Efficacy and Safety Evaluation of Clostridium Botulinum Neurotoxin Type A in Episodic 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 **episodic migraine** (EM) by demonstrating its superiority compared to placebo in reducing monthly migraine days. This is clinically relevant as it aims to provide a more effective treatment option for patients suffering from episodic migraine, potentially improving their quality of life by decreasing the frequency of migraine episodes.

Secondary objectives include:

• Establishing the efficacy of Xeomin Dose B in reducing monthly migraine days compared to placebo.
• Demonstrating the efficacy of Xeomin Doses A and B in reducing monthly headache days compared to placebo.
• Evaluating the reduction in monthly acute migraine medication days with Xeomin Doses A and B compared to placebo.
• Assessing 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 episodic migraine.

The clinical trial investigating the efficacy of **Xeomin Dose A** in the treatment of **episodic migraine** involves a total of 397 participants. The study population includes both male and female subjects, with an age range of 18 years and older, specifically targeting individuals who experienced migraine onset before the age of 50. Participants were selected based on their diagnosis of episodic migraine, with or without aura, as per the International Classification of Headache Disorders criteria, and a history of 6 to 14 migraine days per month. The trial includes individuals who are able to distinguish migraine headaches from other types of headaches. The study population is characterized by a history of up to 14 headache days per month. The trial does not exclude vulnerable populations, indicating a diverse participant group. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is a **randomized**, **double-blind**, **placebo-controlled** study designed to evaluate the efficacy and safety of **Clostridium Botulinum neurotoxin type A (150 kD)** injections for the prevention of **episodic migraine**. The trial is structured in a phase 3 format and includes an extension period. The primary objective is to demonstrate the superiority of the neurotoxin compared to placebo in reducing monthly migraine days. The trial is expected to commence recruitment on October 1, 2025, and conclude by June 30, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, migraine diagnosis, and headache frequency. Eligible participants must be at least 18 years old, have a history of episodic migraine for at least 12 months, and meet specific headache and migraine day criteria. The trial will involve multiple follow-up visits to monitor the participants' response to treatment and any adverse events. The primary endpoint is the change in monthly migraine days from baseline to Month 6, with secondary endpoints including changes in headache days and acute migraine medication days.

The expected length of participant involvement is up to 36 weeks, with the possibility of early termination if participants experience significant adverse events or fail to adhere to the study protocol. The study will utilize a placebo to Clostridium Botulinum neurotoxin type A (150 kD) as a control, and the investigational product will be administered via **intramuscular injection**. The trial will ensure that all procedures are conducted in accordance with ethical standards and regulatory requirements, maintaining the integrity and scientific validity of the study.

The clinical trial involves the administration of **Clostridium Botulinum neurotoxin type A (150 kD), free of complexing proteins**, which is provided in the form of a powder for solution for injection. This experimental medication is administered via **intramuscular injection**. The dosing regimen includes a maximum daily dose of 195 U units, with a total maximum dose of 780 U units over the treatment period. The treatment period is set for a maximum of 36 weeks. The product is specifically labeled and packed for the trial, and it is not a pediatric formulation. The active substance, also known as BoNT/A (150 kilodalton) or IncobotulinumtoxinA, is utilized to evaluate its efficacy in reducing monthly migraine days in patients with episodic migraine.

The study also includes a **placebo** control, which is designed to mimic the experimental treatment without containing the active neurotoxin. The placebo is referred to as "Placebo to Clostridium Botulinum neurotoxin type A (150 kD)" and is used to maintain the double-blind nature of the trial. The placebo is administered in the same manner as the experimental medication, ensuring that participants and investigators remain unaware of the treatment allocation. This allows for an unbiased assessment of the experimental treatment's efficacy and safety compared to the placebo.

The efficacy of the clinical trial will be assessed by evaluating the reduction in monthly migraine days. The primary endpoint is the change in monthly migraine days from baseline to Month 6, specifically weeks 21 to 24 after the first injection, for Dose A. Secondary endpoints include similar assessments for Dose B, changes in monthly headache days, changes in monthly acute migraine medication days, and the 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 evaluated. The incidence of treatment-emergent adverse events (TEAEs) related to treatment will also be assessed during the placebo-controlled period.