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Shift from chronic to episodic migraine frequency in a long-term phase 3 study of galcanezumab

The Journal of Headache and Pain volume 26, Article number: 26 (2025) Cite this article

Abstract

Background

Chronic migraine (CM) is a highly disabling form of migraine in which patients have ≥ 15 headache days per month, of which at least 8 have the features of migraine. Galcanezumab is a monoclonal antibody to calcitonin gene-related peptide which is approved for the preventive treatment of migraine. Ability to convert patients from chronic migraine frequency to episodic migraine (EM) frequency is a clinically relevant and desirable outcome when prescribing preventive treatments to patients with CM.

Methods

Patients aged 18–65 years with an ICHD-3β diagnosis of CM were randomized 2:1:1 to receive monthly injections of placebo (N = 558), galcanezumab 120 mg with a 240-mg loading dose (N = 278), or galcanezumab 240 mg (N = 277) during a 3-month double-blind period of the phase 3 REGAIN trial. Patients could subsequently enter a 9-month open-label extension in which they received galcanezumab 120 mg or 240 mg/month per investigator’s discretion. In this post-hoc analysis, we assessed the percentages of patients who shifted to EM (< 8 migraine headache days or < 15 headache days/month), low frequency EM (LFEM; <8 migraine headache days/month), and very low frequency EM (VLFEM; <4 migraine headache days/month) for at least 3 consecutive months. Double-blind percentage comparisons versus placebo represent modeled estimates from raw rates.

Results

At baseline, patients had a mean of 19.4 migraine headache days per month (SD = 4.5) and 21.4 headache days per month (SD = 4.1). During the 3-month double-blind treatment period, a greater percentage of galcanezumab-treated patients shifted to EM frequency and maintained it across all 3 months (31.5%) than did placebo-treated patients (19.8%, p < 0.001). Among galcanezumab-treated patients across the entire 12-month trial, 65.1% shifted from CM to EM frequency, with 44.2% shifting to LFEM and 21.5% shifting to VLFEM for ≥ 3 consecutive months. Proportions of patients shifting from CM to EM frequency for ≥ 3 consecutive months and until last patient visit were: 55.0% to EM; 33.4% to LFEM; 13.9% to VLFEM.

Conclusion

These results suggest that galcanezumab helped a majority of patients convert from chronic to episodic migraine frequency over the course of this 12-month study.

Trial registration

Clinicaltrials.gov NCT02614261, first registered November 25, 2015.

Peer Review reports

Introduction

Chronic migraine (CM) is a neurological disease associated with very high levels of disability and economic burden [1]. The International Classification of Headache Disorders, 3rd edition (ICHD-3) defines CM as ≥ 15 headache days per month for more than 3 months, with at least 8 of these monthly headache days having the features of migraine [2]. The high disease burden of CM arises from several factors including headache-related disability, acute medication use, healthcare resource utilization, and presence of comorbid conditions [3, 4]. Current oral preventives for CM, recommended by treatment guidelines, are associated with high discontinuation rates, low adherence, and frequent treatment switches due to insufficient efficacy and/or tolerability reasons [5,6,7,8]. Many patients with CM, therefore, rely solely on acute medications to manage their disease, which in turn may lead to further worsening and medication overuse headache [9, 10].

Galcanezumab, a monoclonal antibody that binds to and blocks the physiological activity of calcitonin gene-related peptide (CGRP), belongs to a novel class of molecules specifically designed for migraine prevention [11]. Galcanezumab 120 mg (with a 240-mg loading dose) is approved as a once-monthly subcutaneous injection for the prevention of migraine in adults based on three phase 3 studies: two studies in episodic migraine [12, 13] and one in chronic migraine [14]. The REGAIN study of galcanezumab in patients with CM comprised a 3-month double-blind treatment period and a 9-month open-label extension (OLE) [14, 15]. Patients in the REGAIN study experienced an average of 19.4 migraine headache days/month at baseline. During the double-blind treatment period, galcanezumab 120 mg (with a 240-mg loading dose) and galcanezumab 240 mg led to significantly larger reductions in migraine headache days (overall mean reduction: 120 mg: -4.8; 240 mg: -4.6) compared to placebo (overall mean reduction: -2.7) [14], with continued improvement during the subsequent OLE [15]. Significant improvements were also noted with galcanezumab versus placebo for the proportions of patients who experienced reductions in migraine headache days of ≥ 50% and ≥ 75% from baseline [14], with these proportions increasing during the OLE [15]. In an adaptation of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials framework for CM studies, headache frequency reduction of 1 day/month and a ≥ 30% reduction of headache day frequency from baseline were both examples of outcomes noted as clinically meaningful in the CM population [16]. However, with improvements of 50% or greater, some patients may have crossed the threshold from CM to EM frequency during the trial. Compared with CM, the burden is lower among patients with EM, and the burden decreases as headache frequency decreases [17]. Patients with EM have lower levels of disability, better functioning at work and home, and less headache medication overuse, all of which translates into lower economic costs as well [8, 18,19,20]. Thus, the ability to convert patients from chronic to episodic migraine frequency is a clinically relevant and desirable outcome when prescribing preventive treatments to patients with CM.

To evaluate the ability of galcanezumab to convert patients from chronic to episodic migraine frequency, we conducted a post-hoc analysis of the 12-month REGAIN study to assess the proportions of patients with CM who shifted to episodic frequency during the study. Currently, there are no standard definitions of episodic migraine or its subcategories, although the ICHD-4α proposes an interim definition of EM as “Headache occurring on less than 15 days a month over the last 3 months, which on some days is migraine” [21]. For the purposes of the present analyses, we defined EM frequency as < 8 migraine headache days/month and/or < 15 headache days/month, such that the patient no longer met one or both parts of the frequency elements of CM. We also evaluated the proportions of patients who shifted into the more stringent categories of low frequency EM (LFEM; < 8 migraine headache days/month) and very low frequency EM (VLFEM; < 4 migraine headache days/month), as has been done in previous studies [22, 23]. For the 3-month, randomized, double-blind, placebo-controlled treatment period, we compared the galcanezumab and placebo groups with respect to percentage of patients who had shifted to EM frequency at Month 3 and with respect to percentages who met EM frequency criteria at all 3 months of the double-blind treatment period. For the full 12-month study which included the 9-month open-label period, we looked at the percentage of all galcanezumab-treated patients who shifted to EM frequency for at least 3 consecutive months and those who shifted for at least 3 consecutive months and sustained that shift until their last study visit.

Methods

Study design and patients

REGAIN (Clintrials.gov: NCT02614261) was a phase 3, double-blind, randomized, placebo-controlled trial. The study comprised: (i) a screening and washout period; (ii) a 1-month prospective baseline period; (iii) a 3-month double-blind treatment period; (iv) a 9-month OLE period; and (v) a 4-month post-treatment follow-up period. All procedures of the REGAIN study have been detailed previously [14, 15]. Eligible patients were randomly assigned in a 2:1:1 ratio to receive monthly subcutaneous injections of placebo, galcanezumab 120 mg or 240 mg for 3 months of double-blind treatment. Patients assigned to 120 mg received an initial loading dose of 240-mg.

At the end of the double-blind treatment period, patients could enter the OLE period for an additional 9 months of treatment. Patients entering the OLE received a loading dose of galcanezumab 240-mg/month followed by a dose of 120 mg/month at the subsequent visit a month later. Thereafter, dosing was flexible, with patients receiving either galcanezumab 120 mg or 240 mg/month at the investigator’s discretion. The reasons for dose selection by the investigator were not captured. Throughout the OLE period, patients and investigators remained blinded to the patient’s previous double-blind treatment assignment.

Inclusion and exclusion criteria have been described in detail previously [14], and only key criteria are described here. Briefly, male and female patients 18–65 years of age, with diagnosis of chronic migraine as defined by International Classification of Headache Disorders, 3rd edition, beta version (ICHD-3β) criteria [24] were included. Patients had to have migraine onset prior to age 50 years. As per this definition, patients experienced ≥ 15 headache days per month, ≥ 8 of which had features of migraine headache for more than 3 months prior to screening [7]. Patients had to have a history of at least one headache-free day/month, both during the three months prior to screening and during the prospective baseline period. Patients with persistent daily headache, cluster headache, or certain atypical migraine subtypes as defined by ICHD-3β were excluded [14]. Acute medications could be used as needed, but with certain restrictions such as on the frequency of use of opioid- or barbiturate-containing medication and of corticosteroid injections [14]. Prior to entering the baseline screening period, patients had to discontinue migraine preventives except topiramate or propranolol, for which concomitant use was allowed if they had been on a stable dose for ≥ 2 months prior to the baseline period. Fewer than 15% of patients continued taking topiramate or propranolol during the study [14, 15].

The study was conducted according to Good Clinical Practice and the Declaration of Helsinki. Ethical/institutional review boards at each of the participating sites approved the protocol. Written informed consent was obtained from all patients prior to all study procedures and treatments.

Study objectives, measures, and assessments

The primary objective of the REGAIN study was to assess if galcanezumab 120 mg or 240 mg was superior to placebo in overall mean change from baseline in number of migraine headache days during the 3-month double-blind treatment period. A calendar day on which a migraine headache or probable migraine headache occurred (based on ICHD-3β criteria) and lasted at least 30 min was defined as a migraine headache day. The primary objectives of the 9-month OLE period of REGAIN were to assess the long-term safety and effectiveness of galcanezumab. Throughout the prospective baseline, double-blind treatment period, and OLE, patients used an electronic diary to record daily headache information. This allowed for long-term analysis of changes in monthly migraine headache day frequency.

For the purposes of this study, we defined EM frequency as < 8 migraine headache days/month and/or < 15 headache days/month, such that the patient no longer met one or both parts of the frequency elements of CM per the ICHD-3 criteria. Two subcategories of EM frequency were also evaluated: low frequency EM (LFEM) and very low frequency EM (VLFEM). LFEM was defined as < 8 migraine headache days/month, and VLFEM was defined as < 4 migraine headache days/month. It should be noted that in this study, LFEM includes VLFEM, and EM includes both LFEM and VLFEM. The proportions of patients who shifted from CM frequency at baseline to the different categories of EM frequency during the different time periods of REGAIN study were analyzed.

Statistical analyses

Analyses were performed on all randomized patients who received at least one dose of study drug and who had both a baseline and post-baseline value for monthly migraine headache days. For the double-blind treatment period, we used a pseudo likelihood-based non-linear repeated measures model to compare the model-estimated percentages of patients in each treatment group who met the criteria for the different categories of EM frequency at Month 3 and for those who sustained the criteria for the different categories of EM frequency for all 3 months of the double-blind treatment period. The model included terms for treatment, baseline medication overuse, concomitant preventive medication use, month, treatment-by-month interaction, and baseline number of monthly migraine headache days. The modeled percentage estimates were obtained using an unstructured covariance structure, and the Kenward-Roger approximation was used to estimate denominator degrees of freedom. Odds ratios (ORs) versus placebo, 95% confidence intervals (CIs), and p-values were also determined with this model. This modeling replicates the methodology used for the pre-specified analyses of the primary and secondary objectives for the study. The purpose of the modeling is to increase precision of the estimated treatment effect by controlling for baseline differences between treatment groups.

When presenting data from the entire 12 months of the REGAIN study, the percentages of patients who shifted from CM frequency at baseline to different categories of EM frequency were analyzed in two different ways: (i) shift for ≥ 3 consecutive months, and ii) shift for ≥ 3 consecutive months and until patient’s last visit. Since these analyses only included data collected during galcanezumab treatment, only data from the OLE was included for patients randomized to placebo, while patients randomized to one of the double-blind galcanezumab groups could have data for up to 12 months of treatment (3 months double-blind plus 9 months OLE). Statistical comparisons among the groups were performed.

SAS software (SAS Institute Inc, Cary, NC, USA) was used to conduct statistical analyses. Two-sided p-values < 0.05 were considered statistically significant.

Results

Patient disposition and demographics

Patient disposition and demographics have been described in detail previously for the double-blind [14] and open-label periods [15]. Briefly, 1037 patients completed the double-blind treatment period, of which 1022 patients (98.6%) entered the OLE period. Among the patients who entered OLE, 501 patients previously received placebo, 259 patients previously received galcanezumab 120 mg/month, and 262 patients previously received galcanezumab 240 mg/month. Almost identical baseline demographics and disease characteristics were noted between the full double-blind treatment population and the subset that entered the OLE period [15]. Patient demographics and disease characteristics by treatment group are summarized in Table 1. The total group of patients was mostly female (85.0%), and mean age (standard deviation [SD]) was 41.0 (± 12.1) years. Criteria for acute headache medication overuse [14] was met by 63.8% of patients during the baseline period. With respect to galcanezumab exposure during the OLE period, 64.3% of patients received 2 injections (totaling 240 mg) at the first flexible dosing visit; this percentage progressively increased to a high of 75.8% by Visit 14. Of the 1022 patients who entered the OLE, 825 completed the OLE (80.7%), with low incidence of discontinuations due to an AE (46/1022 [4.5%]) or lack of efficacy (40/1022 [3.9%]).

Table 1 Patient demographics and disease characteristics at baseline
Full size table
Table 2 Percentages of galcanezumab- versus placebo-treated patients who shifted from CM to EM frequency
Full size table

Shift to episodic migraine frequency during double-blind treatment

Significantly larger percentages of patients in the galcanezumab 120 mg (55.9%, p < 0.001) and pooled galcanezumab groups (53.0%, p < 0.01) achieved a shift from CM frequency at baseline to EM frequency at Month 3 compared with placebo (42.3%) (Fig. 1A). Moreover, the percentage of patients who shifted from CM to EM frequency was statistically greater for each galcanezumab group relative to placebo at Months 1 and 2 as well. At Month 1, 41.7% (galcanezumab 120 mg; p < 0.001) and 40.8% (galcanezumab 240 mg; p < 0.001) of patients shifted to EM frequency, compared to 27.8% for placebo. At Month 2, 50.9% (galcanezumab 120 mg; p < 0.001) and 47.8% (galcanezumab 240 mg; p = 0.010) of patients shifted to EM frequency, compared to 37.3% for placebo. Significantly larger percentages of patients in the galcanezumab 120 mg (34.2%, p < 0.001), 240 mg (28.8%, p < 0.01) and pooled groups (31.5%, p < 0.001) maintained the shift to EM frequency at all 3 months of the double-blind period relative to the placebo group (19.8%) (Fig. 1B). The model-estimated rates, 95% CIs, ORs versus placebo, and their p-values are summarized in Table 2.

Similar patterns were seen for the percentages of patients shifting from CM frequency to LFEM. At Month 3, the percentages of patients shifting to LFEM were significantly larger in the galcanezumab 120 mg (p < 0.05) and 240 mg (p < 0.01) groups as well as the pooled group (p < 0.01) relative to placebo, with 30.6% in the pooled galcanezumab group versus 21.7% in the placebo group (Fig. 1A). The percentages of patients maintaining a shift to LFEM at all 3 months of the double-blind period were significantly larger in both galcanezumab dose groups (p < 0.001) relative to placebo (Fig. 1B). Moreover, the percentage of patients shifting from CM frequency to LFEM in the pooled galcanezumab group (12.8%) was significantly greater (p < 0.001) relative to placebo (5.5%).

The percentages of patients shifting to VLFEM at Month 3 or having a sustained shift to this category at all 3 months of double-blind treatment were small but significantly larger in the galcanezumab 240 mg group (14.6%) relative to placebo (8.8%) at Month 3 (p < 0.05; Fig. 1A). The model estimated rates, 95% CIs, odds ratios (ORs) versus placebo, and p-values are summarized in Table 2.

Shift to episodic migraine frequency across the 12-month study

Data obtained during treatment with galcanezumab in the open-label period only (for previous placebo patients) or double-blind plus open-label periods (for previous galcanezumab patients) were included in this analysis of patient proportions shifting to EM frequency for ≥ 3 consecutive months. Across the 12-month period, 63.5–66.2% of patients shifted from CM to EM frequency for ≥ 3 consecutive months. A total of 43.7–45.0% of patients shifted to LFEM, and 19.4–23.4% of patients shifted to VLFEM for ≥ 3 consecutive months (Fig. 2A).

As the EM, LFEM, and VLFEM categories represent overlapping, cumulative counts of patients (i.e., each category includes those patients who meet that criterion or better), we also analyzed results according to non-overlapping categories. Figure 3A shows the distribution of patients according to discrete, mutually exclusive, ranges of headache frequency for the total population of patients who received galcanezumab at any time during the 12-month study, including during the double-blind treatment period and/or the OLE periods. This also includes those patients who received placebo during the double-blind treatment period and then received galcanezumab during the OLE period. Within this total patient population, 20.9% shifted to a frequency of < 15 headache days/month and ≥ 8 migraine headache days/month, 22.7% shifted to ≥ 4 to < 8 migraine headache days/month, and 21.5% shifted to < 4 migraine headache days/month for ≥ 3 consecutive months (Fig. 3A).

With respect to maintenance of response in the total population, lower but substantial proportions of patients shifted from CM frequency at baseline to different categories of EM frequency for ≥ 3 consecutive months and until the patient’s last visit. A total of 53.8–55.7% of patients maintained the shift from CM to EM frequency, 30.9–34.7% maintained the shift to LFEM, and 12.6–15.4% maintained the shift to VLFEM (Fig. 2B). Analysis by discrete, mutually-exclusive headache frequency categories with respect to the percentage of patients who shifted to EM frequency for ≥ 3 consecutive months and maintained that shift until the last visit was as follows: < 15 headache days/month, and ≥ 8 migraine headache days/month: 21.6%; < 8 migraine headache days/month but ≥ 4 migraine headache days/month: 19.5%; and < 4 migraine headache days/month: 13.9% (Fig. 3B).

Shift to episodic migraine frequency among patients only on galcanezumab 120 mg

Of 259 patients who were randomly assigned to the galcanezumab 120 mg group and entered the OLE, 51 patients continued to receive galcanezumab 120 mg throughout the OLE maintenance period. This subset of patients treated consistently with the 120 mg/month regimen showed high rates of shift to EM frequency: 86.3% (44/51) shifted to EM frequency for ≥ 3 consecutive months, and 72.6% (37/51) shifted for ≥ 3 consecutive months and until patient’s last visit. In addition, 68.6% (35/51) shifted to LFEM for ≥ 3 consecutive months, and 51.0% (26/51) maintained LFEM to last visit. A total of 41.2% (21/51) shifted to VLFEM for ≥ 3 consecutive months, and 33.3% (17/51) maintained VLFEM to last visit.

Discussion

Migraine is a debilitating disease in both its episodic and chronic forms, with CM imposing more substantial individual and socioeconomic burden as described by various population-based studies [1, 3, 4]. Approximately 90% of people with CM are estimated to have at least a moderate level of migraine-related disability; about one-half of people with CM are estimated to have very severe migraine-related disability [25, 26]. Studies report acute medication overuse in approximately 30–50% of patients with CM visiting specialty clinics [27]. Healthcare resource utilization including use of specialists, emergency departments, diagnostic tests and migraine drugs is also higher among patients with CM compared with EM, with mean annual direct cost estimates also being significantly higher for individuals with CM compared with EM [18, 25, 28, 29]. Lastly, CM is associated with several comorbidities including sleep disorders, depression, anxiety, other forms of chronic pain and obesity [1]. Several studies show that the above factors driving the overall high burden of CM are of less consequence with EM, with the burden lessening as headache frequency decreases [1, 3, 4, 8, 18,19,20].

Our present analysis of conversion from CM to EM frequency in the phase 3 REGAIN study indicated that during the 3-month double-blind treatment period, the proportions of patients shifting to EM frequency at all three months were significantly larger for individual and pooled galcanezumab dose groups versus placebo. Evaluation of longer-term treatment with galcanezumab in the OLE period also indicated positive results, with the majority of patients converting to EM frequency and doing so in a sustained way.

During the OLE period, patients were given either galcanezumab 120 mg/month or 240 mg/month at investigators’ discretion, with the majority receiving galcanezumab 240 mg/month as their most common dose. Because there were no notable differences in efficacy found between the galcanezumab 120 mg and 240 mg dosage groups for any of the migraine headache frequency-related outcomes [14], this allowed us to pool the dose groups for the 12-month analyses including the OLE data. Across the 12 months, more than half of the patients shifted to EM frequency, with substantial proportions maintaining a shift to either LFEM or VLFEM for ≥ 3 consecutive months and until their last study visit. In addition, a substantial majority (i.e., > 70%) of patients who received 120 mg/month of galcanezumab throughout the entire study maintained the shift to EM frequency until their last visit.

These findings are generally consistent with results from other CM studies using CGRP antibodies or receptor antibodies. In a multicenter prospective observational cohort study performed in Italy, 77% of patients with CM reportedly converted to EM frequency after 6 months of therapy with galcanezumab [30]. In a 12-month observational study, 75% of patients shifted from CM to EM frequency after 1 year of treatment with galcanezumab, with 53% of the patients shifting to either medium frequency EM or LFEM [31]. Results from a 1-year compassionate use program, where 156 patients self-administered erenumab 140 mg monthly, reported that 54.1% of patients converted from CM to EM frequency [32]. In a retrospective analysis of clinical data from a headache center in Germany that included 74 patients with CM, it was reported that 52.7% converted from CM to EM frequency after 3 months of treatment with erenumab [33]. A subgroup analysis of a real-life study performed in Italy with patients with migraine receiving either 70 mg or 140 mg of erenumab reported 68.1% of patients with CM converted to EM frequency by Month 6 [34]. A post-hoc analysis found that more than one-half of patients with CM shifted to EM frequency during a 3-month double-blind study with a 52-week open-label extension for erenumab [35]. Similar rates of frequency conversion were seen with fremanezumab in the HALO CM study [36].

Acute headache medication overuse is common, especially in patients with CM [1, 37, 38]. A total of 63.8% patients in the REGAIN study had acute headache medication overuse at baseline as reported in previous analyses [39, 40]. Those analyses found that galcanezumab reduced the overuse of medication as well as the frequency of migraine headache days [39, 40]. This is in line with the AHS 2023 position paper which states that “CGRP-targeting therapies are effective for migraine prevention in individuals who have pre-existing acute medication overuse and may therefore be particularly useful in this clinical setting.” [41]. Our statistical model in the present analyses controlled for the presence or absence of acute headache medication overuse at baseline, as well as for concomitant prophylactic medication use and baseline number of migraine headache days. Examination of the raw proportions versus estimated proportions of patients who shifted to EM frequency suggested that outcomes were generally similar regardless of acute headache medication use or other baseline factors.

Strengths of the present analyses include that these findings are from a large, phase 3, randomized, double-blind, placebo-controlled study with a long-term OLE. Limitations of the study include the lack of placebo control during the OLE and also the fact that only about 20% of patients from the 120-mg treatment group who continued into the OLE were consistently administered the approved galcanezumab dose of 120 mg/month throughout the maintenance period of the OLE. (Note that all treatment groups received a re-loading dose of 240 mg galcanezumab upon entry into the OLE, with flexible dosing thereafter between 120 and 240 mg/month). Although it is not known what factors contributed to investigators’ selection of dose for a given patient during the OLE, it is likely that patients who stayed on the 120-mg dose did so because they were responding well. This may limit the generalizability of the 120-mg-only subset of results from the OLE. However, results from the pooled galcanezumab dose group are important to consider as multiple studies in CM and EM have demonstrated that galcanezumab 120 mg and 240 mg are comparable in terms of efficacy in preventing migraine. Longer term studies are needed to assess effects of galcanezumab over periods lasting beyond 12 months. Another limitation is that LFEM and VLFEM are not standardized categories of migraine, but are typically proposed ad hoc in order to facilitate classifications within a study.

Conclusions

Results from this 12-month phase 3 study suggest that galcanezumab for the preventive treatment of CM may lead to substantial proportions of patients shifting to EM frequency for ≥ 3 consecutive months. Over a longer-term period of 12 months, treatment with galcanezumab may lead to even larger proportions shifting to EM frequency. The shift to EM frequency over the long term is considered clinically beneficial as it is likely to be accompanied by reductions in disability and economic burden for people with CM.

Fig. 1
figure 1

Percentage of patients shifting from CM to EM frequency during the 3-month double-blind treatment period. The percentage of patients shifting to EM frequency is shown at Month 3 (A) and at all 3 Months (B). EM is defined as < 8 migraine headache days/month or < 15 headache days/month, LFEM as < 8 migraine headache days/month, and VLFEM as < 4 migraine headache days/month. Thus, EM includes LFEM and VLFEM, and LFEM includes VLFEM. *p < 0.05, **p < 0.01, ***p < 0.001 (vs. placebo). Abbreviations: EM, episodic migraine, LFEM, low frequency episodic migraine; VLFEM, very low frequency episodic migraine

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Fig. 2
figure 2

Percentage of patients shifting from CM to EM frequency during the 12-month study. The percentage of patients is shown who maintained a shift to EM frequency from CM for ≥ 3 consecutive months on galcanezumab during the 12-month study (double-blind and OLE periods) (A) and who maintained that ≥ 3-month shift to EM frequency until their endpoint (B). Bars are labeled based on the randomized treatment group assigned at the start of the 3-month double-blind period. Patients who were on placebo during the double-blind period and received galcaneumab during the OLE period only have data from the OLE included in this analysis and are labelled as “From previous placebo.” The “All galcanezumab” group includes all patients who received galcanezumab in either the double-blind or OLE periods, regardless of previous randomized group. EM is defined as < 8 migraine headache days/month or < 15 headache days/month, LFEM as < 8 migraine headache days/month; and VLFEM as < 4 migraine headache days/month. Thus, EM includes LFEM and VLFEM, and LFEM includes VLFEM. Abbreviations: EM, episodic migraine, LFEM, low frequency episodic migraine; OLE, open-label extension; VLFEM, very low frequency episodic migraine

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Fig. 3
figure 3

The distribution of non-overlapping headache frequency categories during the 12-month study. The distribution shown is based on unique categories defined by frequency of migraine headache days that were achieved for at least 3 consecutive months (A) and for at least 3 consecutive months and maintained until the patient’s endpoint (B). The percentage of all patients who shifted to < 4 migraine headache days/month, ≥ 4 migraine headache days/month but < 8 migraine headache days/month, and ≥ 8 migraine headache days/month, but < 15 headache days/month, as well as those who had CM frequency throughout, are shown for the proportion of patients who had a shift for ≥ 3 consecutive months (A) and for those who maintained that shift for ≥ 3 consecutive months and until the patient’s endpoint (B). Abbreviations: CM, chronic migraine; EM, episodic migraine; HDs, headache days; LFEM, low frequency episodic migraine; MHDs, migraine headache days; OLE, open-label extension; VLFEM, very low frequency episodic migraine

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Data availability

Lilly provides access to all individual participant data collected during the trial, after anonymization, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

Abbreviations

CI::

Confidence interval

CM:

Chronic migraine

EM:

Episodic migraine

GMB:

Galcanezumab

HDs:

Headache days

ICHD:

International classification of headache disorders, 3rd edition

LFEM:

Low frequency episodic migraine

MHDs:

Migraine headache days

MIDAS:

Migraine Disability Assessment

MSQ:

Migraine-Specific Quality of Life questionnaire

OLE:

Open-label extension

OR:

Odds ratio

RF-R:

Role function-restrictive domain

SD:

Standard deviation

SE:

Standard error

VLFE:

Very low frequency episodic migraine

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Acknowledgements

Writing support was provided by Michael H. Ossipov, PhD and editorial services were provided by Surayya Taranum, PhD, of Evidera-PPD. Evidera-PPD was contracted by Eli Lilly and Company to provide writing and editorial support.

Funding

This study was sponsored by Eli Lilly and Company.

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Authors and Affiliations

  1. Faculty of Medicine, University Duisburg-Essen, Essen, Germany

    Hans-Christoph Diener

  2. Eli Lilly and Company, Indianapolis, IN, USA

    Kathleen A. Day & Holland C. Detke

  3. Syneos Health, Raleigh, NC, USA

    Sarah Lipsius

  4. Impel Pharmaceuticals, Seattle, WA, USA

    Sheena K. Aurora

  5. Metrodora Institute, West Valley City, UT, USA

    Nada A. Hindiyeh

Authors
  1. Hans-Christoph Diener
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  2. Kathleen A. Day
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  3. Sarah Lipsius
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  4. Sheena K. Aurora
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  5. Nada A. Hindiyeh
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  6. Holland C. Detke
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Contributions

HCD, HD, KAD conceived and designed the work. HCD wrote the main manuscript text. HD, KAD, NAH, SKA, and SL analyzed and/or interpreted data. All authors reviewed the manuscript and provided critical revision of the work for important intellectual content.

Corresponding author

Correspondence to Holland C. Detke.

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Competing interests

H-CD received honoraria for contribution to advisory boards or oral presentations from: Lilly, Lundbeck, Novartis, Pfizer and Teva. The German Research Council (DFG) supports his headache research, and serves on the editorial boards of Cephalalgia, Lancet Neurology and Drugs. HCD and KAD are employees of Eli Lilly and Company. N.A.H is a speaker and consultant for Impel, Eli Lilly and Company, and AbbVie. SKA is a former employee of Eli Lilly and is currently employed by C2N diagnostics. SL is an employee of Syneos Health that was contracted by Eli Lilly and Company for this work.

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Diener, HC., Day, K.A., Lipsius, S. et al. Shift from chronic to episodic migraine frequency in a long-term phase 3 study of galcanezumab. J Headache Pain 26, 26 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-025-01956-x

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-025-01956-x

Keywords

The Journal of Headache and Pain

ISSN: 1129-2377

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