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Sodium Oxybate for Nocturnal Cluster Headache Attacks in Adults with Chronic Cluster Headache: A Phase 2 Randomized, Double‑Blind, Placebo‑Controlled Study

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on Cluster headache, a disorder that causes severe, one‑sided head pain often around the eye and can occur during the night while a person is in bed. The treatment being tested is an oral solution of low sodium oxybate (XYWAV), a medication taken by mouth that is thought to influence sleep patterns and may help reduce the number of nighttime headache attacks.

The purpose of the study is to determine whether the medication can lower the frequency of nocturnal attacks in people with chronic Cluster headache. Participants will be randomly assigned to receive either the active medication or a matching placebo, and neither the participants nor the study staff will know which one is given. The medication will be taken twice each night for about four weeks, with regular visits to check health status and record headache occurrences.

Throughout the trial, safety will be monitored by measuring vital signs such as blood pressure, checking weight, and asking participants to complete simple questionnaires about mood, sleep quality, and overall well‑being. Any side effects, also called adverse events, will be recorded, and participants will keep a diary of their headaches and any rescue medicines they use, such as oxygen or triptans.

The research process

The trial runs in 5 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and receipt of study medication

    After joining the study, you will be assigned by a computer system to receive either low sodium oxybate or a placebo. the assignment is unknown to you and the study staff.

    The medication is provided as an oral solution. each dose contains 9 g of the active substance (or an identical inactive solution for the placebo). you will be instructed to take the dose once each night for the next four weeks.

  2. Step 2

    Daily dosing

    Each night, after you go to bed, you will measure the prescribed amount of the oral solution and swallow it as directed.

    The dose should be taken within the first eight hours after bedtime, because the study focuses on attacks that occur while you are sleeping.

    The medication is taken only once per day and should not be taken at any other time.

  3. Step 3

    Recording headache information

    You will keep a simple diary that you fill in each day. in the diary you will note every nocturnal cluster headache attack, the time it started, how long it lasted, and the pain level on a scale from 0 to 10.

    The diary also includes any daytime attacks, use of rescue medication such as oxygen or triptans, and any side effects you notice.

    The information helps the study assess how the medication changes the frequency and severity of attacks.

  4. Step 4

    Scheduled safety assessments

    During the four‑week treatment period you will attend study visits at the beginning, at week two, and at the end of week four.

    At each visit the study staff will perform safety assessments that include measuring vital signs (blood pressure, heart rate), a brief physical examination that also records weight, and a sleep apnoea screening questionnaire (STOP‑Bang).

    If applicable, a urine pregnancy test will be done to ensure safety.

    You will complete two questionnaires: the Patient Health Questionnaire‑9 (PHQ‑9) for signs of depression and the Columbia‑Suicide Severity Rating Scale (C‑SSRS) for any thoughts of self‑harm.

    Any treatment‑emergent adverse events (new side effects) that you experience will be recorded and evaluated.

  5. Step 5

    End of treatment and final evaluation

    After completing the four‑week dosing period you will return any remaining medication to the study site.

    A final visit will be scheduled to repeat the safety assessments, collect the last diary entries, and answer any remaining questions.

    The study will then analyze the data to determine how the medication affected nocturnal cluster headache attacks and overall safety.

Who can join the trial?

5 criteria

  • Be at least 18 years old and not older than 75 years when you agree to join the study.
  • Have a diagnosis of chronic cluster headache that meets the standards of the International Classification of Headache Disorders (ICHD‑III) – a set of rules doctors use to define this type of headache.
  • Either not be taking any other prophylactic medication (medicine that prevents headaches) for cluster headaches, or be on a stable dose of such medicine for at least 4 weeks without changes.
  • Not have received a Greater Occipital Nerve (GON) injection in the 6 weeks before joining – this is a specific injection given near the back of the head to try to reduce headaches.
  • Experience at least 4 nighttime (nocturnal) cluster headache attacks each week. “Nighttime” means the attacks start after you fall asleep and happen while you are still in bed, with a minimum window of 8 hours after you go to sleep, and the attacks should occur on several different nights, not just one night.

Who cannot join the trial?

15 criteria

  • If you might have another type of headache called a trigeminal autonomic cephalalgia (TAC) and cannot tell it apart from a cluster headache, you cannot join.
  • If you have sleep apnea (a condition where breathing stops briefly during sleep) or an apnea index higher than 15 events per hour.
  • If a screening tool called the STOP‑Bang questionnaire shows you are at high risk for sleep apnea (score of 5 or more).
  • If you have severe depression and are taking medication for it or receiving cognitive therapy (talk therapy that changes thinking patterns).
  • If you have porphyria (a rare disorder that affects the blood’s ability to make heme, a part of hemoglobin).
  • If you have succinic semialdehyde dehydrogenase (SSADH) deficiency (a rare metabolic disorder).
  • If you are currently using any of the following medicines: opiates (pain medicines like morphine), barbiturates (sedatives), valproic acid, phenytoin, ethosuximide, tricyclic antidepressants, topiramate, any form of sodium oxybate other than the study dose, or any sedative such as benzodiazepines (e.g., Valium). Benzodiazepines must be stopped at least one week before the study starts.
  • If your body weight is less than 50 kg (about 110 lb) or more than 120 kg (about 265 lb).
  • If you have serious lung (pulmonary) disease or a serious nerve‑muscle (neuromuscular) disease, as judged by the doctor.
  • If you have an active or unstable mental health condition (psychiatric disease) that the doctor considers significant.
  • If you have a past or current problem with substance abuse or a substance use disorder (misuse of alcohol, drugs, etc.).
  • If you are not willing to limit alcohol to no more than one standard drink per day and stop drinking by 8 pm each evening.
  • If you have a device that can affect sleep or cluster headaches, such as an occipital nerve stimulator (ONS), and its settings have not been stable for at least six weeks before screening.
  • If you have taken part in another clinical trial of a drug or device within the last 30 days.
  • If you are a woman who is pregnant, breastfeeding, or not willing to use reliable birth control methods during the study.
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Investigated drugs

Sodium Oxybate (XYWAV) is an oral liquid medication that contains a low‑sodium form of sodium oxybate. In this study it is being tested as a treatment taken at night to help reduce the number and severity of cluster headache attacks that occur while sleeping. The medicine works by influencing brain pathways that control sleep and pain, which may make headache episodes less frequent and less intense. Researchers are looking at how well it works, how safe it is, and how well patients can tolerate it when used over the study period.

What is already known about the treatment

Sodium Oxybate - Sodium oxybate is taken as an oral solution, usually 9 g taken at night, and is absorbed through the mouth. It is an approved medication for cataplexy and excessive daytime sleepiness in narcolepsy and is being studied for cluster headache, so it is well known in medical literature. The drug helps reduce painful cluster headache attacks by calming brain activity that controls sleep and pain signals. It belongs to the class of central nervous system depressants and works by increasing levels of the neurotransmitter GABA at its receptors.

Investigated diseases

Cluster headache - Cluster headache is a neurological disorder that causes intense, brief pain around one eye or temple. The pain occurs in groups, called clusters, which can last for weeks or months and are followed by periods without attacks. During a cluster period, attacks often happen at the same time each day, frequently during the night. The frequency and intensity of attacks may increase over the cluster phase before they subside.
Trial detailsLast updated 7 Oct 2026
Age18+ yearsPhasePhase IITrial ID2025-523293-17-00Estimated enrolment52 patientsSponsorLeids Universitair Medisch Centrum (LUMC)

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