Migraine Menopause Study

1.0 Purpose of the Study

Hypotheses: The study investigators hypothesize that eptinezumab 300 mg IV will result in a greater reduction in MMDs during weeks 1-12 compared with placebo. The study investigators further hypothesize that eptinezumab will reduce migraine-related disability and acute medication use.

Independent Variable: Randomized treatment allocation (eptinezumab 300 mg IV versus placebo).

Primary Dependent Variable: Change from baseline in average MMDs during weeks 1-12.

Secondary Dependent Variables: Changes in MIDAS scores, PGIC responses, and acute migraine medication-use days.

Exploratory Dependent Variables: Changes in VMS frequency and severity and Menopause Rating Scale (MRS) scores.

2.0 Background / Literature Review / Rationale for the study:

Migraine is a common chronic neurological disorder and is the second leading cause of disability affecting an estimated 1 billion individuals worldwide (1,2). Important sex disparities exist with migraine being twice as common and more severely impacted in females (3). Additionally, periods of hormonal fluctuations across the female reproductive lifespan have demonstrated influences over the migraine experience. Relevant examples include during the early follicular phase of menstruation and in pregnancy/postpartum when migraine frequency may fluctuate in accordance to hormone alterations, namely estrogen levels (4). Specifically, withdrawal of estrogen in the perimenstrual and postpartum periods are thought to be a trigger for migraine, whereas rising stable estrogen levels during active pregnancy tends to be protective, particularly in migraine without aura (4,5). Other periods of reproductive transition, such as menopause, have been less studied and comparably a paucity of knowledge exists with relation to the impact on migraine.

Menopause is a period of hormonal and physiologic change that affects all females during their lifetime as a result of ovarian aging and ultimate cessation of fertility. It can occur naturally or be induced surgically or medically, and typically with natural progression a clinical diagnosis is made retrospectively after a period of amenorrhea for 12 months, a timepoint defined as the final menstrual period (FMP) (6). The years leading up to the FMP are termed the menopausal transition and the menopausal transition plus the 12 months following FMP is termed perimenopause, during which bothersome menopausal symptoms are prevalent including vasomotor symptoms (VMS; night sweats, hot flashes). Perimenopause duration is variable, ranging between 1-10 years (7). During the menopausal transition, the hypothalamic-pituitary-ovarian axis continues to signal, but there is a less consistent response with ovarian aging, resulting in unpredictable and irregular menstrual cycling and erratic hormonal fluctuations (7). The Stages of Reproductive Aging Workshop +10 (STRAW+10) criteria is a classification system that further delineates the stages of menopause, whereby the period following FMP is defined as postmenopause and can be subdivided into early and late stages (8). As postmenopause progresses, hormones reach a steady state with an estrogen nadir and elevated follicle stimulating hormone (FSH) levels and less cycle variability (8). Herein, the relevant terms that pertain to our study population include females in perimenopause and (early) postmenopause, encompassing the timepoint surrounding the final menstrual period with the highest prevalence of VMS.

The influence of menopause on migraine varies depending on the menopausal stage. During perimenopause, females may experience worsening of migraine as a result of frequent and more prominent hormonal fluctuations (namely estrogen withdrawal), along with perimenopause-related increases in comorbid conditions such as anxiety, depression, and sleep disturbances (9-11). This worsening can persist into early postmenopause, but generally with further reproductive aging, migraine improves with the establishment of a stable estrogen nadir (12).

Similarly, migraine itself may influence peri/postmenopause and has been associated with an increased frequency of VMS (13). In the recent prospective cohort study, Nurses' Health Study II, participants with recent migraine in midlife had 30% greater odds of VMS than those without migraine and those with aura were associated with more severe and prolonged VMS (14). The association between migraine and VMS may be due to vascular dysregulation, shared genetic factors, endothelial dysfunction, hypothalamic pathways, and more recent links to calcitonin gene-related peptide (CGRP) (15,16). Elevated CGRP levels, a neuropeptide expressed throughout the nervous system involved in migraine pathophysiology and nociceptor signaling, have also been found during VMS exacerbations, indicating potential overlap with migraine pathophysiology (15). A recent study also showed no differences in CGRP levels were found between postmenopausal females with and without migraine, potentially as a result of estrogen deficiency and stability (17). While CGRP-mediated medications have been used successfully for hormonally exacerbated menstrual-related migraine, limited studies to date have analyzed the use of these medications for migraine in peri/postmenopause. One clinical trial using a singular dose of erenumab evaluated the frequency of moderate to severe daily hot flashes in menopausal females, but the trial did not reach statistical significance after one dose of treatment (24). However, there was a more recent study with more prolonged erenumab treatment that showed a response to flushing in the context of rosacea, which did reach statistical significance (25). Thus, more research is needed to assess the relationship between CGRP antagonism and the impact on VMS, particularly given the dual burden of migraine and menopausal-related VMS (MR-VMS) in midlife remain understudied, despite both negatively impacting the quality of life for middle aged females (18,19).

Migraine management across adulthood includes acute treatments, preventive pharmacotherapy, and nonpharmacological strategies. Acute treatments generally include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), triptans, gepants, and antiemetics. Preventive options include beta-blockers, candesartan, topiramate, tricyclic antidepressants, onabotulinumtoxinA for chronic migraine, and calcitonin gene-related peptide (CGRP)-targeted therapies, including monoclonal antibodies and gepants. Nonpharmacological approaches include lifestyle modifications, identification of migraine triggers, and behavioural therapies. Treatment selection is individualized based on migraine frequency, disability, comorbidities, contraindications, and patient preferences. During perimenopause, hormonal fluctuations may contribute to increased migraine frequency and severity. Established acute and preventive migraine treatments remain appropriate during perimenopause and postmenopause, with additional consideration of hormonal changes, comorbidities, and menopausal hormone therapy where relevant.

Eptinezumab is a specific CGRP monoclonal antibody agent with established efficacy and favourable pharmacokinetics that can show improvement in migraine symptoms within hours to days (20). The use of this medication allows for earlier identification of a treatment effect compared to alternative CGRP-mediated preventatives, resulting in a more efficient trial design.

Our study aims to evaluate eptinezumab for migraine prevention in females during perimenopause and early postmenopause. Changes in vasomotor symptoms will also be characterized as exploratory outcomes to better understand the relationship between migraine, menopausal symptoms, and CGRP-targeted treatment in this population. These exploratory findings may inform future research but are not intended to establish efficacy for the treatment of vasomotor symptoms.

3.0 Methodology:

1. Study Design:

• Phase IV study.
• 12 week randomized, placebo controlled phase followed by open label extension
• Eptinezumab versus placebo for 12 weeks with placebo group then transitioning to eptinezumab open label phase extension for an additional 12 weeks. A randomized, double-blind, placebo-controlled design was selected to minimize selection, performance, and expectation bias and to determine the efficacy of eptinezumab compared with placebo. The 12-week placebo-controlled period corresponds to one eptinezumab treatment cycle and allows assessment of the primary objective, while the subsequent open-label extension provides additional treatment exposure and allows all participants to receive active treatment.

1. Participant recruitment:

• Potential participants will be recruited through study flyers displayed at Alberta Neurologic Centre (ANC), discussions initiated by treating neurologists during routine clinical encounters, and referrals from other headache clinics and healthcare providers. ANC may distribute the approved recruitment flyer broadly to patients on its existing waiting list without reviewing individual medical records or assessing research eligibility. The study may also be advertised through ANC's social media accounts, including Instagram and Facebook, using REB-approved recruitment materials. Interested individuals will be invited to contact the study team directly. Study information will be provided, and eligibility screening will be conducted with the individual's consent. Patient charts will not be reviewed specifically for research recruitment without prior consent. Participant Withdrawal Participants may withdraw from the study at any time without affecting their current or future medical care. If a participant withdraws, no further study-related data will be collected unless the participant provides permission for continued follow-up. Data collected prior to withdrawal will be retained and may be included in the study analyses, unless the participant specifically requests withdrawal of their data where permitted by applicable ethical and regulatory requirements. The reason for withdrawal will be documented when available.

1. Research Methods/Data Collection Procedures Study Sponsorship and Oversight This is an investigator-initiated trial sponsored by Alberta Neurologic Centre Corp. (ANC), with financial and/or material support from Lundbeck. ANC is the GCP sponsor and retains responsibility for study initiation, management, conduct, monitoring, regulatory compliance, safety reporting, and appropriate clinical-trial liability insurance. Dr. Lisa Rosenegger and Dr. Hayley Thornton are responsible for clinical study oversight and participant safety. Lundbeck will receive periodic progress reports, final study results, and required safety reports in accordance with the Investigator-Initiated Trial Agreement. No identifiable participant data will be routinely transferred to Lundbeck. Contractual audit and indemnification arrangements will be governed by the executed agreement. Recruit Participants and Obtain Informed Consent Potential participants will be recruited through REB-approved study flyers displayed at Alberta Neurologic Centre (ANC), discussions initiated by treating neurologists during routine clinical encounters, and referrals from other headache clinics and healthcare providers. ANC may also distribute the approved recruitment flyer broadly to patients on its existing waiting list without reviewing individual medical records or assessing research eligibility. Additional recruitment may occur through ANC's social media accounts using REB-approved materials. Interested individuals will be invited to contact the study team directly. The study coordinator or appropriately delegated study personnel will provide study information and conduct preliminary eligibility screening with the individual's consent. Patient medical records will not be reviewed specifically for research recruitment without prior consent. Total participation for each participant will be approximately 29 weeks, consisting of a five-week screening period followed by 24 weeks of study treatment and follow-up. Screening will include four weeks (28 days) of baseline diary collection, followed by a seven-day period for retrospective diary completion and data finalization. Baseline diary data will be finalized and locked, and eligibility confirmed, before randomization at week 0. Informed consent will be obtained by the principal investigator, co-investigator, or appropriately delegated study personnel prior to any study-specific procedures. Participants will be provided with the consent form and sufficient time to review it and ask questions. Consent will be obtained in person at Alberta Neurologic Centre or electronically/remotely using the approved electronic consent process and will be documented prior to enrollment. Intervention

• Screening (weeks -5 to 0): Four weeks of baseline diary collection (weeks -5 to -1), followed by a seven-day retrospective entry and data finalization period (weeks -1 to 0). Eligible participants will be randomized at week 0 following confirmation of baseline diary completeness and eligibility.
• Eptinezumab 300 mg versus placebo for 12 weeks followed by eptinezumab 300 mg for all participants for additional 12 weeks. Eptinezumab 300 mg was selected based on efficacy demonstrated in previous clinical trials and to maximize the potential treatment effect in this exploratory population. Protocol
• Randomization: Participants will be randomized in a 1:1 ratio to eptinezumab 300 mg or placebo using a computer-generated randomization sequence prepared by an independent, designated member of Alberta Neurologic Centre's IT team who is not involved in participant recruitment, clinical assessments, or outcome evaluation. Permuted block randomization with randomly varying block sizes of 4 and 6 will be used, stratified by migraine classification (episodic versus chronic migraine). The allocation sequence will be securely maintained in a password-protected file accessible only to designated unblinded personnel responsible for randomization and treatment preparation. Investigators, participants, infusion nurses, and personnel conducting outcome assessments will remain blinded throughout the 12-week randomized phase. The original randomized allocation will remain concealed during the open-label extension. Emergency unblinding will be permitted when knowledge of treatment allocation is medically necessary, according to predefined study procedures.
• Blinding: Capsule, a specialty pharmacy and infusion clinic will help with blinding and administer the treatment. Capsule employee preparing the eptinezumab or placebo will be unblinded; infusion nurse and all other staff will be blinded. Blinding covers will be used to cover the placebo or treatment bags in case of any differences in appearance of placebo and eptinezumab. The original treatment allocation during the 12-week double-blind phase will remain concealed from participants, investigators, and other blinded study personnel during the open-label extension.
• Study Infusions and Clinical Assessments: Study infusions will be administered at Biostart Infusions, the infusion clinic associated with Capsule Pharmacy, located in the same building as Alberta Neurologic Centre. Each infusion will be administered intravenously over approximately 30 minutes by appropriately trained healthcare professionals. At week 0, participants will receive eptinezumab 300 mg IV or placebo according to their randomized treatment assignment. At week 12, all eligible participants will receive eptinezumab 300 mg IV as part of the open-label extension. Eligibility to proceed to the open-label extension will be assessed by the study investigators at week 12. Participants who complete the double-blind phase may continue regardless of their original treatment assignment or treatment response, provided they remain willing to participate and have not experienced a clinically significant adverse event, developed a new medical condition, or acquired another contraindication that would make further eptinezumab treatment unsafe. Participants originally assigned to eptinezumab will receive their second infusion at week 12, while those assigned to placebo will receive their first active infusion. Study infusions will be conducted under the supervision of Dr. Lisa Rosenegger and Dr. Hayley Thornton. All personnel performing study-related infusion procedures will be appropriately trained and documented on the delegation log. In-person clinical assessments will occur at screening, week 12, and week 24 at Alberta Neurologic Centre. Remote assessments will occur at weeks 4, 8, 16, and 20 through WeGuide. Week 12 assessments will be completed before administration of the open-label infusion. Vital signs will be recorded during in-person clinical assessments (screening, weeks 12 and 24) and study infusion visits (weeks 0 and 12). Medication use and adverse events will be reviewed throughout the study, including at scheduled follow-up assessments. Routine laboratory investigations are not required.
• Data Collection:
• Migraine and vasomotor symptom diaries: Participants will use WeGuide to record headache/migraine episodes, vasomotor symptoms (including hot flashes and night sweats), and acute medication use as they occur. On days without symptoms or medication use, participants will confirm that no events occurred. WeGuide will permit retrospective diary entries and no-event confirmations for up to seven calendar days. Entries will be automatically locked after this period and cannot be added or modified by participants. Automated daily reminders will support diary completion throughout the study.
• Migraine and Headache Day Definitions: A headache day will be defined as a calendar day on which a participant experiences headache. A migraine day will be defined as a calendar day on which a headache meets ICHD-3 criteria for migraine or probable migraine, or on which a headache is treated with migraine-specific acute medication because the participant recognizes it as a migraine attack. Each calendar day will be counted only once, regardless of the number of headache or migraine episodes.
• These definitions will be applied consistently during the baseline assessment and throughout the study to determine eligibility and calculate monthly migraine days.
• Migraine-related disability and patient-reported outcomes: MIDAS will be administered at baseline, week 12, and week 24, consistent with its three-month recall period. PGIC will be administered at weeks 4, 8, 12, 16, 20, and 24, using baseline as the reference point.
• Menopausal and psychological assessments: MRS, PHQ-9, and GAD-7 will be administered at baseline and weeks 4, 8, 12, 16, 20, and 24. Assessments at weeks 4, 8, 16, and 20 will be completed remotely through WeGuide. Week 12 assessments will be completed before administration of the open-label infusion.
• Medication and Lifestyle: Record any changes in medication use during the trial. Monitor monthly changes in lifestyle factors including exercise, smoking, and alcohol during inpatient follow-ups. Compliance and Adherence
• Treatment Adherence: Study treatment will be administered by qualified healthcare professionals at scheduled infusion visits. WeGuide will send automated daily and weekly reminders to support diary completion and questionnaire adherence.
• Diary Entries: Participants will use WeGuide to record headache/migraine episodes, vasomotor symptoms, and acute medication use as they occur. On days without symptoms or medication use, participants will confirm that no events occurred. Participants may complete diary entries retrospectively, with completion at least once per week considered acceptable. Retrospective entries and no-event confirmations will be permitted for up to seven calendar days, after which entries will be automatically locked and cannot be added or modified by participants. Days without an event entry or no-event confirmation will be considered missing rather than symptom-free. During the four-week baseline period, valid diary information will be required for at least 80% of days (23 of 28 days). Baseline eligibility will require at least 8 headache days, including at least 4 migraine days, during the 28-day baseline period. Baseline diary data will be finalized and locked before eligibility confirmation and randomization. The same seven-day reporting window will apply throughout the study.
• Questionnaires: Study questionnaires will be administered electronically through WeGuide according to the schedule of assessments. Adverse Events Reporting Adverse events will be assessed and documented throughout the study, including during infusion visits and scheduled clinical or remote follow-up assessments. Participants will be provided with study team contact information and instructed to report any adverse events or concerns that arise between scheduled assessments. Participants experiencing a medical emergency will be instructed to seek immediate medical attention. All reported adverse events will be reviewed by the study investigators, Dr. Lisa Rosenegger and Dr. Hayley Thornton, to assess severity, seriousness, potential relationship to study treatment, and the need for further clinical evaluation or intervention. Alberta Neurologic Centre, as the study sponsor, will be responsible for ensuring appropriate adverse-event documentation and reporting in accordance with applicable regulatory requirements, REB requirements, and the study agreement. Reporting will be coordinated with Biostart Infusions/Capsule Pharmacy and Lundbeck to ensure appropriate communication and avoid duplicate submissions. Participant Safety Monitoring and Stopping Criteria Study infusions will be administered by qualified healthcare professionals at Biostart Infusions, with acute monitoring during and immediately following treatment. Dr. Lisa Rosenegger and Dr. Hayley Thornton will provide investigator oversight, including assessment of delayed adverse events and clinically significant safety concerns. Individual study treatment will be discontinued in the event of a serious hypersensitivity reaction, pregnancy, participant preference, or another clinically significant safety concern. The investigators will assess whether unexpected serious safety events warrant suspension of the overall study. Serious adverse events will be documented and reported in accordance with applicable regulatory and ethics requirements. PHQ-9 Safety Monitoring PHQ-9 questionnaires will be completed electronically through WeGuide at baseline and every four weeks during study treatment and follow-up. WeGuide will automatically flag any positive response to Question 9 (thoughts of death or self-harm) and notify designated study team members. Participants endorsing this item will immediately receive an automated message containing crisis resources, including the Canadian Suicide Crisis Helpline (call or text 988), and instructions to call 911 or attend the nearest emergency department if in immediate danger. Flagged responses will be reviewed by a study investigator within one business day. The participant will be contacted for further suicide risk assessment and appropriate follow-up. Participants reporting active suicidal ideation with intent or plan will be directed for immediate emergency assessment. Participants will be informed that WeGuide is not continuously monitored and should not be used for urgent medical or mental health concerns.

1. Data Analysis Procedure Statistical Methods The planned sample size is 120 participants (60 per group), as justified in Section 3(b). Sample-size assumptions were informed by PROMISE-2 and are subject to uncertainty because the present study population differs from that of the original trial. A qualified biostatistician will finalize the statistical analysis plan before database lock and unblinding and oversee the statistical analyses. Data will be analyzed according to the intention-to-treat principle, with all randomized participants included in the intention-to-treat population according to their original treatment assignment, regardless of treatment adherence or study completion. Baseline demographic and clinical characteristics will be summarized using means and standard deviations or medians and interquartile ranges for continuous variables, and frequencies and percentages for categorical variables. Diary Completeness and Missing Data Participants will record headache/migraine episodes, vasomotor symptoms, and acute medication use through WeGuide, including confirmation of days without symptoms or medication use. Entries may be completed retrospectively for up to seven calendar days, after which they will be automatically locked. A diary day will be considered complete when an event has been recorded or the participant has confirmed that no events occurred. Days without an event entry or no-event confirmation within the permitted reporting window will be considered missing. At least 80% diary completion (23 of 28 days) will be required during the four-week baseline diary period. Baseline diary data will be finalized and locked before eligibility confirmation and randomization. Monthly migraine days will be calculated for each four-week period and standardized to 28 days based on available valid diary days, provided at least 80% of days are complete. Periods with less than 80% completion will be considered missing. Participants with incomplete diary data will remain in the intention-to-treat population. The primary ANCOVA will use available evaluable outcome data. Multiple imputation under a missing-at-random assumption will be considered as a sensitivity analysis. The statistical analysis plan will prespecify the handling of incomplete diary periods and missing primary outcomes. The biostatistician will also assess whether a repeated-measures approach is appropriate as a sensitivity analysis to account for partially observed follow-up data. Multiplicity and Open-Label Extension The primary endpoint will be evaluated using a two-sided significance level of 0.05. Secondary and exploratory endpoints will not undergo formal multiplicity adjustment. Results will be presented with effect estimates and 95% confidence intervals and interpreted as exploratory. Outcomes during the open-label extension (weeks 12-24), including monthly migraine days, monthly headache days, acute medication-use days, vasomotor symptom frequency and severity, patient-reported outcomes, and adverse events, will be summarized descriptively and stratified by original randomized treatment assignment. No formal between-group hypothesis testing is planned for this phase. Recruitment Feasibility Review After 12 months of recruitment, recruitment and retention rates will be reviewed to assess the feasibility of achieving the target sample size. This review will not include an unblinded comparison of treatment efficacy between randomized groups.
2. Confidentiality and Data Management. Information collected will include participant demographics, relevant medical history, migraine characteristics, menopausal status and vasomotor symptoms, medication use, lifestyle factors, adverse events, and responses to study diaries and questionnaires (MIDAS, PGIC, MRS, PHQ-9, and GAD-7).

Participant contact information and relevant clinical information will be maintained in Accuro, the Alberta Neurologic Centre electronic medical record. Study data, including electronic diaries and questionnaires, will be collected and stored using the secure Weguide research platform. Participants will access WeGuide through a mobile application installed on their personal devices. Participant names and email addresses will be collected and stored within the WeGuide platform to facilitate access to electronic study diaries, questionnaires, and study-related communications.

Each participant will be assigned a unique study identification number, which will be used for research data whenever possible. The linkage between the study ID and participant identifiers will be stored separately from the research dataset and accessible only to authorized study personnel.

Access to study information will be restricted to authorized members of the research team through individual password-protected accounts and appropriate access controls. Identifiable information will not be included in presentations, publications, or other dissemination of study results; results will be reported in aggregate.

Study records will be retained for 15 years, in accordance with applicable institutional, regulatory, and sponsor requirements for a regulated clinical trial, after which they will be securely destroyed.

Strengths/Limitations:

Strengths: This randomized, double-blind, placebo-controlled trial will prospectively evaluate eptinezumab in a clinically important and understudied population of perimenopausal and early postmenopausal women with migraine and vasomotor symptoms. Strengths include standardized diagnostic criteria, prospective diary-based assessment, validated patient-reported outcome measures, and assessment of both migraine and menopausal symptoms.

Limitations: As a single-centre study requiring both migraine and active vasomotor symptoms, findings may not be generalizable to the broader population of perimenopausal and early postmenopausal females with migraine. The sample-size assumptions are extrapolated from previous eptinezumab trials trials rather than studies specifically conducted in perimenopausal women. The 12-week placebo-controlled period limits assessment of longer-term comparative outcomes, and heterogeneity in menopausal stage and concomitant migraine therapies may contribute to variability in treatment response. Vasomotor symptom outcomes are exploratory, and the study is not specifically powered to establish efficacy for VMS.