Ketamine + Magnesium for Chronic Cluster Headache (KETALGIA) (KETALGIA)

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.

Study Overview

• Status: Completed
• Conditions: Refractory Chronic Cluster Headache
• Intervention / Treatment: Drug: Ketamine + Magnesium sulfate (drug combination)

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 Type: Interventional
• Enrollment (Actual): 93
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Annecy, France, 74370
    • CH Annecy Genevois
  • Bruges, France, 33520
    • Polyclinique Jean Villar
  • Clermont-Ferrand, France, 63000
    • CHU de Clermont-Ferrand
  • Lille, France, 59000
    • CHRU de Lille
  • Lyon, France, 69500
    • Hospices civils de Lyon, Hôpital Pierre Wertheimer
  • Marseille, France, 13005
    • AP-HM Marseille
  • Montpellier, France, 34070
    • Clinique Beau Soleil
  • Montpellier, France, 34295
    • CHU de Montpellier
  • Nantes, France, 44000
    • CHU Nantes, Hopital Nord Laennec
  • Paris, France, 75010
    • Hopital Lariboisiere
  • Rouen, France, 76100
    • CHU Rouen
  • Strasbourg, France, 67098
    • Hôpital de Hautepierre
  • Toulouse, France, 31059
    • Hopital Pierre Paul Riquet
  • Voiron, France, 38500
    • CHU Grenoble-Alpes

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ketamine + Magnesium; 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%.	Drug: Ketamine + Magnesium sulfate (drug combination); A single infusion will be performed over 2 hours with 90 days follow-up.
Active Comparator: Control; 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	Drug: Ketamine + Magnesium sulfate (drug combination); A single infusion will be performed over 2 hours with 90 days follow-up.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	pre-treatment period and day 7-day 13 post-treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of 30% responders	proportion of 30% responders at various time points according to the attack diary	day 7 to day 90
Proportion of 50% responders	proportion of 50% responders at various time points according to the attack diary	day 7 to day 90
Proportion of 75% responders	proportion of 75% responders at various time points according to the attack diary	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)	day 0 to day 90
patient global impression of change (PGIC)	PGIC will be completed and compared between the 2 groups	Day 15
patient global impression of change (PGIC)	PGIC will be completed and compared between the 2 groups	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)	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)	day 1
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	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	day 8
Attacks treatment consumption	Daily attacks treatment consumption (injectable sumatriptan and oxygene)	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	day 0 to day 90
Anxiety evolution	comparison of anxiety (evaluated via the HAD scale) between groups	Day 15
Anxiety evolution	comparison of anxiety (evaluated via the HAD scale) between groups	Day 90
depression evolution	comparison of depression (evaluated via the HAD scale) between groups	Day 15
depression evolution	comparison ofdepression (evaluated via the HAD scale) between groups	Day 90
Proportion of patients necessitating rescue therapy	Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium)	Day 15
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.	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.	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.	pre-treatment period and day 28 - day 34 post-treatment period
Adverse events assessment		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.	Day 0

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand
• Collaborators: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Xavier MOISSET, University Hospital, Clermont-Ferrand

Study record dates

Study Major Dates

• Study Start (Actual): September 15, 2021
• Primary Completion (Actual): December 23, 2025
• Study Completion (Actual): December 23, 2025

Study Registration Dates

• First Submitted: March 18, 2021
• First Submitted That Met QC Criteria: March 22, 2021
• First Posted (Actual): March 24, 2021

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Ketamine; Magnesium; Chronic cluster headache
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Headache Disorders, Primary; Headache Disorders; Trigeminal Autonomic Cephalalgias; Cluster Headache; Sulfur Compounds; Organic Chemicals; Pharmaceutical Preparations; Hydrocarbons; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Inorganic Chemicals; Sulfur Acids; Sulfates; Sulfuric Acids; Magnesium Compounds; Ketamine; Magnesium Sulfate; Drug Combinations
• Other Study ID Numbers: RBHP 2020 MOISSET; 2020-003604-14 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No