Dodick, David W.

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

Background Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine. Methods An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine. Results Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created. Conclusions Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.

Background Ictal cutaneous allodynia, common in chronic migraine, is associated with reduced responses to acute treatment with triptans. Allodynia’s impact on the efficacy of newer preventive treatments such as erenumab is unknown. Methods Post-hoc subgroup analysis of a double-blind, randomized, placebo-controlled 12-week study of erenumab in chronic migraine, contrasting those with no allodynia with those with moderate-severe allodynia assessed with the Allodynia Symptom Checklist-12, was undertaken. Results Of 648 randomized individuals with baseline Allodynia Symptom Checklist-12 scores, 386 (59.6%) had no allodynia and 153 (23.6%) had moderate-to-severe allodynia. Mean (standard deviation) baseline monthly migraine days were 17.6 (4.8) and 18.9 (4.3), respectively. Compared to placebo, the erenumab group had greater reductions in monthly migraine days and monthly acute migraine-specific medication days in both no allodynia and allodynia subgroups. Mean (95% confidence interval) treatment differences in change from baseline for monthly migraine days at week 12 were −2.5 (−3.7, −1.4) in the no allodynia subgroup and −3.3 (−5.3, −1.3) in the moderate-severe allodynia subgroup. Change in acute migraine-specific medication days were −3.3 (−4.3, −2.3) and −2.5 (−4.3, −0.8), respectively. Conclusions Erenumab’s efficacy in reducing monthly migraine days and acute migraine-specific medication days in chronic migraine was not impacted by the presence of moderate-severe ictal allodynia. Trial registration: ClinicalTrials.gov NCT02066415

Objective “Pain interference” and “headache impact” refer to negative consequences that pain and headache have on one’s life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. Methods Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. Results PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. Conclusions Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Abstract Background and Objectives Prior studies have established an association between a history of abuse and the development of migraine. This cross‐sectional observational study explored the relationship between self‐reported abuse history with migraine‐related sensory hypersensitivity symptoms. Methods In total, 588 adult patients with migraine from the American Registry for Migraine Research completed questionnaires: Generalized Anxiety Disorder‐7, Patient Health Questionnaire‐2 for depression, Photosensitivity Assessment Questionnaire, Hyperacusis Questionnaire, and Allodynia Symptom Checklist. Using four binary screening questions, patients were asked to self‐report if they believed they had suffered emotional, physical, or sexual abuse in their lifetime. Differences in questionnaire scores between groups with and without a history of abuse were determined. Regression models adjusted for age, sex, and basic headache features analyzed the relationship between abuse history and sensory hypersensitivity symptoms. Moderation analysis explored the role of headache frequency in this relationship. Mediation analysis assessed the indirect (Mediated) effect (IE) of abuse on sensory hypersensitivity through depression or anxiety. Additional models analyzed relationships between sensory hypersensitivity symptoms and abuse subtypes or the number of abuse subtypes. Results Of 588 participants, 222 (38%) reported a history of abuse. Patients with a history of abuse reported statistically significantly greater average headache frequency (7.6 vs. 4.7 days, p = 0.030). Patients with a history of abuse also reported higher average or median questionnaire scores: anxiety (7.6 vs. 4.7, p < 0.001, d = 0.56), depression (1.7 vs. 1.3, p = 0.009, d = 0.24), photophobia (0.54 vs. 0.44, p < 0.001, d = 0.32), hyperacusis (19.6 vs. 14.9, p < 0.001, d = 0.49), ictal allodynia (6.0 vs. 3.0, p < 0.001, d = 0.46), and interictal allodynia (1.0 vs. 0.0, p < 0.001, d = 0.30). After controlling for patient age, sex and years lived with headache, abuse maintained a significant association with every sensory hypersensitivity measure. Headache frequency significantly moderated the relationship between a history of abuse with increased ictal allodynia ( p = 0.036). Anxiety significantly mediated the relationships between abuse with photophobia (IE = 0.03, 95% CI = 0.01–0.04), hyperacusis (IE = 1.51, 95% CI = 0.91–2.24), ictal allodynia (IE = 0.02, 95% CI = 0.01–0.04), and interictal allodynia (IE = 0.02, 95% CI = 0.01–0.06). Depression significantly mediated the relationship between abuse with photophobia (IE = 0.02, 95% CI = 0.01–0.03) and with hyperacusis (IE = 0.45, 95% CI = 0.11–0.88). The association between the individual subtypes of abuse and the number of subtypes of abuse with sensory hypersensitivity symptoms varied. Conclusion A history of abuse is associated with greater migraine‐related sensory hypersensitivity symptoms. To reduce the impact of abuse on migraine symptoms, future studies should explore mechanistic connections between abuse and migraine‐associated symptoms.

Abstract Objective To determine the potential efficacy of ubrogepant for acute treatment of migraine based on historical experience with triptans. Background Although triptans have improved migraine treatment, their efficacy and tolerability may limit their utility in some individuals. Ubrogepant is a small‐molecule, oral calcitonin gene–related peptide receptor antagonist approved by the Food and Drug Administration for acute treatment of migraine in adults. Methods This post hoc analysis of pooled data from the pivotal trials ACHIEVE I and II, identically designed, randomized, double‐blind, phase 3, single‐attack trials of ubrogepant in adults with a history of migraine with/without aura, examined the efficacy and tolerability of ubrogepant 50 mg versus placebo based on participants’ historical experience with triptans: triptan responder, triptan‐insufficient responder, and triptan naïve. Co‐primary efficacy endpoints were pain freedom and absence of most bothersome migraine‐associated symptom (MBS) 2 h post initial dose. Adverse events (AEs) within historical triptan experience subgroups were evaluated. Results In the pooled analysis population ( n = 1799), 682 (placebo, n = 350; ubrogepant 50 mg, n = 332), 451 (placebo, n = 223; ubrogepant, n = 228), and 666 (placebo, n = 339; ubrogepant, n = 327) participants were triptan responders, triptan‐insufficient responders, and triptan‐naïve, respectively. Response rates on co‐primary efficacy endpoints were higher for ubrogepant versus placebo across all groups. Treatment‐by‐subgroup interaction p values based on odds ratios for pain freedom ( p = 0.290) and absence of MBS ( p = 0.705) indicated no significant impact of historical triptan experience on ubrogepant efficacy. AE incidence for ubrogepant did not differ appreciably across historical triptan experience subgroups. Conclusions Ubrogepant efficacy and tolerability did not differ for the acute treatment of migraine in participants classified as triptan responders, triptan‐insufficient responders, and triptan‐naïve based on their historical experience with triptans.

Abstract The brain vital signs framework is a portable, objective, neurophysiological evaluation of brain function at point-of-care. We investigated brain vital signs at pre- and post-season for age 14 or under (Bantam) and age 16–20 (Junior-A) male ice hockey players to (i) further investigate previously published brain vital sign results showing subconcussive cognitive deficits and (ii) validate these findings through comparison with head-impact data obtained from instrumented accelerometers. With a longitudinal study design, 23 male ice hockey players in Bantam (n = 13; age 13.63 ± 0.62) and Tier II Junior-A (n = 10; age 18.62 ± 0.86) divisions were assessed at pre- and post-season. None were diagnosed with a concussion during the season. Cognitive evoked potential measures of Auditory sensation (N100), Basic attention (P300) and Cognitive processing (N400) were analysed as changes in peak amplitudes and latencies (six standard scores total). A regression analysis examined the relationship between brain vital signs and the number of head impacts received during the study season. Significant pre/post differences in brain vital signs were detected for both groups. Bantam and Junior-A players also differed in number of head impacts (Bantam: 32.92 ± 17.68; Junior-A: 195.00 ± 61.08; P &lt; 0.001). Importantly, the regression model demonstrated a significant linear relationship between changes in brain vital signs and total head impacts received (R = 0.799, P = 0.007), with clear differences between the Bantam and Junior-A groups. In the absence of a clinically diagnosed concussion, the brain vital sign changes appear to have demonstrated the compounding effects of repetitive subconcussive impacts. The findings underscored the importance of an objective physiological measure of brain function along the spectrum of concussive impacts.

Aim Determine the role of calcitonin-gene related peptide in promoting post-traumatic headache and dysregulation of central pain modulation induced by mild traumatic brain injury in mice. Methods Mild traumatic brain injury was induced in lightly anesthetized male C57BL/6J mice by a weight drop onto a closed and unfixed skull, which allowed free head rotation after the impact. We first determined possible alterations in the diffuse noxious inhibitory controls, a measure of net descending pain inhibition called conditioned pain modulation in humans at day 2 following mild traumatic brain injury. Diffuse noxious inhibitory control was assessed as the latency to a thermally induced tail-flick that served as the test stimulus in the presence of right forepaw capsaicin injection that provided the conditioning stimulus. Post-traumatic headache-like behaviors were assessed by the development of cutaneous allodynia in the periorbital and hindpaw regions after mild traumatic brain injury. We then determined if intraperitoneal fremanezumab, an anti-calcitonin-gene related peptide monoclonal antibody or vehicle administered 2 h after sham or mild traumatic brain injury induction could alter cutaneous allodynia or diffuse noxious inhibitory control responses on day 2 post mild traumatic brain injury. Results In naïve and sham mice, capsaicin injection into the forepaw elevated the latency to tail-flick, reflecting the antinociceptive diffuse noxious inhibitory control response. Periorbital and hindpaw cutaneous allodynia, as well as a loss of diffuse noxious inhibitory control, was observed in mice 2 days after mild traumatic brain injury. Systemic treatment with fremanezumab blocked mild traumatic brain injury-induced cutaneous allodynia and prevented the loss of diffuse noxious inhibitory controls in mice subjected to a mild traumatic brain injury. Interpretation Sequestration of calcitonin-gene related peptide in the initial stages following mild traumatic brain injury blocked the acute allodynia that may reflect mild traumatic brain injury-related post-traumatic headache and, additionally, prevented the loss of net descending inhibition within central pain modulation pathways. As loss of conditioned pain modulation has been linked to multiple persistent pain conditions, dysregulation of descending modulatory pathways may contribute to the persistence of post-traumatic headache. Additionally, evaluation of the conditioned pain modulation/diffuse noxious inhibitory controls response may serve as a biomarker of vulnerability for chronic/persistent pain. These findings suggest that early anti-calcitonin-gene related peptide intervention has the potential to be effective both for the treatment of mild traumatic brain injury-induced post-traumatic headache, as well as inhibiting mechanisms that may promote post-traumatic headache persistence.

Abstract Background/Objective To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain‐related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient‐reported outcome measures (PROMs, general health and migraine/headache‐specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter‐rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine‐associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain‐related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one‐third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial‐to‐trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2‐hour post‐treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi‐item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain‐related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient‐centered and statistically robust could improve the conduct of individual trials, facilitate cross‐trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.