Refractory Chronic Cluster HeadachePhase 4KETALGIANCT04814381
Ketamine + Magnesium for Chronic Cluster Headache (KETALGIA)
A Phase 4 study testing Ketamine + Magnesium sulfate (drug combination) in people with Refractory Chronic Cluster Headache, run by University Hospital, Clermont-Ferrand at 14 sites in France.
Trial summary
Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks. Read more about this study
- Who is it for?
- Ages 18 to 75 years
- Conditions the study is for
- Refractory Chronic Cluster Headache
- What is being tested?
- Ketamine + Magnesium sulfate (drug combination)
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 93 participants
- Where
- 14 sitesFrance
- Study dates
- 15 Sep 2021to 23 Dec 2025
- Phase
- Phase 4
- Are there results?
- None posted in the registry
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 years
- Chronic cluster headache diagnosis made according to ICHD-3 criteria
- A mean of at least 2 attacks/day during the 14 days before infusion
- Insufficient efficacy or intolerance or contra-indication to the use of the 3 main validated treatments (verapamil, lithium and sub-occipital steroids injections)
- Stable preventive treatment for at least 7 days before infusion
Who cannot join
- Pregnant or lactating woman
- Contra-indication to ketamine use (uncontrolled high blood pressure, stoke history, severe cardiac failure)
- Ketamine use during the previous year
- Hypersensitivity to the product or their metabolites
- Severe renal insufficiency (creatinine clearance < 30ml/min)
Trial locations and contacts
14 sites in 1 country.
14 sites in 1 country
France14 sites
CH Annecy Genevois
Annecy, 74370
Polyclinique Jean Villar
Bruges, 33520
CHU de Clermont-Ferrand
Clermont-Ferrand, 63000
CHRU De Lille
Lille, 59000
Hospices civils de Lyon, Hôpital Pierre Wertheimer
Lyon, 69500
AP-HM Marseille
Marseille, 13005
Clinique Beau Soleil
Montpellier, 34070
CHU de Montpellier
Montpellier, 34295
CHU Nantes, Hopital Nord Laennec
Nantes, 44000
Hôpital Lariboisière
Paris, 75010
CHU Rouen
Rouen, 76100
Hopital de Hautepierre
Strasbourg, 67098
Hopital Pierre Paul Riquet
Toulouse, 31059
CHU Grenoble-Alpes
Voiron, 38500
About this study
Official title: Evaluation of the Efficacy of a Single Infusion of Ketamine Combined With Magnesium Sulfate to Treat Refractory Chronic Cluster Headache
Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks.
Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.
Read the detailed description
Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks.
Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.
- Conditions
- Refractory Chronic Cluster Headache
- Being tested
- Ketamine + Magnesium sulfate (drug combination)
- Keywords
- Chronic cluster headache, Ketamine, Magnesium
- Medical subject headings
- Cluster Headache
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ketamine + Magnesium sulfate (drug combination)Drug
A single infusion will be performed over 2 hours with 90 days follow-up.
| Study group | Role | What they receive |
|---|---|---|
| Ketamine + Magnesium | Experimental | patients in the experimental group will receive 0.5mg/kg of ketamine over 2 hours, diluted in 50cc of NaCl 0.9% and 3g of magnesium sulfate over 30 minutes diluted in 250cc of NaCl 0.9%. Receives: Drug: Ketamine + Magnesium sulfate (drug combination) |
| Control | Active comparator | patients in the control group will receive 25mg of hydroxyzine over 2 hours, diluted in 50cc of NaCl 0.9% and 250cc of NaCl 0.9% over 30 minutes Receives: Drug: Ketamine + Magnesium sulfate (drug combination) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in weekly attacks between day 7 - day 13 period compared to the pre-treatment period
Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of weekly attacks between day 7 and day 13 period and pre-treatment period
Measured: pre-treatment period and day 7-day 13 post-treatment period
Secondary outcomes (22)
Proportion of 30% responders
proportion of 30% responders at various time points according to the attack diary
Measured: day 7 to day 90
Proportion of 50% responders
proportion of 50% responders at various time points according to the attack diary
Measured: day 7 to day 90
Proportion of 75% responders
proportion of 75% responders at various time points according to the attack diary
Measured: day 7 to day 90
week by week attacks frequency
Area under the curve (AUC) for daily attacks evaluated each week between D0 and D90 (attacks diary)
Measured: day 0 to day 90
patient global impression of change (PGIC)
PGIC will be completed and compared between the 2 groups
Measured: Day 15
patient global impression of change (PGIC)
PGIC will be completed and compared between the 2 groups
Measured: Day 90
Infusion's safety
proportion of patients in each group reporting any side effect during or in the 24 hours after infusion (together with the type and intensity of these side effects)
Measured: day 0
Infusion's safety
proportion of patients in each group reporting any side effect during or in the 24 hours after infusion (together with the type and intensity of these side effects)
Measured: day 1
Proportion of patients necessitating rescue therapy
Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium)
Measured: Day 15
Treatment response according to initial magnesemia
magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment
Measured: day 7
Treatment response according to initial magnesemia
magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment
Measured: day 8
Attacks treatment consumption
Daily attacks treatment consumption (injectable sumatriptan and oxygene)
Measured: day 0 to day 90
Direct medical cost
Direct medical cost (treatments, consultations, hospitalisations) in each group and cost effectiveness ratio taking 50% responder rate as efficacy criteria
Measured: day 0 to day 90
Anxiety evolution
comparison of anxiety (evaluated via the HAD scale) between groups
Measured: Day 15
Anxiety evolution
comparison of anxiety (evaluated via the HAD scale) between groups
Measured: Day 90
depression evolution
comparison of depression (evaluated via the HAD scale) between groups
Measured: Day 15
depression evolution
comparison ofdepression (evaluated via the HAD scale) between groups
Measured: Day 90
Change in weekly attacks between day 14 - day 20 period compared to the pre-treatment period
Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of weekly attacks between day 14 and day 20 post-reatment period and pre-treatment period. The number of weekly attacks will be evaluated using a attacks diary that patients will complete every day.
Measured: pre-treatment period and day 14 - day 20 post-treatment period
Change in weekly attacks between day 21 - day 27 period compared to the pre-treatment period
Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of weekly attacks between day 21 and day 27 post-reatment period and pre-treatment period. The number of weekly attacks will be evaluated using a attacks diary that patients will complete every day.
Measured: pre-treatment period and day 21 - day 27 post-treatment period
Change in weekly attacks between day 28 - day 34 period compared to the pre-treatment period
Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of weekly attacks between day 28 and day 34 post-treatment period and pre-treatment period. The number of weekly attacks will be evaluated using a attacks diary that patients will complete every day.
Measured: pre-treatment period and day 28 - day 34 post-treatment period
Adverse events assessment
Measured: D0 to D90
assessment of blind quality
A blinding questionnaire will be systematically used to assess the quality of the blind. It will be completed by each patient 30 minutes after the end of the 1st infusion at day 0 (Visit 1). The patient will be asked what treatment he thinks he has received.
Measured: Day 0
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Mar 2021
- Study start15 Sep 2021
- Primary completion23 Dec 2025
- Study completion23 Dec 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Refractory Chronic Cluster HeadacheStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- patients will be randomised with 1:1 ratio
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 93 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Hospital, Clermont-Ferrand
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Xavier MOISSET, Principal investigator, University Hospital, Clermont-Ferrand
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04814381
- Sponsor's protocol ID
- RBHP 2020 MOISSET
- Other IDs
- 2020-003604-14
- Acronym
- KETALGIA
- Status last verified
- May 2026
- First submitted
- 18 Mar 2021
- Last updated
- 8 May 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of the Efficacy of a Single Infusion of Ketamine Combined With Magnesium Sulfate to Treat Refractory Chronic Cluster Headache
- ClinicalTrials.gov ID
- NCT04814381
- Acronym / sponsor ID
- KETALGIA / RBHP 2020 MOISSET
- Conditions
- Refractory Chronic Cluster Headache
- Keywords
- Chronic cluster headache, Ketamine, Magnesium
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 93 participants (actual)
- Lead sponsor
- University Hospital, Clermont-FerrandUniversity, hospital or other
- Collaborators
- Institut National de la Santé Et de la Recherche Médicale, France
- Study start
- 15 Sep 2021 (actual)
- Primary completion
- 23 Dec 2025 (actual)
- Study completion
- 23 Dec 2025 (actual)
- First posted
- 24 Mar 2021 (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.
Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks.
Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.
Detailed description
Chronic cluster headache (CCH) is a rare primary headache disorder, defined by episodic attacks that occur for more than one year with no remission period or with remission periods lasting < 3 months (ICHD-3 criteria). In certain cases, CCH patients become drug-resistant and continue to suffer almost daily attacks.
Ketamine appears to be effective in a variety of chronic pain conditions, such as refractory headache, and can show an enhanced analgesic effect when combined with magnesium. A single infusion of ketamine-magnesium combination has been described to reduce attacks in 17 patients with rCCH. The main outcome was a comparison of the number of daily attacks two weeks prior to the infusion and one week after (days 7-8). The number of daily attacks decreased from 4.3±2.4 before treatment to 1.3±1.0 after treatment (p<0.001). 13/17 had at least 50% response. Thus, the goal of this placebo-controlled study is to try to confirm these findings.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Double blind (participant, investigator)
- Number of arms
- 2
- Model description
- patients will be randomised with 1:1 ratio
| Arm | Type | Receives |
|---|---|---|
| Ketamine + Magnesium | Experimental | Drug: Ketamine + Magnesium sulfate (drug combination)patients in the experimental group will receive 0.5mg/kg of ketamine over 2 hours, diluted in 50cc of NaCl 0.9% and 3g of magnesium sulfate over 30 minutes diluted in 250cc of NaCl 0.9%. |
| Control | Active comparator | Drug: Ketamine + Magnesium sulfate (drug combination)patients in the control group will receive 25mg of hydroxyzine over 2 hours, diluted in 50cc of NaCl 0.9% and 250cc of NaCl 0.9% over 30 minutes |
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 years
- Chronic cluster headache diagnosis made according to ICHD-3 criteria
- A mean of at least 2 attacks/day during the 14 days before infusion
- Insufficient efficacy or intolerance or contra-indication to the use of the 3 main validated treatments (verapamil, lithium and sub-occipital steroids injections)
- Stable preventive treatment for at least 7 days before infusion
Key exclusion criteria (5 listed)
- Pregnant or lactating woman
- Contra-indication to ketamine use (uncontrolled high blood pressure, stoke history, severe cardiac failure)
- Ketamine use during the previous year
- Hypersensitivity to the product or their metabolites
- Severe renal insufficiency (creatinine clearance < 30ml/min)
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 |
|---|---|---|
| Ketamine + Magnesium sulfate (drug combination)A single infusion will be performed over 2 hours with 90 days follow-up. | Drug | Control, Ketamine + Magnesium |
Primary outcome
Change in weekly attacks between day 7 - day 13 period compared to the pre-treatment period
Time frame: pre-treatment period and day 7-day 13 post-treatment period
Evaluate the efficacy of a single infusion of ketamine combined with magnesium sulfate compared to a control group receiving hydroxyzine (active placebo) in terms of weekly attacks between day 7 and day 13 period and pre-treatment period
22 secondary outcomes
Proportion of 30% responders
Time frame: day 7 to day 90
Proportion of 50% responders
Time frame: day 7 to day 90
Proportion of 75% responders
Time frame: day 7 to day 90
week by week attacks frequency
Time frame: day 0 to day 90
patient global impression of change (PGIC)
Time frame: Day 15
patient global impression of change (PGIC)
Time frame: Day 90
Infusion's safety
Time frame: day 0
Infusion's safety
Time frame: day 1
Proportion of patients necessitating rescue therapy
Time frame: Day 15
Treatment response according to initial magnesemia
Time frame: day 7
Treatment response according to initial magnesemia
Time frame: day 8
Attacks treatment consumption
Time frame: day 0 to day 90
Direct medical cost
Time frame: day 0 to day 90
Anxiety evolution
Time frame: Day 15
Anxiety evolution
Time frame: Day 90
depression evolution
Time frame: Day 15
depression evolution
Time frame: Day 90
Change in weekly attacks between day 14 - day 20 period compared to the pre-treatment period
Time frame: pre-treatment period and day 14 - day 20 post-treatment period
Change in weekly attacks between day 21 - day 27 period compared to the pre-treatment period
Time frame: pre-treatment period and day 21 - day 27 post-treatment period
Change in weekly attacks between day 28 - day 34 period compared to the pre-treatment period
Time frame: pre-treatment period and day 28 - day 34 post-treatment period
Adverse events assessment
Time frame: D0 to D90
assessment of blind quality
Time frame: Day 0
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2026.
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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. This study is not recruiting at the moment.
Xavier MOISSET principal investigator
University Hospital, Clermont-Ferrand
14 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Ketamine + Magnesium sulfate (drug combination) in people with Refractory Chronic Cluster Headache, run by University Hospital, Clermont-Ferrand at 14 sites in France.
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 5 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: finished, as of the sponsor's last update on 8 May 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 14 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. 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 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in weekly attacks between day 7 - day 13 period compared to the pre-treatment period (time frame: pre-treatment period and day 7-day 13 post-treatment period). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
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 8 May 2026.