Chronic Cluster HeadachePhase 2SUNCETNCT06950281
Efficacy, Safety and Tolerability of Low Sodium Oxybate for Nocturnal Cluster Headache Attacks
A Phase 2 study testing Low Sodium Oxybate in people with Chronic Cluster Headache, run by Leiden University Medical Center.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Chronic Cluster Headache
- What is being tested?
- Low Sodium Oxybate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 52 participants
- Where
- No sites listed yet
- Study dates
- Dec 2026to May 2029
- Phase
- Phase 2
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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 <50kg or >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.
Show all 17Show fewer
- 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.
Trial locations and contacts
No sites are listed yet. Contact the study team or a site near you to ask about taking part.
About this study
Official title: Low Sodium Oxybate Use for Nocturnal Cluster Headache: Safety, Efficacy and Tolerability of JZP-258 (XYWAV) - a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Bi-center Study.
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.
Read the detailed description
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, comparing the LXB group with the placebo group. Nocturnal attacks are defined as attacks occurring between the time a participant goes to bed and the time they get out of bed, with a minimum window of 8 hours after bedtime.
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).
- Conditions
- Chronic Cluster Headache
- Being tested
- Low Sodium Oxybate, Placebo
- Medical subject headings
- Cluster Headache
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Low Sodium OxybateDrug
Also called XYWAV, JZP-258
Low sodium oxybate (LXB) will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. Titration should proceed in an increment of 1.5g per night each 7 days until a 50% reduction in nocturnal headache frequency is achieved or a maximum dose (9g per night) is reached. If a subject is unable to titrate to a higher dose, they may stay at the highest tolerated dose for the duration of the study. Subjects may stop titration or have dose reduction at any time for safety and tolerability reasons.
PlaceboDrug
Placebo with equal appearance
| Study group | Role | What they receive |
|---|---|---|
| Verum | Experimental | Low Sodium Oxybate (LXB) In this study we will use XYWAV, also known as JZP-258, oral solution 0.5 g/mL (Jazz Pharmaceuticals) for deepening sleep. JZP-258 is an oral solution containing LXB and is a central nervous system depressant. LXB will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. Receives: Drug: Low Sodium Oxybate |
| Placebo | Placebo comparator | Placebo will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in average weekly frequency of nocturnal cluster headache attacks (verum vs placebo)
During 4-week fixed stable dose treatment phase compared to baseline. Nocturnal attacks are defined as attacks occurring between the time a participant goes to bed and the time they get out of bed, with a minimum window of 8 hours after bedtime.
(verum vs placebo)
Measured: During 4-week fixed stable dose treatment phase
Secondary outcomes (6)
Change in percentage of participants with a ≥30% reduction in the weekly number of nocturnal Cluster Headache Attacks
At week during 4-week fixed stable dose treatment phase compared to baseline.
Measured: During 4-week fixed stable dose
Change in percentage of participants with a ≥50% reduction in the weekly number of nocturnal Cluster Headache Attacks
During 4-week fixed stable dose treatment phase compared to baseline.
Measured: During 4-week fixed stable dose
Change in weekly frequency of cluster headache attacks in a 24-hr period during
During a 4-week fixed stable dose treatment phase compared to baseline.
Measured: During a 4-week fixed stable dose
Change in percentage of participants with a ≥30% reduction in the weekly number of cluster headache attacks in a 24-hr period (daytime and nocturnal attacks)
During 4-week fixed stable dose treatment phase compared to baseline.
Measured: During 4-week fixed stable dose
Change in percentage of participants with a ≥50% reduction in the weekly number of cluster headache attacks in a 24-hr period (daytime and nocturnal attacks)
During 4-week fixed stable dose treatment phase compared to baseline.
Measured: During 4-week fixed stable dose
Change in pain scale (NRS 0-10)
During 4-week fixed stable dose treatment phase compared to baseline.
Measured: During 4-week fixed stable dose
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted30 Apr 2025
- Study startDec 2026 (estimated)
- Primary completionDec 2028 (estimated)
- Study completionMay 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Cluster HeadacheStudies of the same condition, open and under way.
- More trials run by Leiden University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- A 16 week, randomized, double-blind, placebo- controlled study.
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 52 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Leiden University Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Rolf Fronczek, Leiden University Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06950281
- Sponsor's protocol ID
- 136324
- Acronym
- SUNCET
- Status last verified
- Aug 2026
- First submitted
- 15 Apr 2025
- Last updated
- 25 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Publications
van Liefland M, van Tilborg PJ, Szmukala M, Zhang Z, Kramers C, Lammers GJ, Khatami R, Fronczek R. Efficacy, safety, and tolerability of low sodium oxybate for nocturnal cluster headache attacks in chronic cluster headache: protocol for a phase II randomized, double-blind, placebo-controlled, trial (SUNCET). Pain Manag. 2026 Jul;16(7):703-711. doi: 10.1080/17581869.2026.2660895. Epub 2026 Apr 20.
PubMed 42003380
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Low Sodium Oxybate Use for Nocturnal Cluster Headache: Safety, Efficacy and Tolerability of JZP-258 (XYWAV) - a Phase 2 Randomized, Double-Blind, Placebo-Controlled, Bi-center Study.
- ClinicalTrials.gov ID
- NCT06950281
- Acronym / sponsor ID
- SUNCET / 136324
- Conditions
- Chronic Cluster Headache
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 52 participants (estimated)
- Lead sponsor
- Leiden University Medical CenterUniversity, hospital or other
- Study start
- Dec 2026 (estimated)
- Primary completion
- Dec 2028 (estimated)
- Study completion
- May 2029 (estimated)
- First posted
- 30 Apr 2025 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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, comparing the LXB group with the placebo group. Nocturnal attacks are defined as attacks occurring between the time a participant goes to bed and the time they get out of bed, with a minimum window of 8 hours after bedtime.
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).
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- A 16 week, randomized, double-blind, placebo- controlled study.
| Arm | Type | Receives |
|---|---|---|
| Verum | Experimental | Drug: Low Sodium OxybateLow Sodium Oxybate (LXB) In this study we will use XYWAV, also known as JZP-258, oral solution 0.5 g/mL (Jazz Pharmaceuticals) for deepening sleep. JZP-258 is an oral solution containing LXB and is a central nervous system depressant. LXB will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. |
| Placebo | Placebo comparator | Drug: PlaceboPlacebo will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. |
Who may qualify
- Ages
- 18 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (17 listed)
- 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 <50kg or >120kg.
- Significant active or unstable psychiatric disease in the opinion of the investigator.
- Significant pulmonary or neuromuscular diseases in the opinion of the investigator.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Low Sodium OxybateAlso: XYWAV, JZP-258Low sodium oxybate (LXB) will be administered as a twice nightly regimen. All subjects will undergo an 6 week Treatment Titration and Optimization Phase. Titration should proceed in an increment of 1.5g per night each 7 days until a 50% reduction in nocturnal headache frequency is achieved or a maximum dose (9g per night) is reached. If a subject is unable to titrate to a higher dose, they may stay at the highest tolerated dose for the duration of the study. Subjects may stop titration or have dose reduction at any time for safety and tolerability reasons. | Drug | Verum |
| PlaceboPlacebo with equal appearance | Drug | Placebo |
Primary outcome
Change in average weekly frequency of nocturnal cluster headache attacks (verum vs placebo)
Time frame: During 4-week fixed stable dose treatment phase
During 4-week fixed stable dose treatment phase compared to baseline. Nocturnal attacks are defined as attacks occurring between the time a participant goes to bed and the time they get out of bed, with a minimum window of 8 hours after bedtime. (verum vs placebo)
6 secondary outcomes
Change in percentage of participants with a ≥30% reduction in the weekly number of nocturnal Cluster Headache Attacks
Time frame: During 4-week fixed stable dose
Change in percentage of participants with a ≥50% reduction in the weekly number of nocturnal Cluster Headache Attacks
Time frame: During 4-week fixed stable dose
Change in weekly frequency of cluster headache attacks in a 24-hr period during
Time frame: During a 4-week fixed stable dose
Change in percentage of participants with a ≥30% reduction in the weekly number of cluster headache attacks in a 24-hr period (daytime and nocturnal attacks)
Time frame: During 4-week fixed stable dose
Change in percentage of participants with a ≥50% reduction in the weekly number of cluster headache attacks in a 24-hr period (daytime and nocturnal attacks)
Time frame: During 4-week fixed stable dose
Change in pain scale (NRS 0-10)
Time frame: During 4-week fixed stable dose
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Aug 2026.
- Derived from this study: PubMed 42003380van Liefland M, van Tilborg PJ, Szmukala M, Zhang Z, Kramers C, Lammers GJ, Khatami R, Fronczek R. Efficacy, safety, and tolerability of low sodium oxybate for nocturnal cluster headache attacks in chronic cluster headache: protocol for a phase II randomized, double-blind, placebo-controlled, trial (SUNCET). Pain Manag. 2026 Jul;16(7):703-711. doi: 10.1080/17581869.2026.2660895. Epub 2026 Apr 20.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Low Sodium Oxybate in people with Chronic Cluster Headache, run by Leiden University Medical Center.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 25 Aug 2026. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Martien van Liefland, MD (+31 71 5262587, SUNCET@lumc.nl), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in average weekly frequency of nocturnal cluster headache attacks (verum vs placebo) (time frame: During 4-week fixed stable dose treatment phase). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT06950281, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Aug 2026.