A Randomized, Double-blind, Parallel-group, Active Controlled Trial with Open-label Safety Extension to Evaluate the Tolerability, Safety, and Efficacy of Atogepant versus Topiramate in Subjects Requiring Preventive Treatment of Migraine (TEMPLE)

The primary objective of this study is to evaluate the **tolerability** and safety of atogepant compared to the highest tolerated dose of topiramate in participants requiring preventive treatment for **migraine**. This is clinically relevant as it aims to determine the safety profile of atogepant, potentially offering a safer alternative for migraine prevention.

Secondary objectives include:

• To demonstrate a higher rate of participants treated with atogepant versus topiramate achieving a ≥ 50% reduction in mean monthly migraine days during months 4 to 6 of the double-blind treatment period.

The clinical trial involves a total of **45 participants** diagnosed with **chronic and episodic migraine**. The study population includes both male and female subjects, with an age range that encompasses adults and adolescents. Participants were selected based on a documented history of migraine, with or without aura, for at least 12 months prior to screening, and a history of experiencing four or more migraine days per month, necessitating preventive treatment. The trial includes individuals who are eligible for conventional migraine prophylaxis. The study population is characterized by a diverse group, including vulnerable populations, ensuring a comprehensive evaluation of the treatment's tolerability and safety. Lifestyle factors such as diet, physical activity, and habits were not specified by the sponsor.

The clinical trial is designed as a **randomized**, **double-blind**, parallel-group, active-controlled study with an open-label safety extension. The primary objective is to evaluate the tolerability and safety of **atogepant** compared to the highest tolerated dose of **topiramate** in participants requiring preventive treatment for **chronic and episodic migraine**. The trial is expected to last until June 2026, with recruitment starting in October 2023. Participants will be involved for a maximum of 76 weeks, depending on their assigned treatment group.

The trial will include several key visits: an initial 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 a documented history of migraine for at least 12 months and a history of at least four migraine days per month. Follow-up visits will occur throughout the 24-week double-blind treatment period, during which the primary endpoint of treatment discontinuation due to adverse events will be monitored. Secondary endpoints include the achievement of a 50% reduction in mean monthly migraine days and changes in various patient-reported outcomes.

Participants will be randomly assigned to receive either atogepant, topiramate, or a placebo. The study drugs will be administered orally, with atogepant provided in tablet form and topiramate in capsule form. The maximum daily dose for atogepant is 60 mg, while for topiramate, it is 100 mg. The trial will include an open-label extension phase to further assess long-term safety and efficacy. Conditions that may lead to early termination from the study include significant adverse events or non-compliance with the study protocol. Participants' involvement will be closely monitored to ensure adherence to the trial's rigorous standards and to maintain the integrity of the collected data.

The clinical trial involves the administration of **Atogepant**, a chemical substance formulated as a tablet. The active substance, atogepant, is provided by Allergan Sales, LLC, a subsidiary of AbbVie Inc. The maximum daily dose of atogepant is 60 mg, with a total maximum dose of 31,920 mg over a treatment period of up to 76 weeks. The route of administration is oral, and the pharmaceutical form is a tablet. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Topiramate** is another experimental medication used in this trial, provided in the form of hard capsules. The active substance, topiramate, is chemically derived and administered orally. The capsules are available in 25 mg and 50 mg dosages, with a maximum daily dose of 100 mg and a total maximum dose of 16,100 mg over a 24-week treatment period. The capsules are grey, opaque, and unmarked, created by over-encapsulating topiramate tablets. Compliance with the dosing regimen will be closely monitored.

The trial also includes a **placebo** for topiramate, designed to match the 25 mg and 50 mg topiramate capsules. The placebo is used to maintain the double-blind nature of the study, ensuring that neither the participants nor the investigators know which treatment is being administered. The placebo is administered orally, following the same schedule as the active topiramate capsules.

Additionally, a **placebo** for atogepant tablets is utilized in the trial. This placebo is designed to match the 60 mg atogepant tablets and is administered orally. The placebo serves to maintain the study's double-blind design, ensuring unbiased results by preventing participants and investigators from knowing the treatment allocation. Compliance with the placebo administration schedule will be monitored to ensure adherence to the study protocol.

Efficacy in the clinical trial will be assessed using both primary and secondary endpoints. The primary endpoint is the rate of treatment discontinuation due to adverse events during the 24-week double-blind treatment period. Secondary endpoints include the achievement of a ≥ 50% reduction in mean monthly migraine days (MMD) during months 4 to 6 of the double-blind treatment period, and changes from baseline in mean MMD during the same period. Additional secondary endpoints involve changes from baseline in the Headache Impact Test (HIT-6) total score and the Migraine-Specific Quality of Life Questionnaire (MSQ) Version 2.1 Role Function-Restrictive (RFR) domain score at week 24. Furthermore, the trial will assess the achievement of a rating of "much better" or "very much better" at week 24, as evaluated by the Patient Global Impression of Change (PGIC). Another secondary endpoint is the change from baseline in the Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive Function – Abilities Subset – Short Form 6a Version 2.0 score at week 6.