Randomized, Double-Blind, Placebo-Controlled, Dose-Finding Study of Lu AG09222 for Migraine Prevention in Adults with Episodic and Chronic Migraine

The primary objective of this clinical trial is to evaluate the **efficacy** of Lu AG09222 for the prevention of **migraine**. This is clinically relevant as migraines are a common and debilitating condition, and effective preventive treatments can significantly improve the quality of life for individuals suffering from both episodic and chronic forms of the condition.

Secondary objectives include:

• Evaluating the dose-response relationship for the efficacy of Lu AG09222 in migraine prevention, which is crucial for determining the optimal dosing strategy.
• Assessing the safety and tolerability of Lu AG09222, ensuring that the treatment is not only effective but also safe for long-term use.
• Evaluating the immunogenicity of Lu AG09222, which is important for understanding any potential immune responses that could affect treatment efficacy or safety.

The clinical trial involves a total of **484 participants** who are being evaluated for the efficacy of Lu AG09222 in the prevention of **migraine**. The study population includes both male and female subjects, aged between **18 and 65 years**. Participants were selected based on a confirmed diagnosis of migraine according to ICHD-3 guidelines, with a history of migraine onset at least 12 months prior to the screening visit and an onset age of 50 years or younger. The trial includes individuals who experience at least four migraine days per month, as documented in an eDiary over a 28-day screening period. Participants have also demonstrated compliance with eDiary entries and have a history of treatment failure with at least two to four different migraine preventive medications in the past decade. The trial population is not restricted by specific lifestyle considerations such as diet or physical activity, but it does include a vulnerable population. The selection criteria ensure a representative sample of individuals who have experienced significant challenges in managing their migraine condition.

The clinical trial is designed as an **interventional**, randomized, double-blind, parallel-group, placebo-controlled, dose-finding study to evaluate the efficacy of Lu AG09222 for the prevention of **migraine** in participants with episodic and chronic migraine. The trial is expected to commence recruitment on August 14, 2024, and conclude by June 30, 2026. Participants will be randomly assigned to receive either the investigational medicinal product, Lu AG09222, or a placebo, both administered as a **solution for injection** via the subcutaneous route. The trial will span a maximum treatment period of 8 weeks.

Study visits are structured to ensure comprehensive data collection and participant safety. The initial visit, known as the inclusion or screening visit, will confirm eligibility based on criteria such as a diagnosis of migraine according to ICHD-3 guidelines, a history of migraine onset at least 12 months prior, and previous treatment failures with specific migraine preventive medications. Participants must be aged between 18 and 65 years. Following the screening, participants will enter a 28-day period where compliance with an electronic diary (eDiary) is monitored. This period is crucial for collecting baseline data on migraine and headache days.

Subsequent follow-up visits will occur throughout the 12-week treatment phase, during which primary and secondary endpoints will be assessed. The primary endpoint focuses on the change from baseline in the Monthly Migraine Diary over weeks 1 to 12. Secondary endpoints include dose response, reduction in monthly migraine diaries, changes in monthly headache days, and various safety assessments such as treatment-emergent adverse events (TEAEs) and changes in clinical safety laboratory test values, vital signs, weight, and ECG parameters. The development and characterization of anti-drug antibodies (ADAs) and their impact on pharmacokinetics, efficacy, and safety will also be evaluated.

The end-of-study visit will mark the conclusion of the participant's involvement, where final assessments will be conducted to ensure participant safety and gather any remaining data. The expected length of participant involvement is approximately 12 weeks, with conditions for early termination including non-compliance with study procedures, withdrawal of consent, or adverse events that compromise participant safety. The trial is conducted in accordance with ethical standards and regulatory requirements to ensure the integrity of the data and the welfare of the participants.

The clinical trial involves the administration of **Lu AG09222**, an investigational medicinal product, formulated as a **solution for injection**. The active substance, **LU AG09222**, is a protein of other origin, developed by H. Lundbeck A/S. The solution is administered via the **subcutaneous** route. The dosing schedule is designed to evaluate the efficacy of Lu AG09222 for the prevention of migraine in participants with episodic and chronic migraine. The maximum treatment period is set at 8 weeks, with specific dosing parameters to be determined based on the study protocol. Participant compliance with the dosing regimen will be monitored throughout the trial to ensure adherence to the study protocol.

In addition to the investigational product, a **placebo** is used as a comparator in this randomized, double-blind, parallel-group, placebo-controlled trial. The placebo is designed to match the investigational medicinal product, Lu AG09222, in appearance and administration method, ensuring blinding of both participants and investigators. The placebo is also administered subcutaneously, following the same schedule as the investigational product. This design allows for the assessment of the true efficacy of Lu AG09222 by comparing outcomes between the active treatment and placebo groups.

The efficacy of Lu AG09222 in the prevention of **migraine** will be assessed through a series of primary and secondary endpoints. The primary endpoint is the change from baseline in the Monthly Migraine Diary over Weeks 1 to 12. This will provide a direct measure of the treatment's impact on migraine frequency. Secondary endpoints include the dose response, defined as the change from baseline in the Monthly Migraine Diary over the same period, and the percentage of participants achieving a 50% or 75% reduction in migraine frequency from baseline. Additionally, changes from baseline in Monthly Headache Days will be evaluated.

Data collection will involve the use of a Monthly Migraine Diary, which participants will maintain throughout the trial. This diary will serve as a tool for recording the frequency and characteristics of migraine episodes, allowing for a comprehensive analysis of treatment efficacy. The efficacy assessments will be conducted at specified intervals, with data collected at baseline and then at regular intervals up to Week 12. The analysis will focus on comparing the changes in migraine frequency and severity from baseline to the end of the treatment period.