Prevention Of Episodic Migraine Research Articles

Safety and tolerability of erenumab in individuals with episodic or chronic migraine across age groups: a pooled analysis of placebo-controlled trials

BackgroundErenumab, a fully human monoclonal antibody that targets the calcitonin gene-related peptide receptor, has demonstrated efficacy and safety in the prevention of episodic and chronic migraine. There exists an unmet need to establish the safety of erenumab in older individuals, in view of existing multiple comorbidities, polypharmacy, and age-related physiological changes. This pooled analysis of five large migraine-prevention studies examined the safety of erenumab stratified across age groups, particularly in older populations.MethodsPooled and age-stratified analysis of safety data from the 12-week double-blind treatment phase (DBTP) of five randomized, placebo-controlled Phase 2 and 3 studies of erenumab in participants with episodic or chronic migraine across the age groups < 40 years, 40–49 years, 50–59 years, and ≥ 60 years was completed. The safety of erenumab across age groups was determined by assessing safety endpoints including treatment-emergent adverse events (AEs), serious AEs, and events leading to study drug discontinuation.ResultsOverall, 3345 participants across five studies were randomized to receive either placebo (n = 1359), erenumab 70 mg (n = 1132) or erenumab 140 mg (n = 854); 3176 (94.9%) completed the DBTP, and 169 (5.1%) discontinued, mainly due to participant decision (110; 3.3%). Overall, 1349 (40.6%), 1122 (33.8%), and 850 (25.6%) participants received at least one dose of placebo, erenumab 70 mg, and erenumab 140 mg, respectively.Incidence of treatment-emergent AEs was similar across all age groups for both doses of erenumab (70 mg or 140 mg) and placebo (< 40 years, 44.0% vs 44.4%; 40–49 years, 42.5% vs 49.2%; 50–59 years, 46.5% vs 41.6%; ≥ 60 years, 43.8% vs 59.4%). Incidence of treatment-emergent serious AEs overall, and stratified by age groups for both doses and placebo was low (< 40 years, 0.9% vs 1.2%; 40–49 years, 1.7% vs 1.9%; and 50–59 years, 1.6% vs 1.1%), with no serious AEs reported in participants aged ≥ 60 years. No deaths were reported.ConclusionsErenumab (70 mg or 140 mg) exhibited a similar safety profile compared with placebo across age groups in individuals with episodic or chronic migraine, with no increased emergence of events due to age. Erenumab was well tolerated in older participants with multiple comorbidities, polypharmacy, and age-related physiological changes.Trial registration numberClinicalTrials.gov Identifiers: NCT02066415, NCT02456740, NCT02483585, NCT03096834, NCT03333109.

Recent advances in targeting calcitonin gene-related peptide for the treatment of menstrual migraine: A narrative review.

Menstrual migraine (MM) has a longer duration and higher drug resistance than non-perimenstrual migraine. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in the peripheral and central nervous systems throughout the trigeminovascular system. The CGRP/CGRP receptor axis plays an important role in sensory physiology and pharmacology. CGRP receptor antagonists and anti-CGRP monoclonal antibodies (mAbs) have shown consistent efficacy and tolerability in the prevention of chronic or episodic migraine and are now approved for clinical use. However, few studies have reported the use of these drugs in MM, and no specific treatment for MM has been approved. This review aimed to shed light on the recent advances in targeting calcitonin gene-related peptides for the treatment of menstrual migraines in PubMed. In this review, we first discuss the axis of the CGRP/CGRP receptor. We then discuss the role of CGRP receptor antagonists and anti-CGRP mAbs in MM treatment. Finally, we discuss the role of the combination of anti-CGRP mAbs and CGRP receptor antagonists in migraine treatment and the drugs that inhibit CGRP release. Altogether, the anti-CGRP mAbs or CGRP receptor antagonists showed good efficacy and safety in the treatment of MM.

Atogepant for the Prevention of Episodic Migraine in Adults: A Systematic Review and Meta-Analysis of Efficacy and Safety.

IntroductionThe inhibition of the calcitonin gene-related peptide (CGRP) pathway has attracted interest in pharmacological research on migraine. Atogepant is a potent, selective, orally available antagonist of the CGRP receptor approved as a preventive treatment of episodic migraine. This systematic review with meta-analysis aims to evaluate the efficacy and safety of atogepant for the prevention of episodic migraine in adult patients.MethodsRandomized, placebo-controlled, single or double-blinded trials were identified through a systematic literature search (December week 4, 2021). Main outcomes included the changes from baseline in monthly migraine days and the incidence of adverse events (AEs) and treatment withdrawal due to AEs. Mean difference (MD) and risk ratio (RR) with 95% confidence intervals (95% CIs) were estimated.ResultsTwo trials were included, overall enrolling 1550 patients. A total of 408 participants were randomized to placebo, 314 to atogepant 10 mg, 411 to atogepant 30 mg, and 417 to atogepant 60 mg once daily. The mean age of the patients was 41.0 years and 87.7% were women. The reduction in the mean number of migraine days from baseline across the 12-week treatment period was significantly greater among patients treated with atogepant at either the daily dose of 10 mg (MD − 1.16, 95% CI − 1.60 to − 0.73, p < 0.001), 30 mg (MD − 1.15, 95% CI − 1.54 to − 0.76, p < 0.001), or 60 mg (MD − 1.20, 95% CI − 2.18 to − 0.22, p = 0.016) than with placebo. There were no differences in the occurrence of AEs and drug withdrawal due to AEs between atogepant and placebo groups. Constipation was more commonly observed in patients treated with atogepant at 30 mg/day than placebo (RR 5.19, 95% CI 2.00–13.46; p = 0.001). Treatment with atogepant at the daily dose of 60 mg was associated with a higher risk of constipation (RR 4.92, 95% CI 1.89–12.79; p = 0.001) and nausea (RR 2.73, 95% CI 1.47–5.06; p = 0.001) than placebo.ConclusionAtogepant is an efficacious and overall well-tolerated treatment for the prevention of episodic migraine in adults.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40120-022-00370-8.

Fremanezumab in the prevention of high-frequency episodic and chronic migraine: a 12-week, multicenter, real-life, cohort study (the FRIEND study)

BackgroundFremanezumab has demonstrated to be effective, safe, and tolerated in the prevention of episodic or chronic migraine (CM) in randomized, placebo-controlled trials (RCTs). Real-life studies are needed to explore drug effects in unselected patients in routine circumstances and to provide higher generalizability results. This study explores the effectiveness, safety, and tolerability of fremanezumab in a real-life population of individuals affected by high-frequency episodic (HFEM: 8–14 days/month) or CM.MethodsThis is a 12-week multicenter, prospective, cohort, real-life study. We considered all consecutive patients affected by HFEM or CM visited at 9 Italian headache centers from 28/07/2020 to 11/11/2020. Eligible patients were given subcutaneous fremanezumab at the doses of 225 mg monthly or 675 mg quarterly, according to their preference. Primary study endpoints were the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients at weeks 9–12 compared to baseline. Secondary endpoints encompassed variation in monthly analgesic intake (MAI), Numerical Rating Scale (NRS), HIT-6 and MIDAS scores, and ≥ 50%, ≥ 75% and 100% responder rates at the same time intervals.ResultsSixty-seventh number migraine patients had received ≥ 1 subcutaneous fremanezumab dose and were considered for safety analysis, while 53 patients completed 12 weeks of treatment and were included also in the effectiveness analysis. Fremanezumab was effective in both HFEM and CM, inducing at week 12 a significant reduction in MMDs (-4.6, p < 0.05), MHDs (-9.4, p < 0.001), MAI (-5.7, p < 0.05; -11.1, p < 0.001), NRS (-3.1, p < 0.001; -2.5, p < 0.001), and MIDAS scores (-58.3, p < 0.05; -43.7; p < 0.001). HIT-6 was significantly reduced only in HFEM patients (-18.1, p < 0.001). Remission from CM to episodic migraine and from MO to no-MO occurred in 75% and 67.7% of the patients. The ≥ 50%, ≥ 75% and 100% responder rates at week 12 were 76.5%, 29.4% and 9.9% in HFEM and 58.3%, 25% and 0% in CM. Younger age emerged as a positive response predictor (OR = 0.91; 95% CI 0.85–0.98, p = 0.013). Treatment-emergent adverse events were uncommon (5.7%) and mild. No patient discontinued fremanezumab for any reason.ConclusionsFremanezumab seems more effective in real-life than in RCTs. Younger age emerges as a potential response predictor.

Migraine Prevention with Erenumab: Focus on Patient Selection, Perspectives and Outcomes.

Erenumab is a monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor suitable for episodic and chronic migraine prevention. Randomized clinical trials proved the superiority of erenumab to placebo in a strictly selected population, while real-world studies confirmed treatment efficacy in more severe forms of disease – most patients suffered from chronic migraine with medication overuse headache, had prior treatment failures, and long disease duration. According to guidelines, anti-CGRP pathway monoclonal antibodies should be reserved to patients who failed or have contraindication to several classes of preventive treatments. However, their ease of use, tolerability and efficacy make these monoclonal antibodies ideally suitable for most patients with migraine; cost-effectiveness needs to be considered when looking at expanding current prescription criteria. Also, data from open label extensions of randomized control trials confirmed sustained benefits of prolonged treatment up to 5 consecutive years without significant risk of adverse events. Further studies will provide insights on optimal treatment duration to achieve migraine remission and predictors of treatment response. In the present work, we aimed at reviewing design and results of the main studies on erenumab and discussing treatment use in the current migraine prevention scenario; we also summarized the main ongoing research projects and provided clinical perspectives for the future.

Experience with erenumab: Data from real clinical practice

IntroductionThe development of monoclonal antibodies against calcitonin gene-related peptide has represented a revolution in the treatment of migraine. Erenumab was the first of these drugs to be available in clinical practice in our setting. MethodsWe performed a prospective study of patients from real clinical practice, measuring efficacy (headache days per month and migraine days per month), safety, and disease impact; data were collected at the onset of treatment with erenumab and at 3, 6, 9, and 12 months. ResultsOur sample included 31 patients diagnosed with refractory migraine, presenting a mean of 18.5 headache days and 13.2 migraine days per month. A response rate of 50% was obtained in 58.6%, 65.2%, 69.2%, and 62.5% of patients at 3, 6, 9, and 12 months, respectively. According to Patient Global Impression of Change scale scores, 64.5% of patients rated their clinical improvement as good or excellent at 3 months, 65.2% at 6 months, 84.6% at 9 months, and 100% of cases at 12 months follow-up. A total of 45% of patients experienced mild adverse reactions, the most frequent being constipation. No severe adverse reactions were reported. ConclusionsErenumab is an effective and safe option for the prevention of episodic and chronic migraine. Our results are similar to those obtained in real-world studies; however, results require confirmation in larger numbers of patients.

Effectiveness and safety of erenumab and galcanezumab in the prevention of chronic and episodic migraine: A retrospective cohort study.

WHAT IS KNOWN AND OBJECTIVE?: Erenumab and galcanezumab have shown great results for migraine prevention. However, strict inclusion criteria, absence of concomitant medication and selective outcome report of clinical trials may sometimes be barely representative of the real-world daily practice. Therefore, this study was designed to evaluate effectiveness and safety of these two monoclonal antibodies targeting calcitonin gene-related peptide in real-world patients. METHODS: This observational, retrospective study evaluated the effectiveness and safety of erenumab 140mg and galcanezumab 120mg in 142 real-world patients who had previously not responded to three well-established pharmacological alternatives for migraine prevention. To do so, a combination of objective parameters (monthly headache days and acute migraine-specific medication days) and subjective measurements (Migraine Disability Assessment questionnaire, Headache Impact Test and Visual Analogue Scale), validated for clinical research in migraine, were assessed during clinical interview. RESULTS AND DISCUSSION: Findings here reported show that erenumab and galcanezumab reduced monthly headache days, acute migraine specific medication days per month, Headache Impact Test score, Migraine Disability Assessment Test score and Visual Analogue Scale score after 3 and 6 doses (p<0.01). Additionally, more than 25% of the patients enrolled in the study experienced a reduction by a half in monthly headache days, and more than 50% of the patients also reported a reduction by a half in the number of migraine specific medication days. Both treatments exhibited a great safety profile, rarely leading to discontinuation because of poor tolerance. WHAT IS NEW AND CONCLUSIONS?: Altogether, these results support previous real-life studies regarding effectiveness and safety and provide an interesting insight in how these preventive therapies are also effective in patients diagnosed with difficult to treat migraine who have previously failed, at least, three different drug classes stablished by current neurology guidelines for migraine prevention. Moreover, these data may suggest that erenumab and galcanezumab are able to not only diminish frequency, but also migraine intensity, and that it should be also considered as an effectiveness measure in line with other authors suggestion.

Efficacy and Tolerability of Erenumab for Prevention of Episodic Migraine in India.

Background:EMPOwER, a 12-week, double-blind (DB), randomized, placebo-controlled study evaluated the efficacy and safety of erenumab in adult patients with episodic migraine (EM) from Asia, the Middle East, and Latin America. This study analyzes the Indian experience for the use of erunumab for prevention of episodic migraine.Objective:The study aimed to evaluate the efficacy and tolerability of erenumab (70 mg and 140 mg) in EM patients from India.Methods:Randomized patients received monthly subcutaneous injections of placebo and erenumab 70 mg or 140 mg for 3 months. The primary endpoint was a change from the baseline in monthly migraine days (MMDs) at month 3. Other endpoints included achievement of ≥50%, ≥75%, and 100% reduction in MMD; a change in monthly acute migraine-specific medication treatment days; a change in patient-reported outcomes; and safety assessment.Results:Of the 539 patients screened, 351 patients were randomized (erenumab, 70 mg: n = 133 and 140 mg: n = 94; placebo: n = 124). The mean (±SD) age, disease duration, and MMD were 35.1 (±8.6) years, 6.77 (±6.01) years, and 7.82 (±2.89) days, respectively. The placebo-adjusted difference in mean MMD for erenumab 70 mg was -0.88 (95% CI, -2.16, 0.39; P = 0.174) days, and that for erenumab 140 mg was -1.01 (-2.42, 0.41; P = 0.164) days versus placebo. Secondary and exploratory endpoints demonstrated consistently better results in both erenumab dosage groups versus placebo. Treatment-emergent adverse events were comparable across groups (erenumab, 70 mg: 22.7% and 140 mg: 24.5%; placebo: 25.2%).Conclusion:Both doses of erenumab showed numerical improvement for efficacy endpoints and were well-tolerated in the Indian population. No new safety signals were reported.

Atogepant for the prevention of episodic migraine in adults.

Objective:Atogepant is a newly approved medication for the prevention of migraine. This review aims to discuss the efficacy, safety, cost, and place in therapy of atogepant.Methods:The authors performed a systematic search for sources, including articles, abstracts, and poster presentations. Queried databases were the National Institute of Health, US National Library of Medicine Clinical Trials, PubMed, European PMC, and the Cochrane Library. Search terms included atogepant, QULIPTA™, AGN-241689, MK-803, and N02CD07. Full-text, English language, randomized-controlled trials from 1 February 2012 to 1 February 2022 were included in the review. Additional relevant prescribing information, abstracts, and articles identified through the search were considered for inclusion in this review. A total of 193 database entries were evaluated for inclusion in this narrative review. Three articles representing two randomized controlled trials were reviewed.Results and conclusions:Atogepant, a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist, is a daily oral treatment for migraine prevention. In placebo-controlled clinical trials, atogepant decreased mean monthly migraine days (MMD) over 12 weeks in patients with episodic migraine. Major treatment-related adverse effects include nausea and constipation. Long-term placebo-controlled efficacy and safety studies, chronic migraine studies, and studies in patients that failed more than two classes of preventive therapies are still pending. Atogepant represents one of many novel therapies for the prevention of migraine. To date, no head-to-head comparisons of atogepant versus other agents indicated for migraine prevention have been published. Atogepant offers patients an alternative therapy to injectable or infusion monoclonal antibody treatments and offers an alternative to non-specific migraine medications that are associated with poor tolerability. Due to its high cost and narrower therapeutic indications, atogepant may be reserved for a small subset of migraineurs who prefer oral therapy.

Early Onset and Maintenance Effect of Galcanezumab in Japanese Patients with Episodic Migraine.

PurposeThis study aimed to extensively evaluate the onset and maintenance effect of galcanezumab compared with placebo for the prevention of episodic migraine in Japanese patients.Patients and MethodsThis was a post-hoc analysis of a Phase 2, multicenter, randomized, double-blind, placebo-controlled study conducted between December 2016 and January 2019 (ClinicalTrials.gov: NCT02959177). Patients aged between 18 and 65 years with episodic migraine were randomized to receive a monthly injection of galcanezumab (120 mg: N = 115, 240 mg: N = 114) or placebo (N = 230) for 6 months. Outcome measures included onset of effect at weekly and daily intervals—assessed by change from baseline in the number of migraine headache days and the proportion of patients with migraine headache—with galcanezumab versus placebo. To further confirm the onset and maintenance effect, the 50% response rate was also evaluated.ResultsThe mean change from baseline in weekly migraine headache days was significantly reduced with galcanezumab (–0.97 days) compared with placebo (–0.10 days) at week 1 (p ≤ 0.0001), which was maintained at all subsequent weeks up to week 4 (all p ≤ 0.0001 vs placebo). A significantly smaller proportion of galcanezumab-treated patients had migraine headache compared with placebo-treated patients at day 1 after the first injection (13.6% vs 31.4%, respectively; p ≤ 0.0001), which was also maintained at all subsequent days during the first week after the first injection. Furthermore, the 50% response rate was significantly higher with galcanezumab compared with placebo from week 1 through month 6.ConclusionThe onset of the migraine preventive effect of galcanezumab was rapid compared with placebo, starting from day 1 after the first injection in Japanese patients with episodic migraine. The effect was maintained during the first week and first month, and throughout 6 months of monthly injections of galcanezumab. Galcanezumab is a promising preventive treatment in Japanese patients with episodic migraine.

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs

BackgroundSeveral drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor.MethodsThe present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained.ResultsAlthough being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention.ConclusionsBalancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Percutaneous Interventional Strategies for Migraine Prevention: A Systematic Review and Practice Guideline.

To systematically evaluate the efficacy and effectiveness of percutaneous interventional treatments for prevention of migraine through a qualitative and (when possible) quantitative analysis. An expert panel was asked to develop recommendations for the multidisciplinary preventive treatment of migraine, including interventional strategies. The committee conducted a systematic review and (when evidence was sufficient) a meta-analytic review by using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) criteria and the modified Cochrane Risk of Bias analysis available in the Covidence data management program. Clinical questions addressed adults with migraine who should be offered prevention. Examined outcomes included headache days, acute medication use, and functional impairment. Acute management of migraine was outside the scope of this guideline. The committee screened 1,195 studies and assessed 352 by full text, yielding 16 randomized controlled trials that met the inclusion criteria. As informed by evidence related to the preselected outcomes, adverse event profile, cost, and values and preferences of patients, onabotulinumtoxinA received a strong recommendation for its use for chronic migraine prevention and a weak recommendation against its use for episodic migraine prevention. Greater occipital nerve blocks received a weak recommendation for their use for chronic migraine prevention. For greater occipital nerve block, steroid received a weak recommendation against its use vs the use of local anesthetic alone. Occipital nerve with supraorbital nerve blocks, sphenopalatine ganglion blocks, cervical spine percutaneous interventions, and implantable stimulation all received weak recommendations for their use for chronic migraine prevention. The committee found insufficient evidence to assess trigger point injections in migraine prevention and highly discouraged the use of intrathecal medication.

Long-term (48weeks) effectiveness, safety, and tolerability of erenumab in the prevention of high-frequency episodic and chronic migraine in a real world: Results of the EARLY 2 study.

To evaluate the long-term effectiveness, safety, and tolerability of erenumab in a real-world migraine population, looking for putative predictors of responsiveness. Erenumab proved to be effective, safe, and well tolerated in the prevention of episodic migraine (EM) and chronic migraine (CM) in long-term extension studies of double-blind, placebo-controlled trials in patients with no more than two (EM) or three (CM) prior preventive treatment failures. A 48-week, multicenter, longitudinal cohort real-life study was conducted at 15headache centers across eight Italian regions between December 20, 2018 and July 31, 2020. We considered all consecutive patients with high-frequency episodic migraine (HFEM) or CM aged 18-65years. Each patient was treated with erenumab 70mg, administered monthly. The dose was switched to 140mg in nonresponders and in responders who had become nonresponders for at least 4weeks. Change in monthly migraine days (MMDs) or monthly headache days (MHDs) at Weeks 45-48 compared with baseline was the primary efficacy endpoint. Secondary endpoints encompassed variation in monthly analgesic intake, achievement of a ≥50%, ≥75%, or 100% reduction in migraine or headache days, and any change in the Visual Analogue Scale (VAS) and Headache Impact Test-6 scores (HIT-6) during the same time interval. A total of 242 patients with migraine received at least one dose of erenumab 70mg and were considered for safety analysis, whereas 221 received a monthly erenumab dose for ≥48weeks and were included in the effectiveness and safety analysis set. All patients had previously been treated unsuccessfully with ≥3migraine-preventive medication classes. From baseline to Weeks 45-48, erenumab treatment reduced MMD by 4.3±5.3(mean±SD) in patients with HFEM, and MHD by 12.8±8.9 (mean±SD) in subjects with CM. VAS and HIT-6scores were decreased by 1.8±1.9 (mean±SD) and 12.3±11 (mean±SD) in HFEM, and by 3.0±2.2 (mean±SD) and 13.1±11.2 (mean±SD) in CM. Median monthly analgesic intake passed from 11.0 (interquartile range [IQR] 10.0-13.0) to 5 (IQR 2.0-8.0) in HFEM and from 20.0 (IQR 15.0-30.0) to 6.0 (IQR 3.8-10.0) in CM. The ≥50% responders were 56.1% (32/57) in HFEM and 75.6% (124/164) in CM; ≥75% responders were 31.6% (18/57) and 44.5% (73/164); and 100% responders were 8.8% (5/57) and 1.2% (2/164), respectively. At Week 48, 83.6% (137/164) of patients with CM had reverted to EM. Erenumab was safe and well tolerated. Responsiveness to erenumab was positively associated with cutaneous allodynia (OR: 5.44, 95% CI: 1.52-19.41; p=0.009) in HFEM. In patients with CM, ≥50% responsiveness was positively associated with male sex (OR: 2.99, 95% CI: 1.03-8.7; p=0.044) and baseline migraine frequency (OR: 1.12, 95% CI: 1.05-1.20; p=0.001) and negatively associated with psychiatric comorbidities (OR: 0.37, 95% CI: 0.15-0.87; p=0.023) and prior treatment failures (OR: 0.77, 95% CI: 0.64-0.92; p=0.004). Long-term (48-week) erenumab treatment provides sustained effectiveness, safety, and tolerability in real-life patients with HFEM or CM with ≥3 prior preventive treatment failures. The dose of 140mg was required in most patients along the study and should be taken into consideration as the starting dose. Allodynia (in HFEM), male sex, and baseline migraine frequency (in CM) might represent positive responsiveness predictors. Conversely, psychiatric comorbidities and multiple prior preventive treatment failures could be negative predictors in patients with CM.

Long-Term Effects of Self-Administered Transcranial Direct Current Stimulation in Episodic Migraine Prevention: Results of a Randomized Controlled Trial

Migraine is a multifactorial neurovascular disorder, which affects about 12% of the general population. In episodic migraine, the visual cortex revealed abnormal processing, most likely due to decreased preactivation level. Transcranial direct current stimulation (tDCS) is able to modify cortical excitability and might result in an alleviation of migraine occurrence if used repetitively. To test the hypothesis that self-administered anodal tDCS over the visual cortex significantly decreases the number of monthly migraine days in episodic migraine. The study was single-blind, randomized, and sham-controlled. Inclusion criteria were age 18-80 years and an ICHD-3 diagnosis of episodic migraine. Exclusion criteria were pregnancy, presence of a neurodegenerative disorder, a contraindication against MRI examinations, and less than two migraine days during the 28-day baseline period. Patients in whom the baseline period suggested chronic migraine were excluded. After baseline, participants applied daily either verum (anodal-1mA to 20 min) or sham tDCS (anodal-1mA to 30 sec) at Oz (reference Cz electrode) for 28 days. Headache diaries were used to record the number of migraine days at baseline, during the stimulation period, and during four subsequent 28-day periods. Twenty-eight patients were included; two were excluded after the baseline period because less than two migraine days occurred; three were excluded because their headache diaries suggested the diagnosis of chronic migraine. Twenty-three datasets were taken for further analysis. Compared to sham tDCS (n=12), verum tDCS (n=11) resulted in a lower number of migraine days (p=0.010) across all follow-up periods. We found no significant change in total headache days (p=0.165), anxiety (p=0.884), or depression scores (p=0.535). No serious adverse events occurred; minor side effects were similar in both groups. This study provides Class II evidence that self-administered anodal tDCS over the visual cortex in episodic migraine results in a significantly lower number of monthly migraine days. However, it has neither an immediate nor a long-term effect.

Efficacy and safety of fremanezumab for episodic migraine prevention: Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial in Japanese and Korean patients.

ObjectiveTo evaluate the efficacy and safety of two dosing regimens of fremanezumab in Japanese and Korean patients with episodic migraine.BackgroundEpisodic migraine, which accounts for more than 90% of migraine cases, is inadequately addressed by widely available preventive therapies. Fremanezumab, a monoclonal antibody that selectively targets the trigeminal sensory neuropeptide calcitonin gene‐related peptide involved in migraine pathogenesis, has demonstrated efficacy in international Phase 3 trials of patients with both chronic and episodic migraine.MethodsThis Phase 3 randomized, placebo‐controlled trial randomly assigned patients with episodic migraine to receive subcutaneous fremanezumab monthly (225 mg at baseline, week 4, and week 8), fremanezumab quarterly (675 mg at baseline and placebo at weeks 4 and 8), or matching placebo. The primary endpoint was the mean change from baseline in the monthly average number of migraine days during the 12‐week treatment period after the first dose.ResultsOf 357 patients enrolled (safety set, n = 356; full analysis set, n = 354), the least‐squares mean (±standard error) reductions in the average number of migraine days per month during 12 weeks were significantly greater with fremanezumab monthly (−4.0 ± 0.4, n = 121) and fremanezumab quarterly (−4.0 ± 0.4, n = 117) than with placebo (−1.0 ± 0.4, n = 116; p < 0.0001 for both comparisons). The proportion of patients reaching at least a 50% reduction in the monthly average number of migraine days during the 12‐week period after initial administration was also significantly improved with fremanezumab (fremanezumab monthly, 41.3%; fremanezumab quarterly, 45.3%; placebo, 11.2%; p < 0.0001 for both comparisons) as were other secondary endpoints (p < 0.001 for all comparisons between fremanezumab and placebo). Injection‐site reactions were more common in fremanezumab‐treated patients (fremanezumab monthly, 25.6%; fremanezumab quarterly, 29.7%; placebo, 21.4%).ConclusionFremanezumab prevents episodic migraine in Japanese and Korean patients to a similar extent than in previously reported populations with no new safety concerns.

Galcanezumab for the prevention of high frequency episodic and chronic migraine in real life in Italy: a multicenter prospective cohort study (the GARLIT study)

BackgroundThe clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting.MethodsThis multicenter prospective observational cohort study was conducted between November 2019 and January 2021 at 13 Italian headache centers. Consecutive adult HFEM and CM patients clinically eligible were enrolled and treated with galcanezumab subcutaneous injection 120 mg monthly with the first loading dose of 240 mg. The primary endpoint was the change in monthly migraine days (MMDs) in HFEM and monthly headache days (MHDs) in CM patients after 6 months of therapy (V6). Secondary endpoints were the Numerical Rating Scale (NRS), monthly painkiller intake (MPI), HIT-6 and MIDAS scores changes, ≥50% responder rates (RR), the conversion rate from CM to episodic migraine (EM) and Medication Overuse (MO) discontinuation.ResultsOne hundred sixty-three patients (80.5% female, 47.1 ± 11.7 years, 79.8% CM) were included. At V6, MMDs reduced by 8 days in HFEM and MHDs by 13 days in CM patients (both p < .001). NRS, MPI, HIT-6 and MIDAS scores significantly decreased (p < .001). Ten patients (6.1%) dropped out for inefficacy and classified as non-responders. Patients with ≥50%RRs, i.e. responders, were 76.5% in the HFEM and 63.5% in the CM group at V6. Among CM patients, the V6 responders presented a lower body mass index (p = .018) and had failed a lower number of preventive treatments (p = .013) than non-responders. At V6, 77.2% of CM patients converted to EM, and 82.0% ceased MO. Adverse events, none serious, were reported in up to 10.3% of patients during evaluation times.ConclusionsGalcanezumab in real life was safe, well tolerated and seemed more effective than in RCTs. Normal weight and a low number of failed preventives were positively associated with galcanezumab effectiveness in CM patients.Trial registrationClinicalTrials.govNCT04803513.

Long-term efficacy and safety during open-label erenumab treatment in Japanese patients with episodic migraine.

ObjectiveTo assess long‐term (up to 2 years) efficacy, tolerability, and safety of erenumab for the prevention of episodic migraine (EM) in Japanese patients.BackgroundPreviously published results from the double‐blind treatment phase (DBTP) of a phase 2 clinical study have demonstrated the efficacy and safety of erenumab in Japanese patients with EM.MethodsPatients completing the 24‐week placebo‐controlled DBTP could continue into the 76‐week open‐label treatment phase (OLTP), receiving erenumab 70 mg or 140 mg subcutaneously once monthly. The initial dose in the OLTP was erenumab 70 mg monthly, which was later changed to 140 mg. After study completion, the following were assessed: change from baseline in monthly migraine days (MMD), change from baseline in monthly acute migraine‐specific medication days (MSMD), percentage of patients achieving ≥50% and ≥75% reduction in MMD, change from baseline in the 6‐item Headache Impact Test (HIT‐6™) score, and safety (exposure‐adjusted patient‐incidence of adverse events [AEs], calculated as number of patients per 100 patient‐years).ResultsOf 475 patients enrolled in the DBTP, 459 (96.6%) continued in the OLTP. The mean (SD) MMD was 7.9 (2.3) at baseline with the overall change from baseline at week 100 of –2.9 (4.1) days. The monthly acute MSMD was 5.7 (2.8) at baseline with change from baseline at week 100 of −1.7 (3.7) days. The proportion of patients who achieved ≥50% and ≥75% reduction in MMD from baseline at week 100 was 177/398 (44.5%) and 94/398 (23.6%), respectively. The HIT‐6™ score was 58.4 (5.4) at baseline with a change of −6.4 (8.2) at week 100. The exposure‐adjusted patient‐incidence of AEs during the OLTP was 207.1/100 patient‐years for the combined erenumab group, similar to that observed for either erenumab (271.0/100 patient‐years) or placebo (257.3/100 patient‐years) during the DBTP, and no new safety signals were detected during the OLTP.ConclusionLong‐term erenumab treatment in Japanese patients with EM demonstrated sustained efficacy for up to 2 years, with a safety profile similar to previous studies, supporting erenumab as a potential new therapy for EM prevention in Japan.

Anti-CGRP monoclonal antibodies for migraine prevention: A systematic review and likelihood to help or harm analysis.

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway (anti-CGRP mAbs) have shown promising efficacy in randomised clinical trials for the prevention of episodic and chronic migraine, but no head-to-head comparisons with established treatments are available. We aimed to examine absolute differences in benefit-risk ratios between anti-CGRP mAbs, topiramate and propranolol for the prevention of episodic migraine and between anti-CGRP mAbs, topiramate and onabotulinumtoxinA for the prevention of chronic migraine using a likelihood to help versus harm analysis. The number of patients needed to be treated for a patient to achieve ≥ 50% reduction in migraine days (NNTB50%) was used as an effect size metric of efficacy. The number of patients needed to be treated for a patient to experience an adverse event that led to treatment discontinuation (NNTHD-AE) was used as a measure of risk. Likelihood to help versus harm values - which are the ratios of NNTH:NNTB - were calculated using data from phase 3 randomised clinical trials. All agents tested were more likely to be beneficial than harmful (likelihood to help versus harm > 1) with the exception of topiramate at 200 mg per day for the prevention of episodic migraine. Anti-CGRP mAbs in all tested doses had higher LHH values than propranolol or topiramate for episodic migraine and onabotulinumtoxinA or topiramate for chronic migraine prevention. Fremanezumab had the highest LHH ratio in episodic migraine and galcanezumab in chronic migraine. This analysis showed that anti-CGRP mAbs exhibit a more favourable benefit-risk ratio than established treatments for episodic and chronic migraine. Head-to-head studies are needed to confirm these results.

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***** Goadsby PJ, Dodick DW, Ailani J et al. Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial. Lancet Neurol 2020; 19(9): 727–737

Preventive Oral Treatment of Episodic Migraine: An Overview.

Migraine is a common primary headache disorder and Episodic migraine is characterized by the occurrence of up to 14 headache days in a month. The preventive treatment of migraine is useful in patients with frequent migraine attacks, impaired activities of daily living, failure of acute pain management, disabling aura and limitations in the use of acute treatment. It is aimed at reducing headache frequency and intensity, improve response to acute treatment of migraine and improve the quality of life. To analyze the evidence for the efficacy and tolerability of preventive oral drugs used in the management of episodic migraine. A narrative review of the references were reviewed by searching the literature for the articles published in PubMed in English language using all the following MeSH keywords "preventive treatment", "preventive oral treatment", AND "episodic migraine", "migraine". Out of articles identified in the search, 38 articles were reviewed for evidence and summarized. The various oral drugs used in the prevention of episodic migraine are antihypertensives (beta-blockers, calcium channel blockers and Angiotensin-converting enzyme inhibitors/Angiotensin receptor blockers), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), antiepileptic drugs (valproic acid, topiramate, lamotrigine) and other miscellaneous agents. HURT questionnaire and HALT 30 index are useful in assessing response to treatment in the follow up of migraine patients. An appropriately chosen oral drug is useful in the preventive treatment of episodic migraine. In patients, who fail to respond to the preventive treatment, it is essential to review the diagnosis of migraine, titrate the dosage and duration of preventive treatment and ensure patient compliance. In those patients who fail to respond to monotherapy, polytherapy is a useful option to be considered.