Tepper, Stewart J.

Abstract Objective To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication‐overuse headache (MOH). Background Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene‐related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. Methods PROMISE‐2 (NCT02974153) was a double‐blind, randomized, placebo‐controlled, phase 3 study that comprised a screening visit, a 28‐day pretreatment period, and a 32‐week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1–12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1–24. Results There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg ( n = 139), 300 mg ( n = 147), or placebo ( n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1–12, eptinezumab‐treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = −8.4, difference from placebo [95% confidence interval (CI)] = −3.0 [−4.56, −1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = −8.6, difference from placebo [95% CI] = −3.2 [−4.66, −1.78], p < 0.0001 vs. placebo; placebo, −5.4). Compared with placebo, more eptinezumab‐treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1–12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24‐week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo‐treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication‐overuse thresholds. Conclusions In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Objective To determine reversion rates from chronic migraine to episodic migraine during long-term erenumab treatment. Methods A daily headache diary was completed during the 12-week, double-blind treatment phase of a placebo-controlled trial comparing erenumab 70 mg, 140 mg, and placebo, and weeks 1–12, 21–24, 37–40, and 49–52 of the open-label treatment phase. Chronic migraine to episodic migraine reversion rates were assessed over the double-blind treatment phase; persistent reversion to episodic migraine over 24 weeks (double-blind treatment phase through the first 12 weeks in the open-label treatment phase), long-term persistent reversion to episodic migraine over 64 weeks (double-blind treatment phase plus open-label treatment phase); delayed reversion to episodic migraine through the first 12 weeks of the open-label treatment phase among patients remaining in chronic migraine during the double-blind treatment phase. Results In the double-blind treatment phase, 53.1% (95% confidence interval: 47.8–58.3) of 358 erenumab-treated completers had reversion to episodic migraine; monthly reversion rates to episodic migraine were typically higher among patients receiving 140 mg versus 70 mg. Among 181 completers (receiving erenumab for 64 weeks), 98 (54.1% [95% confidence interval: 46.6–61.6]) had reversion to episodic migraine during the double-blind treatment phase; of those, 96.9% (95% confidence interval: 91.3–99.4) had persistent reversion to episodic migraine, 96.8% (95% confidence interval: 91.1–99.3) of whom had long-term persistent reversion to episodic migraine. Delayed reversion to episodic migraine occurred in 36/83 (43.4% [95% confidence interval: 32.5–54.7]) patients; of these, 77.8% (95% confidence interval: 60.9–89.9) persisted in reversion through week 64. Conclusions Patients with reversion to episodic migraine at week 12 will likely persist as episodic migraine with longer-term erenumab; others may achieve delayed reversion to episodic migraine. Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02066415

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.

Objective The objective of this study was to evaluate the efficacy, tolerability, and safety of 120 mg DFN‐15 vs placebo for the acute treatment of migraine. Background Certain nonsteroidal anti‐inflammatory drugs (NSAIDs) are guideline‐recommended therapies for the acute treatment of migraine, but patients who use them may have issues with gastrointestinal tolerability. Celecoxib, a selective inhibitor of cyclooxygenase‐2, produces analgesia similar to nonselective NSAIDs. DFN‐15 is an oral, ready‐made liquid solution of celecoxib being investigated for the acute treatment of migraine. Methods A randomized, double‐blind, placebo‐controlled, efficacy, tolerability, and safety study in adults with migraine was conducted. Subjects treated a single migraine attack with 120 mg DFN‐15 or placebo as soon as possible after the onset of pain of moderate to severe intensity. The 2 independent coprimary efficacy endpoints were the proportion of subjects with freedom from pain and the absence of the most bothersome symptom (MBS) at 2 hours postdose. A second double‐blind treatment period followed the first, but did not contribute to the primary outcomes and will be reported elsewhere. Results There were 622 subjects randomized (1:1) to double‐blind treatment with either 120 mg DFN‐15 or placebo, and 567 (91.2%) treated a migraine with study drug (n = 285 DFN‐15; n = 282 placebo). Groups were balanced in demographic characteristics; the mean age was 40, and most subjects were female (87% [494/567]). At 2 hours postdose, DFN‐15 was significantly superior to placebo for pain freedom (35.6% [98/275] vs 21.7% [57/263], P < .001), with an odds ratio (95% CI) of 2.00 (1.36, 2.94) and for freedom from the MBS (57.8% [134/232] vs 44.8% [104/232], P = .007), with an odds ratio (95% CI) of 1.68 (1.17, 2.43). A total of 13.3% (38/285) of DFN‐15‐treated subjects and 8.9% (25/282) of placebo‐treated subjects reported a treatment‐emergent adverse event (TEAE). Study drug‐related TEAEs were reported by 9.1% (26/285) of DFN‐15 subjects and 6.0% (17/282) of placebo subjects, the most common of which were dysgeusia (4.2% [12/285] vs 1.4% [4/282]) and nausea (3.2% [9/285] vs 1.8% [5/282]). No subjects treated with DFN‐15 reported TEAEs that were severe or led to withdrawal, and no serious TEAEs or deaths were reported in the study. Conclusions DFN‐15 was significantly more effective than placebo for the acute treatment of migraine, with a generally favorable tolerability and safety profile.

Objective To understand treatment preferences of people with migraine and the relative importance of improvements in efficacy and avoiding adverse events (AEs), such as cognition problems or weight gain. Background Current preventive migraine medicines are associated with poor adherence and tolerability. There is an unmet need for effective migraine‐specific preventive treatments with fewer AEs. Methods In a web‐based discrete‐choice experiment survey, respondents who self‐reported having ≥6 migraine days/month were offered choices between pairs of hypothetical preventive migraine medicines. Six attributes, each with 3 levels, defined the medicines: reduction in headache days per month (10%, 25%, or 50%), frequency of limitations with physical activities (none, 1‐category improvement, or 2‐category improvement), cognition problems (no problems, thinking problems, or memory problems), weight gain (none, 5% body weight gain, or 10% body weight gain), how the medicine is taken (daily oral pill, once‐monthly injection, or twice‐monthly injection), and monthly out‐of‐pocket cost ($5, $60, or $175). The attributes and levels were informed by clinician input, the clinical literature, and 2 focus groups. An experimental design was used to create the pairs of hypothetical medicines for the discrete‐choice experiment questions. Random‐parameters logit was used to estimate the relative importance of the medicine attributes, and the results were used to predict the percentage of respondents who would select one medicine profile over another and to calculate willingness to pay for changes in attribute levels. Results The sample included 300 respondents; 72% indicated that migraines make physical activities difficult all or most of the time, and 81% had taken a prescription medicine to prevent migraine in the last 6 months. Respondents reported having, on average, approximately 16 headache days per month. Among noncost attributes, respondents valued a change from a 10% reduction in migraine days to a 50% reduction more highly than avoiding the worst levels of AEs, but were willing to trade off efficacy for less‐severe AEs. Avoiding memory problems was more important than avoiding thinking problems. Avoiding a 10% weight gain was more important than avoiding thinking and memory problems. Respondents preferred a once‐monthly injection or daily pill to twice‐monthly injection. Respondents, on average, were willing to pay $84 (95% confidence interval [CI], $64‐$103) per month to avoid a 10% weight gain, $59 (95% CI, $42‐$76) per month to avoid memory problems, $35 (95% CI, $20‐$51) per month to avoid a 5% weight gain, and $32 (95% CI, $18‐$46) per month to avoid thinking problems. Conclusions A preventive migraine medicine with improved efficacy and AE profile and a favorable mode of administration would be valuable to migraine sufferers. Patients may be willing to trade off efficacy for better AE profiles. Clinicians should work with patients to select treatments that meet each patient’s needs.

Objective To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications. Background ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention‐to‐treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients’ usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post‐dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications. Methods The ZOTRIP trial was a multicenter, randomized, double‐blind, placebo‐controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran–Mantel–Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo. Results In patients with nausea, 2‐hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group ( P = .005) (odds ratio = 5.11, 95% CI: 1.96–13.30), and 2‐hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo ( P = .009) (odds ratio = 2.86, 95% CI: 1.28–6.43). For those with severe pain, corresponding pain‐free values were 26% (10/39) and 15% (5/33) ( P = .249) (odds ratio = 2.14, 95% CI: 0.60–7.62), and MBS‐free values were 64% (25/39) and 42% (14/33) ( P = .038) (odds ratio = 2.86, 95% CI: 1.05–7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain‐free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively ( P = .006) (odds ratio = 4.29, 95% CI: 1.50–12.31), and 72% (26/36) vs 39% (17/44) were MBS‐free, respectively ( P = .003) (odds ratio = 4.40, 95% CI: 1.61–12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively ( P = .017) (odds ratio = 4.33, 95% CI: 1.24–15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group ( P = .014) (odds ratio = 3.37, 95% CI: 1.27–8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction. Conclusion Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2‐hour headache freedom and 2‐hour MBS freedom) compared with those who received placebo.

Objective This study aimed to identify the essential content and amount of information to be collected from people with migraine via a patient‐facing smartphone‐based migraine tracker for them to share with clinicians during live discussions to assist in optimizing migraine management. The proposed tracker is intended for use in non‐interventional research to evaluate disease burden in episodic migraine and chronic migraine patients as assessed by demographic and clinical characteristics and health resource utilization in an integrated delivery network setting. The proposed tracker is not intended for commercial purposes. Background Epidemiological studies suggest migraine is underdiagnosed and undertreated. Studies of patient‐clinician interactions suggest that effective medical communication may help address these issues. Methods Four migraine practice leaders, an epidemiologist with extensive migraine experience, and a measurement expert took part in a modified Delphi panel process to identify data elements that could be collected from people with migraine through a smartphone‐based migraine tracker. Importantly, the proposed tracker would not be intended to replace the patient‐clinician encounter but to support the encounter through enabling the patient to document migraine symptoms and experiences in a timely and accurate manner for sharing with a clinician as part of a broader face‐to‐face discussion. The panel reviewed questions derived from the existing migraine diaries in the public domain, those used in clinical trials, and patient‐centric surveys assessing the impact of migraine on physical function and other related concepts. Key considerations included identification of the most clinically useful data elements for a shared communication tool for people with migraine under the care of a clinician. The panel also identified numerous functionality requirements for such a tool and provided recommendations on the most effective way to present results to a clinician. Results The expert panel opined that people with migraine may value the ability to capture a relatively broad range of information for their own migraine‐tracking purposes, while clinicians will likely find greater value in a small set of data relevant to the management of migraine. The panel identified the 3 most essential concepts in categories of data for a clinician, for which they coined the term “The 3 Fs”: F requency of days with headache; F requency of acute medication usage; and F unctional impairment. Information on the frequency of days with headache was felt to combine with the information on the frequency of acute medication usage to provide essential insights into current migraine management strategy and its outcomes, and to assist considerations of preventive measures. Functional impairment was treated as an effective surrogate for headache severity and was assessed based on the following: degree of difficulty in performing activities of daily living, impact on absenteeism (taking leave from work or cancelling/avoiding other activities) and presenteeism (performing work or other daily activities, with reduced productivity/capability), and amount of rest required as a result of a migraine attack. The modified Delphi panel process resulted in the selection of 13 questions in 8 categories to elicit sufficient and meaningful data comprising headache occurrence, symptoms, daily/preventive and as‐needed/acute medication usage, triggers, ability to concentrate, and functional impairment. The panel also agreed that the tracker should generate 2 distinct reports: one for people with migraine that would include a wider range of data about symptoms and perceived triggers, and a targeted report for the clinician that would place prime emphasis on the 3 Fs for aggregating the results of each headache occurrence and the trend over time. Conclusions A system that easily captures critical data elements about migraine, with specific feedback displays for patients to share with clinicians during live discussions, may offer some benefit to people with migraine and their clinicians by facilitating more objective communication and optimizing management. The tracker’s output may enable people with migraine to track a wide range of data for their own purposes, allowing them to better understand their condition, while a synthesized view of the selected data may support more informed clinical decision‐making for the clinician and individualized, evidence‐based discussion with the patient. As a result, this shared decision‐making tool may enable patients to more accurately convey essential migraine information during live patient‐clinician discussions to drive improved management and patient outcomes.

Objective To better understand the utility of using pain freedom and most bothersome headache‐associated symptom (MBS) freedom as co‐primary endpoints in clinical trials of acute migraine interventions. Background Adhesive dermally applied microarray (ADAM) is an investigational system for intracutaneous drug administration. The recently completed pivotal Phase 2b/3 study (ZOTRIP), evaluating ADAM zolmitriptan for the treatment of acute moderate to severe migraine, was one of the first large studies to incorporate MBS freedom and pain freedom as co‐primary endpoints per recently issued guidance by the US Food and Drug Administration. In this trial, the proportion of patients treated with ADAM zolmitriptan 3.8 mg, who were pain‐free and MBS‐free at 2 hours post‐dose, was significantly higher than for placebo. Methods We undertook a post‐hoc analysis of data from the ZOTRIP trial to examine how the outcomes from this trial compare to what might have been achieved using the conventional co‐primary endpoints of pain relief, nausea, photophobia, and phonophobia. Results Of the 159 patients treated with ADAM zolmitriptan 3.8 mg or placebo, prospectively designated MBS were photophobia (n = 79), phonophobia (n = 43), and nausea (n = 37). Two‐hour pain free rates in those with photophobia as the MBS were 36% for ADAM zolmitriptan 3.8 mg and 14% for placebo ( P = .02). Corresponding rates for those with phonophobia as the MBS were 14% and 41% ( P = .05). For those whose MBS was nausea, corresponding values were 56% and 16%, respectively ( P = .01). Two‐hour freedom from the MBS for active drug vs placebo were 67% vs 35% ( P < .01) for photophobia, 55% vs 43% ( P = .45) for phonophobia, and 89% vs 58% for nausea ( P = .04). MBS freedom but not pain freedom was achieved in 28%. Only 1 patient (1%) achieved pain freedom, but not MBS freedom. The proportion with both pain and MBS freedom was highest (56%) among those whose MBS was nausea. Conclusion In this study, the use of MBS was feasible and seemed to compare favorably to the previously required 4 co‐primary endpoints.