Ailani, Jessica

Background Atogepant is an oral, small-molecule, calcitonin gene–related peptide receptor antagonist for the preventive treatment of migraine. Methods In the double-blind, phase 3 ADVANCE trial, participants with 4–14 migraine days/month were randomized to atogepant 10 mg, 30 mg, 60 mg, or placebo once daily for 12 weeks. We evaluated the time course of efficacy of atogepant for the preventive treatment of migraine. Analyses included change from baseline in mean monthly migraine days during each of the three 4-week treatment periods, change in weekly migraine days during weeks 1–4, and proportion of participants with a migraine on each day during the first week. Results We analyzed 873 participants (n = 214 atogepant 10 mg, n = 223 atogepant 30 mg, n = 222 atogepant 60 mg, n = 214 placebo). For weeks 1–4, mean change from baseline in mean monthly migraine days ranged from −3.1 to −3.9 across atogepant doses vs −1.6 for placebo ( p < 0.0001). For weeks 5–8 and 9–12, reductions in mean monthly migraine days ranged from −3.7 to −4.2 for atogepant vs −2.9 for placebo ( p ≤ 0.012) and −4.2 to −4.4 for atogepant vs −3.0 for placebo ( p < 0.0002), respectively. Mean change from baseline in weekly migraine days in week 1 ranged from −0.77 to −1.03 for atogepant vs −0.29 with placebo ( p < 0.0001). Percentages of participants reporting a migraine on post-dose day 1 ranged from 10.8% to 14.1% for atogepant vs 25.2% with placebo ( p ≤ 0.0071). Conclusion Atogepant demonstrated treatment benefits as early as the first full day after treatment initiation, and sustained efficacy across each 4-week interval during the 12-week treatment period. Clinical trial registration: ClinicalTrials.gov identifier: NCT03777059

Abstract Background Erenumab is a human anti‐calcitonin gene‐related peptide receptor monoclonal antibody approved for migraine prevention. We sought to further assess the temporal patterns of response to erenumab in patients with chronic migraine (CM), specifically the onset and sustainability of monthly migraine day (MMD) response. Methods This is a post hoc analysis of a 12‐week, randomized, double‐blind, placebo‐controlled study of erenumab for migraine prevention in patients with CM (≥15 headache days/month, including ≥8 migraine days/month). Onset and sustainability were assessed according to MMD reduction from baseline, with the following response categories: responders (≥50% reduction), partial responders (≥30% and <50%), or nonresponders (<30%). Results Among the erenumab 140 mg group ( n = 187), 54.0% (101/187) achieved a response at any month during the study with a median time to onset of monthly response of 1 month. This improvement was maintained in most patients with continued treatment. An initial response was achieved at Month 1 by 28.3% (53/187) of patients; 69.8% (37/53) of whom maintained a response at Months 2 and 3. Although many patients responded early, some patients required longer treatment to achieve a response; 79.4% (27/34) of initial partial responders and 21.0% (21/100) of initial nonresponders subsequently achieved a response. Similar findings were observed for the erenumab 70mg group ( n = 188). Conclusion A majority of erenumab‐treated patients with CM who achieved an initial response at Month 1 sustained this benefit. Many patients responded later with continued treatment. Our data support recommendations to assess outcomes after ≥3 months of preventive treatment with erenumab in CM.

AbstractObjectiveTo systematically evaluate the efficacy and effectiveness of percutaneous interventional treatments for prevention of migraine through a qualitative and (when possible) quantitative analysis.MethodsAn 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.ResultsThe committee screened 1,195 studies and assessed 352 by full text, yielding 16 randomized controlled trials that met the inclusion criteria.Recommendations and ConclusionsAs 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.

Abstract Objectives To describe the methodology and implications of the patient‐identified most bothersome symptom (PI‐MBS) measure used in the phase 3, multicenter, randomized, double‐blind, placebo‐controlled, and parallel‐group PROMISE‐2 trial and to evaluate the contribution of this measure to the assessment of the preventive migraine benefits of treatment. Background Although freedom from MBS is a coprimary endpoint in acute migraine treatment trials, its evaluation in preventive migraine trials is limited. The PROMISE‐2 study assessed a unique PI‐MBS measure as a secondary endpoint. Methods This was a secondary analysis of data from the PROMISE‐2 study. Adults with chronic migraine (CM) were randomized to receive intravenous (IV) eptinezumab 100 mg, eptinezumab 300 mg, or placebo, administered on day 0 and every 12 weeks. At the screening visit, patients were asked to verbally describe the MBS associated with their CM; the question format was open ended. At subsequent visits, patients were asked to rate the overall change in severity of their MBS from study inception to that time point, using a 7‐point ordinal scale ranging from “very much worse” (−3) to “very much improved” (+3). Patients completed the Patient Global Impression of Change (PGIC) assessment during the same visits, using an identical rating scale and recall period. Endpoints were summarized descriptively; post hoc correlations using the methodologies of Pearson and Spearman were calculated to evaluate relationships between PGIC and PI‐MBS and between PGIC and mean monthly migraine days (MMDs; primary efficacy endpoint in PROMISE‐2). Results Altogether, 1072 patients received treatment (eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366) and were included in the analysis. There were 23 unique MBS identified; those reported by ≥10 patients included light sensitivity (18.7%), nausea/vomiting (15.1%), pain with activity (13.7%), pain (12.4%), headache (11.2%), sound sensitivity (7.3%), throbbing/pulsating pain (4.7%), cognitive disruption (4.1%), fatigue (2.4%), mood changes (1.5%), and sensitivity to smell (0.9%). Four weeks after the first dose (week 4), the rates of much or very much improvement in PI‐MBS were higher with eptinezumab 100 mg (45%) and 300 mg (57%) than with placebo (29%). Four weeks after the second dose (week 16), the proportions with much or very much improvement in PI‐MBS had increased to 58%, 65%, and 36%, respectively. At each time point, the percentages of patients with PGIC ratings of much or very much improved were similar to those for patient‐reported improvement in PI‐MBS. Patient ratings of changes in PI‐MBS and PGIC correlated strongly across time points (Pearson, r range, 0.83–0.88; Spearman, r range, 0.83–0.89); the absolute value of the correlations was greater than the correlation among changes in MMDs and PGIC (Pearson, r range, −0.49 to −0.52; Spearman, r range, −0.49 to −0.52). Conclusions Among patients with CM in the PROMISE‐2 study, a broad range of PI‐MBS was reported at baseline. Throughout the study, patients treated with eptinezumab reported greater improvement in their PI‐MBS severity compared with placebo recipients, and this improvement correlated strongly with PGIC findings. Collectively, these results indicate that PI‐MBS is a promising and novel outcome measure for preventive trials of CM and thus may provide a unique patient‐centered approach for identifying and measuring the burden of migraine symptoms that matter most to each patient, as well as the benefits of treatment.

Background Migraine preventive medications are used to reduce headache frequency, severity, and duration. In patients with chronic migraine (CM), reversion to episodic migraine (EM) is an important treatment goal. Objective To evaluate the effect of fremanezumab on the rate of reversion from CM to EM. Methods This phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group trial included a 28‐day pretreatment period and a 3‐month treatment period. Patients with CM received subcutaneous fremanezumab quarterly (675 mg at baseline) or monthly (675 mg at baseline; 225 mg at Weeks 4 and 8), or placebo. Post hoc analyses evaluated the proportion of patients who reverted from CM to EM, defined as either a reduction to an average of <15 headache days per month during the 3‐month treatment period or a reduction to <15 headache days per month in all 3 months of the treatment period. Results This analysis included data from 1088 CM patients (quarterly, n = 366; monthly, n = 365; placebo, n = 357). More fremanezumab‐treated patients with CM reverted to EM using either the monthly average number of headache days criteria for reversion (quarterly: 50.5% [185/366], P = .108; monthly: 53.7% [196/365], P = .012; vs placebo: 44.5% [159/357]) or the monthly headache day count at Months 1, 2, and 3 criteria for reversion (quarterly: 31.2% [114/366], P = .008; monthly: 33.7% [123/365], P = .001; vs placebo: 22.4% [80/357]). Patients with CM who reported previous topiramate or onabotulinumtoxinA use, concomitant preventive medication use, or medication overuse were less likely to revert to EM. Conclusions Fremanezumab may offer the benefit of reversion from CM to EM, based on a reduction in the number of headache days over 3 months of treatment.

Objective To outline strategies for the treatment of migraine which do not require in‐person visits to clinic or the emergency department, and to describe ways that health insurance companies can remove barriers to quality care for migraine. Background COVID‐19 is a global pandemic causing widespread infections and death. To control the spread of infection we are called to observe “social distancing” and we have been asked to postpone any procedures which are not essential. Since procedural therapies are a mainstay of headache care, the inability to do procedures could negatively affect our patients with migraine. In this manuscript we review alternative therapies, with particular attention to those which may be contra‐indicated in the setting of COVID‐19 infection. Design/Results The manuscript reviews the use of telemedicine visits and acute, bridge, and preventive therapies for migraine. We focus on evidence‐based treatment where possible, but also describe “real world” strategies which may be tried. In each section we call out areas where changes to rules from commercial health insurance companies would facilitate better migraine care. Conclusions Our common goal as health care providers is to maximize the health and safety of our patients. Successful management of migraine with avoidance of in‐person clinic and emergency department visits further benefits the current urgent societal goal of maintaining social distance to contain the COVID‐19 pandemic.

Objective To evaluate the efficacy of ubrogepant on patient‐reported functional disability, satisfaction with study medication, and global impression of change. Background Ubrogepant is a small‐molecule, oral calcitonin gene‐related peptide receptor antagonist indicated for the acute treatment of migraine. In 2 phase 3 trials (ACHIEVE I and II), ubrogepant demonstrated efficacy vs placebo on the 2 co‐primary endpoints of headache pain freedom and absence of the most bothersome migraine‐associated symptom at 2 hours post dose for the 50 and 100 mg doses. Patient‐reported outcomes, such as functional disability, satisfaction, and patient global impression of change, can provide additional evidence of the efficacy of an acute treatment for migraine on clinically meaningful and patient‐relevant outcomes. Methods ACHIEVE I and ACHIEVE II were multicenter, randomized, double‐blind, placebo‐controlled, parallel‐group, single‐attack trials in adults (18‐75 years) with migraine. In ACHIEVE I, participants were randomized 1:1:1 to placebo or ubrogepant 50 or 100 mg; in ACHIEVE II, participants were randomized 1:1:1 to placebo or ubrogepant 25 or 50 mg to treat a migraine attack with moderate or severe headache pain. Participants rated ability to perform daily activities on the Functional Disability Scale, before dosing and at 1, 2, 4, and 8 hours after the initial dose; satisfaction with study medication at 2 and 24 hours; and impression of overall change in migraine on the Patient Global Impression of Change scale at 2 hours. In prespecified analyses for each trial, each outcome was compared between each ubrogepant dose group and the relevant placebo group. Data were pooled from the ubrogepant 50 mg and placebo groups of the 2 trials in a post hoc analysis. Results In ACHIEVE I, 559 participants were randomized to placebo, 556 to ubrogepant 50 mg, and 557 to ubrogepant 100 mg; in ACHIEVE II, 563 were randomized to placebo, 561 to ubrogepant 25 mg, and 562 to ubrogepant 50 mg. At 2 hours post dose, significantly higher proportions of ubrogepant‐treated participants vs placebo‐treated participants reported being able to function normally (ACHIEVE I: ubrogepant 50 mg, 40.6% [171/421], P = .0012 vs placebo; ubrogepant 100 mg, 42.9% [192/448], P < .0001 vs placebo; placebo, 29.8% [136/456]; ACHIEVE II: ubrogepant 25 mg, 42.6% [185/434], P = .0015 vs placebo; ubrogepant 50 mg, 40.5% [188/464], P = .0118 vs placebo; placebo, 34.2% [156/456]; pooled 50 mg, 40.6% [359/885], vs pooled placebo, 32.0% [292/912]; P < .0001), were satisfied/extremely satisfied with study medication (ACHIEVE I: 50 mg, 36.3% [147/405], P < .0001 vs placebo; 100 mg, 35.8% [149/416], P = .0002 vs placebo; placebo, 24.1% [104/432]; ACHIEVE II: 25 mg, 35.1% [141/402], P = .0018 vs placebo; 50 mg, 37.8% [163/431], P < .0001 vs placebo; placebo, 24.8% [106/427]; pooled ubrogepant 50 mg, 37.1% [310/836], vs pooled placebo, 24.5% [210/859]; P < .0001), and indicated that their migraine was much/very much better on the Patient Global Impression of Change scale (ACHIEVE I: 50 mg, 34.4% [103/299], P = .0006 vs placebo; 100 mg, 34.3% [102/297], P = .0009 vs placebo; placebo, 22.0% [69/313]; ACHIEVE II: 25 mg, 34.1% [124/364], P < .0001 vs placebo; 50 mg, 33.4% [131/392], P = .0002 vs placebo; placebo, 20.7% [78/376]; pooled 50 mg, 33.9% [234/691], vs pooled placebo, 21.3% [147/689]; P < .0001). Conclusions A significantly higher proportion of participants treated with ubrogepant were able to function normally, were satisfied with the study medication, and reported clinically meaningful improvement compared with those receiving placebo. The results reinforce the potential benefits of ubrogepant on patient‐centered outcomes in the acute treatment of migraine.