Long-Term Safety, Tolerability, and Efficacy of Fremanezumab in Pediatric Episodic and Chronic Migraine: A Multicenter, Open-Label Study

The primary objective of this study is to evaluate the long-term **safety** and tolerability of subcutaneous administration of fremanezumab in pediatric participants aged 6 to 17 years for the preventive treatment of episodic and chronic **migraine**. This is clinically relevant as it aims to ensure that the treatment is safe for long-term use in a pediatric population, which is crucial for managing a condition that can significantly impact quality of life.

Secondary objectives include:

• Evaluating the efficacy of subcutaneous fremanezumab in pediatric participants with migraine, which is important for determining the therapeutic benefit of the treatment.
• Assessing the immunogenicity of fremanezumab and the impact of anti-drug antibodies (ADAs) on clinical outcomes in pediatric participants exposed to the treatment, which is essential for understanding potential immune responses and their effects on treatment efficacy and safety.

The clinical trial involves a total of **227 participants** who are pediatric subjects aged **6 to 17 years**. The study population includes both **male and female** participants, and it is designed to evaluate the long-term safety and tolerability of a subcutaneous investigational medicinal product for the preventive treatment of **migraine**, specifically targeting those with episodic and chronic forms. Participants were selected based on their completion of a pivotal efficacy trial and their ability to comply with trial requirements. They are required to be in good health, as determined by comprehensive medical assessments, and must have received all recommended age-appropriate vaccinations. Lifestyle considerations include maintaining a stable dose of any preventive medications for migraine or other conditions, if applicable. The trial population is considered vulnerable, given the pediatric age range, and informed consent is obtained from parents or legal guardians, with assent from the participants themselves. The study ensures that participants are compliant with trial protocols, including the use of electronic headache diaries and adherence to follow-up evaluations.

The clinical trial is designed to evaluate the long-term safety, tolerability, and efficacy of **fremanezumab** for the preventive treatment of episodic and chronic migraine in pediatric patients aged 6 to 17 years. This is a multicenter, open-label study with a focus on monthly subcutaneous administration of the investigational medicinal product (IMP). The trial is expected to span from October 2020 to March 2026, with participant involvement lasting up to 36 months. The study is structured to include an initial screening visit, followed by regular follow-up visits, and concludes with an end-of-study visit. Participants will be monitored for adverse events, changes in clinical laboratory test results, and any abnormal findings in physical examinations and electrocardiograms throughout the trial.

Participants eligible for inclusion are those who have completed a pivotal efficacy trial and meet specific criteria, such as a minimum weight of 17 kg and a body mass index within the 5th to 120% of the 95th percentile. Compliance with an electronic headache diary is required, and females of childbearing potential must adhere to strict contraceptive measures. The trial will exclude participants who do not meet these criteria or who are unable to comply with trial requirements. The primary endpoints focus on safety, including the occurrence of adverse events and changes in vital signs, while secondary endpoints assess efficacy, such as changes in the number of headache and migraine days.

Study visits are scheduled to assess both safety and efficacy parameters. The inclusion visit involves screening for eligibility, while follow-up visits are conducted to monitor ongoing safety and efficacy, with specific assessments at visits V5, V8, and V11. The end-of-study visit will finalize data collection and ensure participant safety post-treatment. Conditions that may lead to early termination from the study include non-compliance with trial protocols or the occurrence of significant adverse events. The trial aims to provide comprehensive data on the long-term use of fremanezumab in the pediatric population for migraine prevention.

The clinical trial involves the administration of **fremanezumab**, marketed under the name AJOVY, which is a **solution for injection**. The experimental medication is available in two pharmaceutical forms: a pre-filled syringe and a pre-filled pen, each containing 225 mg of the active substance. The medication is administered via **subcutaneous use**. The dosing regimen involves a maximum daily dose of 225 mg, with a total maximum dose of 2025 mg over a treatment period of up to 36 months. The active substance, fremanezumab, is of biological/biotechnological origin, specifically a protein of other origin, and is produced by TEVA GMBH.

The pre-filled syringe form of AJOVY is identified by the marketing authorization number EU/1/19/1358/002 and EU/1/19/1358/001, with the European medicinal product numbers PRD7211603 and PRD7211363, respectively. The pre-filled pen form is identified by the marketing authorization number EU/1/19/1358/003 and EU/1/19/1358/004, with the European medicinal product numbers PRD7707039 and PRD7707078, respectively. Both forms are intended for the preventive treatment of **episodic and chronic migraine** in pediatric patients aged 6 to 17 years. The trial aims to evaluate the long-term safety, tolerability, and efficacy of fremanezumab in this population.

Participant compliance with the dosing schedule is monitored throughout the study to ensure adherence to the prescribed regimen. No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial protocol. The study is designed to assess the investigational product's impact on migraine prevention, with a focus on safety and tolerability over an extended treatment period.

The efficacy of the clinical trial will be assessed through several secondary endpoints. These include the mean change from baseline in the number of headache days of at least moderate severity and the number of migraine days during the 4-week periods following specific visits (V2, V6, and V10). Additionally, the proportion of participants achieving at least a 50% reduction in the number of migraine days and headache days of at least moderate severity during these periods will be evaluated. The mean change from baseline in the number of days of use of any acute headache medications during the same 4-week periods will also be measured.

Furthermore, the trial will assess the mean change from baseline in migraine-related disability scores using the PedMIDAS questionnaire at visits V5, V8, V11, and V12. The development of anti-drug antibodies (ADAs) throughout the trial will be monitored, and the impact of ADAs on safety and efficacy will be analyzed if the number of ADA-positive participants allows. These efficacy parameters will be collected and analyzed at specified timepoints to determine the effectiveness of **fremanezumab** in the preventive treatment of episodic and chronic migraine in pediatric patients.