Efficacy of Botulinum Toxin Type A in Sphenopalatine Ganglion Blockade for Refractory Chronic Cluster Headache Treatment

The primary objective of this study is to evaluate the **efficacy** of botulinum toxin type A in targeting the sphenopalatine ganglion (SPG) for the treatment of refractory chronic cluster headache. This is clinically relevant as chronic cluster headache is a debilitating condition with limited treatment options, and the use of botulinum toxin could offer a novel therapeutic approach for patients who do not respond to conventional treatments.

Secondary objectives include assessing the following parameters:

• **Safety** of the intervention
• Frequency of cluster attacks
• Responder frequencies
• Features of cluster headache attacks
• Frequency of headache days
• Quality of life measures
• Use of medication
• Patient global impression

The clinical trial investigating the efficacy of botulinum toxin towards the **sphenopalatine ganglion** in the treatment of refractory chronic cluster headache involves a total of 21 participants. The study population comprises both male and female subjects, aged between 18 and 85 years. Participants were selected based on their ability to provide informed and written consent, understand and comply with study procedures, and meet specific criteria related to their headache condition, including fulfilling the International Classification of Headache Disorders criteria for chronic cluster headache. The trial includes individuals with a dominant headache laterality, experiencing an average of at least four cluster attacks per week on the dominant side in the three months prior to inclusion. The condition of participants is pharmacologically refractory, with suboptimal effects or intolerable side effects from standard treatments such as verapamil, lithium, or suboccipital steroid injections. Participants are required to maintain their current preventive headache medication regimens throughout the study. The trial also includes women of childbearing potential, who must use highly effective contraception for four weeks post-injection. The study population is considered vulnerable, and the trial aims to ensure the safety and efficacy of the intervention for this specific group.

The clinical trial is designed to evaluate the efficacy of **botulinum toxin type A** in the treatment of refractory **chronic cluster headache**. This study employs a randomized, double-blind, placebo-controlled design to ensure the reliability and validity of the results. Participants will be randomly assigned to either the treatment group receiving botulinum toxin type A or the placebo group. The trial is expected to span from the estimated recruitment start date of November 1, 2018, to the estimated end date of December 31, 2024.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific criteria, such as age, headache characteristics, and previous treatment responses. Following successful screening, participants will be enrolled and randomized into the study. The primary endpoint will be assessed by measuring the difference in the change from baseline in the mean number of cluster headache attacks per week at weeks 5 to 8 post-intervention between the treatment and placebo groups. Secondary endpoints include the occurrence of adverse events, changes in attack frequency and intensity, and the number of therapeutic responders.

The study involves multiple follow-up visits to monitor the participants' response to the treatment and to ensure their safety. These visits will occur at regular intervals throughout the study duration. The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted. The expected length of participant involvement is approximately one year, with conditions for early termination including withdrawal of consent, non-compliance with study procedures, or adverse events that necessitate discontinuation.

The clinical trial involves the administration of two treatments. The first treatment is **Natriumklorid B. Braun 9 mg/ml**, a **sodium chloride** solution for infusion. This pharmaceutical form is a clear solution intended for intravenous administration. The dosage is set at a maximum of 0.5 ml per day, with the total dose not exceeding 0.5 ml over the treatment period. The administration route is via injection, and the treatment duration is limited to one day. This product is manufactured by B.BRAUN MELSUNGEN AG and is classified under the ATC code B05BB01, which pertains to electrolytes. The solution is not a pediatric formulation and serves as a placebo in the trial.

The second treatment is **BOTOX 50 Allergan-enheter**, containing **botulinum toxin type A**. This is provided as a powder for solution for injection. The maximum daily dose is 25 international units (IU), with the total dose also capped at 25 IU for the treatment period. The administration is performed via injection, and the treatment period is similarly restricted to one day. This product is produced by ABBVIE AS and falls under the ATC code M03AX01, which is associated with botulinum toxin. This formulation is not intended for pediatric use and is the test treatment in the study. The trial aims to evaluate the efficacy of botulinum toxin type A in the treatment of refractory chronic cluster headache, specifically targeting the sphenopalatine ganglion using an image-guided surgical device.

The efficacy of the treatment in this clinical trial will be assessed primarily by evaluating the difference in the change from the last 28-day period of the baseline in the mean number of cluster headache attacks per week at weeks 5 to 8 post-intervention between the treatment group and the placebo group. Secondary endpoints include the difference in the occurrence of adverse events (AEs) and serious adverse events (SAEs) between the active and placebo groups, as well as the difference in change from baseline week 5-8 in the mean number of cluster headache attacks per week during weeks 9-12 post-intervention. Additionally, the trial will assess the difference in the number of therapeutic responders, defined as a ≥ 30% reduction in attack frequency, intensity, or both during weeks 5 to 8 post-intervention compared to baseline, and the difference in the number of attack frequency responders, defined as a ≥ 30% reduction in attack frequency during the same period.

These efficacy parameters will be measured and analyzed at specified timepoints, including weeks 5-8 and weeks 9-12 post-intervention. The analysis will also consider prespecified subgroups, such as high and low frequency subgroups and high and low frequency variation subgroups. The trial aims to determine the efficacy of **botulinum toxin type A** in the treatment of refractory chronic cluster headache by targeting the sphenopalatine ganglion using an image-guided surgical device. The study will ensure that participants maintain their current preventive headache medication regimens throughout the trial period to accurately assess the treatment's efficacy.