Ketamine + Magnesium for Chronic Cluster Headache (KETALGIA)

Study Overview
=================
Brief 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. 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.

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

Conditions
-----------------
Refractory Chronic Cluster Headache

Intervention / Treatment
-----------------
* Drug: Ketamine + Magnesium sulfate (drug combination)


Participation Criteria
=================
Eligibility Criteria
-----------------
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)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: patients will be randomised with 1:1 ratio
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine + Magnesium<br>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)<br>* A single infusion will be performed over 2 hours with 90 days follow-up.<br>|
| Active Comparator: Control<br>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)<br>* A single infusion will be performed over 2 hours with 90 days follow-up.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of 50% responders | 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 the proportion of patients with at least 50% daily attacks decrease between the 7 days before infusion and days 7 and 8 after infusion | Day 7 | 
| Proportion of 50% responders | 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 the proportion of patients with at least 50% daily attacks decrease between the 7 days before infusion and days 7 and 8 after infusion | Day 8 | 

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 | 
| attacks intensity | evaluated on the electronic diary for each attack using a numeric rating scale (NRS), will be compared between the 7 days before infusion and the day 7 after infusion | day 7 | 
| attacks intensity | evaluated on the electronic diary for each attack using a numeric rating scale (NRS), will be compared between the 7 days before infusion and the day 8 after infusion | day 8 | 
| 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 8 | 
| 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 29 | 
| 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 | 
| Proportion of patients necessitating rescue therapy | Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium) | 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 | 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 29 | 
| 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 of depression (evaluated via the HAD scale) between groups | Day 29 | 
| depression evolution | comparison ofdepression (evaluated via the HAD scale) between groups | Day 90 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Chronic cluster headache, Ketamine, Magnesium