Refractory Chronic Cluster Headache
Conditions
Keywords
Chronic cluster headache, Ketamine, Magnesium
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.
Interventions
A single infusion will be performed over 2 hours with 90 days follow-up.
Sponsors
Institut National de la Santé Et de la Recherche Médicale, France
University Hospital, Clermont-Ferrand
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
infusion will be prepared by a nurse that is not blinded to the treatment and will not take part to patient evaluation. Active and control treatments are of transparent colour and will not be recognisable.
Intervention model description
patients will be randomised with 1:1 ratio
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in weekly attacks between day 7 - day 13 period compared to the pre-treatment period | 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
| Measure | Time frame | Description |
|---|---|---|
| Proportion of 50% responders | day 7 to day 90 | proportion of 50% responders at various time points according to the attack diary |
| Proportion of 75% responders | day 7 to day 90 | proportion of 75% responders at various time points according to the attack diary |
| week by week attacks frequency | day 0 to day 90 | Area under the curve (AUC) for daily attacks evaluated each week between D0 and D90 (attacks diary) |
| patient global impression of change (PGIC) | Day 15 | PGIC will be completed and compared between the 2 groups |
| Infusion's safety | 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) |
| Proportion of patients necessitating rescue therapy | Day 15 | Proportion of patients necessitating rescue therapy (infusion of ketamine combined with magnesium) |
| Treatment response according to initial magnesemia | day 7 | magnesemia on the infusion day (D0) will be correlated with 50% response at D7-8 among patients receiving active treatment |
| Attacks treatment consumption | day 0 to day 90 | Daily attacks treatment consumption (injectable sumatriptan and oxygene) |
| Proportion of 30% responders | day 7 to day 90 | proportion of 30% responders at various time points according to the attack diary |
| Anxiety evolution | Day 15 | comparison of anxiety (evaluated via the HAD scale) between groups |
| depression evolution | Day 15 | comparison of depression (evaluated via the HAD scale) between groups |
| Change in weekly attacks between day 14 - day 20 period compared to the pre-treatment period | 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. |
| Change in weekly attacks between day 21 - day 27 period compared to the pre-treatment period | 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. |
| Change in weekly attacks between day 28 - day 34 period compared to the pre-treatment period | 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. |
| Adverse events assessment | D0 to D90 | — |
| assessment of blind quality | 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. |
| Direct medical cost | 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 |
Countries
France
Contacts
Primary ContactLise LACLAUTRE
Outcome results
None listed