Efficacy and Safety Evaluation of Botulinum Toxin Type A in Chronic Migraine Prevention 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 chronic migraine significantly impacts patients' quality of life, and effective reduction in MMD can lead to substantial improvements in daily functioning and overall well-being.

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 improvements in function and quality of life (QoL) in adult participants with migraine.
• Evaluating the effect of Dysport compared with placebo on the transition from chronic migraine in adult participants.
• Assessing the efficacy profile of Dysport compared with placebo using 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 investigating the efficacy of Dysport in reducing monthly migraine days involves a total of **602 participants** diagnosed with **chronic migraine**. The study population includes both male and female adults aged 18 years and older, with no vulnerable populations selected. Participants were required to have a diagnosis of chronic migraine for more than 12 months prior to the screening visit, with migraine onset occurring before the age of 50. The trial population was selected based on specific criteria, including a baseline number of monthly headache days of at least 15 and monthly migraine days of at least 8, as recorded in an eDiary. Additionally, participants must have previously used or be currently using preventive pharmacological treatment for migraines. The study does not specify any particular 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 Dysport for the prevention of **chronic migraine** in adult participants. The trial is structured in a parallel-group format with an extension phase and is expected to conclude by December 2025. Participants will be involved in the study for a maximum treatment period of 36 weeks. The trial will commence with a screening visit to confirm eligibility based on specific inclusion criteria, such as a diagnosis of chronic migraine for more than 12 months and a baseline number of monthly headache days of at least 15. Participants must also have a history of using preventive migraine treatments.

Following the screening, eligible participants will be randomized to receive either Dysport or a placebo, administered as a **solution for injection**. The primary endpoint is the change from baseline in monthly migraine days at Week 24. Secondary endpoints include various measures of migraine frequency and severity, as well as quality of life assessments. Study visits will occur every four weeks, during which data on migraine days, headache intensity, and medication use will be collected. Participants will also undergo safety assessments, including monitoring for treatment-emergent adverse events and changes in vital signs.

The end-of-study visit will involve a comprehensive evaluation of the participant's response to treatment and any adverse effects experienced. Participants may be withdrawn from the study early if they experience significant adverse events or if they do not adhere to the study protocol. The trial aims to provide robust data on the potential benefits of Dysport in reducing the burden of chronic migraine, contributing to the understanding of its therapeutic role in this condition.

The clinical trial involves the administration of **Botulinum Toxin Type A** in two different dosages as the experimental treatment. The first formulation is **Botulinum Toxin Type A 300 units**, presented as a powder for solution for injection. This pharmaceutical form is intended for reconstitution prior to administration. The active substance, **Botulinum Toxin Type A - Haemagglutinin Complex**, is classified under the ATC code M03AX01. The product is manufactured by IPSEN LTD and is authorized in the United Kingdom. The maximum daily dose is 424 units, with a total treatment period not exceeding 36 weeks. The route of administration is via injection, and the dosing schedule is determined by the study protocol. Participant compliance is monitored through regular follow-ups and documentation of administered doses.

The second experimental formulation is **Botulinum Toxin Type A 500 units**, also provided as a powder for solution for injection. Similar to the 300-unit formulation, it requires reconstitution before use. The active substance remains the same, and it is also produced by IPSEN LTD with authorization in the United Kingdom. The dosing parameters, including the maximum daily dose and treatment period, are consistent with the 300-unit formulation. Administration is conducted through injection, and adherence to the dosing schedule is ensured through systematic monitoring and recording of each administration.

The study also includes a **placebo** control, referred to as Dysport Placebo Solution for injection. This 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, with injections scheduled according to the study protocol. Compliance with the placebo administration is tracked similarly to the active treatments, ensuring the integrity of the trial data.

The efficacy of Dysport in the prevention of chronic migraine will be assessed in a Phase III, randomized, double-blind, placebo-controlled, multicenter, parallel-group study with an extension phase. The primary endpoint for evaluating efficacy is the change from baseline in monthly migraine days (MMD) at Week 24. Secondary endpoints include changes from baseline in MMD every 4 weeks from Week 4 to Week 24, reduction in MMD by ≥50% and ≥75% every 4 weeks from Week 4 to Week 24, and cumulative number of MMD from Day 1 to Week 24. Additional secondary endpoints involve changes in monthly headache days (MHD) of moderate or severe intensity, reduction in MHD by ≥50% and ≥75%, and cumulative number of MHD of moderate or severe intensity from Day 1 to Week 24.

Further assessments include changes in the number of days per month of acute migraine medication intake, headache medication overuse, and use of acute migraine medication every 4 weeks from Week 4 to Week 24. Patient-reported outcomes will be measured using the Patient Global Impression of Change (PGIC) score at Week 12 and Week 24, with improvements from baseline of ≥1 and ≥2 grades. The Migraine Specific Quality of Life Questionnaire (MSQ) and the Headache Impact Test (HIT-6) will be used to evaluate changes in quality of life and headache impact, respectively, at Week 12 and Week 24. The study will also assess changes in the SF-12 score and chronic migraine status at Week 24, time to onset of effect, incidence of treatment-emergent adverse events, and changes in clinically significant laboratory parameters and vital signs up to Week 24. The presence of binding and neutralizing antibodies to Dysport will also be evaluated.