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Completed

NCT Number: NCT04814381

Ketamine + Magnesium for Chronic Cluster Headache (KETALGIA)

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.

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Key information

Conditions

Refractory Chronic Cluster Headache Brain Diseases Central Nervous System Diseases Cluster Headache Headache Disorders Headache Disorders, Primary Nervous System Diseases Trigeminal Autonomic Cephalalgias

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

CH Annecy Genevois, Annecy, France

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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

Exclusion criteria

  • 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)

Treatment and study plan

Ketamine + Magnesium sulfate (drug combination)

Drug

A single infusion will be performed over 2 hours with 90 days follow-up.

Primary outcomes

  1. 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

Secondary outcomes

  1. Proportion of 30% responders

    Time frame: day 7 to day 90

    proportion of 30% responders at various time points according to the attack diary

  2. Proportion of 50% responders

    Time frame: day 7 to day 90

    proportion of 50% responders at various time points according to the attack diary

  3. Proportion of 75% responders

    Time frame: day 7 to day 90

    proportion of 75% responders at various time points according to the attack diary

  4. week by week attacks frequency

    Time frame: day 0 to day 90

    Area under the curve (AUC) for daily attacks evaluated each week between D0 and D90 (attacks diary)

  5. patient global impression of change (PGIC)

    Time frame: Day 15

    PGIC will be completed and compared between the 2 groups

  6. patient global impression of change (PGIC)

    Time frame: Day 90

    PGIC will be completed and compared between the 2 groups

  7. Infusion's safety

    Time frame: day 0

    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)

  8. Infusion's safety

    Time frame: day 1

    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)

  9. Proportion of patients necessitating rescue therapy

    Time frame: Day 15

    Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium)

  10. Treatment response according to initial magnesemia

    Time frame: day 7

    magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment

  11. Treatment response according to initial magnesemia

    Time frame: day 8

    magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment

  12. Attacks treatment consumption

    Time frame: day 0 to day 90

    Daily attacks treatment consumption (injectable sumatriptan and oxygene)

  13. Direct medical cost

    Time frame: day 0 to day 90

    Direct medical cost (treatments, consultations, hospitalisations) in each group and cost effectiveness ratio taking 50% responder rate as efficacy criteria

  14. Anxiety evolution

    Time frame: Day 15

    comparison of anxiety (evaluated via the HAD scale) between groups

  15. Anxiety evolution

    Time frame: Day 90

    comparison of anxiety (evaluated via the HAD scale) between groups

  16. depression evolution

    Time frame: Day 15

    comparison of depression (evaluated via the HAD scale) between groups

  17. depression evolution

    Time frame: Day 90

    comparison ofdepression (evaluated via the HAD scale) between groups

  18. 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

    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.

  19. 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

    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.

  20. 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

    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.

  21. Adverse events assessment

    Time frame: D0 to D90

  22. assessment of blind quality

    Time frame: Day 0

    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.

Sponsors and collaborators

Lead sponsor

University Hospital, Clermont-Ferrand

Other

Collaborators

  • Institut National de la Santé Et de la Recherche Médicale, France

Registry information

Official study title

Evaluation of the Efficacy of a Single Infusion of Ketamine Combined With Magnesium Sulfate to Treat Refractory Chronic Cluster Headache

Acronym: KETALGIA

Important dates

Study start
2021
Primary completion
2025
Study completion
2025
First posted
Mar 24, 2021
Registry last updated
May 8, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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