Efficacy and Safety Evaluation of Clostridium Botulinum Neurotoxin Type A in Chronic Migraine: A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this clinical trial is to establish evidence of the **efficacy** of Xeomin Dose A in the treatment of **chronic migraine** by demonstrating its superiority compared to placebo in reducing monthly migraine days. This is clinically relevant as it aims to provide a therapeutic option that could significantly decrease the frequency of migraine episodes, thereby improving the quality of life for individuals suffering from chronic migraine.

Secondary objectives include: - Establishing evidence of efficacy of Xeomin Dose B in the treatment of chronic migraine by demonstrating superiority compared to placebo in reducing monthly migraine days. - Establishing evidence of efficacy of Xeomin Dose A and Dose B in reducing monthly headache days. - Establishing evidence of efficacy of Xeomin Dose A and Dose B in reducing monthly acute migraine medication days. - Establishing evidence of a shorter "wear-off period" of Xeomin Dose A compared to Dose B in reducing two-week end-of-cycle migraine days. - Supporting the primary efficacy objective by comparing the 50% responder rates. - Demonstrating the safety and tolerability of Xeomin compared to placebo in participants with chronic migraine.

The clinical trial investigating the efficacy of **Xeomin Dose A** in the treatment of **chronic migraine** includes a total of 313 participants. The study population comprises both male and female subjects, aged 18 years and older, with a history of chronic migraine for at least 12 months. Participants are required to have experienced at least 15 headache days and 8 migraine days per month in the three months prior to screening. The trial includes individuals who are able to distinguish migraine headaches from other types of headaches. The selection process ensures that participants meet specific criteria, including the onset of migraines before the age of 50. The study population is diverse, including vulnerable groups, and considers lifestyle factors such as the ability to maintain a headache diary to track migraine occurrences. The sponsor has not provided additional information regarding specific lifestyle considerations such as diet or physical activity.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of Xeomin® injections for the prevention of **chronic migraine**. The trial is structured to include an initial treatment period followed by an extension period, with the primary objective of demonstrating the superiority of Xeomin Dose A over placebo in reducing monthly migraine days. The study is expected to commence recruitment on October 1, 2025, and conclude by June 30, 2028.

Participants will be involved in the trial for a maximum treatment period of 36 weeks. The study will include several key visits: an inclusion (screening) visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be assessed based on criteria such as age, diagnosis of chronic migraine, and headache frequency. Participants must be at least 18 years old, have a history of at least 15 headache days per month, and at least 8 migraine days per month for the three months preceding the screening.

Following the screening, eligible participants will be randomized to receive either the active treatment, **Clostridium botulinum neurotoxin type A (150KD), free of complexing proteins**, or a placebo. The treatment will be administered via **intramuscular injection**. The primary endpoint is the change in monthly migraine days from baseline to Month 6. Secondary endpoints include changes in monthly headache days, acute migraine medication days, and the frequency of migraine days, as well as the incidence of treatment-emergent adverse events.

Participants will attend regular follow-up visits to monitor efficacy and safety outcomes, with data collected on headache frequency and medication use. The end-of-study visit will involve a comprehensive assessment of the participant's response to treatment and any adverse events experienced. Participant involvement may be terminated early if they experience significant adverse effects or fail to adhere to the study protocol. The trial aims to provide robust evidence on the effectiveness of Xeomin® in reducing the burden of chronic migraine.

The clinical trial involves the administration of **Clostridium botulinum neurotoxin type A (150 kD)**, free of complexing proteins, as the experimental medication. This product is provided in the form of a powder for solution for injection. The active substance, also known as **BoNT/A (150 kilodalton)** or **IncobotulinumtoxinA**, is administered via **intramuscular injection**. The dosing regimen allows for a maximum daily dose of 195 U units, with a total maximum dose of 780 U units over the course of the treatment. The treatment period is capped at 36 weeks. The product is subject to trial-specific labeling and secondary packing to ensure compliance with study protocols.

The study also includes a **placebo** comparator, which is designed to mimic the experimental treatment without containing the active substance. The placebo is intended to provide a control for evaluating the efficacy and safety of the experimental medication. The placebo is administered in a manner consistent with the experimental treatment to maintain the double-blind nature of the trial. Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the protocol and to accurately assess the outcomes of the treatment.

The efficacy of the clinical trial will be assessed by evaluating the reduction in monthly migraine days, with the primary endpoint being the change from baseline to Month 6 (weeks 21 to 24 after the first injection) for **Dose A**. Secondary endpoints include the change in monthly migraine days for **Dose B**, change in monthly headache days for both doses, change in monthly acute migraine medication days for both doses, and the change in frequency of migraine days from baseline to two-week end-of-cycle periods. Additionally, the percentage of participants reporting at least a 50% reduction in mean monthly migraine days from baseline to Month 6 will be measured. The incidence of treatment-emergent adverse events (TEAEs) related to treatment will also be assessed during the placebo-controlled period.