Migraine Menopause Study

Prior treatment

• Systemic hormone therapy: Participants currently using systemic estrogen-based hormonal treatment including for menopause or contraception. Patients on local hormone therapy, progesterone only methods, and/or IUDs will be included.
• Medication Use: Participants may continue stable, non-CGRP migraine preventive medications, including beta-blockers, candesartan, tricyclic antidepressants, and topiramate, provided the dose has remained stable for at least 12 weeks before enrollment. OnabotulinumtoxinA will be permitted in participants receiving treatment for at least nine months (minimum three treatment cycles), with a stable treatment schedule.
  • Participants receiving CGRP-targeted monoclonal antibodies must complete a five-month washout before randomization. Participants receiving oral gepants for migraine prevention, including atogepant, must complete a seven-day washout before beginning the four-week baseline diary period.
  • Acute migraine treatments, including triptans, NSAIDs, acetaminophen, antiemetics, and gepants, will be permitted throughout the study. Acute gepant use will be limited to 16 days per month. Concurrent CGRP-targeted preventive treatment will not be permitted.
  • Discontinuation of an existing preventive treatment will occur only when clinically appropriate following review by the treating neurologist. Participants may continue receiving appropriate clinical care and acute migraine treatment during washout and study participation.
  • Before enrollment, the study investigator will review each participant's treatment history, current migraine control, and ongoing preventive therapies to determine whether placebo exposure is ethically and clinically appropriate under TCPS 2 Article 11.4. Participants for whom discontinuation of effective preventive treatment or potential placebo exposure is considered clinically inappropriate will not be enrolled.
• Pregnancy: Pregnant or breastfeeding females. Females planning pregnancy in the next year. Participants with reproductive potential will be required to use an effective method of pregnancy prevention during study treatment. Permitted methods include nonhormonal contraception, including barrier methods; progestin-only contraception (progestin-only pills, implants, or levonorgestrel-releasing intrauterine devices); tubal ligation; a partner with a confirmed successful vasectomy; or consistent abstinence from sexual activity that could result in pregnancy.
  • Systemic estrogen-containing hormonal therapies, including combined hormonal contraception, are excluded because of their potential effects on migraine and vasomotor symptoms.
  • Pregnancy status and reproductive intentions will be assessed during screening. Participants will be counselled regarding the limited pregnancy safety data for eptinezumab and instructed to notify the study investigators immediately if pregnancy occurs or is suspected. Study treatment will be discontinued if pregnancy occurs.
  • Eligibility criteria were selected to identify a clinically relevant population experiencing both active migraine and vasomotor symptoms during the natural menopausal transition, while reducing factors that could confound assessment of treatment response. Systemic estrogen therapy and surgically/medically induced menopause are excluded because of their potential effects on hormonal exposure, migraine, and vasomotor symptoms. Medication-related exclusions and washout periods are intended to minimize confounding from concurrent CGRP-targeted preventive therapies.

Other illness

• Other Headache Disorders: Participants with other primary headache disorders (e.g. cluster headache) or secondary headache disorders.
• Surgical or Medically-Induced Menopause: Participants with iatrogenic menopause due to an oophorectomy +/- hysterectomy, exposure to anti-estrogen cancer treatment, or radiotherapy
• Other Medical Conditions: Participants with significant medical conditions that could interfere with the study, such as uncontrolled hypertension, cardiovascular disease, osteoporosis, or severe psychiatric disorders.

• Age: Females aged 40-60 years.
• Menopausal Status: Naturally occurring perimenopausal and early postmenopausal patients, based on the Stages of Reproductive Aging Workshop +10 (STRAW+10) criteria using the clinical symptom criteria.
• Migraine Diagnosis: Participants must have a clinical diagnosis of migraine, with or without aura, according to the International Classification of Headache Disorders, Third Edition (ICHD-3).
• Headache and Migraine Frequency: Participants must experience at least 8 headache days per 28-day period, including at least 4 migraine days, as documented during the baseline diary assessment.
• Vasomotor Symptoms: Participants must experience vasomotor symptoms, including hot flashes and/or night sweats, on at least 8 days per month.
• Informed Consent: Participants must be willing and able to provide written informed consent.