Publications by authors named "Jessica Ailani"

43 Publications

The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice.

Headache 2021 Jun 23. Epub 2021 Jun 23.

American Headache Society, Mt Royal, NJ, USA.

Objective: To incorporate recent research findings, expert consensus, and patient perspectives into updated guidance on the use of new acute and preventive treatments for migraine in adults.

Background: The American Headache Society previously published a Consensus Statement on the use of newly introduced treatments for adults with migraine. This update, which is based on the expanded evidence base and emerging expert consensus concerning postapproval usage, provides practical recommendations in the absence of a formal guideline.

Methods: This update involved four steps: (1) review of data about the efficacy, safety, and clinical use of migraine treatments introduced since the previous Statement was published; (2) incorporation of these data into a proposed update; (3) review and commentary by the Board of Directors of the American Headache Society and patients and advocates associated with the American Migraine Foundation; (4) consideration of these collective insights and integration into an updated Consensus Statement.

Results: Since the last Consensus Statement, no evidence has emerged to alter the established principles of either acute or preventive treatment. Newly introduced acute treatments include two small-molecule calcitonin gene-related peptide (CGRP) receptor antagonists (ubrogepant, rimegepant); a serotonin (5-HT ) agonist (lasmiditan); a nonsteroidal anti-inflammatory drug (celecoxib oral solution); and a neuromodulatory device (remote electrical neuromodulation). New preventive treatments include an intravenous anti-CGRP ligand monoclonal antibody (eptinezumab). Several modalities, including neuromodulation (electrical trigeminal nerve stimulation, noninvasive vagus nerve stimulation, single-pulse transcranial magnetic stimulation) and biobehavioral therapy (cognitive behavioral therapy, biofeedback, relaxation therapies, mindfulness-based therapies, acceptance and commitment therapy) may be appropriate for either acute and/or preventive treatment; a neuromodulation device may be appropriate for acute migraine treatment only (remote electrical neuromodulation).

Conclusions: The integration of new treatments into clinical practice should be informed by the potential for benefit relative to established therapies, as well as by the characteristics and preferences of individual patients.
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http://dx.doi.org/10.1111/head.14153DOI Listing
June 2021

Effects of Intravenous Eptinezumab vs Placebo on Headache Pain and Most Bothersome Symptom When Initiated During a Migraine Attack: A Randomized Clinical Trial.

JAMA 2021 06;325(23):2348-2356

Lundbeck La Jolla Research Center, San Diego, California.

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion.

Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack.

Design, Setting, And Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack.

Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine.

Main Outcomes And Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours.

Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred.

Conclusions And Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established.

Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.
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http://dx.doi.org/10.1001/jama.2021.7665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207242PMC
June 2021

Acute Migraine Treatment.

Authors:
Jessica Ailani

Continuum (Minneap Minn) 2021 06;27(3):597-612

Purpose Of Review: Migraine is a disabling disease of attacks of moderate to severe pain with associated symptoms. Every person with migraine requires treatment for acute attacks. Treatments can range from behavioral management and nonspecific medications to migraine-specific medications and neuromodulation. For many with migraine, having a combination of tools allows for effective treatment of all types of attacks.

Recent Findings: Over the past several years, four neuromodulation devices have been cleared by the US Food and Drug Administration (FDA) for treatment of acute migraine, and three medications with novel mechanisms of action have been FDA approved. They add to the arsenal available to people with migraine and focus on migraine-specific pathways to allow for precise care with fewer side effects.

Summary: This article discusses acute migraine therapy, focusing on best-level evidence.
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http://dx.doi.org/10.1212/CON.0000000000000956DOI Listing
June 2021

Patient-identified most bothersome symptom in preventive migraine treatment with eptinezumab: A novel patient-centered outcome.

Headache 2021 May 20;61(5):766-776. Epub 2021 May 20.

Lundbeck La Jolla Research Center, San Diego, CA, USA.

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.
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http://dx.doi.org/10.1111/head.14120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251621PMC
May 2021

Cluster Headache: A Review and Update in Treatment.

Curr Neurol Neurosci Rep 2021 05 5;21(7):31. Epub 2021 May 5.

Department of Neurology, MedStar Georgetown University Hospital, 3800 Reservoir Rd, PHC-7, Washington, DC, 20007, USA.

Purpose Of Review: The treatment of cluster headache has evolved to include a handheld neuromodulation device and a monoclonal antibody in addition to more traditional agents.

Recent Findings: Galcanezumab is an approved treatment for episodic cluster headache. The non-invasive vagal nerve stimulator has been shown to be effective as a treatment for episodic cluster headache. Dedicated pituitary imaging may not be necessary with a normal MRI of the brain. Cluster headache is the most common trigeminal-autonomic cephalalgia, characterized by unilateral, frequent, debilitating attacks associated with ipsilateral autonomic symptoms. Attacks have a circadian and, often, seasonal pattern with periods of remission that can last months to years in episodic patients. Though a rare disease, an increasing number of studies have revealed novel targets for treatment. Treatment in cluster headache should focus on early intervention to reduce frequency of attacks and the length of the cycle, which improves outcomes and disability. Acute therapy is used to treat attacks, while bridging and preventive therapies are combined to reduce cycle length. Case 1: A 43-year-old man presents with the chief complaint of severe headaches. Upon general examination, he seems uncomfortable, agitated, and exhausted. He states that he hasn't "slept in over a week because of debilitating headaches." His headaches start around the same time every night: when he lays down to go to sleep. The pain is described as sharp, like a "hot poker" to his left eye. His partner has noticed that his eye droops and turns red when the pain starts. The attacks come on abruptly and prevent him from sleeping. The severe pain lasts 30 to 45 min, but he has mild-to-moderate pain that lingers for the rest of the night. He has seen his primary care physician, an allergist, and an ear, nose, and throat (ENT) specialist before coming to see a neurologist. Similar headaches occurred last year during the month of October as well. On further questioning, he reports that these headache attacks have been occurring almost yearly for the past 7 years. Each year, these headaches come on as the weather is changing and occur on a nightly basis for about 3 to 4 weeks.
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http://dx.doi.org/10.1007/s11910-021-01114-1DOI Listing
May 2021

Updates on management of headache in women and transgender women.

Authors:
Jessica Ailani

Curr Opin Neurol 2021 Jun;34(3):339-343

Department of Neurology, Medstar Georgetown University Hospital, Washington, DC, USA.

Purpose Of Review: Gender differences exist in headache disorders. A greater understanding of the role of hormones in headache can help the clinician better approach and manage common primary headache disorders.

Recent Findings: Recent studies highlight differences in how migraine and cluster headache present in women and men. Updates to the ongoing debate of how to manage the use of hormones in women with migraine, especially with aura, have been well reviewed in the last 18 months. A new meta-analysis evaluates gender differences in response to triptans.

Summary: This review will focus on recent updates on the role of gender and hormones on migraine and cluster headache and how this may influence treatment.
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http://dx.doi.org/10.1097/WCO.0000000000000926DOI Listing
June 2021

Effect of a change in lasmiditan dose on efficacy and safety in patients with migraine.

Postgrad Med 2021 May 17;133(4):449-459. Epub 2021 Mar 17.

MedStar Georgetown Headache Center, Georgetown University, Washington, DC, USA.

: Lasmiditan is a selective serotonin (1F) receptor agonist approved for acute treatment of migraine with 3 doses: 50, 100, and 200 mg.: To help provide dosing insights, we assessed the efficacy and safety of lasmiditan in patients who treated two migraine attacks with the same or different lasmiditan doses.: Integrated analyses used data from the migraine attack treated in either of two controlled, Phase 3, single attack studies (SAMURAI/SPARTAN), and after the first attack treated in the open-label GLADIATOR extension study. Eight patient groups were created based on the initial dose received in SAMURAI or SPARTAN and the subsequent dose in GLADIATOR: placebo-100, placebo-200, 50-100, 50-200, 100-100, 100-200, 200-100, 200-200. Migraine pain freedom, migraine-related functional disability freedom, most bothersome symptom (MBS) freedom, and pain relief were evaluated at 2-h post-dose. The occurrence of most common treatment-emergent adverse events (MC-TEAE) was evaluated. Shift analyses were performed for pain freedom and ≥1 MC-TEAE. The incidence of patients with a specific outcome from the first and subsequent doses were compared within each dose change group using McNemar's test.: Small, but consistent, increases in incidences of pain freedom, migraine-related functional disability freedom, MBS freedom, and pain relief occurred when the second lasmiditan dose was higher than the initial dose. For patients starting on 50 mg, increasing to 100 or 200 mg provided a positive efficacy-TEAE balance, despite an increase in incidence of ≥1 MC-TEAE. For patients starting on 100 mg, increasing to 200 mg provided a positive efficacy-TEAE balance. If the initial dose was 100 or 200 mg, the incidence of patients experiencing ≥1 MC-TEAE decreased or stayed the same with their subsequent dose, regardless of dose. Decreasing from 200 to 100 mg led to a decrease in patients with pain freedom and ≥1 MC-TEAE, resulting in a neutral efficacy-TEAE balance. Shift analyses supported these findings.: A positive efficacy-TEAE balance exists for patients increasing their lasmiditan dose for treatment of a subsequent migraine attack. These results could be important for optimizing dosing for individual patients.Clinicaltrials.gov: SAMURAI (NCT02439320); SPARTAN (NCT02605174); GLADIATOR (NCT02565186).
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http://dx.doi.org/10.1080/00325481.2020.1860619DOI Listing
May 2021

Sphenopalatine ganglion block in primary headaches: An American Headache Society member survey.

Neurol Clin Pract 2020 Dec;10(6):503-509

Department of Neurology (JGB), Allegheny Health Network, Pittsburgh, PA; Department of Neurology (MSR), Weill Cornell Medical College, Bronx, New York; Department of Neurology (CER), Mayo Clinic, Rochester, MN; Medstar Health Research Institute (MM), Georgetown University Washington DC; Dent Neurologic Institute (NPS), Amherst, NY; Department of Neurology (RBHS), Mayo Clinic, Phoenix, AZ; and Medstar Health Research Institute (JA), Georgetown University Washington, DC.

Background: The sphenopalatine ganglion (SPG), in the pterygopalatine fossa, is a known current and historical target for therapeutic intervention in headache disorders because of its role in cranial autonomics and vasodilation. There remains an overall lack of well-established SPG treatment protocols, particularly with the advent of newer commercial devices.

Methods: A 22 multiple-choice question survey was created to evaluate clinical practice patterns with SPG block and sent to members of the American Headache Society (AHS). Questions focused on determining indications, preferred applicators, medications applied, perceived efficacy, tolerability, and reimbursement.

Results: One hundred seventy-two of 1,346 (12.8%) AHS members participated. Ninety-three respondents (56.3%) had performed SPG blocks on 50 or fewer patients. The SphenoCath (42.4%) and the Tx360 (41.8%) were the most common methods of application. Ease of use was the top reason for provider preference in applicator type. SPG blocks were mostly used as an as-needed one-time procedure. When a scheduled protocol was used, twice weekly for 6 weeks was most common. Chronic migraine was the most commonly treated headache disorder and rated the most likely to respond to SPG block. Experienced clinicians found SPG more helpful as a stand-alone treatment and tended to report that acute relief was not predictive of enduring response.

Conclusions: The variety of responses strongly suggests that clinicians would benefit from formalized protocols for SPG blocks. More experienced clinicians may have developed individualized protocols that they feel are more effective. The lack of evidence-based protocols contribute to clinicians not performing SPG blocks more frequently.
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http://dx.doi.org/10.1212/CPJ.0000000000000773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837428PMC
December 2020

Reversion From Chronic Migraine to Episodic Migraine in Patients Treated With Fremanezumab: Post Hoc Analysis From HALO CM Study.

Headache 2020 Nov 11;60(10):2444-2453. Epub 2020 Nov 11.

MedStar Georgetown University Hospital, Washington, DC, USA.

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.
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http://dx.doi.org/10.1111/head.13997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756262PMC
November 2020

Impact of galcanezumab on total pain burden: findings from phase 3 randomized, double-blind, placebo-controlled studies in patients with episodic or chronic migraine (EVOLVE-1, EVOLVE-2, and REGAIN trials).

J Headache Pain 2020 Oct 17;21(1):123. Epub 2020 Oct 17.

Eli Lilly and Company, Indianapolis, IN, USA.

Background: Focus on the frequency of migraine pain may undervalue the total burden of migraine as pain duration and severity may present unique, additive burden. A composite measure of total pain burden (TPB; frequency, severity, and duration) may provide a more comprehensive characterization of pain burden and treatment response in patients with episodic migraine (EM) or chronic migraine (CM). The impact of galcanezumab versus placebo on TPB among patients with EM or CM was analyzed.

Methods: Patients from randomized, double-blind, placebo-controlled episodic (two 6-month studies pooled) and chronic migraine (3-month) studies received once-monthly subcutaneous injection of galcanezumab 120 mg or placebo. A post hoc analysis of TPB for a given month was calculated as severity-weighted duration by multiplying duration (hours) and maximum pain severity (0 = none, 1 = mild, 2 = moderate, 3 = severe) of migraine for each day and summing these over the days in a month. Least square mean change from baseline in monthly TPB across Months 1-6 (EM, N = 444 galcanezumab, N = 894 placebo) and Months 1-3 (CM, N = 278 galcanezumab, N = 558 placebo) were compared using a mixed-model repeated measures model. Correlation of the Migraine Specific Quality of Life Questionnaire (MSQ) and Migraine Disability Assessment Scale (MIDAS) to TPB at baseline was assessed.

Results: At baseline, the duration of migraine on a given migraine headache day accounted for the greatest unique proportion of variability (EM, 57.4% and CM, 61.1%) to TPB after adjusting for frequency of migraine headache days and maximum pain severity. The decrease from baseline in monthly TPB was greater with galcanezumab than placebo for patients with EM (68.6 versus 36.2) and CM (102.6 versus 44.4). The average percent reduction of TPB from baseline was significantly greater with galcanezumab compared with placebo in patients with EM (50.8% versus 17.2%) and CM (29.7% versus 11.0%). In patients with EM and CM, TPB correlated with MSQ total score (r = - 0.35 and r = - 0.37) and MIDAS (r = 0.34 and r = 0.32).

Conclusions: Greater reduction in TPB was seen in patients with EM and CM treated with galcanezumab 120 mg once-monthly injection relative to placebo. Discussing TPB supports patient-centric conversations regarding treatment expectations when clinicians are evaluating options for migraine prevention.

Trial Registration: ClinicalTrials.gov : # NCT02614183 (I5Q-MC-CGAG; EVOLVE-1), # NCT02614196 (I5Q-MC-CGAH; EVOLVE-2), and # NCT02614261 (I5Q-MC-CGAI; REGAIN) - all 3 trials were registered on 23 November 2015.
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http://dx.doi.org/10.1186/s10194-020-01190-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568830PMC
October 2020

Migraine Treatment in Pregnancy: An American Headache Society Survey.

Headache 2020 11 29;60(10):2594-2596. Epub 2020 Sep 29.

Department of Neurology, Weill Cornell, New York, NY, USA.

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http://dx.doi.org/10.1111/head.13974DOI Listing
November 2020

Safety, tolerability, and efficacy of orally administered atogepant for the prevention of episodic migraine in adults: a double-blind, randomised phase 2b/3 trial.

Lancet Neurol 2020 09;19(9):727-737

AbbVie, Madison, NJ, USA.

Background: Atogepant is an orally administered, small-molecule, calcitonin gene-related peptide (CGRP) receptor antagonist under investigation for treatment of migraine. We aimed to examine a range of oral doses for safety, tolerability, and efficacy for the preventive treatment of migraine.

Methods: In this double-blind, phase 2b/3 trial, adults (aged 18-75 years), with a history (≥1 year) of migraine and 4-14 migraine days per month, were randomly assigned 2:1:2:2:1:1 (by means of a sequence generated by the statistical programming department of the sponsor, and operationalised through an automated interactive web-based response system) to receive placebo or atogepant 10 mg once daily, 30 mg once daily, 60 mg once daily, 30 mg twice daily, or 60 mg twice daily, in matching capsules. Participants, site personnel, and all study sponsor personnel were masked to treatment allocations. The study was done in 78 academic and private practice settings in the USA. The primary outcome was change from baseline in monthly migraine days across 12 weeks of treatment using a modified intention-to-treat approach. The overall type I error rate for multiple comparisons across active treatment doses was controlled at the 0·05 level by means of a graphic approach. The main outcomes to assess safety and tolerability were adverse event recordings. The trial is registered with ClinicalTrials.gov, NCT02848326 and is completed.

Findings: Between Sept 6, 2016, and April 23, 2018, of 1772 individuals screened, 834 were randomly assigned and 825 received one dose or more of study medication: 186 received placebo, 93 atogepant 10 mg once daily, 183 atogepant 30 mg once daily, 186 atogepant 60 mg once daily, 86 atogepant 30 mg twice daily, and 91 atogepant 60 mg twice daily. Overall, 714 (87%) of 825 participants were female, 628 (76%) were white, median migraine duration was 17·5 years (IQR 10·0-28·0), and 232 (28%) had previously used preventive treatment. The primary efficacy analysis included 795 patients: 178 received placebo, 92 atogepant 10 mg once daily, 182 atogepant 30 mg once daily, 177 atogepant 60 mg once daily, 79 atogepant 30 mg twice daily, and 87 atogepant 60 mg twice daily. Across the 12-week treatment period, all five atogepant groups showed significant least-squares mean (SE) change from baseline in mean monthly migraine days versus placebo: atogepant 10 mg once daily -4·0 (0·3; p=0·024), 30 mg once daily -3·8 (0·2; p=0·039), 60 mg once daily -3·6 (0·2; p=0·039), 30 mg twice daily -4·2 (0·4; p=0·0034), and 60 mg twice daily -4·1 (0·3; p=0·0031); placebo -2·9 (0·2). The most common treatment-emergent adverse events (TEAEs) across all groups were nausea (range 5% [5/93] for 10 mg once daily to 12% [22/186] for 60 mg once daily vs 5% [9/186] for placebo) and fatigue (1% [1/93] for 10 mg once daily to 10% [9/91] for 60 mg twice daily vs 3% [6/186] for placebo). Treatment-related TEAE frequency ranged from 18% (17/93) for 10 mg once daily to 26% (24/91) for 60 mg twice daily, versus 16% (30/186) for placebo. Seven participants reported a total of eight serious TEAEs (two participants each in the placebo, 30 mg once-daily, and 60 mg once-daily groups, and one participant in the 10 mg once-daily group). TEAEs leading to discontinuation were reported in 33 (5%) of 639 atogepant participants and 5 (3%) of 186 of those randomised to placebo. All serious TEAEs were unrelated to treatment.

Interpretation: All doses of oral atogepant were associated with a significant decrease in monthly migraine days over 12 weeks compared with placebo. Atogepant was safe and well tolerated over 12 weeks, supporting its phase 3 development for the preventive treatment of migraine.

Funding: Allergan (before its acquisition by AbbVie).
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http://dx.doi.org/10.1016/S1474-4422(20)30234-9DOI Listing
September 2020

Non-invasive vagus nerve stimulation for primary headache: A clinical update.

Cephalalgia 2020 10 27;40(12):1370-1384. Epub 2020 Jul 27.

Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty of the University of Duisburg-Essen, Essen, Germany.

Background: Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified.

Methods: We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS.

Results: Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed.

Conclusion: Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.
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http://dx.doi.org/10.1177/0333102420941864DOI Listing
October 2020

Primary Exercise Headache.

Curr Neurol Neurosci Rep 2020 04 15;20(5). Epub 2020 Apr 15.

Department of Neurology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, 7PHC, Washington, DC, 20007, USA.

Purpose Of Review: Primary exercise headache has gone through many descriptors in the past but generally is a headache that is precipitated by strenuous exercise without significant intracranial pathology. Its presentation can remain vague, often confused with other primary and secondary headache disorders and thus undertreated. This review aims to discuss primary exercise headache in the context of epidemiology, presentation, pathophysiology, differential diagnosis, and treatment.

Recent Findings: Two large epidemiological studies in Iran and Japan have further characterized a predilection for female patients, comorbidity with migraine, and frequent bilateral nature of headache. While large-scale epidemiological studies have aided in further characterization and determining varying prevalence, a lack of randomized clinical trials in the treatment of primary exercise headache remains. Indomethacin and beta-blocker use remain the mainstays of treatment based on case series with several case reports that urge caution when diagnosing said headache.
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http://dx.doi.org/10.1007/s11910-020-01028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160088PMC
April 2020

Characterization of Acute Prescription Migraine Medication Use: Results From the CaMEO Study.

Mayo Clin Proc 2020 04;95(4):709-718

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY.

Objective: To characterize self-reported use of acute prescription medication for migraine in a sample representing the US population.

Patients And Methods: Data were obtained from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. The CaMEO Study is an Internet-based cross-sectional longitudinal survey administered between September 17, 2012, and November 19, 2013. Demographic characteristics, migraine-related disability, symptom severity, quality of life, and psychiatric comorbidity profiles were evaluated.

Results: Data from 13,624 respondents were analyzed, including 3121 (22.9%) self-reported current users of acute prescription medication for migraine, 1719 (12.6%) previous/discontinued users, and 8784 (64.5%) who had never used acute prescription medication for migraine. Mean ± SD monthly headache frequency was 7.3±7.1 days for current users, 5.6±6.6 days for those who discontinued, and 3.9±4.9 days for respondents who never used acute prescription medication for migraine. Current users experienced the highest degree of migraine-related disability based on Migraine Disability Assessment scores and the highest levels of migraine symptom severity based on Migraine Symptom Severity Scale scores. Current users also had the highest scores on the depression and anxiety questionnaires. The most commonly reported prescription medications used or "kept on hand" by current users were triptans (47.2%; 1474 of 3121), opioids (37.3%; 1164 of 3121), nonsteroidal anti-inflammatory drugs (31.9%; 997 of 3121), and barbiturates (12.8%; 399 of 3121), with many people reporting more than 1 medication.

Conclusion: Despite reporting moderate to severe migraine-related disability and impairment, many people with migraine have never used acute prescription migraine medication. The burden related to migraine is great, especially among individuals currently using acute prescription medication for migraine.
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http://dx.doi.org/10.1016/j.mayocp.2019.11.025DOI Listing
April 2020

Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers.

Headache 2020 05 3;60(5):833-842. Epub 2020 Apr 3.

Department of Neurological Sciences, Larner College of Medicine, University of Vermont, Burlington, VA, USA.

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.
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http://dx.doi.org/10.1111/head.13810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228371PMC
May 2020

Ubrogepant, an Acute Treatment for Migraine, Improved Patient-Reported Functional Disability and Satisfaction in 2 Single-Attack Phase 3 Randomized Trials, ACHIEVE I and II.

Headache 2020 04 19;60(4):686-700. Epub 2020 Feb 19.

Allergan plc, Irvine, CA, USA.

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.
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http://dx.doi.org/10.1111/head.13766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7155006PMC
April 2020

Clinical Efficacy and Safety of Ubrogepant for the Acute Treatment of Migraine.

J Fam Pract 2020 Jan/Feb;69(1 Suppl):S13-S22

Medstar Georgetown University Hospital, Washington, DC, USA.

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December 2020

Long-Term Safety Evaluation of Ubrogepant for the Acute Treatment of Migraine: Phase 3, Randomized, 52-Week Extension Trial.

Headache 2020 01;60(1):141-152

Allergan plc, Madison, NJ, USA.

Objective: To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine.

Background: Ubrogepant is an oral, calcitonin gene-related receptor antagonist in development for the acute treatment of migraine. The efficacy of ubrogepant was demonstrated in 2 phase 3 trials in which a significant improvement was observed in migraine headache pain, migraine-associated symptoms, and ability to function.

Methods: This was a phase 3, multicenter, randomized, open-label, 52-week extension trial. Adults with migraine with or without aura entered the trial after completing one of 2 phase 3 lead-in trials and were re-randomized 1:1:1 to usual care, ubrogepant 50 mg, or ubrogepant 100 mg. Randomization to ubrogepant dose was blinded. Those randomized to usual care continued to treat migraine attacks with their own medication. The usual care arm was included in this trial to capture background rates of hepatic laboratory parameters and contextualize hepatic safety assessments. Safety and tolerability were the primary outcome measures. The safety population for the ubrogepant arms included all randomized participants who received at least 1 dose of treatment. All cases of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) elevations of ≥3 times the upper limit of normal were adjudicated by an independent panel of liver experts who were blinded to dose.

Results: The safety population included 1230 participants (404 in the ubrogepant 50-mg group, 409 in the ubrogepant 100-mg group, and 417 in the usual care group). Participants were on average 42 years of age, 90% (1106/1230) female and 85% (1043/1230) white, with an average BMI of 30 kg/m . Throughout the trial, 21,454 migraine attacks were treated with 31,968 doses of ubrogepant. Treatment-emergent adverse events (TEAEs) were reported by 268/404 (66%) participants receiving ubrogepant 50 mg and 297/409 (73%) receiving ubrogepant 100 mg. The most commonly reported TEAE was upper respiratory tract infection (<12%); findings were similar across dose groups. Treatment-related TEAEs were reported by 42/404 (10%) participants in the ubrogepant 50-mg group and 43/409 (11%) in the ubrogepant 100-mg group. Serious adverse events (SAEs) were reported by 9/404 (2%) participants in the ubrogepant 50-mg group and 12/409 (3%) participants in the ubrogepant 100-mg group. Twenty cases of ALT/AST levels of ≥3 times the upper limit of normal were reported and reviewed by an independent clinical adjudication committee of liver experts. There were no cases of Hy's Law.

Conclusions: Long-term intermittent use of ubrogepant 50 and 100 mg given as 1 or 2 doses per attack for the acute treatment of migraine was safe and well tolerated, as indicated by a low incidence of treatment-related TEAEs and SAEs and discontinuations due to adverse events in this 1-year trial.
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http://dx.doi.org/10.1111/head.13682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004213PMC
January 2020

Ubrogepant for the Treatment of Migraine.

N Engl J Med 2019 12;381(23):2230-2241

From the Mayo Clinic, Phoenix, AZ (D.W.D.); Albert Einstein College of Medicine and Montefiore Headache Center, Bronx, NY (R.B.L.); Georgetown University Hospital, Washington, DC (J.A.); and Allergan, Madison, NJ (K.L., M.F., J.M.T., A.S.).

Background: Ubrogepant is an oral, small-molecule calcitonin gene-related peptide receptor antagonist for acute migraine treatment.

Methods: We conducted a randomized trial to evaluate the efficacy, safety, and side-effect profile of ubrogepant. We assigned adults with migraine, with or without aura, in a 1:1:1 ratio to receive an initial dose of placebo, ubrogepant at a dose of 50 mg, or ubrogepant at a dose of 100 mg for treatment of a single migraine attack, with the option to take a second dose. The coprimary efficacy end points were freedom from pain at 2 hours after the initial dose and absence of the most bothersome migraine-associated symptom at 2 hours. Secondary end points included pain relief (at 2 hours), sustained pain relief (from 2 to 24 hours), sustained freedom from pain (from 2 to 24 hours), and absence of symptoms associated with migraine (photophobia, phonophobia, and nausea) at 2 hours.

Results: A total of 1672 participants were enrolled; 559 were assigned to receive placebo, 556 to receive 50 mg of ubrogepant, and 557 to receive 100 mg of ubrogepant. The percentage of participants who had freedom from pain at 2 hours was 11.8% in the placebo group, 19.2% in the 50-mg ubrogepant group (P = 0.002, adjusted for multiplicity, for the comparison with placebo), and 21.2% in the 100-mg ubrogepant group (P<0.001). The percentage of participants who had freedom from the most bothersome symptom at 2 hours was 27.8% in the placebo group, 38.6% in the 50-mg ubrogepant group (P = 0.002), and 37.7% in the 100-mg ubrogepant group (P = 0.002). Adverse events within 48 hours after the initial or optional second dose were reported in 12.8% of participants in the placebo group, in 9.4% in the 50-mg ubrogepant group, and in 16.3% in the 100-mg ubrogepant group. The most common adverse events were nausea, somnolence, and dry mouth (reported in 0.4 to 4.1%); these events were more frequent in the 100-mg ubrogepant group (reported in 2.1 to 4.1%). Serious adverse events reported within 30 days in the ubrogepant groups included appendicitis, spontaneous abortion, pericardial effusion, and seizure; none of the events occurred within 48 hours after the dose.

Conclusions: A higher percentage of participants who received ubrogepant than of those who received placebo had freedom from pain and absence of the most bothersome symptom at 2 hours after the dose. The most commonly reported adverse events were nausea, somnolence, and dry mouth. Further trials are needed to determine the durability and safety of ubrogepant for acute migraine treatment and to compare it with other drugs for migraine. (Funded by Allergan; ClinicalTrials.gov number, NCT02828020.).
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http://dx.doi.org/10.1056/NEJMoa1813049DOI Listing
December 2019

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

Headache 2020 02 22;60(2):337-347. Epub 2019 Nov 22.

Mayo Clinic, Phoenix, AZ, USA.

Background: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants.

Methods: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments.

Results: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics.

Conclusions: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.
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http://dx.doi.org/10.1111/head.13688DOI Listing
February 2020

Effect of Ubrogepant vs Placebo on Pain and the Most Bothersome Associated Symptom in the Acute Treatment of Migraine: The ACHIEVE II Randomized Clinical Trial.

JAMA 2019 11;322(19):1887-1898

Allergan plc, Madison, New Jersey.

Importance: Ubrogepant is an oral calcitonin gene-related peptide receptor antagonist under investigation for acute treatment of migraine.

Objective: To evaluate the efficacy and tolerability of ubrogepant compared with placebo for acute treatment of a single migraine attack.

Design, Setting, And Participants: Phase 3, multicenter, randomized, double-blind, placebo-controlled, single-attack, clinical trial (ACHIEVE II) conducted in the United States (99 primary care and research clinics; August 26, 2016-February 26, 2018). Participants were adults with migraine with or without aura experiencing 2 to 8 migraine attacks per month.

Interventions: Ubrogepant 50 mg (n = 562), ubrogepant 25 mg (n = 561), or placebo (n = 563) for a migraine attack of moderate or severe pain intensity.

Main Outcomes And Measures: Co-primary efficacy outcomes were pain freedom and absence of the participant-designated most bothersome migraine-associated symptom (among photophobia, phonophobia, and nausea) at 2 hours after taking the medication.

Results: Among 1686 randomized participants, 1465 received study treatment (safety population; mean age, 41.5 years; 90% female); 1355 of 1465 (92.5%) were evaluable for efficacy. Pain freedom at 2 hours was reported by 101 of 464 participants (21.8%) in the ubrogepant 50-mg group, 90 of 435 (20.7%) in the ubrogepant 25-mg group, and 65 of 456 (14.3%) in the placebo group (absolute difference for 50 mg vs placebo, 7.5%; 95% CI, 2.6%-12.5%; P = .01; 25 mg vs placebo, 6.4%; 95% CI, 1.5%-11.5%; P = .03). Absence of the most bothersome associated symptom at 2 hours was reported by 180 of 463 participants (38.9%) in the ubrogepant 50-mg group, 148 of 434 (34.1%) in the ubrogepant 25-mg group, and 125 of 456 (27.4%) in the placebo group (absolute difference for 50 mg vs placebo, 11.5%; 95% CI, 5.4%-17.5%; P = .01; 25 mg vs placebo, 6.7%; 95% CI, 0.6%-12.7%; P = .07). The most common adverse events within 48 hours of any dose were nausea (50 mg, 10 of 488 [2.0%]; 25 mg, 12 of 478 [2.5%]; and placebo, 10 of 499 [2.0%]) and dizziness (50 mg, 7 of 488 [1.4%]; 25 mg, 10 of 478 [2.1%]; placebo, 8 of 499 [1.6%]).

Conclusions And Relevance: Among adults with migraine, acute treatment with ubrogepant compared with placebo led to significantly greater rates of pain freedom at 2 hours with 50-mg and 25-mg doses, and absence of the most bothersome migraine-associated symptom at 2 hours only with the 50-mg dose. Further research is needed to assess the effectiveness of ubrogepant against other acute treatments for migraine and to evaluate the long-term safety of ubrogepant among unselected patient populations.

Trial Registration: ClinicalTrials.gov Identifier: NCT02867709.
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http://dx.doi.org/10.1001/jama.2019.16711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865323PMC
November 2019

Rapid Onset of Effect of Galcanezumab for the Prevention of Episodic Migraine: Analysis of the EVOLVE Studies.

Headache 2020 02 11;60(2):348-359. Epub 2019 Nov 11.

Eli Lilly and Company, Indianapolis, IN, USA.

Objective: To evaluate onset of effect of galcanezumab in patients with episodic migraine.

Background: Galcanezumab is a monoclonal antibody that binds to calcitonin gene-related peptide and is indicated for preventive treatment of migraine.

Design/methods: Data on the primary outcome measure were analyzed from 2 previously published double-blind, Phase 3 studies (EVOLVE-1 [N = 858] and EVOLVE-2 [N = 915]) wherein adult patients with episodic migraine were randomized to receive monthly subcutaneous injections of galcanezumab 120 mg (with 240-mg loading dose) or 240 mg or placebo for up to 6 months. Monthly onset of effect was defined as the earliest month at which galcanezumab achieved and subsequently maintained statistical superiority to placebo on the mean change from baseline in the number of monthly migraine headache days (MHDs). If onset occurred in Month 1, weekly onset was evaluated and defined as the earliest week at which galcanezumab statistically separated from placebo and maintained statistical separation for remaining weeks in that month. Day of onset of effect was also analyzed, as were monthly and weekly onset, for occurrence of ≥50% reduction from baseline in number of MHDs.

Results: For both studies, change from baseline in monthly MHDs showed a statistically significant separation of galcanezumab from placebo at Month 1 and each subsequent month (each P < .001). Analysis of the first month for both studies indicated onset of effect in the first week, with galcanezumab-treated patients having significantly higher odds of having fewer MHDs in the first week (odds ratio [95% confidence interval] for EVOLVE-1, 2.71 [2.00, 3.66], and for EVOLVE-2, 2.88 [2.16, 3.86]; both P < .001) and each subsequent week compared with placebo-treated patients (P ≤ .004). Daily analysis showed onset of effect at Day 1 (first day after injection day). Galcanezumab also demonstrated superiority to placebo on occurrence of ≥50% reduction in MHDs starting at Week 1 (percentage of patients with 50% response in galcanezumab group vs placebo group for EVOLVE-1, 54.3% vs 32.4% [P < .001], and for EVOLVE-2, 59.4% vs 38.0% [P < .001]).

Conclusion: Rapid onset of preventive effect on the first day after injection of galcanezumab was confirmed in both studies of episodic migraine.
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http://dx.doi.org/10.1111/head.13691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028148PMC
February 2020

Discontinuation of Acute Prescription Medication for Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

Headache 2019 11 22;59(10):1762-1772. Epub 2019 Sep 22.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA.

Objective: This analysis assessed migraine-related burden and treatment decisions in Chronic Migraine Epidemiology and Outcomes (CaMEO) Study survey respondents who stopped taking acute prescription medications for migraine.

Background: Migraine is a common yet underdiagnosed and undertreated neurological disease often associated with significant disability. Acute prescription medications are underused, in part because patients discontinue treatment. Rates and reasons for discontinuing acute prescription medications require exploration.

Methods: The CaMEO Study is a longitudinal, Internet-based survey that identified and followed people who met modified ICHD-3 migraine criteria. For this analysis, eligible respondents had used acute prescription medication for migraine in the past but no longer used or kept these treatments on hand (discontinued users). Respondents who reported discontinuing acute prescription treatment answered questions about length of time since last use and reasons for stopping. Reasons for discontinuing were thematically summarized. Monthly headache day frequency, Migraine Disability Assessment (MIDAS), Patient Health Questionnaire 9-item depression screener, Generalized Anxiety Disorder 7-item screener, and the 12-item Allodynia Symptom Checklist were also assessed.

Results: Of 13,624 respondents with migraine, 4840 (35.5%) had ever used acute prescription medications and 1719 (35.5%) of those were discontinued users. Discontinued users had a mean (SD) age of 42.1 (14) years, and 1348/1719 (78.4%) were female. Monthly headache frequency of 0-4 days was reported by 1073/1719 (62.4%) of respondents, 5-9 days by 322/1719 (18.7%), 10-14 days by 135/1719 (7.9%), and ≥15 days by 189/1719 (11.0%). Two-thirds (1160/1719 [67.5%]) of discontinued users reported a receiving migraine (or chronic migraine) diagnosis from a doctor or other health professional in the past. Although all had spoken to a doctor about their headaches, 1504/1719 (87.5%) had stopped having their headaches managed or treated by a doctor for at least 12 months. Only 1 in 5 discontinued users reported being able to work or function normally with a headache, and 717/1719 (41.7%) had moderate to severe disability (MIDAS). Among the most commonly reported reasons for prescription medication discontinuation were switching to non-prescription pain medication (782/1719 [45.5%]), as well as concerns about prescription medication efficacy (484/1719 [28.2%]) and tolerability (428/1719 [24.9%]). Nearly half of respondents who reported either efficacy or tolerability concerns had moderate to severe disability.

Conclusions: People with migraine who discontinue acute prescription medication have a high level of unmet treatment need. The majority cannot work or function normally with headaches, with 646/1719 (37.6%) of discontinued users reporting 5 or more headache days per month.
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http://dx.doi.org/10.1111/head.13642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899725PMC
November 2019

Efficacy and safety of lasmiditan in patients using concomitant migraine preventive medications: findings from SAMURAI and SPARTAN, two randomized phase 3 trials.

J Headache Pain 2019 Jul 24;20(1):84. Epub 2019 Jul 24.

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA.

Objective: To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications.

Background: While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives.

Methods: SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes.

Results: In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications.

Conclusions: Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications.

Trial Registration: SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.
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http://dx.doi.org/10.1186/s10194-019-1032-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734212PMC
July 2019

Neuromodulation for the Acute and Preventive Therapy of Migraine and Cluster Headache.

Headache 2019 07;59 Suppl 2:33-49

Department of Neurology, Weill Cornell Medicine, New York, NY, USA.

Headache disorders are among the most common and disabling medical conditions worldwide. Pharmacologic acute and preventive treatments are often insufficient and poorly tolerated, and the majority of patients are unable to adhere to their migraine treatments due to these issues. With improvements in our understanding of migraine and cluster headache pathophysiology, neuromodulation devices have been developed as safe and effective acute and preventive treatment options. In this review, we focus on neuromodulation devices that have been studied for migraine and cluster headache, with special attention to those that have gained food and drug administration (FDA) clearance. We will also explore how these devices can be used in patients who might have limited pharmacologic options, including the elderly, children, and pregnant women.
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http://dx.doi.org/10.1111/head.13586DOI Listing
July 2019

Traditional and Novel Migraine Therapy in the Aging Population.

Curr Pain Headache Rep 2019 May 11;23(6):42. Epub 2019 May 11.

Department of Neurology, Med star Georgetown University Hospital, 3800 Reservoir Road NW, 7 PHC, Washington, DC, 20007, USA.

Migraine is a common disabling disorder that affects 36 million Americans. The clinical features of migraine are less typical in the people above age 60, making the diagnosis and treatment difficult in this group. In this review, we will discuss migraine-specific drugs and their use in populations about age 60 who suffer from migraine. This discussion will include an overview of traditional treatments for the acute and preventive treatment of migraine, and considerations for their use in patient populations above age 60. In addition, we will discuss newer agents that show a more promising safety profile.
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http://dx.doi.org/10.1007/s11916-019-0789-6DOI Listing
May 2019

A Review of Spontaneous Intracranial Hypotension.

Curr Neurol Neurosci Rep 2019 03 19;19(5):22. Epub 2019 Mar 19.

Department of Neurology, Medstar Georgetown Headache Center, Medstar Georgetown University Hospital, 3800 Reservoir Road NW 7PHC, Washington, DC, 20007, USA.

Purpose Of Review: Spontaneous intracranial hypotension (SIH) is an underdiagnosed phenomenon predominantly presenting with low cerebrospinal fluid (CSF) pressure and postural headache in setting of CSF leak. The goal of this paper is to provide updates on the pathology, diagnosis, and management of SIH. The utility of multiple imaging modalities and the use of epidural blood patches and fibrin glue polymers are explored.

Recent Findings: In regard to diagnosis, new non-invasive modalities in detection of SIH including transorbital ultrasound and serum biomarkers are found. In addition, increased efficacy of large volume and repeated placement of multiple epidural blood patches (EBP) are seen. In addition, the management of refractory SIH using fibrin glue polymers has proved efficacious in recent case series. While the diagnosis may be challenging for clinicians, future research in SIH is leading to more rapid detection methods. Future studies may target optimal use of EBP in comparison to fibrin glue polymers, in addition to new developments in increased understanding of SIH physiology and phenotype.
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http://dx.doi.org/10.1007/s11910-019-0938-7DOI Listing
March 2019

Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial.

JAMA Neurol 2018 09;75(9):1080-1088

Eli Lilly and Company, Indianapolis, Indiana.

Importance: Migraine is a disabling neurological disease characterized by severe headache attacks. Treatment options reduce migraine frequency for many patients, but adverse effects lead to discontinuation in many patients.

Objective: To demonstrate that galcanezumab is superior to placebo in the prevention of episodic migraine with or without aura.

Design, Setting, And Participants: The EVOLVE-1 (Evaluation of LY2951742 in the Prevention of Episodic Migraine 1) trial was a double-blind, randomized, placebo-controlled (January 11, 2016, to March 22, 2017) trial comparing galcanezumab (120 mg and 240 mg) vs placebo. Patients received treatments once monthly for 6 months (subcutaneous injection via prefilled syringe) and were followed up for 5 months after their last injection. It was a multicenter, clinic-based study involving 90 sites in North America. Participants in the study were adults (aged 18 to 65 years) with at least a 1-year history of migraine, 4 to 14 migraine headache days per month and a mean of at least 2 migraine attacks per month within the past 3 months, and were diagnosed prior to age 50 years. During the study, no other preventive medications were allowed. A total of 1671 patients were assessed; 809 did not meet study entry or baseline criteria, and 858 were included in the intent-to-treat population.

Interventions: Patients were randomized (2:1:1) to monthly placebo, galcanezumab, 120 mg, and galcanezumab, 240 mg.

Main Outcomes And Measures: The primary outcome was overall mean change from baseline in the number of monthly migraine headache days during the treatment period. Secondary measures included at least 50%, at least 75%, and 100% reduction in monthly migraine headache days, migraine headache days with acute medication use, and scores from the Migraine-Specific Quality of Life questionnaire, Patient Global Impression of Severity, and Migraine Disability Assessment. Treatment-emergent adverse events and serious adverse events were reported.

Results: Of the 1671 patients assessed, 858 (mean age, 40.7 years; 718 women [83.7%]) met study entry criteria and received at least 1 dose of investigational product. The primary objective was met for both galcanezumab doses; treatment with galcanezumab significantly reduced monthly migraine headache days (both P < .001) by 4.7 days (120 mg) and 4.6 days (240 mg) compared with placebo (2.8 days). All key secondary objectives were also significant after multiplicity adjustment. There were no meaningful differences between 120-mg and 240-mg doses of galcanezumab on measures of efficacy. Completion rate during treatment was high (81.9%; n = 718), and the incidence of discontinuation owing to adverse events was less than 5% across all treatment groups.

Conclusions And Relevance: Galcanezumab 120-mg and 240-mg monthly injections provided clinical benefits and improved functioning. The incidence rate of adverse events was low, demonstrating the favorable tolerability profile of galcanezumab.

Trial Registration: ClinicalTrials.gov Identifier: NCT02614183.
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http://dx.doi.org/10.1001/jamaneurol.2018.1212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143119PMC
September 2018

An Up to Date Review of Pseudotumor Cerebri Syndrome.

Curr Neurol Neurosci Rep 2018 05 2;18(6):33. Epub 2018 May 2.

Department of Neurology, Medstar Georgetown University Hospital, 3800 Reservoir Road NW, 7-PHC, Washington, DC, 20007, USA.

Purpose Of Review: Idiopathic intracranial hypertension (IIH), pseudotumor cerebri syndrome (PTCS), and benign intracranial hypertension are all terms that have been used for a neurologic syndrome consisting of elevated intracranial pressure (ICP), headache and vision loss without mass lesion or underlying infection or malignancy. In this review article, categorization, diagnostic criteria, symptom management strategies, and disease treatment options for pseudotumor cerebri syndrome will be discussed.

Recent Findings: The Idiopathic Intracranial Hypertension Treatment Trial has now proven that acetazolamide should be the first line therapy in primary PTCS, but other treatment options exist in patients who cannot tolerate acetazolamide or in selected cases, which requires surgical intervention for PTCS which acutely threatens vision. Headache has also been shown to require focused treatment beyond therapies that lower ICP, specifically targeting coexistent primary headache disorders and medication overuse. Advances in treatment and diagnostic modalities have improved understanding of PTCS types and their treatment. The pathophysiology of primary PTCS, however, remains incompletely understood, but continued evaluation of cerebrospinal fluid flow dynamics, aquaporins, hormones, natriuretic peptides, and the link with female gender and obesity may lead to future answers.
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http://dx.doi.org/10.1007/s11910-018-0839-1DOI Listing
May 2018
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