Headache/migraine-related stigma, quality of life, disability, and most bothersome symptom in adults with current versus previous high-frequency headache/migraine and medication overuse: results of the Migraine Report Card survey.

BACKGROUND: High-frequency headache/migraine (HFM) and overuse of acute medication (medication overuse [MO]) are associated with increased disability and impact. Experiencing both HFM and MO can potentially compound impacts, including stigma; however, evidence of this is limited. The objective of this report was to evaluate self-reported stigma, health-related quality of life (HRQoL), disability, and migraine symptomology in US adults with HFM + MO from the Harris Poll Migraine Report Card survey. METHODS: US adults (≥ 18 yrs., no upper age limit) who screened positive for migraine per the ID Migraine™ screener completed an online survey. Participants were classified into "current HFM + MO" (≥ 8 days/month with headache/migraine and ≥ 10 days/month of acute medication use over last few months) or "previous HFM + MO" (previously experienced HFM + MO, headaches now occur ≤ 7 days/month with ≤ 9 days/month of acute medication use). Stigma, HRQoL, disability, and most bothersome symptom (MBS) were captured. The validated 8-item Stigma Scale for Chronic Illnesses (SSCI-8) assessed internal and external stigma (scores ≥ 60 are clinically significant). Raw data were weighted to the US adult population. Statistically significant differences were determined by a standard t-test of column proportions and means at the 90% (p < 0.1) and 95% (p < 0.05) confidence levels. RESULTS: Participants (N = 550) were categorized as having current (n = 440; mean age 41.1 years; 54% female; 57% White, not Hispanic; 24% Hispanic; 11% Black, not Hispanic) or previous (n = 110; mean age 47.2 years; 49% female; 75% White, not Hispanic; 13% Hispanic; 4% Black, not Hispanic) HFM + MO. Compared to those with previous HFM + MO (21%), adults with current HFM + MO were more likely to experience clinically significant levels of stigma (47%). Men with current HFM + MO (52% compared to men with previous HFM + MO [25%] and women with current [41%] or previous [18%] HFM + MO), non-Hispanic Black (51% compared to White, not Hispanic [45%] and Hispanic [48%] current HFM + MO groups and White, not Hispanic previous HFM + MO [12%]), current HFM + MO aged 18-49 years (50% compared to those with current HFM + MO aged ≥ 50 years [33%] and those with previous HFM + MO aged 18-49 [34%] and ≥ 50 years [4%]), and employed respondents (53% current and 29% previous compared to those not employed [32% current and 12% previous]) reported higher rates of clinically significant stigma. Those with current HFM + MO were more likely to have worse HRQoL and disability due to headache/migraine. Respondents aged ≥ 50 years with current HFM + MO were more likely than respondents aged 18-49 years with current HFM + MO to indicate that their overall quality of life (66% vs. 52%) and their ability to participate in hobbies/activities they enjoy were negatively impacted by headache/migraine (61% vs. 49%). Pain-related symptoms were identified as the MBS. CONCLUSIONS: Together these data suggest that current and previous HFM + MO can be associated with undesirable outcomes, including stigma and reduced HRQoL, which were greatest among people with current HFM + MO, but still considerable for people with previous HFM + MO.

Long-term effectiveness of eptinezumab in the treatment of patients with chronic migraine and medication-overuse headache.

OBJECTIVE: This post hoc analysis of the PREVAIL study explored the effectiveness of eptinezumab for up to 2 years of open-label treatment in the subgroup of patients with chronic migraine who had a confirmed diagnosis of medication-overuse headache (MOH) at screening. BACKGROUND: MOH is a disabling and costly secondary headache disorder characterized by increased headache frequency and/or severity with increased acute headache medication use. Eptinezumab, an anti-calcitonin gene-related peptide monoclonal antibody, reduces headache frequency, severity, and associated disability and improves functioning and health-related quality of life as a preventive migraine therapy; short-term benefits in patients with concurrent MOH have also been reported. METHODS: Participants received up to eight quarterly intravenous infusions of eptinezumab 300 mg in the phase 3, single-arm, open-label PREVAIL study. Safety and patient-reported outcome measures (Migraine Disability Assessment [MIDAS], 6-item Headache Impact Test [HIT-6], patient-identified most bothersome symptom [PI-MBS], Patient Global Impression of Change [PGIC], and 36-item Short-Form Health Survey [SF-36]) were conducted at predefined intervals. Patients were observed up to 20 weeks after their last infusion (Week 104). RESULTS: A total of 49/128 (38.3%) patients enrolled in PREVAIL had an MOH diagnosis at screening. In the MOH subgroup, long-term eptinezumab treatment was associated with reductions in headache frequency (43/49 [87.8%] patients reported ≥50% reduction in MIDAS-derived headache days at ≥1 visit), severity (2.2-point reduction [on a 10-point scale]), disability (mean MIDAS total score reduction of 51.9 points), and impact (mean HIT-6 total score reduction of 9.7 points) at Week 104. Most patients described a "much improved" or "very much improved" status by Week 48 (PI-MBS, 31/46 [67.4%]) and Week 104 (PGIC, 31/36 [86.1%]). Health-related quality of life improvements in the SF-36 were also observed. CONCLUSION: Eptinezumab preventive therapy in patients with chronic migraine showed benefits that extended to the subset of patients with concomitant MOH.

Harris Poll Migraine Report Card: population-based examination of high-frequency headache/migraine and acute medication overuse.

BACKGROUND: Migraine is a disabling neurologic disease that can fluctuate over time in severity, frequency, and acute medication use. Harris Poll Migraine Report Card was a US population-based survey to ascertain quantifiable distinctions amongst individuals with current versus previous high-frequency headache/migraine and acute medication overuse (HFM+AMO). The objective of this report is to compare self-reported experiences in the migraine journey of adults with HFM+AMO to those who previously experienced HFM+AMO but currently have a sustained reduction in headache/migraine frequency and acute medication use. METHODS: An online survey was available to a general population panel of adults (≥18 years) with migraine per the ID Migraine™ screener. Respondents were classified into "current HFM+AMO" (within the last few months had ≥8 headache days/month and ≥10 days/month of acute medication use; n=440) or "previous HFM+AMO" (previously had HFM+AMO, but within the last few months had ≤7 headache days/month and ≤9 days/month of acute medication use; n=110). Survey questions pertained to demographics, diagnosis, living with migraine, healthcare provider (HCP) communication, and treatment. RESULTS: Participants in the current HFM+AMO group had 15.2 monthly headache days and 17.4 days of monthly acute medication use in last few months compared to 4.2 and 4.1 days for the previous HFM+AMO group, respectively. Overall, current preventive pharmacologic treatment use was low (15-16%; P>0.1 for current vs previous) in both groups. Previous HFM+AMO respondents reported better current acute treatment optimization. More respondents with current (80%) than previous HFM+AMO (66%) expressed concern with their current health (P<0.05). More than one-third of both groups wished their HCP better understood their mental/emotional health (current 37%, previous 35%; P>0.1 for current vs previous) and 47% (current) to 54% (previous) of respondents worried about asking their HCP too many questions (P>0.1 for current vs previous). CONCLUSION: Apart from optimization of acute medication, medical interventions did not significantly differentiate between the current and previous HFM+AMO groups. Use of preventive pharmacological medication was low in both groups. Adults with current HFM+AMO more often had health concerns, yet both groups expressed concerns of disease burden. Optimization of acute and preventive medication and addressing mental/emotional health concerns of patients are areas where migraine care may impact outcomes regardless of their disease burden.

Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial.

OBJECTIVE: To evaluate the effect of eptinezumab on patient-reported outcomes in patients with chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect. METHODS: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient-reported outcomes: 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), patient-identified most bothersome symptom (PI-MBS), and 36-item Short-Form Health Survey (SF-36). RESULTS: A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE-2 population [n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT-6 total scores by week 4 and remained improved throughout the 24-week study. Responder rates for individual HIT-6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab-treated patients indicated the PGIC was "much" or "very much" improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI-MBS and SF-36 scores. CONCLUSIONS: This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient-reported outcomes.

Patient preferences for attributes of injected or infused preventive migraine medications: Findings from a discrete choice experiment.

OBJECTIVE: To assess preferences among adults with migraine for differentiating attributes of injected or infused preventive treatment options and evaluate their importance in determining a treatment choice. BACKGROUND: Adults with migraine and health-care providers consider many factors when making treatment decisions. Injected or infused preventive migraine treatment options differ in several attributes, including mode of administration and dosing frequency, which may be preferentially selected or avoided by patients. Understanding a patient's preference is important for clinicians as they advise on various treatment options. METHODS: A total of 604 US adults diagnosed with migraine participated in an online survey that captured information on demographics, migraine history, and treatment preferences. A discrete choice experiment (DCE) was used to evaluate participants' preferences for specific attributes of injected/infused preventive migraine therapies. The DCE data were utilized to estimate attribute importance (expressed as a percentage) and identify subgroups that had different distributions of preferences. RESULTS: In the overall migraine population, mode of administration (28.8%), durability of effectiveness (27.0%), and speed of onset (25.5%) had the highest relative importance, whereas administration setting (9.9%) and dosing frequency (8.8%) had the lowest. Four distinct subgroups were identified: Group 1 (n = 128) preferred self-injection administration and durability of effectiveness; Group 2 (n = 189) expressed aversion to cranial injections; Group 3 (n = 158) prioritized rapid speed of onset; and Group 4 (n = 129) favored health-care provider administration and durability of effectiveness. CONCLUSIONS: Speed of onset, durability of effectiveness, and mode of administration are key moderators of treatment preference among US adults with migraine. Certain segments of the migraine population prioritize specific treatment attributes over others, with intravenous infusion not considered a barrier in three of four identified segments. Clinicians can best help their patients find the right medication if they understand which medication attributes are most and least important to them.

Using artificial intelligence to identify patients with migraine and associated symptoms and conditions within electronic health records.

BACKGROUND: Real-world evidence (RWE)-based on information obtained from sources such as electronic health records (EHRs), claims and billing databases, product and disease registries, and personal devices and health applications-is increasingly used to support healthcare decision making. There is variability in the collection of EHR data, which includes "structured data" in predefined fields (e.g., problem list, open claims, medication list, etc.) and "unstructured data" as free text or narrative. Healthcare providers are likely to provide more complete information as free text, but extracting meaning from these fields requires newer technologies and a rigorous methodology to generate higher-quality evidence. Herein, an approach to identify concepts associated with the presence and progression of migraine was developed and validated using the complete patient record in EHR data, including both the structured and unstructured portions. METHODS: "Traditional RWE" approaches (i.e., capture from structured EHR fields and extraction using structured queries) and "Advanced RWE" approaches (i.e., capture from unstructured EHR data and processing by artificial intelligence [AI] technology, including natural language processing and AI-based inference) were evaluated against a manual chart abstraction reference standard for data collected from a tertiary care setting. The primary endpoint was recall; differences were compared using chi square. RESULTS: Compared with manual chart abstraction, recall for migraine and headache were 66.6% and 29.6%, respectively, for Traditional RWE, and 96.8% and 92.9% for Advanced RWE; differences were statistically significant (absolute differences, 30.2% and 63.3%; P < 0.001). Recall of 6 migraine-associated symptoms favored Advanced RWE over Traditional RWE to a greater extent (absolute differences, 71.5-88.8%; P < 0.001). The difference between traditional and advanced techniques for recall of migraine medications was less pronounced, approximately 80% for Traditional RWE and ≥ 98% for Advanced RWE (P < 0.001). CONCLUSION: Unstructured EHR data, processed using AI technologies, provides a more credible approach to enable RWE in migraine than using structured EHR and claims data alone. An algorithm was developed that could be used to further study and validate the use of RWE to support diagnosis and management of patients with migraine.

Reduction in migraine-associated burden after eptinezumab treatment in patients with chronic migraine.

OBJECTIVE: To examine changes in the occurrence, severity, and symptoms of headache episodes in patients with chronic migraine following eptinezumab treatment. METHODS: PROMISE-2 was a double-blind, placebo-controlled, parallel-group trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo IV every 12 weeks for up to 24 weeks (2 infusions). Headache episodes (migraine and non-migraine) and their characteristics were reported in daily electronic diaries during the 28-day baseline and throughout the 24-week treatment period. RESULTS: A total of 1072 patients were included in this post hoc analysis. Mean monthly headache days decreased by 8.9 (100 mg) and 9.7 (300 mg) compared to a 7.3 decrease in placebo over the first 4-week interval post initial dose and reductions were maintained throughout the 24-week treatment period. Mean monthly headache episodes also decreased by 8.4 (100 mg) and 9.0 (300 mg) compared to a decrease of 7.1 with placebo. The proportion of headache episodes that were migraine attacks decreased by 11.2% (100 mg), 12.4% (300 mg), and 3.9% (placebo), and among remaining headaches decreases in severe pain, nausea, phonophobia, photophobia, and physical activity limitations were numerically greater than placebo. CONCLUSIONS: Patients with chronic migraine treated with eptinezumab decreased the monthly severity and frequency of headache days and episodes more than placebo. Beyond decreased headache frequency, patients treated with eptinezumab reported a reduction in the percent of remaining headache episodes that were migraine attacks, as well as a decrease in burdensome symptoms of headache episodes, indicating additional decreased headache severity after eptinezumab treatment.Trial registration: ClinicalTrials.gov Identifier: NCT02974153; registered November 23, 2016.

Efficacy and safety of eptinezumab in patients with migraine and self-reported aura: Post hoc analysis of PROMISE-1 and PROMISE-2.

BACKGROUND: This post hoc subgroup analysis evaluated the efficacy and safety of eptinezumab for migraine prevention in patients with migraine and self-reported aura. METHODS: PROMISE-1 (NCT02559895; episodic migraine) and PROMISE-2 (NCT02974153; chronic migraine) were randomized, double-blind, placebo-controlled trials that evaluated eptinezumab for migraine prevention. In both studies, the primary outcome was the mean change from baseline in monthly migraine days over Weeks 1-12. Patients in this analysis included those who self-reported migraine with aura at screening. RESULTS: Of patients with episodic migraine, ∼75% reported a history of aura at screening; of patients with chronic migraine, ∼35% reported a history of aura. Changes in monthly migraine days over Weeks 1-12 were -4.0 (100 mg) and -4.2 (300 mg) with eptinezumab versus -3.1 with placebo in patients with episodic migraine with aura, and were -7.1 (100 mg) and -7.6 (300 mg) with eptinezumab versus -6.0 with placebo in patients with chronic migraine with aura. Treatment-emergent adverse events were reported by 56.0% (100 mg), 57.4% (300 mg), and 55.4% (placebo) of patients. CONCLUSIONS: The preventive migraine efficacy of eptinezumab in patients in the PROMISE studies who self-reported aura was comparable to the overall study populations, demonstrating a similarly favorable safety and tolerability profile.Trial registration: ClinicalTrials.gov Identifiers: NCT02559895 and NCT02974153.

Long-term reductions in disease impact in patients with chronic migraine following preventive treatment with eptinezumab.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide humanized monoclonal antibody approved for the preventive treatment of migraine in adults. The PREVAIL study demonstrated a favorable safety profile with sustained reductions in overall migraine-related burden in patients with chronic migraine (CM). This post hoc analysis aimed to examine item-level changes in the Migraine Disability Assessment (MIDAS) questionnaire over 2 years in participants with CM on eptinezumab treatment. METHODS: PREVAIL was an open-label, phase 3 trial that included 96 weeks of treatment where 128 adults received intravenous eptinezumab administered over 30 min every 12 weeks (wks) for up to 8 doses of 300 mg. MIDAS was administered at baseline, Wk12, and every 12wks thereafter. Two supplementary MIDAS items not included in the total score calculation assessed number of headache days in the past 3 months (MIDAS headache) and average headache pain severity (from 0 [none] to 10 [worst]). MIDAS total scores were summed from 5 items, each quantifying the number of days in the past 3 months with migraine-related disability. Items 1, 3, and 5 assessed absenteeism, namely how many days the patient missed work/school (Q1), household work (Q3), or family/social/leisure activities (Q5). Items 2 and 4 were measures of presenteeism, namely how many days the patient had reduced productivity in work/school (Q2) or household work (Q4). RESULTS: Mean MIDAS headache days decreased from 47.4 (baseline) to 17.1 (Wk12) and 16.3 (Wk104). The average headache pain severity score (0‒10) decreased from a mean of 7.3 (baseline) to 5.5 (Wk12) to 4.5 (Wk104). Mean MIDAS scores measuring absenteeism (Q1, 3, 5) changed from 9.7 days at baseline to 3.2 days (Wk12) and to 3.9 days (Wk104). Mean MIDAS scores measuring presenteeism (Q2, 4) at Wk12 decreased from 14.2 days at baseline to 5.2 days (Wk12, 104). Patients categorized with very severe MIDAS disability had a mean total MIDAS score of 84.8, with an average reduction of 56.7 days (Wk12), which was maintained at 32 days at Wk104. CONCLUSIONS: Long-term treatment with eptinezumab in patients with CM suggested sustained reductions in MIDAS-quantified disability, consistent with the sustained reductions in headache frequency and pain severity. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02985398 .

Shift in diagnostic classification of migraine after initiation of preventive treatment with eptinezumab: post hoc analysis of the PROMISE studies.

BACKGROUND: Monthly headache frequency directly correlates with personal/societal burden and impacts severity and preventive treatment decisions. This post hoc analysis identified shifts from higher to lower frequency headache categories over 6 months in patients with migraine participating in the PROMISE clinical trials receiving two eptinezumab doses. METHODS: Headache frequency at baseline and over study months 1-6 was categorized into 4 groups: chronic migraine (CM; ≥ 15 monthly headache days [MHDs]), high-frequency episodic migraine (HFEM; 10-14 MHDs), low-frequency episodic migraine (LFEM; 4-9 MHDs), and ≤ 3 MHDs. Outcomes included the percentage of patients within each MHD category, the percentage of patients improving by ≥ 1 MHD category, and the number of months with reduction of ≥ 1 MHD category. Data from patients who received approved eptinezumab doses (100 mg or 300 mg) or placebo were included. RESULTS: Mean headache frequency at baseline in PROMISE-1 was 10 MHDs; most patients were classified as having HFEM (48.6%) or LFEM (43.9%). At Month 1, 62/221 (28.1%), 75/222 (33.8%), and 45/222 (20.3%) patients who received eptinezumab 100 mg, 300 mg, and placebo had ≤ 3 MHDs, with 97/221 (43.9%), 108/222 (48.6%), and 84/222 (37.8%), respectively, falling below the diagnostic EM threshold at Month 6. More than one-third (79/221 [35.7%], 83/222 [37.4%], and 68/222 [30.6%] of patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively), had 6 months of reduction of ≥ 1 frequency category. At baseline in PROMISE-2, mean headache frequency was 20.5 MHDs. All patients (100%) in the eptinezumab 100 mg and placebo groups had CM, as did 99.4% of patients receiving eptinezumab 300 mg. At Month 1, 209/356 (58.7%), 216/350 (61.7%), and 167/366 (45.6%) patients treated with eptinezumab 100 mg, 300 mg, and placebo had ≤ 14 MHDs, with 240/356 (67.4%), 249/350 (71.1%), and 221/366 (60.4%), respectively, falling below CM threshold at Month 6. Additionally, 153/356 (43.0%), 169/350 (48.3%), and 116/366 (31.7%) patients in the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, had 6 months of reduction of ≥ 1 frequency category. CONCLUSION: In the PROMISE studies, episodic and chronic migraine patients treated with eptinezumab were more likely to reduce their headache frequency versus placebo, which directly and in a sustained way improved their diagnostic category classification. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02559895, NCT02974153.

Rapid resolution of migraine symptoms after initiating the preventive treatment eptinezumab during a migraine attack: results from the randomized RELIEF trial.

BACKGROUND: Eptinezumab is an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody approved for the preventive treatment of migraine. In the phase 3 RELIEF study, eptinezumab resulted in shorter time to headache pain freedom and time to absence of most bothersome symptom (MBS; including nausea, photophobia, or phonophobia) compared with placebo when administered during a migraine attack. The objective of this exploratory analysis was to examine the earliest time points that eptinezumab separated from placebo (P < .05) on headache- and migraine-associated symptoms when administered during a migraine attack. METHODS: RELIEF, a multicenter, parallel-group, double-blind trial, occurred from November 7, 2019, through July 8, 2020. Adults considered candidates for preventive treatment were randomized to eptinezumab 100 mg (N = 238) or placebo (N = 242) administered intravenously over 30 min within 1-6 h of migraine onset. Outcome measures included headache pain freedom/relief and absence of MBS, patient's choice of photophobia, phonophobia, or nausea, at regular intervals from 0.5 to 48 h after infusion start. Censoring was applied at time of acute rescue medication use. RESULTS: At hour 1, more eptinezumab-treated patients achieved headache pain freedom (9.7%), headache pain relief (38.7%), and absence of MBS (33.2%) versus placebo (4.1%, 26.9%, and 22.1%, respectively; P < .05 all), with separation from placebo (P < .05) through hour 48. Eptinezumab separated from placebo (P < .05) at hour 1 in absence-of-photophobia (29.4% vs 17.0%) and absence-of-phonophobia (41.2% vs 27.2%) and through hour 48. Initial separation from placebo (P < .05) in absence-of-nausea occurred at end-of-infusion (0.5 h; 36.7% vs 25.4%, respectively). CONCLUSION: Preventive treatment with eptinezumab initiated during a migraine attack resulted in more patients achieving headache pain freedom/relief and absence of MBS, with separation from placebo (P < .05) as early as 0.5-1 h following the start of infusion. Rapid resolution of headache- and migraine-associated symptoms by a peripherally acting, intravenously administered antibody suggest a peripheral site of pharmacological action for CGRP blockade. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 .

Likelihood of response with subsequent dosing for patients with migraine and initial suboptimal response with eptinezumab: A post hoc analysis of two placebo-controlled randomized clinical trials.

OBJECTIVE: To develop a multivariable model assessing factors predicting a second-dose response to eptinezumab treatment over weeks 13-24 in patients with migraine initially reporting a suboptimal response over weeks 1-12. BACKGROUND: Eptinezumab is a monoclonal antibody used for migraine prevention, administered every 12 weeks. In the PROMISE-1 and PROMISE-2 studies, the first-dose response to eptinezumab treatment (≥50% monthly migraine day [MMD] reduction over weeks 1-12) occurred in ~50-60% of patients with episodic (EM) and chronic migraine (CM), respectively. METHODS: This post hoc analysis included patients with suboptimal first-dose response (<50% MMD reduction over weeks 1-12) with EM and CM, with patient-reported outcome data at weeks 12 and 24. Eptinezumab 100 and 300 mg doses were pooled. RESULTS: The analysis included 416/888 patients (46.8%) from PROMISE-1 and 479/1072 patients (44.7%) from PROMISE-2 with suboptimal first-dose response. The proportion of suboptimal first-dose responders who were second-dose responders was 37.0% (71/192; eptinezumab) and 33.9% (42/124; placebo) in PROMISE-1 and 28.8% (79/274) and 18.5% (38/205) in PROMISE-2. Significant first-dose predictors of second-dose response were percent change in MMDs across weeks 1-12 (PROMISE-1, odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.95, 0.98, p = 0.0001; PROMISE-2, OR: 0.94, CI: 0.92, 0.96, p < 0.0001) and change in 6-item Headache Impact Test (HIT-6) total score (PROMISE-2 only, OR: 0.92; CI: 0.87, 0.98; p = 0.027). In PROMISE-1, the probability of second-dose response ranged from 21.7% in patients with first-dose 0% MMD change to 56.0% in patients with first-dose 45% MMD reduction. In PROMISE-2, depending on HIT-6 total score, probability of second-dose response ranged from 5.9-12.1% in patients with first-dose 0% MMD change to 54.2%-72.3% in patients with first-dose 45.0% MMD reduction. CONCLUSION: Individuals with migraine not experiencing ≥50% MMD response to their first dose of eptinezumab may benefit from a second dose.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

OBJECTIVE: To assess the utility of the novel patient-identified (PI) most bothersome symptom (MBS) measure from PROMISE-2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. BACKGROUND: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI-MBS could improve clinical decision-making. METHODS: In PROMISE-2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI-MBS was an exploratory outcome requiring each patient to self-report their MBS in response to an open-ended question. At baseline and week 12, patients rated overall improvement in PI-MBS. The relationships among PI-MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9-12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6-item Headache Impact Test total, EuroQol 5-dimensions 5-levels visual analog scale, and 36-item Short-Form Health Survey component scores were assessed. RESULTS: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI-MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI-MBS at week 12 correlated with changes in MMDs (ρ = -0.49; p < 0.0001) and other patient-reported outcomes. Controlling for changes in MMDs, PI-MBS improvement predicted other patient-reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI-MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. CONCLUSIONS: Improvement in PI-MBS at week 12 was associated with improvement in other patient-reported outcome measures, and PI-MBS may be an important patient-centered measure of treatment benefits in patients with chronic migraine.

Eptinezumab for migraine prevention in patients 50 years or older.

OBJECTIVE: To evaluate the efficacy and safety of eptinezumab versus placebo in patients ≥50 years old with episodic (EM) or chronic migraine (CM). MATERIALS AND METHODS: This post hoc analysis included data from two phase 3, parallel-group, randomized, double-blind, placebo-controlled studies in adults with EM (PROMISE-1) or CM (PROMISE-2). Patients ≥50 years at baseline treated with eptinezumab 100 mg, 300 mg, or placebo were pooled from both studies to evaluate efficacy and safety. RESULTS: A total of 385/1960 (19.6%) EM and CM patients who were ≥50 years old at baseline (range, 50-71 and 50-65 years, respectively) received eptinezumab 100 mg (n = 132), 300 mg (n = 127), or placebo (n = 126) over Weeks 1-12. Reductions in mean monthly migraine days (MMDs) in ≥50-year-old EM patients were -3.8 (100 mg) and -4.4 (300 mg) with eptinezumab versus -2.6 with placebo. In ≥50-year-old CM patients, mean changes in MMDs were -7.7 (100 mg) and -8.6 (300 mg) with eptinezumab versus -6.0 with placebo. Changes in MMDs were comparable to total study results. A ≥50% MMD reduction over Weeks 1-12 was achieved by 57.9% of eptinezumab-treated versus 35.7% of patients who received placebo, and a ≥75% reduction by 30.5% versus 13.5%, respectively. The incidence of treatment-emergent adverse events (TEAEs) in EM and CM patients ≥50 years old was similar across treatment groups, with ≥96% of TEAEs mild or moderate in severity. CONCLUSIONS: Treatment with eptinezumab was efficacious, tolerable, and safe in patients ≥50 years with EM or CM, congruent with results from the overall study population.

Patient-reported outcomes, health-related quality of life, and acute medication use in patients with a ≥ 75% response to eptinezumab: subgroup pooled analysis of the PROMISE trials.

BACKGROUND: PROMISE-1 and PROMISE-2 evaluated the preventive efficacy, tolerability, and safety of eptinezumab, a calcitonin gene-related peptide-targeted monoclonal antibody, in adults with episodic (EM) and chronic migraine (CM), finding significant reductions in migraine frequency. This post hoc analysis compared patient-reported outcomes (PROs), health-related quality of life (HRQoL) and acute medication use in patients with a ≥ 75% migraine responder rate (MRR) after treatment with eptinezumab to patients with a ≥ 50- < 75% MRR. METHODS: PROMISE-1 and PROMISE-2 were phase 3, randomized, double-blind, placebo-controlled studies. This analysis included patients from both studies treated with eptinezumab 100 mg or 300 mg who experienced ≥ 75% and ≥ 50-< 75% MRR over Weeks 1-12 (wks1-12). In both studies, HRQoL was measured by the 36-item Short-Form Health Survey (SF-36) and acute medication usage. PROMISE-2 also included the 6-item Headache Impact Test (HIT-6), patient-identified most bothersome symptom (PI-MBS), and Patient Global Impression of Change (PGIC). RESULTS: In PROMISE-1, a total of 115/443 (26.0%; 100 mg, n = 49, 300 mg, n = 66) and 120/443 (27.0%; 100 mg, n = 61, 300 mg, n = 59) eptinezumab-treated patients achieved ≥ 75% and ≥ 50-< 75% MRR over wks1-12, respectively. In PROMISE-2, a total of 211/706 (30.0%; 100 mg, n = 95; 300 mg, n = 116) and 209/706 (29.6%; 100 mg, n = 110, 300 mg, n = 99) eptinezumab-treated patients achieved ≥ 75% and ≥ 50-< 75% MRR over wks1-12, respectively. EM and CM patients with ≥ 75% and ≥ 50-< 75% MRR over wks1-12 showed reduced use of acute headache medication and increased HRQoL to normative levels across SF-36 domains of bodily pain, social functioning, and physical functioning. In CM patients with ≥ 75% and ≥ 50-< 75% MRR over wks1-12, the mean change in HIT-6 total score with eptinezumab (pooled) was - 11.7 and - 7.6, respectively. "Very much" or "much" improvement responses were reported in 41.8% and 16.5% on PI-MBS and 36.2% and 20.0% on PGIC in ≥ 75% and ≥ 50-< 75% MRR, respectively. CONCLUSION: Eptinezumab treatment induced a ≥ 75% MRR over wks1-12 in the majority of patients. This patient subgroup reported substantial improvements in PROs associated with headache-related life impact and HRQoL, and reductions in acute headache medication use, which were more marked than those in the ≥ 50-< 75% responders. This study supports the clinical meaningfulness of ≥ 75% MRR for patients with either EM or CM. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02559895 (PROMISE-1), NCT02974153 (PROMISE-2).

Development and validation of a novel model for characterizing migraine outcomes within real-world data.

BACKGROUND: In disease areas with 'soft' outcomes (i.e., the subjective aspects of a medical condition or its management) such as migraine or depression, extraction and validation of real-world evidence (RWE) from electronic health records (EHRs) and other routinely collected data can be challenging due to how the data are collected and recorded. In this study, we aimed to define and validate a scalable framework model to measure outcomes of migraine treatment and prevention by use of artificial intelligence (AI) algorithms within EHR data. METHODS: Headache specialists defined descriptive features based on routinely collected clinical data. Data elements were weighted to define a 10-point scale encompassing headache severity (1-7 points) and associated features (0-3 points). A test data set was identified, and a reference standard was manually produced by trained annotators. Automation (i.e., AI) was used to extract features from the unstructured data of patient encounters and compared to the reference standard. A threshold of 70% close agreement (within 1 point) between the automated score and the human annotator was considered to be a sufficient extraction accuracy. The accuracy of AI in identifying features used to construct the outcome model was also evaluated and success was defined as achieving an F1 score (i.e., the weighted harmonic mean of the precision and recall) of 80% in identifying encounters. RESULTS: Using data from 2,006 encounters, 11 features were identified and included in the model; the average F1 scores for automated extraction were 92.0% for AI applied to unstructured data. The outcome model had excellent accuracy in characterizing migraine status with an exact match for 77.2% of encounters and a close match (within 1 point) for 82.2%, compared with manual extraction scores-well above the 70% match threshold set prior to the study. CONCLUSION: Our findings indicate the feasibility of technology-enabled models for validated determination of soft outcomes such as migraine progression using the data elements typically captured in the real-world clinical setting, providing a scalable approach to credible EHR-based clinical studies.

Early response to eptinezumab indicates high likelihood of continued response in patients with chronic migraine.

BACKGROUND: A clinical ability to describe the response trajectory of patients receiving preventive migraine treatment could expedite and improve therapeutic management decisions. This post hoc analysis of the PROMISE-2 study evaluated the consistency and predictive power of Month 1 treatment response on later response in patients with chronic migraine. METHODS: PROMISE-2 was a double-blind, placebo-controlled trial that randomized adults with chronic migraine to eptinezumab 100 mg, 300 mg, or placebo administered IV every 12 weeks for up to 24 weeks (2 infusions over 6 study months). Migraine responder rates (MRRs) were calculated from monthly migraine days over 4-week intervals compared with baseline. Patients were grouped by MRR during Month 1 (< 25%, 25-< 50%, 50-< 75%, and ≥ 75%), with the number of subsequent study months (Months 2-6) with ≥50% and ≥ 75% MRR calculated in each subgroup. A similar analysis was conducted using Patient Global Impression of Change (PGIC) rating to define Month 1 subgroups (very much improved, much improved, minimally improved, and no change/worse) and rates of very much improved or much improved PGIC during Months 2-6. RESULTS: In the eptinezumab 100 mg, 300 mg, and placebo groups, respectively, 194/356 (54.5%), 212/350 (60.6%), and 132/366 (36.1%) patients were ≥ 50% migraine responders during Month 1. More eptinezumab-treated patients were ≥ 75% migraine responders (100 mg, 110/356 [30.9%]; 300 mg, 129/350 [36.9%]; placebo, 57/366 [15.6%]) and more placebo-treated patients were < 25% migraine responders (eptinezumab 100 mg, 103/356 [28.9%]; 300 mg, 80/350 [22.9%]; placebo, 153/366 [41.8%]). Among patients who achieved ≥75% migraine response in Month 1, more than one-third attained ≥75% migraine response for all 5 subsequent study months and more than two-thirds achieved ≥75% migraine response for ≥3 months. More than two-thirds of those in the very much improved (PGIC) subgroup at Month 1 were much or very much improved for all 5 subsequent months. CONCLUSIONS: In this post hoc analysis of data from PROMISE-2, more eptinezumab-treated than placebo-treated patients were early (Month 1) responders, and most early responders went on to achieve a high level of response for at least half of the 24-week treatment period. Potential for later response in early non-responders was also observed. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02974153 ; registered November 23, 2016.

Optimization of acute medication use following eptinezumab initiation during a migraine attack: post hoc analysis of the RELIEF study.

BACKGROUND: The benefits of preventive treatment on the effectiveness of migraine management have rarely been examined. This post hoc analysis investigated the impact of eptinezumab on the optimization of acute medication effectiveness using the 4-item Migraine Treatment Optimization Questionnaire (mTOQ-4) to measure acute medication optimization over 4 weeks post-infusion. METHODS: RELIEF was a 12-week, phase 3, multicenter, parallel-group, double-blind, placebo-controlled clinical trial conducted in patients aged 18-75 years with a ≥ 1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized 1:1 to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack. The mTOQ-6 and 6-item Headache Impact Test (HIT-6) were administered at screening visit and week 4. From the mTOQ-6, we calculated the mTOQ-4 using the following items: "2-h pain free," "24-h relief," "able to plan," and "feeling in control" to measure acute medication optimization. RESULTS: A total of 238 patients received eptinezumab 100 mg and 226 provided week 4 data; 242 received placebo and 232 provided week 4 data. In the eptinezumab arm, the proportion of patients with moderate/maximal optimization increased from 31.4% at baseline to 58.0% (26.6 percentage point increase) at week 4. The corresponding proportions in the placebo group were 40.5% to 50.4% (9.9 percentage point increase). Eptinezumab treatment was associated with numerically larger improvements in HIT-6 at week 4. Relative improvements with eptinezumab vs. placebo from baseline to week 4 in HIT-6 were greater in those with poor treatment optimization at baseline. CONCLUSIONS: In comparison with placebo, treatment with eptinezumab was associated with improvements in acute medication optimization as measured by mTOQ and reductions in headache impact, as measured by HIT-6. These benefits were greater in those with poor acute treatment optimization prior to preventive treatment with eptinezumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT04152083 .

Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study.

BACKGROUND: Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2. METHODS: PROMISE-2 was a double-blind, placebo-controlled trial conducted in adults with CM. Patients were randomized to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously once every 12 weeks for up to two doses. Patients recorded headache/AHM information daily and for each event in an electronic diary; data from all days with daily reports were included. Shifts in headache frequency and AHM use were assessed in the three populations: total CM population, patients with CM and medication-overuse headache (MOH), and patients with CM and MOH who were ≥ 50% responders during treatment (response over weeks 1-24). RESULTS: A total of 1072 adults with CM received treatment (eptinezumab, n = 706; placebo, n = 366). Mean baseline headache frequency was 20.5 days; mean baseline AHM days was 13.4; 431 patients had MOH, of which 225 (52.2%) experienced ≥50% response over weeks 1-24. Relative to baseline, the proportion of days with both headache and AHM use decreased 25.1% (eptinezumab) versus 17.0% (placebo) in the total population (N = 1072), 29.2% versus 18.4% in the MOH subpopulation (n = 431), and 38.3% versus 31.5% in the CM with MOH population with ≥50% response subgroup (n = 225) during weeks 1-24. The proportion of days with headache and triptan use decreased 9.1% (eptinezumab) versus 5.8% (placebo), 11.8% versus 7.2%, and 14.5% versus 12.6%, respectively. Reductions in other AHM types were smaller. CONCLUSIONS: In this post hoc analysis, eptinezumab use in patients with CM was associated with greater decreases in days with headache with AHM overall and with triptans in particular. The magnitude of effect was greater in the subgroup of CM patients with MOH and ≥ 50% response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02974153 . Eptinezumab reduces headache frequency and acute medication use in patients with chronic migraine.

Eptinezumab treatment initiated during a migraine attack is associated with meaningful improvement in patient-reported outcome measures: secondary results from the randomized controlled RELIEF study.

BACKGROUND: Demonstrating therapeutic value from the patient perspective is important in patient-centered migraine management. The objective of this study was to investigate the impact of eptinezumab, a preventive migraine treatment, on patient-reported headache impact, acute medication optimization, and perception of disease change when initiated during a migraine attack. METHODS: RELIEF was a randomized, double-blind, placebo-controlled trial conducted between 2019 and 2020 in adults with ≥1-year history of migraine and 4-15 migraine days per month in the 3 months prior to screening. Patients were randomized (1:1) to a 30-min infusion of eptinezumab 100 mg or placebo within 1-6 h of a qualifying migraine attack onset. The 6-item Headache Impact Test (HIT-6) and 6-item Migraine Treatment Optimization Questionnaire (mTOQ-6) were administered at baseline and week 4, and the Patient Global Impression of Change (PGIC) at week 4. A post hoc analysis of these measures was conducted in patients who reported headache pain freedom at 2 h after infusion start. RESULTS: Of 480 patients enrolled and treated, 476 completed the study and are included in this analysis. Mean baseline HIT-6 total scores indicated severe headache impact (eptinezumab, 65.1; placebo, 64.8). At week 4, the eptinezumab-treated group demonstrated clinically meaningful improvement in HIT-6 total score compared with placebo (mean change from baseline: eptinezumab, - 8.7; placebo, - 4.5; mean [95% CI] difference from placebo: - 4.2 [- 5.75, - 2.63], P < .0001), with greater reductions in each item score vs placebo (P < .001 all comparisons). Change in HIT-6 total score in the subgroup with 2-h headache pain freedom was - 13.8 for the eptinezumab group compared with - 4.9 for the placebo group. mTOQ-6 total score mean change from baseline favored eptinezumab (change, 2.1) compared with placebo (1.2; mean [95% CI] difference: 0.9 [0.3, 1.5], P < .01). More eptinezumab-treated patients rated PGIC as much or very much improved than placebo patients (59.3% vs 25.9%). CONCLUSIONS: When administered during a migraine attack, eptinezumab significantly improved patient-reported outcomes after 4 weeks compared with placebo, with particularly pronounced effects in patients reporting headache pain freedom at 2 h after infusion start. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04152083 . November 5, 2019.