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

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 a 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.

Inclusion criteria Age ≥18 and ≤75 at the time of consent. Diagnosed with chronic cluster headache according to the International Classification of Headache Disorders (ICHD-III) criteria. Free of other cluster headache prophylactic medication OR on stable dose for at least 4 weeks. Not having received a GON (Greater Occipital Nerve) injection or oral prednisone in the previous 3 months. At least 4 nocturnal cluster headache attacks per week (defined as occurring after sleep onset during the night between 22:00 and 08:00), not exclusively appearing during a single night, but spread across multiple nights. Exclusion criteria Suspected of having another trigeminal autonomic cephalalgia (TAC). Other headaches if the patient cannot reliably distinguish them from cluster headache attacks. Weight at inclusion of \120kg. Significant active or unstable psychiatric disease in the opinion of the investigator. Significant pulmonary or neuromuscular diseases in the opinion of the investigator. A history of or current indication of substance abuse or substance use disorder. Unwillingness to refrain from consuming ≤ 1 alcohol unit per day and not later than 8 pm. Stimulator devices which could influence sleep or cluster headache symptoms, such as an occipital nerve stimulator (ONS), when settings have not been stable for at least three months prior to screening. Participation in a clinical trial of an investigation drug or device in the past 30 days. Women who are pregnant/breastfeeding. Woman of childbearing age need to agree to sufficient contraception during the trial. Contraindications for using LXB: * Sleep apnoea syndrome or increased apnoea index (AI \> 15/h). * High risk of sleep apnoea syndrome, indicated by the STOP-Bang questionnaire (score ≥ 5). * Currently suffering from severe depression and using medication or receiving cognitive therapy. Final choice is at the discretion of the principal investigator. * Porphyria. * Succinic semialdehyde dehydrogenase (SSADH-)deficiency. * Use of opiates, barbiturates, valproic acid, phenytoin, ethosuximide, tricyclic antidepressants, topiramate, LXB (except for the intervention dose) or sedatives including benzodiazepines during the study. If benzodiazepines are used prior to inclusion, they must be discontinued at least one week before the baseline phase.