Change In Monthly Migraine Days Research Articles

Efficacy and Safety of Monoclonal Antibody Against Calcitonin Gene-Related Peptide or Its Receptor for Migraine: A Systematic Review and Network Meta-analysis.

Background: The optimal monoclonal antibody against calcitonin gene-related peptide (CGRP) for adult patients with migraine has yet to be determined. Therefore, we aimed to compare the effectiveness of different monoclonal antibodies against CGRP or its receptor for adult patients with migraine through a network meta-analysis of randomized controlled trials. Methods: We systematically searched the MEDILNE, Embase, ClinicalTrials.gov, and Cochrane Library databases for relevant publications from inception until October 30, 2020. Only randomized clinical trials of adults with migraine that assessed any calcitonin gene-related peptide monoclonal antibody and reported clinical outcomes were included. The primary outcomes were changes in monthly migraine days and treatment-emergent adverse events Results: We initially retrieved 2,070 publications, and ultimately, 18 randomized clinical trials totaling 8,926 patients were included. In terms of efficacy, eptinezumab (MD −1.43, 95% CrI −2.59 to −0.36), erenumab (MD −1.61, 95% CrI −2.40 to −0.84), fremanezumab (MD −2.19, 95% CrI −3.15 to −1.25), and galcanezumab (MD −2.10, 95% CrI −2.76 to −1.45) significantly reduced MMDs compared with placebo. In terms of safety, only galcanezumab increased the incidences of TEAEs (RR 1.11, 95% CrI 1.01–1.22) and serious adverse events (RR 2.95, 95% CrI 1.41–6.87) compared with placebo. Conclusion: Most drugs performed similarly and were superior to placebo in most of our analyses. Further head-to-head research on different types of CGRP monoclonal antibodies is necessary to validate the present findings.

Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial.

Background and purposeAlthough erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long‐term therapy.MethodsThis study was an open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially received open‐label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine‐specific medication (AMSM) days, and health‐related quality of life.ResultsOf 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open‐label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was −5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was −4.4 (0.3) days at the end of 5 years. Patient‐reported outcomes indicated stable improvements in disability, headache impact, and migraine‐specific quality of life. Exposure‐adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient‐years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient‐years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure.ConclusionsTreatment with erenumab was associated with reductions in migraine frequency and improvements in health‐related quality of life that were maintained for at least 5 years. No new safety signals were observed.

Early outcomes of migraine after erenumab discontinuation: data from a real-life setting.

Monoclonal antibodies targeting the calcitonin gene-related peptide, including erenumab, are migraine-specific preventive treatments, whose long-term effectiveness has still to be evaluated in real-life settings. We assessed early outcomes of erenumab discontinuation after a 52-week treatment in patients with a continuous positive response to the drug. We evaluated the early outcomes after treatment completion in migraineurs from a real-life multicenter register. All patients received monthly erenumab for 52weeks and attended a 8-week follow-up after treatment completion. Primary outcomes were responder rates and changes in monthly migraine days (MMDs), acute medications days (AMDs), and pain intensity on a Numerical Rating Scale (NRS score) during weeks 1-4 after erenumab treatment completion. The 32 included patients reported a decrease in MMDs, AMDs, and NRS score during the last 4weeks of treatment compared with baseline (P<0.001). During weeks 1-4 after treatment completion, all the outcome measures increased compared with the last 4weeks of treatment (P < 0.001) despite staying lower than baseline (MMDs and AMDs P < 0.001, NRS score P = 0.005). Over the same time frame, 18 (56%) patients maintained a ≥ 50% reduction from baseline in MMDs. At week 4 after treatment completion, 10 (31%) patients restarted treatment due to disease rebound to baseline levels. More than half patients had an early disease worsening, while the remaining patients maintained their responder status during weeks 1-4 after treatment completion. Further studies might identify predictors of prolonged response to erenumab and define the optimal treatment duration according to patients' characteristics.

Effectiveness and Acceptability of Noninvasive Brain and Nerve Stimulation Techniques for Migraine Prophylaxis: A Network Meta-Analysis of Randomized Controlled Trials

Background: Current pharmacologic prophylactic strategies for migraine have exhibited limited efficacy, with response rates as low as 40%–50%. In addition to the limited efficacy, the acceptability of those pharmacologic prophylactic strategies were unacceptable. Although noninvasive brain/nerve stimulation strategies may be effective, the evidence has been inconsistent. The aim of this network meta-analysis (NMA) was to compare strategies of noninvasive brain/nerve stimulation for migraine prophylaxis with respect to their effectiveness and acceptability. Methods: The PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, Web of Science, and ClinicalTrials.gov databases were searched for randomized controlled trials (RCTs). Patients with diagnosis of migraine, either episodic migraine or chronic migraine, were included. The primary outcome was the changes in monthly migraine days and response rate, and the acceptability was defined as the drop-out rate. All NMA procedures were conducted under the frequentist model. Findings: Nineteen randomized controlled trials were included (N=1493; mean age=38.2 years; 82.0% women). We determined that the high frequency repetitive transcranial magnetic stimulation (rTMS) over C3 yielded the most decreased monthly migraine days among all the interventions [mean difference=-8.70 days, 95% confidence intervals (95%CIs): -14.45 to -2.95 compared to sham/control groups]. In addition, high-frequency (100 Hz) transcutaneous occipital nerve stimulation (tONS) over the Oz provided the highest response rate in migraine prophylaxis [rate ratio (RR)=9.00, 95%CIs: 1.24 to 65.16 compared to sham/control groups]. Only alternative frequency (2/100 Hz) tONS over the Oz (RR=0.36, 95%CIs: 0.16 to 0.82) yielded a significantly lower drop-out rate than the sham/control groups did. Interpretation: The current study provided a new direction for the design of more methodologically robust and larger RCTs based on the findings of the potentially beneficial effect on migraine prophylaxis in participants with migraine by different noninvasive brain/nerve stimulation, especially the application of rTMS and tONS. Funding Information: None. Declaration of Interests: The authors report no financial interests or potential conflicts of interest.

Open Label Prospective Experience of Supplementation with a Fixed Combination of Magnesium, Vitamin B2, Feverfew, Andrographis Paniculata and Coenzyme Q10 for Episodic Migraine Prophylaxis.

Background: To investigate the efficacy and safety of supplementation with a fixed combination of magnesium, vitamin B2, feverfew, andrographis paniculata and coenzyme Q10 in episodic migraine (EM) prevention. Methods: A pilot, single-arm, open-label study was conducted. After a one-month baseline period, the above-described supplementation was introduced in 113 EM Greek patients, who were prospectively followed-up for three months. The primary endpoint was the change in monthly migraine days between baseline period (BSL) and the third month of supplementation (T3). Secondary endpoints included changes in mean intensity of migraine and in days with use of acute migraine medications. Changes in scores of Migraine Disability Assessment questionnaire (MIDAS), Headache Impact Test-6 (HIT-6), Migraine Therapy Assessment questionnaire (MTAQ), Migraine-Specific Quality-of-life questionnaire (MSQ-QOL), Hospital Anxiety and Depression Scale (HADS) were also evaluated. Those with ≥50% reduction in monthly migraine days at T3, compared to BSL were considered supplementation-responders. Results: The mean number of migraine days was significantly decreased between BSL and T3 (9.4 ± 3.7 vs. 6.1 ± 3.5; p < 0.001). Likewise, days with peak headache intensity of >4/10 (5.7 ± 3.4 vs. 4.9 ± 3.1; p < 0.001) as well as days using acute headache medications per month (8.9 ± 3.6 vs. 5.7 ± 3.4; p < 0.001) were significantly reduced. At T3, 64 patients (56.6%) were classified as responders. The beneficial effect of supplementation was also associated with significant changes in HIT-6, MIDAS, MTAQ and MSQ-QOL scores. There were no safety concerns. Conclusions: The supplementation we have tested appears to be an effective and well-tolerated preventive approach against EM. A randomized, placebo-controlled study is needed to confirm our results.

Erenumab in the prevention of high-frequency episodic and chronic migraine: Erenumab in Real Life in Italy (EARLY), the first Italian multicenter, prospective real-life study.

To assess the effectiveness, safety, and tolerability of erenumab in a real-life migraine population, while trying to identify responsiveness predictors. Erenumab is a fully human Ig-2 monoclonal antibody blocking the calcitonin gene-related peptide receptor, indicated for migraine prophylaxis. Phase II and III trials demonstrated that erenumab is effective, safe, and well tolerated in the prevention of episodic and chronic migraine (CM), showing an early onset of action. This is a multicenter, prospective, cohort, and real-life study. We considered for enrolment all consecutive patients aged 18-65 affected by high-frequency episodic migraine (HFEM) or CM, with or without medication overuse, visited at nine Italian Headache Centers from December 20, 2018 to September 30, 2019. Each patient was treated with erenumab 70mg, administered subcutaneously every 4weeks. Treatment duration was planned to last from 6 to 12months, depending on the patient's response. The primary endpoint was the change in monthly migraine days (MMDs) at weeks 9-12 compared to baseline. Secondary endpoints included changes in monthly analgesics intake, ≥50%, ≥75%, and 100% responder rates and any variation in the Visual Analog Scale (VAS) and Headache Impact Test scores (HIT). In total, 372 migraine patients were treated with at least one dose of erenumab 70mg. At weeks 9-12, erenumab decreased MMDs by 4.5±4.1days (mean±SD) in patients with HFEM and by 9.3±9.1 (mean±SD) days in those with CM compared to baseline. At weeks 9-12 VAS score was reduced by 1.9±1.9 (mean±SD), HIT score by 10.7±8.8 (mean±SD), and median monthly analgesics intake passed from 12.0 (interquartile range [IQR] 10.0-14.0) to 5.0 (IQR 3.0-7.0) in HFEM. In CM patients, VAS was reduced by 1.7±2.0 (mean±SD), HIT by 9.7±10.4 (mean±SD), and median monthly analgesics intake passed from 20.0 (IQR 15.0-30.0) to 8.0 (IQR 5.0-15.0). At week 12, ≥50% responders were 60/101 (59.4%) for HFEM and 146/263 (55.5%) for CM, ≥75% responders were 17/101 (16.8%) and 59/263 (22.4%) and 100% responders 1/101 (1.0%) and 3/263 (1.1%), respectively. Erenumab responsiveness in HFEM was positively associated with unilateral pain localization (OR: 3.03, 95% CI: 1.24-7.40; p=0.015), whereas in CM responsiveness was positively associated with and baseline migraine frequency (OR: 1.06, 95% CI:1.02-1.11; p=0.031), dopaminergic symptoms (OR: 2.01, 95% CI: 1.14-3.52; p=0.015), and negatively associated with psychiatric comorbidities (OR: 0.43, 95% CI: 0.20-0.93; p=0.003). Erenumab 70mg is effective, safe, and well tolerated in real life. Easily obtainable clinical features might be of help in predicting patient's responsiveness.

The Spectrum of Response to Erenumab in Patients With Episodic Migraine and Subgroup Analysis of Patients Achieving ≥50%, ≥75%, and 100% Response.

ObjectiveTo assess the efficacy of erenumab at the ≥50%, ≥75%, and 100% reduction in monthly migraine days (MMD) response thresholds, using data from the 6‐month double‐blind treatment phase (DBTP) of the Study to Evaluate the Efficacy and Safety of Erenumab in Migraine Prevention (STRIVE) pivotal clinical trial.MethodsEnrolled patients with episodic migraine (EM; ≥4 MMD and <15 monthly headache days) were randomized (1:1:1) to erenumab 70 mg (n = 312), erenumab 140 mg (n = 318), or placebo (n = 316) once monthly. We determined the proportions of patients with ≥50%, ≥75% and 100% reduction in MMD over the last 3 months of the STRIVE DBTP (months 4 through 6) and conducted post hoc analyses to contextualize the treatment benefit in patient subgroups achieving, and not achieving, these response thresholds. Outcome measures included changes in MMD, acute migraine‐specific medication days (MSMD), and patient‐reported outcomes.ResultsThe proportions of patients with a reduction in MMD from baseline were greater for erenumab than for placebo at all response thresholds. As previously reported for the ≥50% response threshold, 135/312 (43.3%) of patients on erenumab 70 mg and 159/318 (50.0%) on erenumab 140 mg responded, vs 84/316 (26.6%) for placebo. At months 4 through 6, 65/312 (20.8%) and 70/318 (22.0%) of those on erenumab 70 mg and erenumab 140 mg, respectively, achieved ≥75% reductions vs 25/316 (7.9%) on placebo. A reduction of 100% response, which required no migraine days over 3 consecutive months based on observed data, was achieved by 10/312 (3.2%) of patients treated with erenumab 70 mg and 16/318 (5.0%) for erenumab 140 mg, vs 9/316 (2.8%) for placebo. At all response thresholds, responders achieved numerically greater reductions in mean MMD and MSMD, and greater improvements in disability than did the overall population; importantly, these remarkable responses were noted early. Meanwhile, 60/312 (19.2%) and 53/318 (16.7%) patients on erenumab 70 and 140 mg, respectively, had no reduction in MMD from baseline in months 4 through 6, compared with 104/316 (32.9%) patients on placebo.ConclusionsThe responses at the ≥50%, ≥75%, and 100% thresholds provide context for establishing realistic patient and physician expectations regarding the magnitude of treatment benefit that may be achieved by patients with EM responding to erenumab (STRIVE, NCT02456740).

A Head-to-Head Comparison of Percutaneous Mastoid Electrical Stimulator and Supraorbital Transcutaneous Stimulator in the Prevention of Migraine: A Prospective, Randomized Controlled Study

This prospective, randomized, multicenter head-to-head outcome study was performed to compare the efficacy and safety of Percutaneous Mastoid Electrical Stimulator (PMES) and Supraorbital Transcutaneous Stimulator (STS) in migraine prevention. This was a prospective, randomized, head-to-head outcome study that involved three medical centers. After a one-month run-in, episodic patients with at least two migraine attacks/month were randomized to receive PMES daily for 45 min or STS daily for 20 min for three months. The primary outcomes were change in monthly migraine days and the 50% response rate. A total of 90 patients were included in this study. We observed statistically significant reduction of migraine days in the third month treatment both in the PMES group and STS group. The difference between the two groups was not significant (60.5% vs. 53.8%, p = 0.88). Of note, 77.8% patients in the PMES group and 62.2% patients in the STS group had a ≥50% reduction of migraine days in the third month (p = 0.070). The change in monthly migraine days, monthly migraine attacks, severity of migraine days, accompanying symptoms during migraine and monthly acute anti-migraine drug intake were not significantly different between the two groups. The change of Headache Impact Test-6 (HIT-6) from run-in to the third-month treatment in the STS group was more remarkable than that in the PMES group (36.5% vs. 25.6%, p = 0.041). The occurrence of discomfort paresthesia was higher in the STS group (13.3% vs. 0%, p = 0.026). PMES and STS treatment were both effective in migraine prevention. The safety and efficacy of PMES and STS were comparable.

Erenumab in Chronic Migraine Patients Who Previously Failed Five First-Line Oral Prophylactics and OnabotulinumtoxinA: A Dual-Center Retrospective Observational Study.

Background: German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA).Methods: We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period.Results: Erenumab (starting dose 70 mg) led to a reduction of −3.7 (95% CI 2.4–5.1) monthly headache days after the first treatment and −4.7 (95% CI 2.9–6.5) after three treatment cycles (p < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9–12. Only 4.3% of the patients terminated erenumab treatment due to side effects.Conclusion: In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.

Comparison of 3 Treatment Strategies for Medication Overuse Headache

Medication overuse headache (MOH) is a disabling, globally prevalent disorder representing a well-known and debated clinical problem. Evidence for the most effective treatment strategy is needed. To compare 3 treatment strategies for MOH. This open-label, randomized clinical trial with 6 months of follow-up was conducted in the tertiary sector at the Danish Headache Center, Glostrup, from October 25, 2016, to June 28, 2019. Of 483 patients with MOH referred during the inclusion period, 195 met the criteria consisting of migraine and/or tension-type headache, 18 years or older, eligibility for outpatient treatment, no severe physical or psychiatric disorder, no other addiction, and not pregnant or breastfeeding. Of these, 75 refused participation and 120 were included. Data were analyzed from July 3 to September 6, 2019. Random assignment (1:1:1 allocation) to 1 of the 3 outpatient treatments consisting of (1) withdrawal plus preventive treatment, (2) preventive treatment without withdrawal, or (3) withdrawal with optional preventive treatment 2 months after withdrawal. The primary outcome was change in headache days per month after 6 months. Predefined secondary outcomes were change in monthly migraine days, use of short-term medication, pain intensity, number of responders, patients with remission to episodic headache, and cured MOH. Of 120 patients, 102 (mean [SD] age, 43.9 [11.8] years; 81 women [79.4%]) completed the 6-month follow-up. Headache days per month were reduced by 12.3 (95% CI, 9.3-15.3) in the withdrawal plus preventive group, by 9.9 (95% CI, 7.2-12.6) in the preventive group, and by 8.5 (95% CI, 5.6-11.5) in the withdrawal group (P = .20). No difference was found in reduction of migraine days per month, use of short-term medication, or headache intensity. In the withdrawal plus preventive group, 23 of 31 patients (74.2%) reverted to episodic headache, compared with 21 of 35 (60.0%) in the preventive group and 15 of 36 (41.7%) in the withdrawal group (P = .03). Moreover, 30 of 31 patients (96.8%) in the withdrawal plus preventive group were cured of MOH, compared with 26 of 35 (74.3%) in the preventive group and 32 of 36 (88.9%) in the withdrawal group (P = .03). These findings corresponded to a 30% (relative risk, 1.3; 95% CI, 1.1-1.6) increased chance of MOH cure in the withdrawal plus preventive group compared with the preventive group (P = .03). All 3 treatment strategies were effective, but based on these findings, withdrawal therapy combined with preventive medication from the start of withdrawal is recommended as treatment for MOH. ClinicalTrials.gov Identifier: NCT02993289.

PND102 CORRELATION ANALYSIS OF THE CHANGE IN THREE SF-36 DOMAINS WITH CHANGE IN PATIENT-IDENTIFIED MOST BOTHERSOME SYMPTOM AND MONTHLY MIGRAINE DAYS IN PATIENTS WITH CHRONIC MIGRAINE: RESULTS OF THE PROMISE-2 STUDY

A previous PROMISE-2 analysis demonstrated that Patient Global Impression of Change responses are more closely correlated with changes in patient-identified most bothersome symptom (MBS) (r=0.83) than changes in monthly migraine days (MMDs) (r=0.51). It is not known whether changes in health-related quality of life (HRQOL) are more closely associated with changes in MBS or MMDs in patients with migraine. This analysis evaluated the relationship between changes in 36-item Short-Form Heath Survey (SF-36) domains most impacted in patients with migraine and changes in patient-identified MBS and MMDs among patients with chronic migraine (CM). PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled trial evaluating eptinezumab (100mg, 300mg) for the preventive treatment of CM (N=1072). Unlike MBS in acute trials, patients verbally identified any MBS associated with migraine attacks at screening and rated changes using a 7-point Likert scale ranging from “very much worse” to “very much improved.” The SF-36 measures overall HRQOL; this analysis focuses on HRQOL changes from baseline in bodily pain (BP), role-physical (RP), and social functioning (SF) domains. Associations between variables were evaluated with Spearman correlations in the total pooled population. At Weeks 4 and 12, improvements for both eptinezumab doses versus placebo were noted in change from baseline in MMDs, MBS, and SF-36 scores. All SF-36 scores were numerically more closely correlated with MBS than with MMDs at Week 4 (BP: MBS, r=0.40; MMDs, r=−0.32; RP: MBS, r=0.39; MMDs, r=−0.29; SF: MBS, r=0.30; MMDs, r=−0.23). At Week 12, the correlations were similar (BP: MBS, r=0.35; MMDs, r=−0.32; RP: MBS, r=0.33; MMDs, r=−0.29; SF: MBS, r=0.26; MMDs, r=−0.27). After initial administration of eptinezumab, changes in MBS and MMDs were similarly correlated with improvements in SF-36 domains most impacted in patients with migraine at the end of 12 weeks, supporting MBS as an important influence on HRQOL.

PND9 NOVEL METHOD OF ADJUSTMENT FOR HETEROGENEOUS ROUTES OF ADMINISTRATION WITHIN A COST-EFFECTIVENESS ANALYSIS: A CASE STUDY IN MIGRAINE

Placebo can affect subjective outcomes like pain. Cost-effectiveness analyses (CEAs) that compare interventions versus no intervention (rather than “sham intervention/placebo”) should account for the placebo effect. We demonstrate a method to adjust network meta-analysis (NMA) for placebo effects (specifically, by route of treatment administration [ROA]). A Cochrane review of pain treatments estimated a standardized mean placebo effect, which was assumed to reflect the difference between no treatment and mean placebo effect. Bannuru 2015 estimated differences in placebo effect between three ROAs. It was assumed that three levels of placebo in Bannuru 2015 center around the mean placebo effect as estimated by Cochrane and that distribution of these ROAs correspond to the differences between subcutaneous (SC), intramuscular (IM), and intravenous (IV) ROAs. We applied these to an NMA of change in monthly migraine days (MMDs) informing a CEA of monoclonal antibody calcitonin gene-related peptide inhibitors (both IV and SC) or onabotulinumtoxinA (IM) over weeks 1-4 in patients with chronic migraine. We evaluated the impact of placebo adjustment on observed outcomes modeled as the additive effect of placebo and treatment. Compared to no adjustment, estimates for SC treatments with adjustment had decreased treatment effect (increase in MMDs) over weeks 1-4, ranging from 0.59 to 1.51 days depending on the specific treatment. Results over weeks 1-4 for IM treatment showed an improvement in treatment effect of -0.74 days, while IV treatment showed an improved treatment effect of -1.92 days. When added to the treatment effect, inclusion of the adjustment resulted in IV treatment having higher absolute improvements over all other treatments. Results were consistent with an analysis of weeks 9-12. This case study illustrates the importance of addressing varying placebo responses in indirect treatment comparisons informing CEAs.

Galcanezumab in migraine prevention: a systematic review and meta-analysis of randomized controlled trials.

Background:Galcanezumab, along with three other monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, represents the latest disease-specific and mechanism-based treatment for the prophylaxis of migraine. Galcanezumab shares data also for the prophylaxis of cluster headache.Objective:To provide a pooled safety and efficacy analysis of all phase III randomized controlled trials of galcanezumab in the preventive therapy of migraine.Methods:A computer-based literature search was conducted on MEDLINE and the US National Institutes of Health Clinical Trials Registry for phase III randomized controlled trials of galcanezumab in migraine prevention. The primary outcome was the mean change in monthly migraine days (MMDs). The proportions of patients who reported at least one adverse event (AE), at least one serious adverse event (SAE) or withdrew from the study were used as safety outcomes.Results:Two trials were included in the efficacy meta-analysis and three in the safety meta-analysis. Migraine preventive treatment with subcutaneous galcanezumab, at both 120 mg and 240 mg dosages, was associated with a significantly greater reduction in the mean number of MMDs versus placebo (120 mg, MD = –1.98, 95% CI = –2.33 to –1.63; p < 0.0001) or (240 mg, MD = –1.86, 95% CI = –2.20 to –1.53; p < 0.0001). Galcanezumab was found to be more efficacious in all key secondary outcomes as well. Regarding safety, most of the adverse events were mild to moderate, while drop-out rates and serious adverse events were low.Conclusions:Galcanezumab is an efficacious and well-tolerated preventive treatment for migraine. Larger clinical trials with longer follow-up periods need to be conducted in order to provide more safety data of the above-mentioned drug.

The spectrum of response to erenumab in patients with chronic migraine and subgroup analysis of patients achieving ≥50%, ≥75%, and 100% response.

To assess the efficacy of erenumab across the spectrum of response thresholds (≥50%, ≥75%, 100%) based on monthly migraine days (MMD) reduction in patients with chronic migraine from a 12-week, randomized study (NCT02066415). Patients (n = 667) received (3:2:2) placebo or erenumab 70/140 mg once-monthly. The proportion of patients achieving a given response threshold was assessed. A post-hoc analysis was conducted to contextualize the actual treatment benefit in subgroups of patients achieving (or not) specified response thresholds. Outcome measures included MMD, acute migraine-specific medication treatment days (MSMD) and disability. The proportion of patients responding to erenumab exceeded that of placebo at the ≥50% and ≥75% response thresholds. At month 3, 39.9% and 41.2% of patients on erenumab 70 and 140 mg, respectively, achieved ≥50% response versus placebo (23.5%). Similarly, at month 3, 17.0% and 20.9% of patients on erenumab 70 and 140 mg, respectively, achieved ≥75% response versus placebo (7.8%). Compared with the overall erenumab-treated population (change in MMD: -6.6 [both 70 and 140 mg]), ≥50% responders showed MMD reductions of -12.2/-12.5 for 70 mg/140 mg versus -2.6/-2.2 for those not achieving ≥50% response. ≥75% responders showed MMD reductions of -13.9/-14.8 for 70 mg/140 mg versus -5.0/-4.3 for those not achieving ≥75% response. Relative improvements in MSMD and disability were observed in responders versus overall erenumab-treated population. For erenumab-treated patients achieving ≥50% response, the actual reduction in MMD was almost twice that of the overall population. These findings provide context for setting realistic expectations regarding actual treatment benefit experienced by patients responding to treatment.

Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination

BackgroundMonoclonal antibodies (mAbs) targeting the CGRP pathway are safe and efficacious therapies for the prevention of migraine. In this study we assessed the effects of discontinuation of preventive erenumab and galcanezumab treatment in patients with chronic migraine.MethodsThis retrospective pooled analysis included completers of the open-label extension study phase for the preventive treatment of chronic migraine with galcanezumab (NCT02614261; 9 months) and erenumab (NCT02174861; 12 months) in a single headache center. We compare migraine data until week 12 after open-label treatment completion, when patients did not have any pharmacological preventive medication, to study baseline values of the double-blind trial period, and to the last 4 weeks of the open-label extension. The assessment included changes in monthly migraine days, headache hours, days with severe headache and acute headache medication use.ResultsData from 16 patients after galcanezumab (n = 9) and erenumab (n = 7) open-label treatment completion were analyzed. The mean number of monthly migraine days was 18.38 ± 3.74 at baseline, and 12.19 ± 4.53 in the last 4 weeks of the open-label extension (p < 0.001). Monthly migraine days remained significantly reduced compared to baseline during the entire 12-week observation period after open-label termination (p = 0.002), with a reduction of 5.38 ± 4.92 in weeks 1–4 (p = 0.001), 4.75 ± 4.15 in weeks 5–8 (p = 0.001), and 3.93 ± 5.45 in weeks 9–12 (p = 0.014). There was no significant difference in monthly migraine days between the 12 weeks after open-label termination and the last 4 weeks of the open-label phase (p = 0.228). All other analyses revealed numerical improvement through week 12 in comparison to baseline.ConclusionsIn this small, self-selected cohort, the results indicate a therapeutic effect of monoclonal antibodies targeting the CRGP pathway in chronic migraine prevention after treatment termination up to 12 weeks.

Erenumab in chronic migraine with medication overuse: Subgroup analysis of a randomized trial.

ObjectiveTo determine the effect of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody, in patients with chronic migraine and medication overuse.MethodsIn this double-blind, placebo-controlled study, 667 adults with chronic migraine were randomized (3:2:2) to placebo or erenumab (70 or 140 mg), stratified by region and medication overuse status. Data from patients with baseline medication overuse at baseline were used to assess changes in monthly migraine days, acute migraine-specific medication treatment days, and proportion of patients achieving ≥50% reduction from baseline in monthly migraine days.ResultsOf 667 patients randomized, 41% (n = 274) met medication overuse criteria. In the medication overuse subgroup, erenumab 70 or 140 mg groups had greater reductions than the placebo group at month 3 in monthly migraine days (mean [95% confidence interval] −6.6 [−8.0 to −5.3] and −6.6 [−8.0 to −5.3] vs −3.5 [−4.6 to −2.4]) and acute migraine-specific medication treatment days (−5.4 [−6.5 to −4.4] and −4.9 [−6.0 to −3.8] vs −2.1 [−3.0 to −1.2]). In the placebo and 70 and 140 mg groups, ≥50% reductions in monthly migraine days were achieved by 18%, 36% (odds ratio [95% confidence interval] 2.67 [1.36–5.22]) and 35% (odds ratio 2.51 [1.28–4.94]). These clinical responses paralleled improvements in patient-reported outcomes with a consistent benefit of erenumab across multiple measures of impact, disability, and health-related quality of life. The observed treatment effects were similar in the non–medication overuse subgroup.ConclusionsErenumab reduced migraine frequency and acute migraine-specific medication treatment days in patients with chronic migraine and medication overuse, improving disability and quality of life.Clinicaltrials.gov identifierNCT02066415.Classification of evidenceThis study provides Class II evidence that erenumab reduces monthly migraine days at 3 months in patients with chronic migraine and medication overuse.

Cost-effectiveness analysis of erenumab for the preventive treatment of episodic and chronic migraine: Results from the US societal and payer perspectives.

Objectives To assess the cost-effectiveness of erenumab 140 mg ("erenumab") for the prophylactic treatment of episodic migraine and chronic migraine. Study design A hybrid Monte Carlo patient simulation and Markov cohort model was constructed to compare erenumab to no preventive treatment or onabotulinumtoxinA among adult ( ≥ 18 years) patients with episodic migraine and chronic migraine who failed prior preventive therapy from the US societal and payer perspectives. Methods Patients entered the model one at a time and were assigned to a post-treatment monthly migraine day category based on baseline monthly migraine days and treatment effect. Using monthly cycles, patients were followed for 2 years and accumulated costs and utilities associated with their post-treatment monthly migraine days. The primary outcome included the incremental cost-effectiveness ratio presented as cost per quality-adjusted life year gained. Results With an annual drug price of erenumab of $6900, treatment with erenumab in the societal perspective ranges from a dominant strategy versus no preventive treatment among chronic migraine patients to an incremental cost-effectiveness ratio of $122,167 versus no preventive treatment among episodic migraine patients. When excluding indirect costs (i.e. payer perspective), the incremental cost-effectiveness ratios are cost-effective among chronic migraine patients ($23,079 and $65,720 versus no preventive treatment and onabotulinumtoxinA, respectively), but not among episodic migraine patients ($180,012 versus no preventive treatment). Model results were sensitive to changes in monthly migraine days, health utilities, and treatment costs. Conclusion The use of erenumab may be a cost-effective approach to preventing monthly migraine days among patients with chronic migraine versus onabotulinumtoxinA and no preventive treatment in the societal and payer perspectives, but is less likely to offer good value for money for those with episodic migraine, unless lost productivity costs are considered.

Estimating the clinical effectiveness and value-based price range of erenumab for the prevention of migraine in patients with prior treatment failures: a US societal perspective

Background: Frequent migraine with four or more headache days per month is a common, disabling neurovascular disease. From a US societal perspective, this analysis models the clinical efficacy and estimates the value-based price (VBP) for erenumab, a fully human monoclonal antibody that inhibits the calcitonin gene-related peptide receptor.Methods: A Markov health state transition model was developed to estimate the incremental costs, quality-adjusted life-years (QALYs), and value-based price range for erenumab in migraine prevention. The model comprises “on preventive treatment”, “off preventive treatment”, and “death” health states across a 10-year time horizon. The evaluation compared erenumab to no preventive treatment in episodic and chronic migraine patients that have failed at least one preventive therapy. Therapeutic benefits are based on estimated changes in monthly migraine days (MMD) from erenumab pivotal clinical trials and a network meta-analysis of migraine studies. Utilities were estimated using previously published mapping algorithms. A VBP analysis was performed to identify maximum erenumab annual prices at willingness-to-pay (WTP) thresholds of $100,000–$200,000 per QALY. Estimates of VBP under different scenarios such as choice of different comparators, assumptions around inclusion of placebo effect, and exclusion of work productivity losses were also generated.Results: Erenumab resulted in incremental QALYs of 0.185 vs supportive care (SC) and estimated cost offsets due to reduced MMD of $8,482 over 10 years, with an average duration of treatment of 2.01 years. The estimated VBP at WTP thresholds of $100,000–$200,000 for erenumab compared to SC ranged from $14,238–$23,998. VBP estimates including the placebo effect and excluding work productivity ranged from $7,445–$13,809; increasing to $12,151–$18,589 with onabotulinumtoxinA as a comparator in chronic migraine.Conclusion: Erenumab is predicted to reduce migraine-related direct and indirect costs, and increase QALYs compared to SC.

Effect of percutaneous electrical nerve stimulation for the treatment of migraine.

Background:This study aimed to assess the effectiveness and safety of percutaneous electrical nerve stimulation (PENS) in migraine treatment.Methods:Sixty-two patients with at least 2 migration attacks each month were recruited and randomly divided into a verum PENS group and a sham PENS group in a ratio of 1:1. All patients received verum or sham PENS 30 minutes daily, 5 times weekly for 12 weeks. The primary outcomes were change in monthly migraine days (MMD) and the 50% responder rate (RR). Secondary outcomes were evaluated using the monthly migraine attacks (MMA), monthly headache days (MHD), and monthly acute antimigraine drug intake (MAADI). All outcome measurements were performed at treatment initiation to establish a baseline and again after 12 weeks of treatment.Results:At the end of the 12 weeks, the group receiving verum PENS exhibited statistically significant decrease in the mean MMD compared with the group receiving sham PENS intervention (P < .05). Additionally, the 50% RR was significantly higher in the verum PENS group than that in the sham PENS group (P < .05). Furthermore, the MMA, MHD, and MAADI were also significantly lower in the verum PENS group that those in the sham PENS group (P < .05).Conclusion:The results of this study demonstrated that verum PENS is more effective and safe than Sham PENS for the treatment of migraine.

Preventing Episodic Migraine With Caloric Vestibular Stimulation: A Randomized Controlled Trial.

To evaluate the safety and efficacy of a novel solid-state, caloric vestibular stimulation (CVS) device to provide adjuvant therapy for the prevention of episodic migraine in adult migraineurs. Migraine causes significant disability in ∼12% of the world population. No current migraine preventive treatment provides full clinical relief, and many exhibit high rates of discontinuation due to adverse events. Thus, new therapeutic options are needed. CVS may be an effective and safe adjuvant-therapy for the prevention of episodic migraine. In a multicenter, parallel-arm, block-randomized, placebo-controlled clinical trial (clinicaltrials.gov: NCT01899040), subjects completed a 3-month treatment with the TNM™ device for CVS (refer to Fig. 2 for patient enrollment and allocation). The primary endpoint was the change in monthly migraine days from baseline to the third treatment month. Secondary endpoints were 50% responder rates, change in prescription analgesic usage and difference in total subjective headache-related pain scores. Device safety assessments included evaluation of any impact on mood, cognition, or balance. Per-protocol, active-arm subjects showed immediate and continued steady declines in migraine frequency over the treatment period. After 3months of treatment, active-arm subjects exhibited significantly fewer migraine days (-3.9±0.6 from a baseline burden of 7.7±0.5 migraine days). These improvements were significantly greater than those observed in control subjects (-1.1±0.6 from a baseline burden = 6.9±0.7 migraine days) and represented a therapeutic gain of -2.8 migraine days, CI=-0.9 to -4.7, P=.012. Active arm subjects also reported greater reductions in acute medication usage and monthly pain scores compared to controls. No adverse effects on mood, cognition, or balance were reported. Subjects completed the trial with an average rate of 90% treatment adherence. No serious or unexpected adverse events were recorded. The rate of expected adverse events was similar across the active and the placebo groups, and evaluation confirmed that subject blinding remained intact. The TNM™ device for CVS appears to provide a clinically efficacious and highly tolerable adjuvant therapy for the prevention of episodic migraine.