This pooled analysis included patients from 3 randomized, double-blinded, placebo-controlled, clinical trials of similar design (HALO EM [ClinicalTrials.gov Identifier: NCT02629861], HALO CM [ClinicalTrials.gov Identifier: NCT02621931], and FOCUS [ClinicalTrials.gov Identifier: NCT03308968]) [17,18,19]. All 3 trials included a screening visit and 28-day baseline period before a 12-week, double-blind, placebo-controlled treatment period.

The study protocols and primary results have been previously reported, and the study design and patient selection criteria are summarized briefly here [17,18,19]. Participants were eligible for all studies if they were 18 to 70 years of age, with a history of migraine based on the International Classification of Headache Disorders 3 (ICHD-3), with onset at or prior to age 50 years and for at least 12 months prior to screening [17,18,19]. The HALO EM study included patients with EM (≥ 6 and < 15 headache days per month, with ≥ 4 days fulfilling the ICHD-3 beta criteria for migraine) with or without aura, probable migraine, or use of triptans or ergot derivatives [17]. Patients were included in the HALO CM study if they had CM (≥ 15 headache days per month, with ≥ 8 days fulfilling the ICHD-3 beta criteria for migraine, over a 3-month period) [19] with or without aura, probable migraine, or use of triptans or ergot derivatives. The FOCUS study included patients with EM or CM who had experienced 2 to 4 documented inadequate responses (based on a lack of clinically meaningful improvement, poor tolerability, or contraindication) to any of the following pharmacological classes of migraine preventive medications within the last 10 years: β-blockers, anticonvulsants, tricyclic antidepressants, calcium channel blockers, angiotensin II receptor antagonists, onabotulinumtoxinA, or valproic acid [18].

The study protocols used for the trials included in this analysis were approved by relevant ethics committees and institutional review boards [17,18,19]. Additionally, these trials were conducted in accordance with the International Conference for Harmonization Guidelines for Good Clinical Practice, the Declaration of Helsinki, and relevant national and local regulations. Each patient provided written informed consent before any study procedures or assessments were performed [17,18,19].

In the HALO EM and HALO CM studies, randomization was stratified by sex, country, and baseline preventive medication use [17, 19]. In the FOCUS study, randomization was stratified by migraine classification (CM or EM), sex, country, and failure to 2 or 3 migraine preventive classes plus valproic acid or valproate [18]. In these studies, the sponsor, investigator, study staff, and participants were blinded to treatment assignment during the treatment period.

Across all 3 studies, patients with EM or CM were randomly assigned 1:1:1 to receive quarterly fremanezumab (months 1/2/3: 675 mg fremanezumab/placebo/placebo), monthly fremanezumab (months 1/2/3: EM: 225 mg fremanezumab/225 mg fremanezumab/225 mg fremanezumab; CM: 675 mg fremanezumab/225 mg fremanezumab/225 mg fremanezumab), or matched monthly placebo by subcutaneous injection during the 12-week treatment period [17,18,19].

HIT-6 and MIDAS are validated patient-reported tools that assess the impact of headache on function and measure migraine-related disability, respectively [21, 22]. HIT-6 utilizes a 6-item questionnaire that is scored on a 5-point Likert scale (6 = never, 8 = rarely, 10 = sometimes, 11 = very often, 13 = always) [22]. Scores can range between 36 and 78, with scores of greater numerical value indicating greater impact [22]. Four groups (referred to here as “disability categories”) have been derived to aid in the interpretation of HIT-6 results: scores ≤49 indicate little or no impact; scores ≥50 to ≤55 indicate some impact; scores ≥56 to ≤59 indicate substantial impact; and scores ≥60 indicate severe impact [22]. HIT-6 scores were evaluated in the HALO CM and FOCUS studies [18, 19].

MIDAS utilizes a 5-item questionnaire that is scored by the number of days affected by headache symptoms [23]. Similar to HIT-6, scores with greater numerical value indicate more severe disability [22, 23]. Scores are stratified into disability grades to aid in the interpretation of MIDAS results: scores ≥0 to ≤5 indicate little to no disability; scores ≥6 to ≤10 indicate mild disability; scores ≥11 to ≤20 indicate moderate disability; and scores ≥21 indicate severe disability [23]. MIDAS scores were evaluated in the HALO EM and FOCUS studies [17, 18].

In this pooled analysis, demographic and baseline characteristics were evaluated. Disability responses, based on HIT-6 and MIDAS scores, were assessed at the end of treatment based on the criteria defined in the AHS Consensus Statement (Table 1) [7]. The proportion of patients with a change in HIT-6 disability category or MIDAS disability grade from baseline at the end of treatment was also assessed, along with the overall proportion of patients with a 1-, 2-, or 3-category shift down in disability category or grade from baseline.

For the assessment of baseline and demographic characteristics, patients included in this pooled analysis were from the safety analysis sets from the HALO EM, HALO CM, and FOCUS studies. The safety populations for all 3 studies included all randomly assigned patients who received ≥1 dose of study drug. For the analyses of disability outcomes, patients included in this pooled analysis were from the HALO EM and HALO CM full analysis set (FAS) and the FOCUS modified intent-to-treat (mITT) populations. The FAS populations for the HALO EM and HALO CM studies and the mITT population for the FOCUS study included all randomly assigned patients who received ≥1 dose of study drug and had ≥10 days of postbaseline efficacy assessments for the primary efficacy endpoint (HALO CM, change from baseline in the monthly average number of headache days of at least moderate severity; HALO EM and FOCUS, change from baseline in the monthly average number of migraine days) [17,18,19].

For the analyses of HIT-6 score responses and changes in disability severity category, data were pooled from the HALO CM and FOCUS studies. For the analyses of MIDAS scores responses and changes in disability severity grade, data were pooled from the HALO EM and FOCUS studies. HIT-6 and MIDAS score responses were also evaluated for patients with CM (HALO CM population pooled with the population of patients with CM from FOCUS) and patients with EM (HALO EM population pooled with the population of patients with EM from FOCUS) separately. Baseline and demographic characteristics were evaluated separately for the overall populations used for HIT-6 analyses (HALO CM and FOCUS) and for MIDAS analyses (HALO EM and FOCUS studies).

For assessments of baseline and demographic characteristics, continuous variables were summarized using descriptive statistics (mean and standard deviation [SD]) and categorical variables were summarized using counts and percentages. Proportions of patients achieving HIT-6 or MIDAS disability responses per the AHS Consensus Statement, as well as proportions of patients with a shift in HIT-6 or MIDAS disability severity, were summarized using counts and percentages. For all assessments, P values for between-group comparisons were based on a Cochran-Mantel-Haenszel (CMH) test stratified by study.