Methods

Standard protocol approvals, registrations, and patient consents
The study (NCT02621931; https://clinicaltrials.gov/ct2/show/NCT02621931) was conducted in accordance with the International Conference for Harmonisation guidelines for Good Clinical Practice, the Declaration of Helsinki, and relevant national and local regulations, and it followed the established study protocol [16]. The protocol was approved by relevant ethics committees and institutional review boards, and written informed consent was obtained from each patient prior to performing any study procedures or assessments [16].

Study design, patients, and treatments
A description of the randomized, double-blind, placebo-controlled, parallel-group phase 3 HALO CM study (NCT02621931), which included a screening visit, 28-day pretreatment period, 12-week treatment period, and final evaluation (week 12), has been published previously [16].
Briefly, adults aged 18 to 70 with a history of migraine (according to the International Classification of Headache Disorders, third edition [ICHD-3] beta criteria [17]) for ≥12 months prior to screening and prospectively confirmed CM (headache on ≥15 days and ≥8 days fulfilling ICHD-3 beta criteria for migraine, probable migraine, or use of triptan or ergot medications) during the 28-day pretreatment baseline period were eligible to participate [16]. Patients who used opioids (including codeine) or barbiturates on >4 days per month were excluded from the trial. Additional inclusion and exclusion criteria are provided in a Table in Additional file 1.
Eligible patients were randomized 1:1:1 to receive subcutaneous injections of either fremanezumab quarterly (675 mg of fremanezumab at baseline and placebo at weeks 4 and 8), fremanezumab monthly (675 mg of fremanezumab at baseline and 225 mg at weeks 4 and 8), or placebo (matching placebo at baseline and at weeks 4 and 8) [16].

Outcomes
The primary endpoint of the study, mean change from baseline (28-day pretreatment period) in the monthly average number of headache days of at least moderate severity during the 12-week treatment period, has been previously described [16]. Herein, post hoc analyses were conducted to assess the impact of fremanezumab in patients with and without MO. Patients were grouped based on the presence or absence of baseline MO, which was defined as use of acute headache medication on ≥15 days, migraine-specific acute medication on ≥10 days, or combination medications for headache on ≥10 days during the 28-day pretreatment period [17].
The following outcomes were assessed in patients with and without MO based on mean change from baseline (28-day pretreatment period) in the: monthly average number of headache days of at least moderate severity during the 12-week treatment period; monthly average number of migraine days during the 12-week treatment period; and monthly average number of days of any acute headache medication use. Also assessed was the proportion of patients with a ≥ 50% reduction from baseline (28-day pretreatment period) in the monthly average number of headache days of at least moderate severity during the 12-week treatment period; mean change from baseline (day 0) in scores on the six-item Headache Impact Test (HIT-6; scores range from 36 to 78, with higher scores indicating greater impact of headache on functional status and well-being) [18] at 4 weeks after the last dose of study drug; mean change from baseline (day 0) in domain scores on the Migraine-Specific Quality of Life (MSQoL) questionnaire (domains assessed: role function–restrictive [RFR; seven items on how migraines limit daily activities], role function–preventive [RFP; four items on how migraines prevent these activities], emotional function [EF; three items on the emotional effects of migraines]; scores range from 0 to 100, with higher scores indicating better health-related quality of life) [19] at 4 weeks after the last dose of study drug; and mean change from baseline (day 0) in scores on the nine-item Patient Health Questionnaire (PHQ-9; scores range from 0 to 27, with depression severity categorized as no or minimal [0 to 4], mild [5 to 9], moderate [10 to 14], moderately severe [15 to 19], and severe [20 to 27]) [20] at 4 weeks after the last dose of study drug.
Additionally, patients with MO at baseline were assessed for reversion to no MO, where reversion was defined as no longer meeting criteria for MO over the 12-week period, or continued MO during the 12-week treatment period. Outcomes assessed in these subgroups included those previously described.

Statistical analyses
The post hoc analyses reported here were performed on subgroups of patients in the full analysis set (FAS) population: randomized patients who received ≥1 dose of study drug and had ≥10 days of post-baseline efficacy assessments on the primary endpoint (i.e., a daily headache diary) [16]. The subgroups included patients with MO at baseline versus without MO at baseline; and patients who did revert from MO at baseline to no MO during the study versus patients who did not revert from MO at baseline to no MO during the study. Least-square (LS) mean changes from baseline were evaluated using an analysis of covariance with treatment, sex, region, and baseline preventive migraine medication use as fixed effects, and baseline values and years since onset of migraines as covariates. The Cochran-Mantel-Haenszel test was used to analyze treatment differences between proportions of patients, with baseline preventive medication use as the stratification variable. Patients who prematurely discontinued from the study were considered as non-responders for overall analysis. For subgroups defined by treatment outcomes (i.e., patients who did or did not revert from MO at baseline to no MO during the study), data were summarized using descriptive statistics.