Baseline In Monthly Migraine Days Research Articles

A real-world prospective observational study of eptinezumab in Asian patients with migraine.

To evaluate the real-world effectiveness of eptinezumab for migraine prevention in Asian patients. Eptinezumab is a monoclonal antibody that targets calcitonin gene-related peptide (CGRP), a potent vasodilator with an important role in migraine pathophysiology. Although there is robust clinical evidence from pivotal Phase 3 placebo-controlled trials of the efficacy of eptinezumab for migraine prevention, there are limited data on the real-world effectiveness of eptinezumab in Asian patient cohorts. This was a non-interventional, prospective, multisite cohort study of adults with migraine (International Classification of Headache Disorders, 3rd edition criteria) in Singapore who were prescribed eptinezumab (100 mg at baseline and Month 3, administered intravenously) and were followed until Month 6. The primary endpoint was change from baseline in monthly migraine days (MMDs) at Month 3 and Month 6. Secondary endpoints were ≥30% and ≥50% responder rates, and change from baseline in the Headache Impact Test-6 (HIT-6), Migraine Disability Assessment (MIDAS), Migraine-Specific Quality of Life (MSQ), patient-identified most bothersome symptom (PI-MBS), acute medication use at Month 3 and Month 6, and safety. Enrolled patients (completed = 29/30) had on average 3.4 (SD 2.9) previous preventive treatments; 29/30 of the patients had trialed at least one previous preventive treatment without benefit. Most had previously trialed oral preventives (87%, 26/30) and anti-CGRP (70%, 21/30). Relative to baseline, mean MMDs decreased by 4.3 days (95% CI 2.1-6.4; p < 0.001) at Month 3 and 4.9 days (95% CI 2.1-7.7; p < 0.001) at Month 6. At Month 3 and Month 6, 14/30 (47%) and 15/29 (52%) of the patients were ≥30% responders, and 6/30 (20%) and 8/29 (28%) patients were ≥50% responders, respectively. The number of patients with severe life impairment based on the HIT-6 score (total score 60-78) decreased from 24/30 (80%) at baseline to 19/30 (63%) at Month 3 and 19/29 (66%) at Month 6. The mean MIDAS score decreased by 24.6 points (95% CI 2.82-46.38; p = 0.028) at Month 6, and the mean MSQ score increased by 12.2 points (95% CI 5.18-19.20; p = 0.001) at Month 3 and 13.6 points (95% CI 4.58-22.66; p = 0.004) at Month 6. Most patients reported improvement in the PI-MBS at Month 3 (73%, 22/30) and Month 6 (55%, 16/29). Acute medication use for headache relief decreased by 3.3 days/month (95% CI 1.0-5.6; p = 0.007) at Month 3 and 4.7 days/month (95% CI 1.7-7.7; p = 0.003) at Month 6. Treatment-emergent adverse events (TEAEs) were reported in 16/30 (54%) patients, mostly mild/moderate in severity. No serious TEAEs led to treatment discontinuation. Quarterly eptinezumab administration was effective and well-tolerated in Asian patients with chronic migraine.

Early Use of Erenumab vs Nonspecific Oral Migraine Preventives

Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. ClinicalTrials.gov Identifier: NCT03927144.

Assessing the Long-Term (48-Week) Effectiveness, Safety, and Tolerability of Fremanezumab in Migraine in Real Life: Insights from the Multicenter, Prospective, FRIEND3 Study.

Long-term (1-year) fremanezumab treatment proved to be effective, safe, and well tolerated in individuals with migraine and < 2 medication clusters in a randomized controlled trial (RCT). We aimed to assess real-world evidence (RWE), long-term effectiveness, tolerability, and safety of fremanezumab in people with high-frequency episodic migraine (HFEM) or chronic migraine (CM) with > 3 treatment failures and various comorbidities. A 48-week, prospective, multicenter (n = 26), cohort study assessed fremanezumab's effectiveness, safety, and tolerability in consecutive adults with HFEM or CM with > 3 treatment failures. Primary endpoint was variation from baseline in monthly migraine days (MMD) in HFEM and monthly headache days (MHD) in CM at weeks45-48. Secondary endpoints were changes in monthly analgesic medications, Numerical Rating Scale (NRS), Headache Impact Test (HIT-6), and the Migraine Disability Assessment Scale (MIDAS) scores and ≥ 50%, ≥ 75%, and 100% responder rates. Of 533 participants who had received ≥ 1 fremanezumab dose, 130 were treated for ≥ 48weeks and considered for effectiveness analysis. No participant missed any treatment dosage every other consecutive month during the 12-month period. fremanezumab significantly (p < 0.001) reduced both MMD (- 6.4) in HFEM and MHD (- 14.5) in CM. Secondary endpoints: a significant reduction (p < 0.001) was observed in monthly analgesic medications (HFEM -6.0; CM -16.5), NRS (HFEM -3.4; CM -3.4), HIT-6 (HFEM -16.9; CM -17.9) and MIDAS score (HFEM -50.4; CM -76.6). The ≥ 50%, ≥ 75%, and 100% response rates to fremanezumab were 75.5%, 36.7%, and 2% in HFEM and 71.6%, 44.4%, and 3.7% in CM. Corresponding response rates were 60.5%, 37.2%, and 2.3% in individuals with psychiatric comorbidities, 74.2%, 50%, and 4.8% in CM with medication overuse, and 60.9%, 39.1%, and 4.3% in CM with medication overuse and psychiatric comorbidities. Mild and transient treatment-emergent adverse events occurred in 7.8% of the participants. No subject discontinued the treatment for any reason. This RWE study documents that long-term fremanezumab treatment is highly effective and remarkably well tolerated in subjects with HFEM or CM with multiple (> 3) therapeutic failures, even in the presence of concomitant medication overuse, psychiatric comorbidities, or both. The effectiveness-to-tolerability ratio appears to be better in RWE than in RCTs.

Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18-80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were -1·9 (SE 0·4) with placebo and -4·2 (0·4) with atogepant (least squares mean difference -2·4, 95% CI -3·2 to -1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. Allergan (now AbbVie).

Eptinezumab Demonstrated Efficacy Regardless of Prior Preventive Migraine Treatment Failure Type: Post Hoc Analyses of the DELIVER Study.

In the DELIVER study, eptinezumab reduced monthly migraine days (MMDs) more than placebo in patients with 2-4 prior preventive migraine treatment failures. This post hoc analysis evaluated the efficacy of eptinezumab across the 24-week placebo-controlled period of the DELIVER study in subgroups defined by prior treatment failure type. DELIVER (NCT04418765) randomized adults with migraine to eptinezumab 100mg, 300mg, or placebo, administered intravenously every 12weeks. Changes from baseline in MMDs and percentages of patients with ≥ 50% reduction from baseline in MMDs (≥ 50% migraine responder rates [MRRs]) were summarized in subgroups of patients defined by prior treatment failure type. Subgroups were not mutually exclusive and included patients for whom topiramate, beta blockers (metoprolol, propranolol), amitriptyline, and/or flunarizine had failed. Across Weeks 1-12 in all subgroups, patients treated with eptinezumab experienced greater reductions from baseline in MMDs than those receiving placebo (reductions ranged from 4.5-5.5 vs 1.6-2.4, respectively), with larger reductions over Weeks 13-24. Similarly, ≥ 50% MRRs were consistently higher with eptinezumab than placebo and increased following a second infusion. In all subgroups, regardless of prior preventive treatment failure type, eptinezumab demonstrated greater reductions in MMDs and higher MRRs compared with placebo. ClinicalTrials.gov (Identifier: NCT04418765).

Real-world experience with calcitonin gene-related peptide-targeted antibodies for migraine prevention: a retrospective observational cohort study at two Japanese headache centers

BackgroundAlthough randomized controlled trials (RCTs) have shown that calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (CGRP mAbs) are an efficacious and safe therapeutic modality for migraine prevention, their clinical benefits have not been well validated in Japanese patients in the real-world setting. The present study aimed to evaluate the real-world efficacy and safety of galcanezumab, fremanezumab, and erenumab in Japanese patients with migraine.MethodsThis observational retrospective cohort study was conducted at two headache centers in Japan. Patients with migraine who had experienced treatment failure with at least one traditional oral migraine preventive agent were treated with a CGRP mAb de novo. The primary efficacy endpoints were the changes from baseline in monthly migraine days (MMDs) and Headache Impact Test-6 (HIT-6) score after 3 dosing intervals (V3). We explored whether demographic and clinical characteristics predicted therapeutic outcomes at V3.ResultsSixty-eight patients who completed three doses of a CGRP mAb (85.3% female [58/68], mean age: 46.2 ± 13.1 years) were included in the analysis. There were 19 patients with chronic migraine. The baseline MMDs were 13.4 ± 6.0. After 3 doses, the MMDs significantly decreased to 7.4 ± 5.5 (p < 0.0001), and the 50% response rate was 50.0%. HIT-6 score was significantly reduced from 66.7 ± 5.4 to 56.2 ± 8.7 after 3 doses (P = 0.0001). There was a positive correlation between the changes in MMDs and HIT-6 score from baseline after 2 doses (p = 0.0189). Those who achieved a ≥ 50% therapeutic response after the first and second doses were significantly more likely to do so at V3 (crude odds ratio: 3.474 [95% CI: 1.037 to 10.4], p = 0.0467). The most frequent adverse event was constipation (7.4%). None of the adverse events were serious, and there was no need for treatment discontinuation.ConclusionsThis real-world study demonstrated that CGRP mAbs conferred Japanese patients with efficacious and safe migraine prevention, and an initial positive therapeutic response was predictive of subsequent favorable outcomes. Concomitant measurement of MMDs and HIT-6 score was useful in evaluating the efficacy of CGRP mAbs in migraine prevention.

Long-term effectiveness of eptinezumab in patients with migraine and prior preventive treatment failures: extension of a randomized controlled trial

BackgroundEptinezumab demonstrated efficacy in adults with migraine and prior preventive treatment failures in the placebo-controlled phase of the DELIVER clinical trial; its long-term effectiveness in this population has not yet been reported. The objective of this study was to evaluate the long-term effectiveness of eptinezumab in a migraine patient population during the 48-week extension phase of DELIVER.MethodsDELIVER was conducted June 1, 2020 to September 15, 2022. 865 adults with migraine, with documented evidence of 2–4 prior preventive migraine treatment failures and with completion of the 24-week placebo-controlled period of DELIVER received eptinezumab (100 or 300 mg) during the dose-blinded extension, either continuing their randomized dose or, if originally receiving placebo, were randomized 1:1 to an eptinezumab dose (100 or 300 mg). A mixed model for repeated measures was used to evaluate changes from baseline in the number of monthly migraine days (MMDs).ResultsOf 865 patients entering the extension (eptinezumab 100 mg, n = 433; 300 mg, n = 432), 782 (90.4%) completed and 11 (1.3%) discontinued due to an adverse event. Eptinezumab was associated with early and sustained reductions in migraine frequency. Mean MMDs at baseline were approximately 14 days across groups. Mean (standard error) change from baseline in MMDs over the final dosing interval (weeks 61–72) was −6.4 (0.50) with placebo/eptinezumab 100 mg, –7.3 (0.49) with placebo/eptinezumab 300 mg, –7.1 (0.39) with eptinezumab 100 mg, and −7.0 (0.39) with eptinezumab 300 mg. During weeks 61–72, 63–70% of patients demonstrated ≥ 50% reduction in MMDs, and 36–45% demonstrated ≥ 75% reduction. Headache severity and acute medication use reductions, and patient-reported improvements in most bothersome symptom, disease status, quality of life, and work productivity, were observed. Adverse events were generally mild, transient, and similar in frequency/type to previous eptinezumab trials.ConclusionsThe long-term effectiveness and safety/tolerability of eptinezumab in patients with migraine and 2–4 prior preventive treatment failures was demonstrated by high completion rates and migraine-preventive benefits sustained for up to 18 months, implying that eptinezumab is a viable long-term treatment option for patients still seeking successful migraine treatments.Trial registrationClinicalTrials.gov (Identifier: NCT04418765; URL: https://www.clinicaltrials.gov/ct2/show/NCT04418765); EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25).Graphical

Very-low-calorie ketogenic diet vs hypocaloric balanced diet in the prevention of high-frequency episodic migraine: the EMIKETO randomized, controlled trial

BackgroundMigraine is the second world’s cause of disability. Among non-pharmacological treatments, nutritional intervention, particularly ketogenic diet, represents one of the most promising approaches.MethodsThis a prospective, single center, randomized, controlled study aimed at evaluating the efficacy of a very low-calorie ketogenic diet (VLCKD) compared to a hypocaloric balanced diet (HBD) in migraine prophylaxis in patients affected by high-frequency episodic migraine (HFEM) with a Body Mass Index (BMI) > 27 kg/m2. Fifty-seven patients were randomly assigned to a VLCKD (group 1) or HBD (group 2). Group 1 patients followed a VLCKD for 8 weeks, followed by a low calorie diet (LCD, weeks 9–12), and a HBD (weeks 13–24), whereas group 2 patients followed a HBD from week 0 to 24. Anthropometric indexes, urine and blood chemistry were assessed at enrollment, baseline, weeks 4, 8, 12, and 24. Migraine characteristics were evaluated at baseline, weeks 8, 12 and 24. Change in monthly migraine days (MMDs) at weeks 5–8 compared to baseline was the primary endpoint. Secondary endpoints encompassed changes in visual analogue scale (VAS), Headache Impact Test-6 (HIT-6) and Short Form Health Survey-36 (SF-36) scores. We also studied effects on circulating lymphocytes and markers of inflammation, changes in plasma aldosterone and renin levels before and after VLCKD or HBD treatment.ResultsReduction from baseline in MMDs was greater in VLCKD compared to HBD group at week 8 (p = 0.008), at week 12 (p = 0.007), when ketosis had been interrupted by carbohydrates reintroduction, and at week 24 (p = 0.042), when all patients were following the same dietary regimen. Quality of life scores (SF-36) were improved in VLCKD group at week 8 and 12, and were also improved in HBD group, but only at week 12. Weight-loss was significantly higher in VLCKD group at week 8 (p = 0.002) and week 12 (p = 0.020). At the end of the study weight loss was maintained in VLCKD group whereas a slight weight regain was observed in HBD group. Inflammatory indexes, namely C reactive protein (CRP), neutrophil to lymphocyte ratio (NLR) and total white blood cell count (WBC) were significantly reduced (p < 0.05) in VLCKD group at week 12. Aldosterone plasma level were significantly increased in both groups at week 8, particularly in VLCKD group. However, electrolytes and renin plasma levels were never altered throughout the study in both groups.ConclusionsVLCKD is more effective than HBD in reducing MMD in patients with HFEM and represents an effective prophylaxis in patients with overweight/obesity.Trial registration ClinicalTrials.gov identifier: NCT04360148.

Efficacy of Erenumab for Migraine Prevention in Japanese Patients with Episodic and Chronic Migraine: Results of a Post-Hoc Pooled Analysis.

Erenumab, a fully human monoclonal antibody against the calcitonin gene-related peptide receptor, is approved in Japan for the prevention of adult migraine. This post-hoc analysis evaluated the efficacy of erenumab in Japanese patients with low-frequency episodic migraine (LFEM) versus those with high-frequency episodic migraine (HFEM) and chronic migraine (CM). A pooled analysis of data from the 24-week double-blind treatment phases (DBTPs) of phase 2 and 3 studies evaluated the efficacy of once-monthly erenumab 70mg in Japanese patients. Patients were categorized into subgroups by monthly migraine days (MMD): LFEM and HFEM/CM. The main efficacy outcomes were change from baseline in MMD, acute migraine-specific medication treatment days (MSMD), and six-item Headache Impact Test (HIT-6™) scores. Patients with migraine (n=532) were included in the analysis (LFEM, n=215; HFEM, n=215; CM, n=102). Overall, mean age was 44years, 86.5% were female, and 63.3-88.2% had used or were taking migraine preventive treatment at baseline. Throughout the DBTP, the placebo-adjusted mean change from baseline in MMD, MSMD, and HIT-6 scores with erenumab was similar across LFEM and HFEM/CM subgroups. The proportion of patients achieving at least 50% or 75% reduction from baseline in MMD and MSMD was similar across migraine frequency groups. Reduction in MMD moderately correlated with improvement in HIT-6 scores in the LFEM and HFEM/CM groups. Furthermore, the proportion of patients converting from HFEM/CM to LFEM during the DBTP was higher in the erenumab group than in the placebo. In Japanese patients with different migraine frequencies, erenumab treatment resulted in significant improvements in MMD, MSMD, and headache impact. This pooled analysis of data from phase 2 and 3 studies increases confidence that erenumab is efficacious in patients with high MMD, which is associated with increased disability.

Long-term efficacy and safety of erenumab in Japanese patients with episodic and chronic migraine: results from a 28-week open-label treatment period of a randomised trial

ObjectivesTo evaluate the 1-year efficacy and safety of once-monthly erenumab 70 mg following a 24-week double-blind treatment period (DBTP) of a phase III randomised study of Japanese patients with episodic...

Comparison of indirect treatment methods in migraine prevention to address differences in mode of administration.

Aim: Indirect treatment comparisons (ITCs) are anchored on a placebo comparator, and the placebo response may vary according to drug administration route. Migraine preventive treatment studies were used to evaluate ITCs and determine whether mode of administration influences placebo response and the overall study findings. Materials & methods: Change from baseline in monthly migraine days produced by monoclonal antibody treatments (subcutaneous, intravenous) was compared using fixed-effects Bayesian network meta-analysis (NMA), network meta-regression (NMR), and unanchored simulated treatment comparison (STC). Results: NMA and NMR provide mixed, rarely differentiated results between treatments, whereas unanchored STC strongly favors eptinezumab over other preventive treatments. Conclusion: Further investigations are needed to determine which ITC best reflects the impact of mode of administration on placebo.

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Responder Rates With Eptinezumab Over 24 Weeks in Patients With Prior Migraine Preventive Treatment Failures (S47.007)

Adding eptinezumab to brief patient education to treat chronic migraine and medication-overuse headache: Protocol for RESOLUTION-A phase 4, multinational, randomized, double-blind, placebo-controlled study.

Migraine is a highly prevalent and disabling neurological disease. Excessive use of acute medications can lead to medication-overuse headache (MOH), occurring when a patient experiences an increasing number of headache and migraine days, despite taking greater amounts of acute medication. To treat MOH, a preventive migraine treatment and/or withdrawal of the overused medication(s) are advised. Brief Educational Intervention (BEI) has been shown to be an effective tool with promising results for MOH. Here, we report the design of a clinical trial that aims to evaluate the efficacy of eptinezumab, an anti-calcitonin gene-related peptide preventive migraine treatment, as an add-on to BEI for treatment of MOH in those with chronic migraine. RESOLUTION will be a phase 4, multi-national, randomized, double-blind, placebo-controlled study. This study will enroll approximately 570 participants with dual diagnoses of chronic migraine and MOH. Eligible patients will be randomly allocated to one of two treatment groups, BEI and eptinezumab (100 mg; n = 285) or BEI and placebo (n = 285), in a 1:1 ratio. The primary endpoint is the change from baseline in monthly migraine days over weeks 1-4. Secondary and exploratory endpoints will assess monthly migraine days over weeks 1-12, MOH remission, transition from chronic to episodic migraine, health-related quality of life, work productivity, and the safety and tolerability of eptinezumab in this patient population. This study will be conducted in accordance with good clinical practice. All patients will be fully informed about the study, including the risks and benefits of participation, and all participants will provide informed consent for participation in the trial and dissemination of results.

A phase 3, randomised, placebo-controlled study of erenumab for the prevention of chronic migraine in patients from Asia: the DRAGON study

AbstactBackgroundDRAGON was a phase 3, randomised, double-blind, placebo-controlled study which evaluated the efficacy and safety of erenumab in patients with chronic migraine (CM) from Asia not adequately represented in the global pivotal CM study.MethodsDRAGON study was conducted across 9 Asian countries or regions including mainland China, India, the Republic of Korea, Malaysia, the Philippines, Singapore, Taiwan, Thailand, and Vietnam. Patients (N = 557) with CM (aged 18–65 years) were randomised (1:1) to receive once-monthly subcutaneous erenumab 70 mg or matching placebo for 12 weeks. The primary endpoint was the change in monthly migraine days (MMD) from baseline to the last 4 weeks of the 12-week double-blind treatment phase (DBTP). Secondary endpoints included achievement of ≥ 50% reduction in MMD, change in monthly acute headache medication days, modified migraine disability assessment (mMIDAS), and safety. Study was powered for the primary endpoint of change from baseline in MMD.ResultsAt baseline, the mean (SD) age was 41.7 (± 10.9) years, and 81.5% (n = 454) patients were women. The mean migraine duration was 18.0 (± 11.6) years, and the mean MMD was 19.2 (± 5.4). 97.8% (n = 545) randomised patients completed the DBTP. Overall, demographics and baseline characteristics were balanced between the erenumab and placebo groups except for a slightly higher proportion of women in the placebo group. At Week 12, the adjusted mean change from baseline in MMD was − 8.2 days for erenumab and − 6.6 days for placebo, with a statistically significant difference for erenumab versus placebo (adjusted mean difference vs placebo: − 1.57 [95%CI: − 2.83, − 0.30]; P = 0.015). A greater proportion of patients treated with erenumab achieved ≥ 50% reduction in MMD versus placebo (47.0% vs 36.7%, P = 0.014). At Week 12, greater reductions in monthly acute headache medication days (− 5.34 vs − 4.66) and mMIDAS scores (− 14.67 vs − 12.93) were observed in patients treated with erenumab versus placebo. Safety and tolerability profile of erenumab was comparable to placebo, except the incidence of constipation (8.6% for erenumab vs 3.2% for placebo).ConclusionDRAGON study demonstrated the efficacy and safety of erenumab 70 mg in patients with CM from Asia. No new safety signals were observed during the DBTP compared with the previous trials.Trial registrationNCT03867201

Erenumab versus topiramate: post hoc efficacy analysis from the HER-MES study

ObjectiveHER-MES was the first head-to-head, phase 4 trial to assess the tolerability and effectiveness of erenumab against standard of care treatment (topiramate). This post hoc analysis compared the efficacy of erenumab with topiramate in patients who completed the trial on study medication.MethodsPost hoc sensitivity analysis was performed using the full analysis set. Outcomes assessed included the proportion of patients with a ≥50% reduction in monthly migraine days (MMD) from baseline (50% responder rate), over the last 3 months (months 4, 5, and 6) of the double-blind treatment phase (DBTP), the 50% responder rate during the first month of the DBTP, and change from baseline in MMD during the DBTP. Multiple imputation was done for efficacy values of patients who discontinued study treatment.ResultsPatients (N = 777) were randomly assigned (1:1) to either 70 or 140 mg/month erenumab (N = 389) or 50–100 mg/day topiramate (N = 388). Of these, 334 patients (85.9%) receiving erenumab, and 231 patients (59.5%) receiving topiramate completed the DBTP on study medication. Patients on study medication until the end of the DBTP received a mean dose of 119 mg/month for erenumab and 92 mg/day for topiramate. At month 1, a significantly greater proportion of patients receiving erenumab (39.2%) reported ≥50% reduction in MMD from baseline compared with those receiving topiramate (24.0%; p < 0.001). In the last 3 months, a significantly larger proportion of patients receiving erenumab (60.3%) achieved ≥50% reduction in MMD from baseline compared with those receiving topiramate (43.3%; p < 0.001). Patients receiving erenumab demonstrated significantly greater reductions in MMD during the last 3 months from baseline versus those receiving topiramate (− 6.13 vs − 4.90; 95% CI: − 1.87 to − 0.61; p < 0.001).ConclusionsThis post hoc analysis demonstrated significantly superior efficacy of erenumab versus topiramate in achieving a ≥50% reduction in MMD with an early onset of efficacy.Trial registrationClinicalTrials.gov NCT03828539.

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.

Long-term efficacy and safety of erenumab in patients with chronic migraine in whom prior preventive treatments had failed: A subgroup analysis.

ObjectiveTo assess the long‐term efficacy and safety of erenumab in the subgroup of patients with chronic migraine (CM) in whom prior preventive treatments had failed (TF) (≥1, ≥2, and ≥3 TF medication categories) and never failed (preventive naïve or prior preventive treatments had not failed), using the data from a 52‐week, open‐label treatment period (OLTP) of the parent study.BackgroundErenumab is a fully human monoclonal antibody that selectively binds to and inhibits the canonical calcitonin gene‐related peptide receptor. There are limited long‐term data evaluating the efficacy and safety of erenumab in patients with CM in whom prior preventive treatments had failed.MethodsPatients who had completed the 12‐week double‐blind treatment period (DBTP) in the parent study were eligible to participate in the 52‐week OLTP, during which they received erenumab every 4 weeks. The TF subgroups (≥1, ≥2, and ≥3 TF medication categories) were not mutually exclusive; patients in whom prior preventive treatments from ≥3 medication categories had failed were also counted in the ≥2 and ≥1 medication categories. Endpoints included monthly migraine days (MMD), monthly acute migraine‐specific medication days (MSMD), achievement of ≥50%, ≥75%, and 100% reduction from baseline in MMD, and exposure‐adjusted patient incidence rates of adverse events (AEs; per 100 patient‐years).ResultsErenumab treatment provided sustained mean reductions in MMD and MSMD relative to the parent study baseline throughout the 52 weeks of the OLTP across all TF subgroups. At Week 52, the mean MMD change was −8.6 (SD 6.6) (baseline: 18.4 [SD 4.5] days) in the ≥1 TF subgroup. A post hoc completer analysis (52 weeks [OLTP] erenumab) showed that compared with erenumab 70 mg, the 140 mg dose was associated with numerically greater reductions in the mean MMD (Week 40: −8.6 and −7.2 days; Week 52: −9.7 and −7.9 days [≥1 TF subgroup]) and a higher proportion of patients achieved ≥50%, ≥75%, and 100% response thresholds across all subgroups at Weeks 40 and 52. Overall the exposure‐adjusted patient incidence rates of AEs did not increase during the OLTP versus the DBTP (≥1 TF subgroup: 141.9/100 versus 317.9/100 patient‐years), and no new safety signals occurred.ConclusionThe long‐term treatment with erenumab was well tolerated and showed sustained efficacy in patients with CM in whom prior preventive treatments had failed, with numerically greater treatment effects for 140 mg versus 70 mg.

Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2.

BackgroundThis post hoc subgroup analysis evaluated the efficacy and safety of eptinezumab for migraine prevention in patients with migraine and self-reported aura.MethodsPROMISE-1 (NCT02559895; episodic migraine) and PROMISE-2 (NCT02974153; chronic migraine) were randomized, double-blind, placebo-controlled trials that evaluated eptinezumab for migraine prevention. In both studies, the primary outcome was the mean change from baseline in monthly migraine days over Weeks 1–12. Patients in this analysis included those who self-reported migraine with aura at screening.ResultsOf patients with episodic migraine, ∼75% reported a history of aura at screening; of patients with chronic migraine, ∼35% reported a history of aura. Changes in monthly migraine days over Weeks 1–12 were –4.0 (100 mg) and –4.2 (300 mg) with eptinezumab versus –3.1 with placebo in patients with episodic migraine with aura, and were –7.1 (100 mg) and –7.6 (300 mg) with eptinezumab versus –6.0 with placebo in patients with chronic migraine with aura. Treatment-emergent adverse events were reported by 56.0% (100 mg), 57.4% (300 mg), and 55.4% (placebo) of patients.ConclusionsThe preventive migraine efficacy of eptinezumab in patients in the PROMISE studies who self-reported aura was comparable to the overall study populations, demonstrating a similarly favorable safety and tolerability profile.Trial registration: ClinicalTrials.gov Identifiers: NCT02559895 and NCT02974153

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.

Impact of age and sex on the efficacy of fremanezumab in patients with difficult-to-treat migraine: results of the randomized, placebo-controlled, phase 3b FOCUS study

BackgroundMigraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex.MethodsIn the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups.ResultsThe modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.6 days; placebo, − 0.3 days; P < 0.001; female: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.9 days; placebo, − 0.6 days; P < 0.001). Fremanezumab also reduced monthly headache days of at least moderate severity, monthly days of acute medication use, and improved Migraine Disability Assessment scores across subgroups.ConclusionsThese results demonstrate the efficacy of fremanezumab in patients with difficult-to-treat migraine for reducing migraine and headache days, acute medication use, and disability, regardless of age or sex.Trial registrationClinicalTrials.gov Identifier NCT03308968 (FOCUS), registered October 13, 2017.