Migraine Headache Days Research Articles

Efficacy and Safety of Galcanezumab for the Preventive Treatment of Migraine: A Narrative Review.

Migraine is a debilitating neurologic disease. People who experience migraine can have substantial disability, impaired functioning and a decreased quality of life (QoL). Expert recommendations suggest that people with frequent migraine attacks or severe impairment related to attacks may benefit from preventive treatment. Despite these recommendations and the existence of evidence-based guidelines for the use of preventive medication, many people who are candidates for preventive therapies do not receive them. Thus, there is still a substantial unmet need for preventive migraine treatment. Calcitonin gene-related peptide (CGRP) has a demonstrated role in the pathophysiology of migraine. Galcanezumab-gnlm (galcanezumab) is a humanized monoclonal antibody that binds to the CGRP ligand and prevents binding to its receptor. It is administered as a once-monthly subcutaneous injection. The aim of this review is to present a comprehensive overview of the existing short- and long-term efficacy and safety data for galcanezumab in patients with migraine. Data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2 and REGAIN studies show that galcanezumab treatment for 3 or 6 months results in overall reduction in mean monthly migraine headache days in patients with episodic (EVOLVE-1 and EVOLVE-2) and chronic (REGAIN) migraine. Greater proportions of patients with episodic migraine receiving galcanezumab versus placebo demonstrated a ≥ 50%, ≥ 75% and 100% response to therapy and reported a lower level of disability and an improvement in functioning and QoL. Similarly, when compared with placebo, greater proportions of patients with chronic migraine treated with galcanezumab demonstrated a ≥ 50% and ≥ 75% response and reported improved functioning. A 12-month open-label study demonstrated the continued efficacy of galcanezumab for up to 12 months. In all studies galcanezumab was well tolerated. In conclusion, data from pivotal studies show that galcanezumab may fulfill an unmet need in the treatment of patients with migraine who require preventive therapy.

Sustained Reduction of Migraine Headache Days in Patients with Episodic Migraine During Months 4 to 6 of Treatment with Galcanezumab (1768)

Sustained Reduction of Migraine Headache Days in Patients with Episodic Migraine During Months 4 to 6 of Treatment with Galcanezumab (1768)

Erenumab in prophylaxis of migraine – pilot study

The aim of preventive treatment of episodic and chronic migraine is to reduce the frequency and severity of attacks and thereby improve patient’s quality of life. It is suggested that calcitonin gene related peptide (CGRP) plays a critical role in migraine patophysiology. In last few decades a new class of drugs was developed – monoclonal antibodies against CGRP. One of them is erenumab, which has been available in Poland since November 2018. The aim of this study was to assess the efficacy and tolerability of erenumab in migraine prophylaxis in polish patients with episodic and chronic migraine. Adult patients diagnosed with migraine (according to ICHD 3) with at least 4 migraine headache days in month were included in this study. The primary endpoint was the proportion of patients with more than 50% reduction in number of migraine headache days after the first month of treatment. From December 2018 to April 2019 9 women (24–66 years; average 43.8 years) were included. The average migraine headache days in this study group was 9 (5–20). The participants were treated with subcutaneously delivered erenumab in daily dose of 70 mg. After the first month of treatment in 7 from 9 women (77.5 %) primary endpoint was reached. In 3 of 9 (30%) patients itch was noted. The results of this study suggest efficacy and good tolerability profile of erenumab in polish patients with episodic and chronic migraine. The future study are needed with larger groups of participants.

Safety and tolerability of monthly galcanezumab injections in patients with migraine: integrated results from migraine clinical studies

BackgroundGalcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days in phase 2 and 3 trials. In these analyses, we aimed to evaluate the safety and tolerability of galcanezumab compared with placebo for prevention of episodic or chronic migraine.MethodsData were integrated from three double-blind clinical studies for the up to 6-month galcanezumab exposure group (N = 1435), and from five clinical studies for the up to 1-year all-galcanezumab exposure group (N = 2276). Patients received a monthly 120 mg subcutaneous injection of galcanezumab (with a 240 mg loading dose in month 1), 240 mg galcanezumab, or placebo. Outcomes measured were treatment-emergent adverse events (TEAEs), serious AEs (SAEs), and discontinuation due to AEs (DCAEs). Laboratory results, vital signs, electrocardiogram (ECG), suicidal ideation and behavior results were evaluated.ResultsTEAEs that occurred more frequently in galcanezumab-treated patients included injection site pain, injection site reactions excluding pain, constipation, vertigo, and pruritus. The proportion of DCAEs among galcanezumab-treated patients ranged between 1.8 and 3.0%, and differed from placebo group for galcanezumab 240 mg (P < 0.05). Fewer than 2.0% of patients in either galcanezumab dose-group compared with 1.0% of placebo-treated patients reported a SAE. There were no clinically meaningful differences between galcanezumab and placebo in laboratory measures, vital signs including blood pressure, ECGs, cardiovascular-related AEs, or suicidal ideation and behavior.ConclusionsGalcanezumab demonstrated a favorable safety and tolerability profile for up to 1 year of treatment for the prevention of migraine.Trial registrationClinical Trials CGAB = NCT02163993, EVOLVE-1 = NCT02614183, EVOLVE-2 = NCT02614196, REGAIN = NCT02614261, and CGAJ = NCT02614287. All were first posted on 25 November 2015, except CGAB posted on 16 June 2014, and before enrolling the first patient.

Efficacy and safety of galcanezumab for prevention of migraine headache in Japanese patients with episodic migraine: A phase 2 randomized controlled clinical trial

Objective: This study was designed to assess the efficacy and safety of galcanezumab in comparison with placebo for the prevention of migraine in Japanese patients with episodic migraine. Methods: In this double-blind, placebo-controlled study, which was conducted over 6 months, randomized adult patients received subcutaneous injections of galcanezumab (120 mg n = 115, 240 mg n = 114) or placebo ( n = 230) once monthly. The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days. The key secondary outcome measures were response rates (≥50%, ≥75%, and 100%); the Migraine-Specific Quality-of-Life Questionnaire Role Function-Restrictive score; monthly migraine headache days requiring acute treatment; and Patient Global Impression of Severity (PGI-S). Results: The mean change from baseline in monthly migraine headache days over months 1–6 was significantly ( p &lt; 0.001) greater for the 120-mg galcanezumab dose (−3.60 days) and the 240-mg galcanezumab dose (−3.36 days) compared with placebo (−0.59 days). Both the 120-mg and 240-mg doses of galcanezumab were superior compared with placebo for each of the key secondary endpoints except for PGI-S (only the 240-mg dose was superior). The most commonly reported treatment-emergent adverse events were local injection-site reactions; erythema, swelling, pruritus, and pain were more commonly reported by patients who were treated with galcanezumab than those treated with placebo. Conclusion: The number of monthly migraine headache days was reduced with both doses of galcanezumab, and both doses were safe and well tolerated in Japanese patients with episodic migraine.

Efficacy of galcanezumab in patients with episodic migraine and a history of preventive treatment failure: results from two global randomized clinical trials.

Background and purposeThe efficacy of galcanezumab, a monoclonal antibody for migraine prevention, has been demonstrated in two pivotal trials in patients with episodic migraine.MethodsEVOLVE‐1 and EVOLVE‐2 were identical phase 3, randomized, double‐blind, placebo‐controlled studies in patients with episodic migraine. Mean migraine headache days per month at baseline was 9. Patients were randomized 2:1:1 to monthly injections of placebo, galcanezumab 120 mg/240 mg during the 6‐month double‐blind treatment period. Key efficacy outcomes were assessed in subgroups amongst patients for whom, previously, for efficacy and/or safety/tolerability reasons (i) one or more (≥1) preventives failed, (ii) two or more (≥2) preventives failed and (iii) preventives were never used, or used but not failed (no prior failure).ResultsIn an integrated analysis of EVOLVE studies, galcanezumab 120 mg/240 mg versus placebo led to larger overall mean (SE) reductions in monthly migraine headache days across 6 months in patients with prior preventive failures (P < 0.001): ≥1 failure: 120 mg: −4.0 (0.4); 240 mg: −4.2 (0.5); placebo: −1.3 (0.4); ≥2 failures: 120 mg: −3.1 (0.7); 240 mg: −3.8 (0.8); placebo: −0.5 (0.6). Similar results were observed amongst patients with no prior failure, but the placebo response was larger: 120 mg: −4.7 (0.2); 240 mg: −4.5 (0.2); placebo: −3.0 (0.2) (P < 0.001 versus placebo). Significant improvements were observed with galcanezumab versus placebo for ≥50% and ≥75% reduction in monthly migraine headache days.ConclusionIn patients with episodic migraine treated with galcanezumab, those with ≥1 or ≥2 prior preventive failures had significantly larger improvements, versus placebo, in efficacy outcomes. Similar results were observed in patients with no prior failure, with a larger placebo response.

Fremanezumab in the prevention of migraine: a profile of its use

Fremanezumab (fremanezumab-vfrm; Ajovy®), a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), is indicated for the prevention of migraine in adults in the EU and USA. Subcutaneous fremanezumab 225 mg once monthly or 675 mg once every 3 months was effective in reducing monthly migraine days or headache days in patients with episodic or chronic migraine in pivotal, 12-week clinical trials. Both regimens also reduce acute headache medication use and headache-related disability. Improvements were maintained through ≤ 52 weeks of additional treatment in a longer-term extension study. In a trial in treatment-resistant migraine, both fremanezumab regimens reduced monthly migraine days in patients who had failed 2–4 classes of preventive medications. Fremanezumab is generally well tolerated, with most adverse events (AEs) being injection site reactions of mild or moderate severity.

Efficacy of fremanezumab by country in patients with documented inadequate response to 2-4 classes of migraine preventive medications in the multicentre, randomised, placebo-controlled focus study

The FOCUS phase 3b study of fremanezumab was the first and largest study of a migraine preventive treatment in adults with episodic or chronic migraine (EM or CM) and documented inadequate response (poor response, intolerability, or contraindication/unsuitability) to 2-4 classes of migraine preventive medications. Efficacy by country was an exploratory endpoint. After IRB approval, 838 patients were randomised (1:1:1) to monthly fremanezumab (month1: CM, 675mg; EM, 225mg; months2/3: 225mg), quarterly fremanezumab (month1: 675mg; months2/3: placebo), or matched monthly placebo for 12 weeks of double-blind treatment. Change from baseline in the monthly average number of migraine headache days over 12 weeks (primary endpoint) was evaluated by country for all migraine patients (EM and CM combined). Of 14 countries contributing data, the Czech Republic (n=188;22%), United States (n=120;14%), and Finland (n=85;10%) enrolled the most patients. Baseline monthly average numbers of migraine headache days were lower in the Czech Republic (Table). Changes from baseline in the monthly average numbers of migraine headache days over 12 weeks were significantly greater with both fremanezumab dosing regimens versus placebo for patients in the Czech Republic, United States, or Finland (all P ≤0.0123; Table). Monthly and quarterly fremanezumab significantly reduced the monthly average number of migraine headache days versus placebo regardless of country and continent (North America versus Europe) in migraine patients with documented inadequate response to 2-4 migraine preventive medication classes.

Sustained reduction of migraine headache days in patients with episodic migraine during months 4–6 of treatment with galcanezumab

Sustained reduction of migraine headache days in patients with episodic migraine during months 4–6 of treatment with galcanezumab

Two randomized migraine studies of galcanezumab

ObjectiveTo evaluate changes from baseline in patient-reported outcomes for measures of functioning and disability among patients with migraine treated with galcanezumab or placebo.MethodsPatients with episodic migraine (4–14 monthly migraine headache days) were treated with either galcanezumab (Evaluation of LY2951742 in the Prevention of Episodic Migraine [EVOLVE]–1: 120 mg n = 210, 240 mg n = 208; EVOLVE-2: 120 mg n = 226, 240 mg n = 220) or placebo (EVOLVE-1 n = 425; EVOLVE-2 n = 450) during 6 months of treatment. Migraine-Specific Quality of Life Questionnaire v2.1 (MSQv2.1) measured the effect of migraine on patient functioning (physical and emotional) in 3 domains, and the Migraine Disability Assessment (MIDAS) quantified headache-related disability associated with missed or reduced productivity at work or home and social events. Both were collected at baseline and during the treatment period (MSQv2.1 = monthly; MIDAS = months 3 and 6 only).ResultsDifferences in MSQv2.1 total score least squares (LS) mean change from baseline (month 4–6) for galcanezumab (120 and 240 mg, respectively) were superior to placebo (EVOLVE-1 = 7.3 and 6.7 [both p < 0.001]; EVOLVE-2 = 8.5 and 7.3 [both p < 0.001]). Differences were similar for all domain scores (p < 0.001 for both galcanezumab doses compared with placebo), were observed as early as month 1, and were sustained for 6 months for most domains. Differences of MIDAS LS mean change from baseline (month 6) for galcanezumab (120 and 240 mg, respectively) compared with placebo were: EVOLVE-1 = −6.3 (p < 0.001) and −5.2 (p = 0.002); EVOLVE-2 = −9.2 and −8.2 (both p < 0.001).ConclusionsPatients with episodic migraine treated with galcanezumab reported significant and clinically meaningful improvements in daily functioning and decreased disability compared with patients who received placebo.Classification of evidenceThis study provides Class II evidence that for patients with migraine, galcanezumab (120 mg or 240 mg) given once monthly improved functioning and reduced disability.

Galcanezumab in episodic migraine: subgroup analyses of efficacy by high versus low frequency of migraine headaches in phase 3 studies (EVOLVE-1 & EVOLVE-2)

BackgroundPatients with high-frequency episodic migraine (HFEM) have a greater disease burden than those with low-frequency episodic migraine (LFEM). Acute treatment overuse increases the risk of migraine chronification in patients with HFEM. Galcanezumab, a humanized monoclonal antibody binding calcitonin gene-related peptide (CGRP), is effective for migraine prevention with a favorable safety profile. Here, we investigate whether there are differences in galcanezumab efficacy in patients with LFEM or with HFEM.MethodsData were pooled from two double-blind, placebo-controlled phase 3 trials; EVOLVE-1 and EVOLVE-2. Patients were 18–65 years old, experienced 4–14 monthly migraine headache days (MHDs) for ≥1 year prior, with onset at < 50 years of age. Migraine headaches were tracked via electronic patient-reported outcome system and randomization was stratified by low (LFEM; 4–7 monthly MHDs) or high (HFEM; 8–14 monthly MHDs) frequency. Subgroup analysis compared the HFEM and LFEM subgroups with a linear or generalized linear mixed model repeated measures approach.ResultsThe intent-to-treat patients (N = 1773) had a mean age of 41.3 years, were mostly white (75%), female (85%), and 66% of patients had HFEM. In both the LFEM and HFEM subgroups, the overall (Months 1–6) and monthly changes from baseline in monthly MHDs and monthly MHDs with acute medication use compared with placebo were statistically significantly reduced for galcanezumab 120-mg and 240-mg. Galcanezumab (120-mg and 240-mg) significantly decreased the overall and monthly MHDs with nausea and/or vomiting, and with photophobia and phonophobia versus placebo in patients with LFEM or HFEM. In both subgroups, the mean overall (Months 1–6) and monthly percentages of patients with ≥50%, ≥75%, and 100% reduction in monthly MHDs from baseline were statistically significantly greater in patients receiving either dose of galcanezumab versus placebo. Galcanezumab (120-mg and 240-mg) significantly improved the Migraine-Specific Quality of Life Questionnaire role function-restrictive domain score as well as the Migraine Disability Assessment total score versus placebo for patients with LFEM or HFEM. There were no significant subgroup-by-treatment interactions.ConclusionsGalcanezumab was as effective in patients with HFEM as in those with LFEM. Associated symptoms, quality of life, and disability were similarly improved in patients with HFEM or LFEM.Trial registrationNCT02614183, NCT02614196.

Evaluating the Psychometric Properties of the Migraine Functional Impact Questionnaire (MFIQ).

BackgroundMigraine is a chronic neurologic disease that can be associated with significant migraine‐related impact, disability, and burden. Patient‐reported outcome measures (PRO) are included in clinical trials of migraine interventions to capture treatment effects from a patient perspective. Clinical and regulatory guidelines also encourage use of PROs in trials. The Migraine Functional Impact Questionnaire (MFIQ) is a novel PRO measure, assessing the impact of migraine on Physical Function (PF), Usual Activities (UA), Social Function (SF), and Emotional Function (EF), in the past 7 days. Scientific methods recommended to meet the requirements of the U.S. Food and Drug Administration were followed, to ensure that the MFIQ content included outcomes that were relevant to adults with migraine and were clinically relevant, specifically to evaluate preventive treatments for migraine.ObjectiveThe objective of this study was to conduct item analyses informing item reduction and scoring, and to evaluate the psychometric properties of the MFIQ.MethodsIn a prospective, observational study, adults with migraine completed the MFIQ as well as additional clinical and PRO instruments, including the Headache Impact Test (HIT‐6TM), Patient‐Reported Outcomes Measurement Information System Physical Function Short Form 10a (PROMIS‐PF), Migraine‐Specific Quality‐of‐Life Questionnaire (MSQ), and Patient Global Rating of Change (PGIC). Item‐level evaluation, item response theory (IRT), and factor analysis were used to select final MFIQ items, identify domains, and inform scoring. Psychometric properties of the MFIQ were evaluated to assess reliability (internal consistency and test–retest), validity (construct and known‐groups), and responsiveness.ResultsThe study enrolled 569 adults with migraine. Subjects had an average age of 39.9 years (SD 12.0), 87.2% were female, and 80.8% were white. Five items were dropped from the draft version based on results of item‐level analyses reviewed in the context of previous qualitative research to produce the final 26‐item MFIQ (v.2). Four domain scores (PF, UA, SF, and EF) and a global item score for impact on UA were identified. Higher scores on a 0‐100 scale represent greater impact. All scores exhibited high internal consistency (α ≥ 0.89) and moderate test–retest reliability among stable subjects (ICCs ≥ 0.47). Construct validity was demonstrated by significant correlations (all P < .0001) between MFIQ domain scores, related PRO scores, and the frequency of migraine days and headache days. All domain scores differentiated between subgroups (“known groups”) defined based on established levels of clinical severity: number of monthly migraine and headache days, migraine interference levels and scores on other PRO instruments (P < .05). Improvements in MFIQ scores corresponded with clinical improvement (percent reduction in monthly migraine days), improvement in migraine interference with daily activities, and related improvements in PRO scores (P < .05), demonstrating that the MFIQ was responsive to changes in migraine impact.ConclusionsThe MFIQ is a reliable and valid measure that can be used to collect data about migraine impact. The MFIQ is being used to evaluate outcomes of migraine interventions in clinical trials and observational studies. It could potentially also be used in clinical practice both for initial and ongoing assessments for monitoring outcomes and to enhance communication between patients and healthcare professionals for the management of migraine.

PND73 DIFFERENTIATION OF EPISODIC MIGRAINE AND CHRONIC MIGRAINE USING A MACHINE LEARNING TECHNIQUE

Chronic migraine (CM) and episodic migraine (EM) are part of the spectrum of migraine disorders, but they are distinct clinical entities. EM is characterized as up to 14 migraine days per months, while CM is defined as 15 or more headache days per months, at least 8 out of which have to be typical migraine headache days. We seek to use a machine learning technique to produce the classification hence infer the severity of the disease. The diagnosis codes in the MarketScan database were used to produce three cohorts containing CM, EM and non-headache patients (a negative control group). Features were derived and a list of supervised machine learning algorithms were explored including random forest, neural networks, gradient boost, and stacked model. Particle swarm optimization algorithm was applied to explore the optimal parameters of the machine learning algorithms. 395 features were constructed. Each CM, EM or negative control group had 18,832 patients. The gradient boost algorithm produced the best result, which reported the accuracy and kappa at 0.75 and 0.63, respectively. After applying thresholds in the optimized gradient boost model, the accuracy and kappa were further increased to 0.81 and 0.72 with prediction decision made to 80% of the dataset. Collinearity and high correlation were found with features within the group regarding cost, resource, and medication use. 27% of CM and 9% of EM patients received wrong predictions from the fine-tuned random forest, gradient boost, and neural network. Migraine-related costs were ranked as top important features. Migraine patients with higher cost, resource use and medications use were more likely to have a diagnosis of CM vs EM, with higher migraine-related costs as the top indicators of a patient having CM. Further research on a data source with more migraine specific clinical outcomes is deemed.

Onset of efficacy and duration of response of galcanezumab for the prevention of episodic migraine: a post-hoc analysis

Background and objectiveAs new migraine prevention treatments are developed, the onset of a preventive effect, how long it is maintained and whether patients initially non-responsive develop clinically meaningful responses with...

Preventive effects of galcanezumab in adult patients with episodic or chronic migraine are persistent: data from the phase 3, randomized, double-blind, placebo-controlled EVOLVE-1, EVOLVE-2, and REGAIN studies

BackgroundMaintenance of effect following treatment with galcanezumab compared to placebo in adult patients with episodic or chronic migraine was evaluated.MethodsIn 2 similarly designed studies of patients with episodic migraine (6 months) and 1 study of patients with chronic migraine (3 months), patients randomized in a 1:1:2 ratio received a subcutaneous injection of galcanezumab 120 mg/month (after an initial loading dose of 240 mg) or 240 mg/month or placebo. Maintenance of effect during the double-blind phase was evaluated based on a comparison of the percentages of galcanezumab- and placebo-treated patients with maintenance of 30, 50, 75, and 100% response (defined as ≥30, ≥50, ≥75, and 100% reduction from baseline in monthly migraine headache days [MHD]) at an individual patient level. Logistic regression analyses were used for between treatment comparisons.ResultsA total of 1773 adult patients with episodic migraine (n = 444 for galcanezumab 120 mg; n = 435 for galcanezumab 240 mg; n = 894 for placebo for 2 studies pooled) and 1113 patients with chronic migraine (n = 278 for galcanezumab 120 mg; n = 277 for galcanezumab 240 mg; n = 558 for placebo) were evaluated. In patients with episodic migraine, ≥50% response was maintained in 41.5 and 41.1% of galcanezumab-treated patients (120 mg and 240 mg, respectively) for ≥3 consecutive months (until patient’s endpoint) and 19.0 and 20.5%, respectively, for 6 consecutive months and was significantly greater than the 21.4 and 8.0% of placebo-treated patients at ≥3 and 6 months consecutively (P < 0.001). Approximately 6% of galcanezumab-treated patients maintained ≥75% response all 6 months versus 2% of placebo-treated patients. Few galcanezumab-treated patients maintained 100% response. In patients with chronic migraine, 29% of galcanezumab-treated patients maintained ≥30% response all 3 months compared to 16% of placebo patients while ≥50% response was maintained in 16.8 and 14.6% of galcanezumab-treated patients (120 mg and 240 mg) and was greater than placebo (6.3%; p < 0.001). Few patients maintained ≥75% response.ConclusionsTreatment with galcanezumab 120 mg or 240 mg demonstrated statistically significant and clinically meaningful persistence of effect in patients with episodic migraine (≥3 and 6 consecutive months) and in patients with chronic migraine (for 3 months).Study identification and trial registrationStudy Identification: EVOLVE-1 (I5Q-MC-CGAG); EVOLVE-2 (I5Q-MC-CGAH); REGAIN (I5Q-MC-CGAI)Trial RegistrationClinicalTrials.gov; NCT02614183 (EVOLVE-1); NCT02614196 (EVOLVE-2); NCT02614261 (REGAIN)

Retrospective review of thienopyridine therapy in migraineurs with patent foramen ovale.

We retrospectively reviewed our clinical experience using off-label thienopyridine agents in patients with migraine headache (MHA) and patent foramen ovale (PFO). Between 2011 and 2017, MHA/PFO patients referred to our practice were clinically treated with clopidogrel specifically for MHA. Those with ≥50% reduction in monthly MHA days compared with baseline were deemed MHA responders. MHA nonresponders with inadequate platelet inhibition by PRU testing were offered prasugrel. Thienopyridine-responsive patients were then offered PFO closure. Of 136 patients (86% female, mean age 37.9 years, mean MHA burden 14.7 days/month), 80 (59%) were MHA responders to clopidogrel. The clopidogrel responder rate was equivalent in episodic, chronic, aura, and nonaura subgroups. A total of 19/45 (40%) MHA nonresponders had inadequate platelet inhibition by PRU testing on clopidogrel. Sixteen of those patients received prasugrel, were adequately platelet inhibited by PRU, and 10/16 (62%) converted to MHA responders. A total of 56/90 thienopyridine-responsive patients underwent subsequent PFO closure with thienopyridine discontinuation after 3 months. Ninety-four percent had ongoing MHA relief. A total of 8/8 responders who stopped thienopyridine without PFO closure had resumption of MHA symptoms. Successful P2Y12 platelet inhibition seemed to reduce MHA symptoms in some patients with PFO, suggesting a platelet-based mechanism/trigger. The nearly parallel response to PFO closure may mechanistically link venous platelet activation with the right-to-left shunt of PFO. Thienopyridine responsiveness could be used to enrich the study population for a new MHA/PFO trial. This study provides Class IV evidence that in patients with PFO, P2Y12 inhibition improved MHA symptoms.

Analysis of Initial Nonresponders to Galcanezumab in Patients With Episodic or Chronic Migraine: Results From the EVOLVE-1, EVOLVE-2, and REGAIN Randomized, Double-Blind, Placebo-Controlled Studies.

ObjectiveTo examine the likelihood of response with continued galcanezumab treatment in patients with episodic or chronic migraine without initial clinical improvement.BackgroundA percentage of patients with migraine may require additional time on pharmacotherapy but discontinue treatment prematurely. Additionally, recognizing when continued treatment is unlikely to provide improvement limits unnecessary exposure.MethodsPost hoc analysis of response after continued galcanezumab treatment was conducted in a subset of patients with episodic (N = 879) and chronic (N = 555) migraine who did not achieve “good” early improvement (episodic, ≥50% reduction in baseline migraine headache days [MHD] and chronic, ≥30% reduction) after 1 month of dosing (NR‐1; episodic, n = 450 and chronic, n = 306). This subset was categorized by level of reduction in MHD during 1 month of treatment: “modest” (>30% to <50% fewer MHD for episodic and >10% to <30% fewer MHD for chronic), “limited” (episodic only; >10% to ≤30% fewer MHD), or “minimal/no” early improvement (≤10% fewer MHD to ≤10% more MHD), or “worsening” (>10% more MHD). The percentages of patients having “better” (≥75% fewer MHD for episodic and ≥50% for chronic), “good,” or “little‐to‐no” (≤10% fewer MHD) response during the remaining treatment period were calculated for each category. Similarly, the subset of NR‐1 patients who did not achieve “good” early improvement after 2 months of treatment (NR‐2; episodic, n = 290 and chronic, n = 240) were categorized by level of their average monthly reduction across 1 and 2 months using similar categories.ResultsOf NR‐1 patients with episodic migraine having “modest” early improvement, 62% (96/155) achieved “good” and 20% (31/155) achieved “better” responses with continued treatment. A percentage of patients with “limited” (43%; 46/108) or “minimal/no” (34%; 29/85) early improvement, or “worsening” (20%; 20/102) achieved a “good” response after continued treatment. A percentage of NR‐1 patients with chronic migraine having “modest” early improvement achieved “good” (38%; 44/116) and “better” (13%; 15/116) responses with continued treatment. A “good” response was achieved for a percentage of patients with “minimal/no” early improvement (17%; 23/133). Similar patterns were observed for the NR‐2 subset, though percentages were lower.ConclusionsGalcanezumab‐treated patients with episodic or chronic migraine without response following 1 or 2 months of treatment appear to have a reasonable likelihood of continued improvement in months following initial treatment and this opportunity is more likely in patients showing greater early improvements. While a small percentage of patients with episodic or chronic migraine who experienced worsening in the number of MHD following initial treatment responded with continued treatment, most do not show substantial reduction in MHD. Overall benefit of therapy should be determined collaboratively between the patient and physician.

Galcanezumab in chronic migraine

ObjectiveTo evaluate the efficacy and safety of galcanezumab, a humanized monoclonal antibody that selectively binds to calcitonin gene-related peptide, in the preventive treatment of chronic migraine.MethodsA phase 3, randomized, double-blind, placebo-controlled study of LY2951742 in patients with chronic migraine (Evaluation of Galcanezumab in the Prevention of Chronic Migraine [REGAIN]) was a phase 3 study with a 3-month double-blind, placebo-controlled treatment phase and a 9-month open-label extension. Eligible patients 18 to 65 years of age with chronic migraine were randomized 2:1:1 to monthly subcutaneous injections of placebo (n = 558), galcanezumab 120 mg (with a 240-mg loading dose, n = 278), or galcanezumab 240 mg (n = 277). The primary endpoint was the overall mean change from baseline in the number of monthly migraine headache days (MHDs) during the 3-month double-blind treatment phase.ResultsMean number of monthly MHDs at baseline was 19.4 for the total sample. Both galcanezumab dose groups demonstrated greater overall mean reduction in the number of monthly MHDs compared to placebo (placebo −2.7, galcanezumab 120 mg −4.8, galcanezumab 240 mg −4.6) (p < 0.001 for each dose compared to placebo). There were no clinically meaningful differences between galcanezumab doses and placebo on any safety or tolerability outcome except for a higher incidence of treatment-emergent injection-site reaction (p < 0.01), injection-site erythema (p < 0.001), injection-site pruritus (p < 0.01), and sinusitis (p < 0.05) in the galcanezumab 240-mg group relative to placebo.ConclusionsBoth doses of galcanezumab were superior to placebo in reducing the number of monthly MHDs. Galcanezumab appears efficacious, safe, and well tolerated for the preventive treatment of chronic migraine.ClinicalTrials.gov identifierNCT02614261.Classification of evidenceThis interventional study provides Class I evidence that galcanezumab is superior to placebo in the reduction of the number of monthly MHDs.

A phase 3, long-term, open-label safety study of Galcanezumab in patients with migraine

BackgroundGalcanezumab, a humanized monoclonal antibody that selectively binds to the calcitonin gene-related peptide, has demonstrated in previous Phase 2 and Phase 3 clinical studies (≤6-month of treatment) a reduction in the number of migraine headache days and improved patients’ functioning. This study evaluated the safety and tolerability, as well as the effectiveness of galcanezumab for up to 12 months of treatment in patients with migraine.MethodsPatients diagnosed with episodic or chronic migraine, 18 to 65 years old, that were not exposed previously to galcanezumab, were randomized to receive galcanezumab 120 mg or 240 mg, administered subcutaneously once monthly for a year. Safety and tolerability were evaluated by frequency of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), and adverse events (AEs) leading to study discontinuation. Laboratory values, vital signs, electrocardiograms, and suicidality were also analyzed. Additionally, overall change from baseline in the number of monthly migraine headache days, functioning, and disability were assessed.ResultsOne hundred thirty five patients were randomized to each galcanezumab dose group. The majority of patients were female (> 80%) and on average were 42 years old with 10.6 migraine headache days per month at baseline. 77.8% of the patients completed the open-label treatment phase, 3.7% of patients experienced an SAE, and 4.8% discontinued due to AEs. TEAEs with a frequency ≥ 10% of patients in either dose group were injection site pain, nasopharyngitis, upper respiratory tract infection, injection site reaction, back pain, and sinusitis. Laboratory values, vital signs, or electrocardiograms did not show anyclinically meaningful differences between galcanezumab dosesOverall mean reduction in monthly migraine headache days over 12 months for the galcanezumab dose groups were 5.6 (120 mg) and 6.5 (240 mg). Level of functioning was improved and headache-related disability was reduced in both dose groups.ConclusionTwelve months of treatment with self-administered injections of galcanezumab was safe and associated with a reduction in the number of monthly migraine headache days. Safety and tolerability of the 2 galcanezumab dosing regimens were comparable.Trial registrationClinicalTrials.gov as NCT02614287, posted November 15, 2015. These data were previously presented as a poster at the International Headache Congress 2017: PO-01-184, Late-Breaking s of the 2017 International Headache Congress. (2017). Cephalalgia, 37(1_suppl), 319–374.

100% Response Rate to Galcanezumab in Patients With Episodic Migraine: A Post Hoc Analysis of the Results From Phase 3, Randomized, Double‐Blind, Placebo‐Controlled EVOLVE‐1 and EVOLVE‐2 Studies

ObjectiveTo characterize adult patients with episodic migraine who achieved 100% response to galcanezumab treatment.BackgroundGalcanezumab is a humanized monoclonal antibody that selectively binds to the calcitonin gene‐related peptide (CGRP) and has demonstrated efficacy in reducing migraine headache days (MHD) in patients with episodic and chronic migraine.MethodsA post hoc analysis of the proportion of patients with 100% response (100% reduction from baseline in monthly MHD) was calculated for each month from pooled data of 2 double‐blind, 6‐month galcanezumab studies in patients with episodic migraine (4 to 14 MHD and ≥2 migraine attacks per month at baseline). The patients were randomized (1:1:2) to monthly subcutaneous galcanezumab, 120 mg (after 240 mg initial loading dose) or 240 mg, or placebo. A generalized linear mixed model with effects for baseline MHD, treatment, month, and treatment‐by‐month interaction was used to estimate the mean monthly response rate.ResultsThe analysis included 1739 patients treated with galcanezumab, 120 mg (n = 436) or 240 mg (n = 428), or placebo (n = 875). The mean monthly 100% response rate on an average month in the 6‐month double‐blind phase was greater for galcanezumab 120 mg (13.5%) and 240 mg (14.3%) groups vs placebo (5.9%) with odds ratios of 2.5 (95% confidence interval [CI] 1.9, 3.2) and 2.6 (95% CI 2.0, 3.4), respectively (P < .001). The rate of 100% monthly response increased at each month over the 6‐month double‐blind phase with higher rates for galcanezumab dose groups (9 to 21%) than placebo (2 to 10%) (P < .02). Evaluation of 100% response by the number of months showed a greater proportion of galcanezumab‐treated patients in either dose group, compared to placebo, were able to achieve a 100% response (P < .001 up to 3 months); however, though greater than placebo, few galcanezumab patients had ≥4 months of 100% response (P < .02). The proportions of patients with 100% response were greatest in the last 3 months of the treatment. Considering the average number days between nonconsecutive MHD across the 6‐month period (not just during the times of 100% response), the duration of migraine headache‐free periods in the galcanezumab groups was 29 days for those with at least 1 month of 100% response and 55 days for those with at least 3 months of 100% response. This gap was approximately 6 to 11 times greater than the mean gap of 5 days observed at baseline.ConclusionsMore than a third of the patients with episodic migraine treated with galcanezumab 120 mg or 240 mg achieved 100% response for at least 1 month. More patients had 100% monthly response in the last 3 months of the 6‐month double‐blind period. For those with 100% response for at least 1 month, the average time between nonconsecutive MHD for the entire treatment period was nearly 1 month and approached 2 months for patients with 3 or more months of 100% response.