Study design and patients
The RELIEF study (NCT04152083), including detailed methods, was previously described . This was a 4-week, phase 3, parallel-group, double-blind, placebo-controlled clinical trial in which patients received IV eptinezumab 100 mg or placebo over 30 min within 1–6 h of a qualifying migraine attack (day 0). The use of rescue medication (any acute medication to treat migraine or migraine-associated symptoms) was not permitted in the 24-h period prior to receiving study treatment or within 2 h of infusion start. Only after 2 h post infusion start were patients permitted to use rescue medication.
RELIEF was conducted between November 2019 and July 2020 at 42 sites in the United States and 5 sites in the country of Georgia. The study was approved by a centralized institutional review board (or independent ethics committee at each study site, if required), with written informed consent obtained for each participant prior to the study’s initiation.
Eligible patients were 18–75 years of age with ≥1-year history of migraine (defined by the International Classification of Headache Disorders, 3rd edition [ICHD-3] criteria) , with onset of first migraine ≤50 years of age. All patients were required to have experienced migraine on 4–15 days per month in the 3 months prior to screening (screening occurred up to 8 weeks before dosing) to ensure that only patients eligible for preventive treatment were enrolled. Patients were required to have typical migraine attacks (4–72 h untreated), with headache pain of moderate to severe intensity, migraine-associated features, and a most bothersome symptom (MBS) of nausea, photophobia, or phonophobia. Additionally, patients were required to have a history of active or previous triptan use for migraine to help ensure a migraine diagnosis. Patients could not receive any monoclonal antibody treatment for any reason within 6 months prior to screening or any experimental, unregistered therapy within 30 days or 5 plasma half-lives (whichever was longer) prior to screening.
Patient-reported outcome measures
This report focuses on the 6-item Headache Impact Test (HIT-6) ,6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) , and Patient Global Impression of Change (PGIC) . HIT-6 and mTOQ-6 outcomes were captured at the screening visit and 4 weeks after infusion, with PGIC captured at week 4. Site staff reviewed questionnaires for completeness and clarity, and asked patients to complete any unanswered questions prior to patients leaving the clinic; the HIT-6 or mTOQ-6 total score was treated as missing if a patient response was missing the answer to ≥1 questions.
HIT-6, as detailed in Additional file 1, Table 1, measures the impact on the ability to function normally in daily life when a headache occurs . It is a 6-question, Likert-type, self-reporting questionnaire with each question scored as never = 6, rarely = 8, sometimes = 10, very often = 11, and always = 13. The HIT-6 total score is calculated from summing individual items (score range of 36–78 points), with score ranges representing the following burdens of migraine: severe impact = ≥60, substantial impact = 56–59, some impact = 50–55, and little to no impact = ≤49.
The mTOQ-6 assesses the optimization of acute treatment in persons with migraine . The mTOQ-6 is a 6-question, Likert-type, self-reporting questionnaire, detailed in Additional file 1, Table 1, with each item scored as never = 1, rarely = 2, less than half the time = 3, or half the time or more = 4. The mTOQ-6 total score is calculated by summing the score for each individual question (score range of 6–24 points), with a higher score indicating better treatment optimization.
The PGIC includes a single question concerning the subject’s impression of the change in the severity of their illness since the start of the study . Patients were asked, “Since receiving study drug in this study, how would you describe the change (if any) in activity limitations, symptoms, emotions, and overall quality of life as related to your migraine?” Answers were categorized into one of 7 categories: “very much improved”, “much improved”, “minimally improved”, “no change”, “minimally worse”, “much worse”, or “very much worse”. At the week 4 visit, patients were asked to review brief instructions and then complete the assessment.
For the HIT-6 and mTOQ-6, item and total scores were summarized by treatment group at screening and week 4 visits and change from baseline to the week 4 visit was calculated. An analysis of covariance (ANCOVA) model was used to test for a difference between treatment arms for the total score, with the model using change from baseline at week 4 as the response variable. Baseline value, treatment group, and the stratification variables of concomitant preventive migraine treatment (use vs no use) and region (North America vs Georgia) were the independent variables. A similar ANCOVA was fitted for each item of the HIT-6 and mTOQ-6. In the current analyses, the value from the week 4 visit was used for both outcome measures, regardless of whether it was an actual week 4 assessment or an early-termination assessment. The frequency distribution of PGIC responses at the week 4 visit was summarized descriptively.
An exploratory, post hoc analysis was undertaken to evaluate the ability of treatment to provide a clinically meaningful change in HIT-6 total score and item scores. A clinically meaningful within-person improvement in HIT-6 total score was defined as a 5-point or greater decrease, in line with the 2019 American Headache Society (AHS) position statement . A further analysis based on a categorical HIT-6 analysis in patients with chronic migraine was also conducted , where a clinically meaningful within-person improvement was defined as a ≥ 6-point decrease in HIT-6 total score, a ≥ 1-category decrease in items 1–3, and a ≥ 2-category decrease in items 4–6.
As part of the efficacy assessment reported in Winner et al. , key secondary endpoints included headache pain freedom and absence of MBS at 2 h after infusion start, and additional secondary endpoints included headache pain freedom and absence of MBS at 4 h after infusion start. To evaluate the potential clinical meaningfulness of these improvements for changes in PROMs, a post hoc subgroup analysis of HIT-6 total score was conducted in patients who did and did not achieve these secondary endpoints. In addition to evaluating HIT-6 total score, the percentage of patients reporting a new migraine within the study period was calculated in each subgroup; the incidence of a new migraine was captured in an electronic diary from day 3 following treatment until a new migraine was reported (up to day 28).