale (PGIc) and Clinical Global Impressions Scale (CGIc) vi) improvement of sleep quality, sleep onset, sleep maintenance and sleep efficiency by diary. Optionally, two wearable skin sensors (Actiheart and CALERA Research) will be added for objective sleep and circadian rhythm measurements (including tri-axonal actigraphy, heart rate variability, core body temperature).