Efficacy and Safety Evaluation of Botulinum Toxin Type A in Preventing Episodic Migraine in Adults: A Randomized, Double-Blind, Placebo-Controlled Study

The primary objective of this study is to evaluate the **efficacy** of Dysport compared with placebo in reducing monthly migraine days (MMD) in adult participants. This is clinically relevant as it aims to provide a potential therapeutic option for individuals suffering from episodic migraine, potentially improving their quality of life by decreasing the frequency of migraine episodes.

Secondary objectives include:

• Evaluating the efficacy of Dysport compared with placebo in reducing monthly headache days (MHD) of moderate or severe intensity in adult participants.
• Assessing the reduction in acute migraine/headache medication use in adult participants with migraine.
• Evaluating the participant's assessment of overall change in migraine.
• Assessing the improvement in function/quality of life (QoL) in adult participants with migraine.
• Evaluating the effect of Dysport compared with placebo on the transition to chronic migraine in adult participants.
• Assessing the efficacy profile of Dysport compared with placebo with secondary efficacy measures.
• Evaluating the time to onset of MMD response in adult participants.
• Demonstrating the safety profile of Dysport compared with placebo in adult participants with migraine.

The clinical trial involves a total of **617 participants** diagnosed with **episodic migraine**. The study population includes both male and female adults aged 18 years and older. Participants were selected based on specific criteria, including a diagnosis of migraine with or without aura for more than 12 months prior to the screening visit, and a migraine onset before the age of 50. The trial excludes vulnerable populations. Participants must have a baseline number of monthly headache days of less than 15 and monthly migraine days of at least 6, as recorded in an eDiary during the 4 weeks closest to randomization. Additionally, participants are required to have at least 22 valid diary days within this period. All participants have previously used or are currently using preventive pharmacological treatment for migraines. The trial aims to evaluate the efficacy of Dysport compared to a placebo in reducing monthly migraine days in this adult population.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy and safety of Dysport for the prevention of **episodic migraine** in adult participants. The trial will be conducted in multiple centers and will include an extension phase. The primary objective is to assess the reduction in monthly migraine days (MMD) in participants receiving Dysport compared to those receiving a placebo. The trial is expected to last until December 31, 2025, with recruitment starting on October 27, 2023.

Participants will be involved in the study for a maximum treatment period of 36 weeks. The study will include several key visits: an initial screening visit to confirm eligibility, regular follow-up visits every four weeks to monitor progress and collect data, and an end-of-study visit to assess the overall outcomes and any adverse events. The inclusion criteria require participants to be at least 18 years old, have a diagnosis of migraine for more than 12 months, and meet specific baseline criteria for headache and migraine days. Participants must also have prior experience with preventive migraine treatments.

Throughout the trial, participants will be monitored for changes in MMD, with primary and secondary endpoints evaluated every four weeks from Week 4 to Week 24. The study will also assess the incidence of treatment-emergent adverse events, changes in vital signs, and the presence of antibodies to Dysport. Participants may be withdrawn from the study if they experience significant adverse effects or if they do not adhere to the study protocol. The trial aims to provide comprehensive data on the safety and efficacy of Dysport in reducing the frequency and severity of episodic migraines in adults.

The clinical trial involves the administration of **Botulinum Toxin Type A** in two different dosages as the experimental treatment. The first experimental medication is **Botulinum Toxin Type A 500 units**, presented as a powder for solution for injection. This biologic product is manufactured by IPSEN LTD and is authorized under the marketing authorization number PL 34926/0009 in the United Kingdom. The active substance, **Botulinum Toxin Type A - Haemagglutinin Complex**, is derived from a protein of other origin. The pharmaceutical form is a solution for injection, and the route of administration is intramuscular injection. The maximum daily dose is 424 U units, with a total maximum dose of 424 U units over a treatment period of up to 36 weeks.

The second experimental medication is **Botulinum Toxin Type A 300 units**, also presented as a powder for solution for injection. This product is similarly manufactured by IPSEN LTD and holds the marketing authorization number PL 34926/0015 in the United Kingdom. It shares the same active substance, **Botulinum Toxin Type A - Haemagglutinin Complex**, and is also a biologic product. The pharmaceutical form and route of administration are consistent with the 500-unit formulation, being a solution for injection administered intramuscularly. The dosing schedule allows for a maximum daily dose of 424 U units, with a total maximum dose of 424 U units over a 36-week treatment period.

The study also includes a **placebo** control, identified as Dysport Placebo Solution for injection. The placebo is used to maintain the double-blind nature of the trial, ensuring that neither the participants nor the investigators are aware of the treatment allocation. The placebo is administered in the same manner as the active treatments, via intramuscular injection, to ensure consistency in the administration process across all study arms.

The efficacy of Dysport for the prevention of episodic migraine in adult participants will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the number of monthly migraine days (MMD), measured every 4 weeks from Week 4 to Week 24. Secondary endpoints include a reduction from baseline in MMD by ≥50% and ≥75%, cumulative number of MMD from Day 1 to Week 24, and changes in MMD of moderate or severe intensity. Additionally, changes in monthly headache days (MHD) of moderate or severe intensity, reduction in MHD by ≥50% and ≥75%, and cumulative MHD of moderate to severe intensity will be evaluated.

Further assessments involve changes in the number of days per month of acute migraine medication intake, the use of acute migraine medication, and the Patient’s Global Impression of Change (PGIC) score. The Migraine Specific Quality of Life Questionnaire (MSQ) and the 6-item Headache Impact Test (HIT-6) will be used to evaluate changes in quality of life and headache impact, respectively. The transition to chronic migraine status and the time to onset of effect, defined as the first time point post-randomization where MMD is reduced from baseline by ≥50%, will also be analyzed. Safety assessments include the incidence of treatment-emergent adverse events (TEAEs), changes in vital signs, laboratory parameters, and the presence of antibodies to Dysport®.