Monthly Migraine Headache Days Research Articles

Underrecognition of migraine-related stigmatizing attitudes and social burden: Results of the OVERCOME Japan study.

Migraine-related stigma (MiRS) and social burden is increasingly recognized. We assessed perspectives and attitudes toward migraine in people with and without migraine in Japan. OVERCOME (Japan) was a cross-sectional, population-based web survey of people with and without migraine (July-September 2020). People with migraine were individuals who met the modified International Classification of Headache Disorders criteria or had self-reported physician-diagnosed migraine. People without migraine were selected per quota sampling to represent the Japanese adult population. People with migraine reported their experiences on stigma and social burden and answered how frequently they experienced stigma using the MiRS questionnaire. Associations between MiRS and disability and MiRS and interictal burden were examined using the migraine disability assessment and Migraine Interictal Burden Scale-4. People without migraine reported their experiences and attitudes toward people with migraine by answering an 11-item attitudinal migraine questionnaire. A total of 17,071 and 2008 people with and without migraine, respectively, completed the survey. Overall, 11,228 (65.8%) respondents with migraine reported that they have never experienced stigma or burden; however, of the 12,383 employed respondents, 5841 (47.2%) reported that their current employers are not "extremely" or "very" understanding about their conditions. Moreover, ∼30%-40% of respondents "sometimes," "often," or "very often" hid their migraine from others. The proportion of respondents who experienced stigma often or very often, as assessed by MiRS, was 16.5%; this increased with the increasing number of monthly migraine headache days. The proportion of respondents with moderate-to-severe disability and interictal burden increased with increasing stigma. Among respondents without migraine, the proportion holding a stigmatizing attitude toward those with migraine was low (<15%); ∼80% had never experienced work- or family-related stigma or burden. MiRS and burden exist but may be hidden and underrecognized in Japan. Disease awareness and education may be important to prevent and reduce stigma and burden.

Lipopolysaccharide, VE-cadherin, HMGB1, and HIF-1α levels are elevated in the systemic circulation in chronic migraine patients with medication overuse headache: evidence of leaky gut and inflammation

ObjectiveMedication overuse headache (MOH) was recently shown to be associated with leaky gut in rodents. We aimed to investigate whether chronic migraine (CM) patients with MOH have elevated lipopolysaccharide levels and inflammatory molecules in blood circulation.Materials and methodsThe study included women participants (40 CM patients with NSAID overuse headache, 35 episodic migraine (EM) patients, and 20 healthy non-headache sufferers). Migraine duration, monthly migraine headache days, MigSCog, HADS-D, HADS-A, and HIT-6 scores were recorded. Serum samples were collected to measure circulating LPS, LPS binding protein (LBP), tight junction protein occludin, adherens junction protein vascular endothelial cadherin (VE-cadherin), CGRP, HMGB1, HIF-1α, IL-6, and IL-17 levels.ResultsSerum LPS, VE-Cadherin, CGRP, HIF-1α, and IL-6 levels were significantly higher in the CM + MOH group compared to the EM group and healthy controls while serum LBP and HMGB1 were higher in the CM + MOH group compared to healthy controls. IL-17 and occludin levels were comparable between the three groups. Serum HMGB1 levels in EM patients were higher compared to the control group. Mig-SCog and HIT-6 scores were higher in the CM + MOH group compared to EM patients. HADS-A and HADS-D scores were significantly higher in the CM + MOH group compared to EM patients and healthy controls, and they were also higher in EM patients compared to healthy subjects. LPS levels were correlated with VE-cadherin and occludin levels. The number of monthly migraine headache days was positively correlated with serum LPS, HIF-1α, VE-cadherin, and IL-6 levels, HADS-A, HADS-D, HIT-6, and MigSCog scores.ConclusionWe have evidence for the first time that CM + MOH is associated with elevated serum LPS and LBP levels suggestive of LPS leak into the systemic circulation. Higher levels of nociceptive and/or pro-inflammatory molecules such as HMGB1, HIF-1α, IL-6, and CGRP may play a role in trigeminal sensitization and neurobiology of MOH. Intestinal hyperpermeability and consequent inflammatory response should be considered as a potential contributory factor in patients with MOH.Graphical

Generalizability of clinical trial efficacy results to a real-world population: An example in migraine prevention.

Health care decision makers are often concerned about the external validity of randomized controlled trials (RCTs), as their results may not apply to certain patients in the real world who intend to receive treatment. To demonstrate a methodology for assessing the generalizability of clinical trial results to a real-world population, before sufficient and appropriate real-world effectiveness data are available, using individual patient-level data from an RCT and aggregated baseline data from a real-world French registry in migraine. The analyses were conducted in 2 steps. First, individual patient-level baseline data from the multinational CONQUER RCT were weighted to match aggregated real-world InovPain registry patient characteristic data. Matched patient characteristics were sex, age, migraine type and duration, number of monthly migraine headache days, and number of monthly headache days at baseline. Second, the weighted CONQUER patient data were used to reanalyze the primary endpoint of CONQUER (least squares mean change from baseline in the number of monthly migraine headache days during the 3-month double-blind treatment phase) using predefined methodology. Sensitivity analyses were conducted to assess the robustness of findings. A total of 462 patients with migraine were randomized and treated with galcanezumab or placebo in CONQUER; aggregated InovPain data were available from 130 patients with migraine. We identified no important differences in baseline patient characteristics between the 2 prespecified populations, suggesting good external validity for CONQUER. Although this limited the extent of observed differences between the original and matched CONQUER populations, weighting of CONQUER data did help harmonize the 2 datasets and allow the results obtained in CONQUER to be generalized to patients more representative of the real-world French population with migraine. Results of weighted analyses suggested that galcanezumab would be superior to placebo for reducing monthly migraine headache days in a clinical trial in patients with episodic or chronic migraine who reflected the characteristics of patients eligible to receive the drug in France. Findings suggest that our methods may be helpful for assessing the generalizability of clinical trial results to a real-world population before the availability of substantial real-world clinical data.

Galcanezumab in patients with episodic migraine: results from the open-label period of the phase 3 PERSIST study

BackgroundThe phase 3 randomized PERSIST study demonstrated the efficacy and tolerability of galcanezumab, a humanized anti-calcitonin gene-related peptide (CGRP) monoclonal antibody for prevention of episodic migraines. We present findings from the open-label extension (OLE) of PERSIST, which evaluated the long-term efficacy and safety of galcanezumab in patients from China, India, and Russia.MethodsPatients completing the 3-month double-blind period of PERSIST were eligible for the 3-month OLE. Patients previously randomized to galcanezumab (GMB/GMB group) continued to receive galcanezumab 120 mg at all three visits during the OLE whereas patients randomized to placebo received a 240 mg loading dose of galcanezumab and then two 120 mg doses (PBO/GMB group). The primary outcome was the mean change (from double-blind baseline) in the number of monthly migraine headache days (MHDs) to month 6. Other endpoints included percent reduction in monthly MHDs from double-blind baseline to month 6, functional outcomes, safety and tolerability.ResultsOverall, 99% of patients completing the double-blind period entered the OLE, and 96% completed through month 6. Patients in the GMB/GMB group achieved continued improvements in efficacy, with the reduction from baseline in the mean number of monthly MHDs, and slightly increasing from 4.01 days at the end of the double-blind period to 4.62 at the end of the OLE. Of patients who were ≥ 50% responders to galcanezumab at month 3, 66% maintained this response through to month 6. Patients in the PBO/GMB group experienced a rapid reduction in the number of monthly MHDs after initiation of galcanezumab, with a mean reduction from baseline of 4.56 days by month 6. The long-term benefits of galcanezumab were also supported by improvements in other efficacy and functional endpoints. All safety findings were consistent with the known long-term safety profile of galcanezumab; no patients experienced a treatment-related serious adverse event.ConclusionsGalcanezumab was efficacious and well-tolerated in patients with episodic migraine from China, India and Russia, for up to 6 months.Trial registrationClinicalTrisABSTRACT_pals.gov NCT03963232, registered May 24, 2019.

Treatment with Galcanezumab in Patients with Episodic Migraine: Results from the Open-Label Phase of the PERSIST Study (P10-12.006)

<h3>Objective:</h3> To assess efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in adult patients with episodic migraine. <h3>Background:</h3> Migraine is a neurological disorder with high disease burden and unmet clinical need. <h3>Design/Methods:</h3> This was a phase 3, double-blind (DB), randomized, placebo-controlled, 3-month study with a 3-month open-label extension (OLE). Eligible patients with episodic migraine were randomized to monthly subcutaneous injections of placebo (N=259) or galcanezumab 120mg with a 240mg loading dose (N=261). Patients entering OLE received galcanezumab 120mg/month. Efficacy measures included number of monthly migraine headache days (MHDs), ≥50% reduction in monthly MHDs, and Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive (MSQ-RFR) domain score. Change from baseline in continuous and categorical measures was analyzed using mixed model repeated measures analysis and generalized linear mixed models, respectively. OLE results are reported by prior DB treatment assignment. <h3>Results:</h3> Of the patients who completed DB treatment, 484 (99.4%) entered OLE, with 96.3% completing Month 6. From a baseline of 8.23 monthly MHDs at the beginning of DB, patients at month 6 in the prior placebo and galcanezumab groups had a mean change of −4.56 and −4.62, respectively. At Month 6, the percentage of patients with ≥50% response was 67.2% and 70.9%, respectively. Of the 142 galcanezumab-treated patients with ≥50% response at Month 3, 66.2% maintained that response throughout OLE. At Month 6, patient functioning on the 100-point MSQ-RFR increased from baseline by 24.9 and 23.7 points, respectively. The common (&gt;2%) treatment-emergent adverse events were injection site reaction (3.3%), upper respiratory tract infection (2.7%), and injection site pruritus (2.5%) during the OLE. Three patients (0.6%) discontinued due to an adverse event. There were no clinically meaningful changes in any safety parameters. <h3>Conclusions:</h3> Galcanezumab was effective, safe, and well tolerated during the PERSIST open-label extension in patients with episodic migraine. <b>Disclosure:</b> Prof. Yu has nothing to disclose. Prof. Zhou has nothing to disclose. Dr. Zhuang has received personal compensation for serving as an employee of Eli Lilly. Miss Liu has nothing to disclose. Ms. Qian has received personal compensation for serving as an employee of Eli Lilly.

Efficacy and safety of different doses of subcutaneous galcanezumab in chronic and episodic migraine: A pooled analysis of 3651 patients (P10-12.003)

<h3>Objective:</h3> In this systematic review and meta-analysis, we aimed to assess the efficacy and safety of galcanezumab doses in chronic and episodic migraines. <h3>Background:</h3> Migraine is a severe kind of headache and is represented by 14% of the population and up to 18% of women. Galcanezumab is a humanized monoclonal antibody that binds to calcitonin gene-related peptides and is used to prevent migraines. <h3>Design/Methods:</h3> In September 2022, we conducted a comprehensive search in five databases, including EMBASE, PubMed, Cochrane Library, Web of Science, and SCOPUS. We appraised each study using the Cochrane risk of bias tool. Our primary outcome was the change in the monthly migraine headache days (MMDs). Data were extracted and analyzed using RevMan version 5.4. <h3>Results:</h3> We included eight randomized controlled trials with 3651 migraine patients. In episodic migraine, galcanezumab (120–150 and 240–300mg) showed a significant reduction in MMDs compared to placebo after six months. Also, in chronic migraine, galcanezumab (120mg) reduced MMDs compared to placebo after three months. The analysis was conducted according to each month’s records, and the mean difference change ranged from −1.62 to −2.86 (P-value &lt; 0.001). All doses showed a significantly higher rate in ≥50%, ≥75%, and 100% response rates. Regarding safety outcomes, galcanezumab was associated with injection site-related complications such as pruritis, reaction, swelling, or erythema. In contrast, the two groups showed no difference regarding any adverse or serious adverse events, upper respiratory tract infection, oropharyngeal pain, injection site pain, back pain, sinusitis, and diarrhea. <h3>Conclusions:</h3> Subcutaneous galcanezumab reduced MMDs and increased response rates in chronic and episodic migraine patients. It is generally safe except for injection-related complications. <b>Disclosure:</b> Mohamed Sayed Zaazouee has nothing to disclose. Mr. Elsnhory has nothing to disclose. Ms. Ebrahim has nothing to disclose. Dr. Alaraj has nothing to disclose. Dr. Saad has nothing to disclose. Dr. Zaki has nothing to disclose. Mr. Ali has nothing to disclose. Dr. Fahmy Fawy has nothing to disclose. Dr. Ahmed has nothing to disclose. Dr. Elshennawy has nothing to disclose. Dr. Eleyan has nothing to disclose. Dr. Alahmad has nothing to disclose. Dr. Abo Hamra has nothing to disclose. Dr. AbuEl-Enien has nothing to disclose. Dr. Elromely has nothing to disclose. Dr. Elshanbary has nothing to disclose.

What trade-offs are patients willing to make when selecting between novel preventive treatments for migraine? Evidence from a Discrete Choice Experiment (P7-12.001)

<h3>Objective:</h3> To quantify the trade-offs people with episodic migraine (EM) are willing to make between the attributes of calcitonin gene-related peptide monoclonal antibodies and gepants for the prevention of migraine. <h3>Background:</h3> The introduction of new treatments for migraine prevention, such as CGRP-mAbs injectables and lately oral gepants, means that current and future treatment options differ in administration mode, efficacy, and the adverse event profile. Understanding patients’ treatment preferences can help improve how needs of patients with migraine are addressed. <h3>Design/Methods:</h3> An online discrete choice experiment (DCE) among people with self-reported EM diagnosis in the US elicited treatment preferences based on: a) treatment administration; b) chance of ≥50% reduction in monthly migraine headache days; c) onset time; d) impact of migraines on daily activities; and e) reduction in the number of days with acute medication use. Relative attribute importance (RAI) scores and maximum acceptable attribute trade-offs were obtained from a mixed logit model. <h3>Results:</h3> A total of 301 patients, mean age (standard deviation) of 45 (13) years completed the DCE. Patients were mostly female (63%), and mostly experienced with migraine preventive treatments (70%). The chance of achieving ≥50% response was the largest driver of treatment preferences (RAI: 38%), followed by onset time (RAI:20%). Treatment administration was the least important attribute (RAI: 8%). Despite differences in RAI, patients were willing to trade-off all attributes when making decisions. For example, on average, patients were willing to take a self-injectable treatment instead of a novel oral for an additional 7% chance in achieving ≥50% response. <h3>Conclusions:</h3> Preferences of patients with EM are driven by a range of treatment aspects, with chance of achieving ≥50% reduction in MHD being most important to them and administration being least important to them. The findings suggest that a patient-centric treatment strategy jointly considers and weighs all treatment aspects. <b>Disclosure:</b> Dr. Whichello has received personal compensation for serving as an employee of Evidera. Antje Tockhorn-Heidenreich has received personal compensation for serving as an employee of Eli Lilly and Company. An immediate family member of Antje Tockhorn-Heidenreich has received personal compensation for serving as an employee of Evidera. Antje Tockhorn-Heidenreich has received stock or an ownership interest from Eli Lilly and Company . An immediate family member of Antje Tockhorn-Heidenreich has received stock or an ownership interest from PPD. Dr. Quaife has received personal compensation for serving as an employee of Evidera. Ms. Trapali has received personal compensation for serving as an employee of Evidera. Tommi Tervonen has received personal compensation for serving as an employee of Evidera. Lars Viktrup has received personal compensation for serving as an employee of Lilly. Lars Viktrup has received stock or an ownership interest from Lilly. Dr. Naegeli has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Naegeli has stock in Eli Lilly and Company.

Validation and meaningful within-patient change in work productivity and activity impairment questionnaire (WPAI) for episodic or chronic migraine

BackgroundNo available studies demonstrate validity and meaningful change thresholds of Work Productivity and Activity Impairment (WPAI) questionnaire in patients with migraine. In this post-hoc analysis, we assessed reliability, validity, responsiveness, and meaningful within-patient change from baseline to Month 3 for Work Productivity and Activity Impairment (WPAI) domain scores in patients with episodic migraine (EM) or chronic migraine (CM).MethodThe Phase 3, multicenter, randomized, double-blind, placebo-controlled CONQUER study (NCT03559257, N = 462) enrolled patients with EM or CM who failed two to four categories of prior preventive medication in past ten years. The analyses were performed for WPAI domain scores (absenteeism, presenteeism, overall work productivity, and non-work-related activity impairment). Migraine Specific Quality of Life Questionnaire version 2.1 (MSQv2.1) domain scores (Role Function-Restrictive [RFR] and Role Function-Preventive [RFP]), and monthly migraine headache days were used as anchors. Responder criteria were changes from baseline to Month 3 for each of these anchors and were defined as: increase in MSQ-RFR by ≥ 25.71 points and MSQ-RFP by ≥ 20.00 points and a 50% reduction in monthly migraine headache days. Assessments were performed for overall population, and patients with EM or CM. The meaningful change threshold was determined based on Youden index, Phi coefficient and sensitivity.ResultsOf 462 randomized patients, 444 who completed WPAI questionnaire were included in post-hoc analysis. Test–retest reliability over 3 months in a stable subgroup revealed moderate correlations for non-work-related Activity Impairment (ICC = 0.446) presenteeism (ICC = 0.438) and a fair correlation for overall work productivity loss (ICC = 0.360). At baseline, all correlations between WPAI domain scores and continuous anchor variables exceeded recommended threshold of ≥ 0.30, except for WPAI domain scores with number of monthly migraine headache days. Patients achieving pre-specified responsiveness thresholds for monthly migraine headache days, and MSQ-RFP, MSQ-RFR from baseline to Month 3 (responders) showed significant improvements in WPAI domain scores compared with non-responders (P < 0.001). The meaningful change thresholds of -20 (% unit) were identified for WPAI domain scores.ConclusionIn conclusion, WPAI has sufficient validity, reliability, responsiveness, and appropriate interpretation standards to assess the impact of EM or CM on presenteeism and overall work productivity loss and non-work-related activity impairment.Trial registrationNCT number of CONQUER study, NCT03559257.

Efficacy and Safety of Galcanezumab as a Preventive Treatment for Episodic Migraine in South Korean Patients: A Post-Hoc Analysis of a Phase 3 Clinical Trial.

The estimated prevalence of migraines in South Korea is 6.0%, with affected patients having unmet needs. The efficacy, safety, and tolerability of galcanezumab, a humanized monoclonal antibody, for episodic migraine (EM) prevention was evaluated in South Korean patients. During the double-blind period of the EVOLVE-2 phase 3 trial, patients with EM were randomized into placebo, 120 mg-galcanezumab, and 240-mg galcanezumab treatment groups. The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days during the 6-month double-blind period. We conducted a post-hoc analysis of the South Korean cohort in EVOLVE-2. Among 98 South Korean patients in the intent-to-treat population, significant changes from baseline were observed in the number of monthly migraine headache days in the 240-mg galcanezumab group compared with the placebo group (-2.64, p=0.013), in the percentage of patients with ≥50% reduction in the number of monthly migraine headache days (120 mg: odds ratio=2.43, p=0.030; 240 mg: odds ratio=2.60, p=0.019), in the number of monthly migraine headache days with acute medication use (120 mg: -2.22, p=0.006; 240 mg: -2.23, p=0.005), and in the Migraine-Specific Quality-of-Life Role Function-Restrictive (120 mg: 8.34, p=0.040). Numerical improvements from baseline were observed relative to the placebo group in at least one galcanezumab group for: the percentage of patients with ≥75% reduction in the number of monthly migraine headache days functional impairment, and disease severity. The most common treatment-emergent adverse event in the combined galcanezumab group was injection site reaction, which led to treatment discontinuation for one patient. Galcanezumab treatment demonstrated efficacy and a favorable safety and tolerability profile in South Korean patients with EM.

Reductions in acute medication use and healthcare resource utilization in patients with chronic migraine: a secondary analysis of a phase 3, randomized, double-blind, placebo-controlled study of galcanezumab with open-label extension (REGAIN)

Aims To analyze secondary objectives of the REGAIN study related to acute headache medication use and healthcare resource utilization (HCRU) in patients with chronic migraine treated with galcanezumab, a monoclonal antibody to calcitonin gene-related peptide. Methods Adults with chronic migraine (N = 1,113) were randomized (2:1:1) and treated with double-blind monthly injections of placebo, galcanezumab-120 mg, or galcanenzumab-240 mg for 3 months, followed by a 9-month open-label extension with 120 or 240 mg/month galcanezumab. Headache and medication information was collected by daily eDiary. HCRU was reported for the 6 months before randomization, monthly thereafter, and converted to rate per 100-patient-years. Results At baseline, 63–64% of patients met criteria for acute headache medication overuse. At Month 3, incidence of headache medication overuse in the galcanezumab groups (33% and 33%) was significantly lower than in the placebo group (46%, both p < .001) and was 16% and 23% in the previous-galcanezumab groups at Month 12. From a baseline of 14.5 to 15.5, reduction in mean number of monthly migraine headache days with acute headache medication use was also significantly greater in the galcanezumab groups at Month 3 (−4.2 and −4.9) than in placebo (−2.6, both p < .001), with reductions of −6.8 and −7.6 in the previous-galcanezumab groups at Month 12. Migraine-specific HCRU rates decreased for all groups, with no significant between-group differences at Month 3. At Month 12, in the two previous-galcanezumab groups, emergency room visits decreased by 58% and 75%, hospital admissions by 100%, and healthcare professional visits by 54% and 67%. Limitations Only 3 months of double-blind, placebo-controlled data, a longer HCRU recall period for baseline than postbaseline, and patients receiving care in the clinical trial itself, may limit generalizability. Conclusions Treatment with galcanezumab resulted in significant reductions in headache medication overuse and migraine headache days requiring acute medication use, with notable reductions in migraine-specific HCRU.

Galcanezumab in episodic migraine: the phase 3, randomized, double-blind, placebo-controlled PERSIST study

BackgroundGalcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated efficacy and good tolerability in patients with episodic migraine in previous phase 3 trials. We report results from the PERSIST study, which was designed to assess the efficacy and safety of galcanezumab in patients with episodic migraine from China, India, and Russia.MethodsThis phase 3 study was conducted at 40 centers in China (n = 26), India (n = 10), and Russia (n = 4). Eligible adult patients with episodic migraine were randomized in a 1:1 ratio to receive monthly galcanezumab 120 mg (with 240 mg loading dose) or placebo during a double-blind, 3-month treatment period. The primary endpoint was the overall mean change from baseline in monthly migraine headache days (MHDs). Key secondary endpoints were the mean proportion of patients with ≥ 50%, ≥ 75%, and 100% reductions from baseline in MHDs and mean change in the Migraine-Specific Quality of Life Questionnaire (MSQ) Role Function-Restrictive domain score.ResultsIn total, 520 patients were randomized and received at least one dose of galcanezumab (N = 261) or placebo (N = 259). The least squares (LS) mean reduction from baseline in monthly MHDs over 3 months was significantly greater with galcanezumab compared with placebo (-3.81 days vs. -1.99 days; p < 0.0001). Significantly greater mean proportions of patients with galcanezumab versus placebo had ≥ 50%, ≥ 75%, and 100% reductions from baseline in MHDs (all p < 0.0001). The overall mean improvement from baseline in MSQ Role Function-Restrictive score over 3 months was significantly greater with galcanezumab versus placebo (p < 0.0001). There were no clinically meaningful differences between the galcanezumab and placebo group on any safety parameters except for a higher incidence of injection site pruritus (5.0% vs. 0.0%), injection site reaction (3.8% vs. 0.4%), and injection site discomfort (2.3% vs. 0.0%). TEAEs related to injection sites were mild in severity, except in 1 patient who had a moderate injection site reaction. Six serious adverse events were reported by 6 patients (2 galcanezumab, 4 placebo).ConclusionsGalcanezumab 120 mg once monthly was effective and well tolerated in patients with episodic migraine from China, India, and Russia.Trial registrationClinicalTrials.gov Identifier NCT03963232 (PERSIST), registered May 24, 2019.

P.019 Interictal burden of migraine: correlations with other measures of migraine burden and effects of galcanezumab migraine-preventive treatment

Background: Typical migraine clinical trial endpoints assess only ictal burden. Methods: Adults (N=462) with episodic or chronic migraine with previous failure of 2-4 preventive medication categories were randomized 1:1 to 3-month double-blind treatment with placebo or galcanezumab 120mg. Primary endpoint was mean change from baseline in monthly migraine headache days. Migraine Interictal Burden Scale-4 (MIBS-4) measured migraine-related burden on non-headache days for past 4 weeks (0=no burden, 1-2=mild, 3-4=moderate, 5-12=severe). Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life Questionnaire (MSQ), Patient Global Impression-Severity (PGI-S), depression (Patient Health Questionaire-9 [PHQ-9]), and anxiety (Generalized Anxiety Disorder Scale [GAD-7]) were assessed. Relationships among measures were assessed at baseline using Spearman’s rank correlation coefficient. Results: MIBS-4 was moderately correlated with PHQ-9 (r=.55) and MSQ total (r=−.53). Other correlations with MIBS-4 were low (GAD-7, r=0.42; MIDAS, r=0.41; PGI-S, r=0.32) or negligible (migraine headache days, r=0.22). After 3 months, from a mean baseline of 13.2 monthly migraine headache days, galcanezumab patients improved by 4.4 vs 1.3 days for placebo (p&lt;.0001). From mean MIBS-4 baseline of 5.5, galcanezumab patients improved by 1.8 vs 0.8 points for placebo (p&lt;.0001). Conclusions: Galcanezumab significantly reduced ictal and interictal burden of migraine. Results suggest interictal burden is a distinct effect of the disease.

Long-term treatment with galcanezumab in patients with chronic migraine: results from the open-label extension of the REGAIN study

Background Galcanezumab, a monoclonal antibody to calcitonin gene-related peptide, was found to be safe and efficacious for the preventive treatment of chronic migraine based on the randomized, placebo-controlled double-blind period of the REGAIN study. Long-term safety and efficacy were assessed in an open-label extension. Methods Patients 18–65 years old with chronic migraine completing the 3-month double-blind period of REGAIN could enter a 9-month open-label extension (OLE; months 4–12). Upon entering the OLE, patients received a 240-mg galcanezumab loading dose, then 120 mg at the next month, with flexible dosing thereafter (120 or 240 mg/month). The primary efficacy measure was the mean change in the number of monthly migraine headache days from double-blind baseline to month 12. Other endpoints included response rates (based on percent reduction in monthly migraine headache days from double-blind baseline to month 12), safety and tolerability. Results Of patients who completed double-blind treatment, 1022 (99%) entered the OLE, with 81% completing month 12. From a baseline of 19.4 monthly migraine headache days at the beginning of the double-blind period, patients at month 12 in the previous placebo, 120-mg, and 240-mg galcanezumab groups had a mean change of −8.5, −9.0, and −8.0, respectively (SE = 0.43 to 0.55, within-group p’s < .001). At month 12, the percentage of patients with ≥50% response was 57%, 57%, and 53%, respectively. Percentage with ≥75% response was 32%, 31%, and 30%, respectively. Percentage with 100% response was 8%, 6%, and 6%, respectively. There were no significant new safety findings during the open-label period. The incidence of discontinuation from the OLE due to adverse events was 5%. Conclusion Galcanezumab was effective, safe, and well-tolerated, with high adherence, for up to 12 months of treatment in patients with chronic migraine. Trial Registration Clinicaltrials.gov identifier: NCT02614261; www.clinicaltrials.gov/ct2/show/NCT02614261

Long-Term Safety and Tolerability of Fremanezumab for Migraine Preventive Treatment in Japanese Outpatients: A Multicenter, Randomized, Open-Label Study.

IntroductionEarly discontinuation and poor adherence are common limitations of conventional preventive migraine medications that limit their long-term efficacy. Therefore, a migraine preventive medication with favorable long-term safety is warranted.ObjectiveThis study aimed to evaluate the long-term safety and tolerability of fremanezumab for the preventive treatment of chronic or episodic migraine in Japanese patients.MethodsIn this 52-week, randomized, open-label, parallel-group study, fremanezumab monthly or quarterly was administered in newly enrolled Japanese patients with chronic migraine or episodic migraine. Safety was assessed by monitoring of treatment-emergent adverse events, including injection-site reactions, laboratory and vital sign assessments. Newly enrolled patients and rollover patients from previous phase IIb/III trials who did not receive fremanezumab in this study were included in the immunogenicity testing cohort (n = 587). Efficacy outcomes included changes from baseline in the average monthly migraine days and headache days of at least moderate severity. Other efficacy outcomes included changes in disability scores.ResultsA total of 50 patients were enrolled with chronic migraine (monthly, n = 17; quarterly, n = 17) or episodic migraine (monthly, n = 8; quarterly, n = 8). The most commonly reported treatment-emergent adverse events were nasopharyngitis (64.0%) and injection-site reactions (erythema, 24.0%; induration, 10.0%; pain, 8.0%; pruritus, 6.0%). The discontinuation rate was low (4.0% from adverse events, 2.0% from a lack of efficacy) and no deaths were reported. The incidence of anti-drug antibody development was low (2.4%). Fremanezumab reduced monthly migraine days and headache days of at least moderate severity from 1 month after initial administration, and this effect was maintained with no worsening throughout 12 months. Fremanezumab also led to sustained reductions in any acute headache medication use and headache-related disability at 12 months.ConclusionsFremanezumab administered monthly and quarterly was well tolerated in patients with chronic migraine and episodic migraine and led to sustained improvements in monthly migraine days and headache days of at least moderate severity throughout 12 months.Clinical Trial RegistrationClinicalTrials.gov Identifier: NCT03303105.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01119-2.

Efficacy of galcanezumab in patients with migraine and history of failure to 3\u20134 preventive medication categories: subgroup analysis from CONQUER study

BackgroundChronic migraine (CM) and episodic migraine (EM) are associated with substantial headache-related disability, poor quality of life and global societal burden. In this subgroup analysis from the CONQUER study, we report efficacy outcomes from a pre-specified analysis of galcanezumab versus placebo in patients with CM or EM and 3–4 prior preventive medication category failures due to inadequate efficacy (after at least 2 months at maximum tolerated dose), or safety or tolerability reasons. The patient population is of particular interest due to evidence of decreased quality of life and increased economic burden among patients with migraine that is inadequately managed and is of interest to decision-makers globally.MethodsKey outcomes included overall mean change from baseline in monthly migraine headache days and proportions of patients achieving ≥30% (CM), ≥50%, and ≥ 75% reduction (response rates) in monthly migraine headache days across Months 1–3. Patient functioning and disability were evaluated at Month 3.ResultsOf the 462 randomized patients, 186 (40.3%) had a history of 3–4 preventive category failures. Galcanezumab versus placebo resulted in significantly (P ≤ .001) larger overall mean reduction in monthly migraine headache days (total: − 5.49 versus − 1.03; CM: − 6.70 versus − 1.56; EM: − 3.64 versus − 0.65). Similarly, the ≥50% response rate was significantly (P ≤ .001) higher with galcanezumab versus placebo (total: 41.0 versus 12.7; CM: 41.5 versus 8.4; EM: 41.1 versus 16.5). In the CM group, the ≥30% response rate was significantly higher in the galcanezumab group than the placebo group (CM, 57.5 versus 19.8, P ≤ .0001) as was the ≥75% response rate (13.3 versus 2.6, P ≤ .05). Galcanezumab also resulted in significant (P < .0001) improvements in patient functioning and reductions in disability.ConclusionsGalcanezumab was effective in a difficult-to-treat population of patients with CM or EM who had failed 3–4 prior preventive medication categories.Trial registrationCONQUER. Clinicaltrials.gov identifier: NCT03559257.

Benefit-Risk Assessment of Galcanezumab Versus Placebo for the Treatment of Episodic and Chronic Migraine Using the Metrics of Number Needed to Treat and Number Needed to Harm.

IntroductionSubcutaneous galcanezumab was an effective, well-tolerated preventive treatment for adults with episodic (EM) or chronic migraine (CM) in 4 phase 3 randomized controlled trials: EVOLVE-1, EVOLVE-2, REGAIN, and CONQUER. Number needed to treat (NNT) and to harm (NNH) are metrics of effect size used to evaluate benefit–risk profiles. This study evaluated NNT, NNH, and benefit–risk profiles (measured as likelihood to be helped or harmed, LHH) of galcanezumab 120 mg versus placebo in patients with EM or CM.MethodsPrimary efficacy outcomes were responses defined as ≥ 30%, ≥ 50%, and ≥ 75% reductions from baseline in number of monthly migraine headache days in patients with EM (EVOLVE-1; EVOLVE-2; CONQUER) and CM (REGAIN; CONQUER); corresponding NNTs to achieve respective responses; and corresponding NNHs for discontinuations due to adverse events (DCAEs) among the safety population. Secondary efficacy outcomes were responses for patients with ≥ 2 failed prior preventive treatments due to lack of efficacy and/or for tolerability reasons. All LHHs were based on ≥ 50% response and DCAEs.ResultsDuring double-blind treatment periods with galcanezumab 120 mg, NNT to achieve ≥ 30% and ≥ 50% responses ranged from 4 to 10 and NNT to achieve ≥ 75% responses ranged from 5 to 23 in individual trials. NNH ranged from 93 to 1000, while LHH ranged from 18.6 to 104.6. NNTs were generally more robust among patients with EM than with CM; however, in patients with failure of ≥ 2 prior preventive treatments, NNTs to achieve ≥ 30% and ≥ 50% responses were similar between patients with CM and EM. NNHs were imputed as 1000 for both migraine types. Resulting LHHs were 178.8 (EM) and 127 (CM).ConclusionAcross 4 trials, galcanezumab 120 mg demonstrated a favorable benefit–risk profile versus placebo, based on low NNTs to achieve response and high NNHs associated with DCAEs. LHH values consistently far exceeded 1.Trial Registration NumbersEVOLVE-1: ClinicalTrials.gov identifier, NCT02614183; EVOLVE-2: ClinicalTrials.gov identifier, NCT02614196; REGAIN: ClinicalTrials.gov identifier, NCT02614261; CONQUER: ClinicalTrials.gov identifier, NCT03559257.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-01848-x.

Efficacy of galcanezumab in patients with migraine who did not benefit from commonly prescribed preventive treatments

BackgroundGalcanezumab is a calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) indicated for the preventive treatment of migraine. While galcanezumab has demonstrated efficacy in patients who did not respond to prior preventive medications in general, its efficacy in patients who did not benefit from individual, commonly prescribed preventive treatments due to inadequate efficacy or safety/tolerability remains unknown.MethodsCONQUER was a 3-month, randomized, double-blind, placebo-controlled, phase 3b study that enrolled patients with episodic or chronic migraine who had 2 to 4 migraine preventive medication category failures in the past 10 years. Patients were randomly assigned 1:1 to receive placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). Post hoc analyses were conducted to determine the efficacy of galcanezumab in patients who had not benefited from six of the most commonly prescribed migraine preventive medications. The mean change from baseline in monthly migraine headache days and ≥ 50 % response rates were assessed over months 1–3. Improvement in Migraine-Specific Questionnaire Role Function-Restrictive (MSQ-RFR) scores were assessed at month 3. The endpoints were estimated via mixed model with repeated measures.ResultsThe most common treatment failures due to inadequate efficacy or safety/tolerability, which at least 20 % of patients reported trying without benefit, included topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and metoprolol. Patients who had not previously benefited from these treatments had a greater mean reduction in monthly migraine headache days across months 1–3 in the galcanezumab group compared to placebo (all p < 0.01). More patients treated with galcanezumab experienced a ≥ 50 % reduction from baseline in monthly migraine headache days across months 1–3 compared to placebo (all p < 0.05). Galcanezumab-treated patients had a greater improvement in mean MSQ-RFR scores at month 3 compared to placebo (all p < 0.01).ConclusionsIn this population, galcanezumab was effective in reducing monthly migraine headache days, improving response rates, and enhancing quality of life in patients who had not previously benefited from topiramate, amitriptyline, propranolol, valproate or divalproex, onabotulinum toxin A, and/or metoprolol due to inadequate efficacy or safety/tolerability.Trial registrationClinicalTrials.gov NCT03559257 (CONQUER).

Treatment Satisfaction of Galcanezumab in Japanese Patients with Episodic Migraine: A Phase2 Randomized Controlled Study.

IntroductionThis analysis evaluated the treatment satisfaction of Japanese patients receiving galcanezumab (GMB) as a preventive medication for episodic migraine (4–14 monthly migraine headache days).MethodsThis phase 2, randomized, double-blind, placebo-controlled study enrolled patients aged 18–65 years at 40 centers in Japan. Patients were randomized 2:1:1 to receive monthly subcutaneous injections of placebo (PBO, n = 230), GMB 120 mg (n = 115), or GMB 240 mg (n = 114) for 6 months. Patients’ experience with treatment was measured using the Patient Global Impression of Severity (PGI-S), Patient Global Impression of Improvement (PGI-I), and Patient Satisfaction with Medication Questionnaire-Modified (PSMQ-M) scales. PGI-S was administered at baseline and months 1–6, PGI-I at months 1–6, and PSMQ-M at months 1 and 6. Prespecified analyses were differences between GMB and PBO in PGI-I and the change from baseline in PGI-S, and evaluating positive responses for the PGI-I and PSMQ-M.ResultsAverage change ± SE from baseline across months 1–6 was − 0.09 ± 0.05 (PBO), − 0.17 ± 0.07 (GMB 120 mg, p = 0.33), and − 0.30 ± 0.07 (GMB 240 mg, p = 0.013) for PGI-S. Average PGI-I across months 1–6 was 3.39 ± 0.05 (PBO), 2.55 ± 0.07 (GMB 120 mg, p < 0.05), and 2.71 ± 0.07 (GMB 240 mg, p < 0.05). Reductions of 2.8–3.0 monthly migraine headache days corresponded to 25–31% higher positive PGI-I response rates with GMB compared with PBO. Positive PSMQ-M response rates for satisfaction and preference were statistically significantly higher for GMB compared with PBO (odds ratio [95% confidence interval], all p < 0.05 vs. PBO): satisfaction GMB 120 mg (3.142 [1.936–5.098]) and GMB 240 mg (3.924 [2.417–6.369]), and preference GMB 120 mg (3.691 [2.265–6.017]) and GMB 240 mg (3.510 [2.180–5.652]).ConclusionJapanese patients with episodic migraine receiving preventive treatment with GMB are significantly more satisfied than those receiving PBO.Trial RegistrationClinicalTrials.gov, NCT02959177 (registered November 7, 2016).Graphical Plain Language Summary Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-021-00236-5.

Early onset of effect following galcanezumab treatment in patients with previous preventive medication failures

BackgroundGalcanezumab is a monoclonal antibody (mAb) that binds calcitonin gene-related peptide (CGRP) and is indicated for the preventive treatment of migraine. Galcanezumab demonstrated early onset of effect in patients with migraine but it is unknown whether the same holds true for patients who have not benefited from multiple prior migraine preventives.MethodsPatients with episodic or chronic migraine from a 3-month, randomized, double-blind, placebo-controlled, phase 3b study (CONQUER) who had 2 to 4 migraine preventive medication category failures in the past 10 years were randomized 1:1 to placebo (N = 230) or galcanezumab 120 mg/month (240 mg loading dose; N = 232). In this post-hoc analysis, change from baseline in number of monthly and weekly migraine headache days was assessed. Monthly onset of effect was the earliest month at which significant improvement with galcanezumab compared to placebo was achieved and maintained at all subsequent months. Weekly onset was the initial week at which statistical separation was achieved and maintained at all subsequent weeks during that month. Proportion of patients with migraine headache days in the first week of treatment, and patients achieving ≥50%, ≥75%, and 100% response by month and week were also assessed.ResultsGalcanezumab-treated patients had a significantly greater reduction in monthly migraine headache days starting at month 1, which remained significant for all subsequent months compared to placebo (all p ≤ 0.0001, month 1 mean change from baseline: placebo − 0.7; galcanezumab − 4.0). Weekly migraine headache days was significantly reduced in galcanezumab-treated patients starting at week 1 and continued for each subsequent week of month 1 compared to placebo (all p < 0.01, week 1 mean change from baseline: placebo − 0.2; galcanezumab − 1.1). A significantly smaller percentage of patients had a migraine headache on the first day after galcanezumab treatment compared to placebo (28.4% vs 39.2%) and at each subsequent day during week 1 (all p < 0.05). A greater proportion of galcanezumab-treated patients achieved ≥50%, ≥75%, and 100% response at months 1–3 (all p < 0.05) and at weeks 1–4 of month 1 compared to placebo (all p < 0.01).ConclusionGalcanezumab showed early onset of effect beginning the day after treatment initiation in patients who had not previously benefited from migraine preventive treatments.Trial registrationClinicalTrials.gov, NCT03559257. Registered 18 June 2018.

Effect of galcanezumab on severity and symptoms of migraine in phase 3 trials in patients with episodic or chronic migraine

BackgroundGalcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days compared with placebo. Here, we analyze data from 3 randomized clinical trials (2 episodic trials [EVOLVE-1, EVOLVE-2] and 1 chronic trial [REGAIN]), to examine if galcanezumab also alleviates the severity and symptoms of migraine.MethodsThe episodic migraine trials were 6-month, double-blind studies in patients with episodic migraine (4–14 monthly migraine headache days). The chronic migraine trial was a 3-month, double-blind study in patients with chronic migraine (≥ 15 headache days per month, where ≥ 8 met criteria for migraine). Patients (18–65 years) were randomized to placebo or galcanezumab 120 mg with a 240-mg loading dose or 240 mg. Patients recorded headache characteristics, duration, severity, and presence of associated symptoms with each headache. The outcomes analyzed were changes from baseline in number of monthly migraine headache days with nausea and/or vomiting, photophobia and phonophobia, aura, and prodromal symptoms other than aura. Additional outcomes analyzed included the number of moderate-to-severe monthly migraine headache days, number of severe migraine headache days, and mean severity of remaining migraine headache days. Change from baseline in the proportion of days with nausea and/or vomiting and the proportion of days with photophobia and phonophobia among the remaining monthly migraine headache days were also analyzed.ResultsGalcanezumab was superior to placebo in reducing the frequency of migraine headache days with associated symptoms of migraine such as nausea and/or vomiting, photophobia and phonophobia, and prodromal symptoms. Galcanezumab reduced the frequency of migraine headache days with aura in the episodic migraine studies. There was a significant reduction in the proportion of remaining migraine headache days with nausea and/or vomiting for the episodic and chronic migraine studies, and with photophobia and phonophobia for the episodic migraine studies. Galcanezumab was superior to placebo in reducing the number of monthly moderate-to-severe migraine headache days and the overall and monthly severe migraine headache days.ConclusionsGalcanezumab reduces the frequency of migraine headache days and can alleviate potentially disabling non-pain symptoms on days when migraine is present in patients with episodic or chronic migraine.Trial registrationNCT, NCT02614183 (EVOLVE-1), registered 25 November 2015; NCT, NCT02614196, (EVOLVE-2), registered 25 November 2015; NCT, NCT02614261 (REGAIN), registered 25 November 2015.