Evaluation of Ketamine Hydrochloride and Magnesium Sulfate Heptahydrate Infusion Efficacy in Refractory Chronic Cluster Headache Treatment

The primary objective of this study is to evaluate the **efficacy** of a single infusion of ketamine combined with magnesium sulfate in patients with refractory chronic cluster headache. This is compared to a control group receiving hydroxyzine, an active placebo. The clinical relevance of this objective lies in addressing the unmet need for effective treatment options for patients who do not respond to currently recommended therapies for this debilitating condition.

Secondary objectives include:

• Evaluating the effect of the infusion on anxiety and depression in patients with chronic cluster headache, compared to a non-analgesic anxiolytic treatment.
• Assessing the tolerance of the ketamine and magnesium sulfate infusion in these patients.
• Evaluating the intensity of headache crises.
• Assessing the effect of the infusion on management costs compared to a non-analgesic anxiolytic treatment.

The clinical trial focuses on individuals diagnosed with **refractory chronic cluster headache**. The study population includes both male and female participants aged 18 years and older. Participants are required to have a diagnosis of chronic cluster headache as per ICHD-3 criteria, with an average of at least two crises per 24 hours during the 14 days preceding the ketamine infusion. The trial excludes vulnerable populations and requires participants to have experienced insufficient effectiveness, intolerance, or contraindication to the use of the three major treatments for cluster headaches: verapamil, lithium, and corticosteroids. The sponsor has not provided information regarding the total number of participants. Participants were selected based on specific inclusion criteria, including the ability to provide informed consent. Lifestyle factors such as diet and physical activity are not specified as part of the selection criteria.

The clinical trial is designed to evaluate the efficacy of a single infusion of **ketamine** combined with **magnesium sulfate** in the treatment of refractory chronic cluster headache. This study is structured as a randomized, double-blind, controlled trial, with participants being randomly assigned to receive either the active treatment or an active placebo, **hydroxyzine**. The trial is expected to run from September 2021 to December 2026, with participant involvement lasting up to 90 days from the initial infusion.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), diagnosis of chronic cluster headache according to ICHD-3 criteria, and insufficient response to standard treatments like verapamil, lithium, and corticosteroids. Following the screening, eligible participants will receive the infusion treatment. Subsequent follow-up visits will occur at specified intervals to monitor changes in the frequency and intensity of headache crises, assess treatment response, and evaluate any adverse effects. The primary endpoint is the change in weekly frequency of crises from day 7 to day 13 compared to the pre-treatment period. Secondary endpoints include crisis frequency and intensity over subsequent weeks, responder rates, and assessments of anxiety, depression, and overall clinical evaluation.

The end-of-study visit will occur on day 90, where final assessments will be conducted, including the evaluation of direct medical costs and the quality of blinding. Participants may be withdrawn from the study early if they experience significant adverse effects, require additional treatment beyond the study protocol, or withdraw consent. The trial aims to provide valuable insights into the potential repurposing of ketamine and magnesium sulfate for managing chronic cluster headaches unresponsive to conventional therapies.

The clinical trial involves the administration of several treatments, including both experimental and non-experimental medications. **Sodium chloride** 0.9% Baxter, a solution for infusion, is utilized as a comparator in the study. This pharmaceutical form is a solution for infusion, administered via **intravenous infusion**. The maximum daily dose is 300 ml, with a total maximum dose of 600 ml over a treatment period of up to 2 days. This product is manufactured by Baxter SAS and is not a pediatric formulation.

**Ketamine hydrochloride**, marketed as Ketamine Renaudin 50 mg/ml, is one of the test treatments in the trial. It is provided as a solution for injection and is administered through intravenous infusion. The dosing regimen allows for a maximum daily dose of 0.5 mg/kg, with a total maximum dose of 1 mg/kg over a 2-day period. This product is produced by Laboratoire Renaudin and is classified as a general anesthetic for the central nervous system.

Another test treatment is **magnesium sulfate heptahydrate**, available as Sulfate de Magnesium Lavoisier 15% (0.15 g/ml), a solution for injection in ampoule form. This medication is also administered via intravenous infusion. The maximum daily dose is 3 g, with a total maximum dose of 6 g over a 2-day treatment period. It is manufactured by Laboratoires Chaix et du Marais.

**Hydroxyzine hydrochloride**, under the brand name Hydroxyzine Renaudin 100 mg/2 mL, serves as an active placebo in the study. This solution for injection is administered through intravenous infusion. The dosing schedule permits a maximum daily dose of 25 mg, with a total maximum dose of 50 mg over a 2-day period. This product is also produced by Laboratoire Renaudin.

The efficacy of the clinical trial titled "KETALGIA: Evaluation of the effectiveness of a ketamine infusion combined with magnesium sulfate in the treatment of chronic refractory cluster headache" will be assessed using both primary and secondary endpoints. The primary endpoint is the change in the weekly frequency of crises over the period from Day 7 to Day 13 compared to the pre-treatment period. Secondary endpoints include the change in weekly frequency of crises over subsequent periods (Day 14-20, Day 21-27, Day 28-34), the proportion of responders at 30%, 50%, and 75% each week post-infusion, and the response to treatment according to initial serum magnesium levels.

Additional secondary endpoints involve the weekly frequency and intensity of crises between the 7 days preceding the infusion and each week post-infusion, crisis treatment intake, and anxiety and depression scoring using the Hospital Anxiety and Depression (HAD) scale. The Patient Global Impression of Change (PGIC) scoring will be used for overall clinical evaluation on Day 15 and Day 90. The proportion of patients requiring additional treatment on Day 15, direct medical costs, evaluation of adverse effects, and the quality of blinding will also be assessed. These efficacy parameters will be measured and collected at specified timepoints throughout the trial to ensure comprehensive analysis.