Dodick, David W.

Abstract Background Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method A systematic literature review, following a pre‐specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine‐specific outcome, 39.6% (106/268) examined ≥1 headache‐specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache‐related patient‐reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non‐headache‐specific PROM. Furthermore, 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 across publications. Conclusion Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross‐trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

Abstract Background Calcitonin gene‐related peptide (CGRP) inhibitors were introduced in the United States (US) in 2018. To understand the changing patterns of preventive treatment following the introduction of these new agents, we must first characterize the patterns which preceded their introduction. Objective To characterize the burden, unmet need, and treatment patterns in patients with migraine initiating preventive migraine medications before the introduction of CGRP inhibitors in the US. Methods Between March 2016 and October 2017, we enrolled episodic (EM) and chronic migraine (CM) patients initiating or changing preventive treatment at primary care or neurology clinic visits in the US, in a real‐world observational study using a prospective cohort design. At baseline and monthly thereafter for 6 months, we collected data from study sites and patients on migraine frequency, treatment modifications, migraine impact on functioning, and work productivity for a descriptive analysis of migraine patient experience and treatment patterns. Results From the sample of 234 completers, 118 had EM (50.4%) and 116 had CM (49.6%). Mean age at enrollment was 41 years (SD = 12) and mean age at first migraine diagnosis was 22 years (SD = 11). Most participants were females ( n = 204/234; 87.2%) and white ( n = 178/234; 76.1%). The majority ( n = 164/234; 70.1%) had not used preventive migraine treatment in the 5 years prior to enrollment (treatment naïve). At baseline, mean monthly migraine days were 9.6 days (SD = 5.0) for the preventive treatment naïve group and 12.4 days (SD = 7.0) for treatment experienced patients. The majority had severe Migraine Disability Assessment (Grade IV, total score ≥21), including 67.1% ( n = 110/164) of the preventive treatment naïve and 77.1% ( n = 54/70) of the preventive treatment experienced patients. Headache Impact Test total scores indicating severe impairment (score >59) occurred in 88.4% ( n = 145/164) of the treatment naïve and 88.6% ( n = 62/70) of treatment experienced patients. Mean work productivity loss as measured by the Work Productivity and Activity Impairment questionnaire in the subsample of employed patients was 53.3% loss. The most used acute medications at baseline were nonsteroidal anti‐inflammatory agents ( n = 124/234; 53.0%), acetaminophen‐based products ( n = 112/234; 47.9%), and triptans ( n = 105/234; 44.9%). The most commonly initiated preventive treatments were topiramate ( n = 100/234; 42.7%), tricyclic antidepressants ( n = 39/234; 16.7%), beta‐blockers ( n = 26/234; 11.1%), and onabotulinumtoxinA ( n = 24/234; 10.3%). Over the 6‐month follow‐up period, almost half of patients ( n = 116/234, 49.6%) modified their preventive treatment and discontinued treatment ( n = 88/312 total modifications; 28.2%) or modified their pattern of use by increasing, decreasing, or skipping doses ( n = 224/312 total modifications; 71.8%), often without seeking medical advice. Avoiding side effects was the main reason reported among patients who discontinued ( n = 52/88; 59.1%), decreased frequency or dose ( n = 37/89; 41.6%), and skipped doses ( n = 29/86; 33.7%). Perceived lack of efficacy was another frequent reason reported among those who discontinued ( n = 20/88; 22.7%), decreased frequency or dose ( n = 15/89; 16.9%), and skipped doses ( n = 18/86; 20.9%). Despite initiation of preventive treatment and improvements observed in number of headache and migraine days, migraine patients continued to experience substantial disability, headache impact, and reduced productivity throughout the 6‐month follow‐up period. Conclusions Prior to 2018, the burden of migraine was high for patients initiating preventive treatments. Despite having more than 9 days of migraine per month on average, the majority (70.1%) of patients initiating prevention had been treatment naïve, indicating underuse of preventive treatments. The preventive treatments used in this study were poorly tolerated and were reported by patients to lack efficacy, resulting in suboptimal adherence. The high discontinuation rates suggest that the preventive medications being offered during the period of the study did not meet the treatment needs of patients. In addition, the decisions by about half of patients to alter their prescribed treatment plan without consulting their provider can pose substantial health risks. These findings pertain to the broad set of preventive treatments initiated in this study and do not support inferences about individual preventive treatments, due to limitations in sample size. These findings suggest the need for more effective and better tolerated preventive treatment options.

Abstract Objective To assess the real‐world efficacy, tolerability, and safety of ubrogepant in a tertiary headache center. Background The efficacy and safety of ubrogepant for the acute treatment of migraine were established in phase 3 randomized controlled trials. However, there is no real‐world data of patient experience with ubrogepant in a population in which the majority of patients have chronic migraine, multiple prior unsuccessful treatments, complex medical comorbidities, and concurrent use of other migraine‐specific medications. Method This was a post‐market cohort study conducted at Mayo Clinic Arizona. All patients prescribed ubrogepant were tracked and contacted 1–3 months after the prescription to answer a list of standardized questions. Demographic information and additional headache history were obtained from chart review. Results We obtained eligible questionnaire responses from 106 patients. Chronic migraine accounted for 92/106 (86.8%) of the population. Complete headache freedom (from mild/moderate/severe to no pain) and headache relief (from moderate/severe to mild/no pain or mild to no pain) for ≥75% of all treated attacks at 2 hours after taking ubrogepant were achieved in 20/105 (19.0%) and 50/105 (47.6%) patients, respectively. A total of 33/106 (31.1%) patients reported being “very satisfied” with ubrogepant. Adverse events were reported in 42/106 (39.6%) patients, including fatigue in 29/106 (27.4%), dry mouth in 8/106 (7.5%), nausea/vomiting in 7/106 (6.6%), constipation in 5/106 (4.7%), dizziness in 3/106 (2.8%), and other adverse events in 7/106 (6.6%). Predictive factors for being a “good responder” to ubrogepant, defined as headache relief for ≥75% of all treated attacks at 2 hours after taking ubrogepant, included migraine with aura, episodic migraine, <5 prior unsuccessful preventive or acute treatment trials. Additionally, prior treatment responses to a CGRP monoclonal antibody and onabotulinumtoxinA injections are predictive of treatment responses and patient satisfaction to ubrogepant. For the 62/106 (58.5%) patients concurrently using a CGRP monoclonal antibody, there was no difference in the “good responder” rate or adverse event rate compared to those who were not on a CGRP monoclonal antibody, though the rate of moderate, as opposed to mild adverse events was higher, 11/62 (47.8%) versus 3/44 (17.6%), p = 0.048. Additionally, 16 patients had a history of significant cardiovascular or cerebrovascular diseases. No severe adverse events were reported in any patient. Conclusion Our study confirms and extends the efficacy profile and tolerability of ubrogepant in a real‐world tertiary headache clinic and identifies factors that may predict efficacy. Adverse event rates were higher than reported in clinical trials. Further studies are needed to confirm these findings and to evaluate the long‐term efficacy and safety of ubrogepant.

Abstract Objective To describe headache characteristics, medication use, disability, and quality of life in a large patient cohort from the United States who have chronic migraine (CM) and medication overuse headache (MOH). Methods In all, 610 adult patients were enrolled into the Medication Overuse Treatment Strategy trial from 34 healthcare clinics, including headache specialty, general neurology, and primary care clinics. Descriptive statistics characterize baseline demographics, headache characteristics, medication use, disability (Headache Impact Test 6 [HIT‐6] and Migraine Functional Impact Questionnaire [MFIQ]), pain interference (PROMIS Pain Interference), and quality of life (EQ‐5D‐5L). Relationships with headache frequency were assessed. Results Mean age was 45 years (SD 13) and 531/608 (87.3%) were females. Mean headache days per 30 was 24.3 (SD 5.5), including 13.6 (SD 7.1) with moderate to severe headache. Daily headaches were reported by 36.1% (219/607) of patients. Acute headache medications were used on 21.5 (SD 7.5) per 30 days. The most commonly overused medications were simple analgesics (378/607, 62% of patients), combination analgesics (246/607, 41%), and triptans (128/607, 21%). HIT‐6, MFIQ, PROMIS Pain Interference, and EQ‐5D‐5L scores demonstrated substantial negative impact from CM with MOH on patient functioning and quality of life. Higher headache frequency was associated with more moderate–severe headache days, more frequent acute headache medication use, greater headache‐related disability, and lower quality of life. Only 272/606 (44.9%) were taking migraine preventive medication. Conclusions CM with MOH is associated with a large burden on patients in the United States. Higher headache frequency is associated with greater impact on functioning, pain interference, and quality of life.

AbstractBackground and purposeAlthough erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long‐term therapy.MethodsThis study was an open‐label, 5‐year treatment phase following a 12‐week, double‐blind, placebo‐controlled trial in adults with episodic migraine. Patients initially received open‐label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine‐specific medication (AMSM) days, and health‐related quality of life.ResultsOf 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open‐label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was −5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was −4.4 (0.3) days at the end of 5 years. Patient‐reported outcomes indicated stable improvements in disability, headache impact, and migraine‐specific quality of life. Exposure‐adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient‐years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient‐years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure.ConclusionsTreatment with erenumab was associated with reductions in migraine frequency and improvements in health‐related quality of life that were maintained for at least 5 years. No new safety signals were observed.

Abstract Objective We sought to assess factors associated with the frequency of self‐reported prescription opioid use in persons with migraine, including demographic variables, comorbidities, headache characteristics, and patterns of consultation. Background Despite the dose‐dependent effect of opioids on migraine progression and the association with negative outcomes, migraine treatment often includes opioids. The Migraine in America Symptoms and Treatment Study focuses on individuals with migraine who receive prescription acute medications, including those receiving and those not receiving opioids. Methods This web‐based panel survey identified people in the United States with migraine using a validated screener. This analysis stratified people with migraine into 4 groups based on days of monthly opioid use: non‐opioid users, ≤3 days, 4‒9 days, and ≥10 days per month. Results Of 15,133 respondents with migraine, 4701 (31%) reported acute prescription medication use for headache/migraine in the previous 3 months (mean age 45 years, 71.6% [3367/4701] female), of whom 32.5% (1528/4701) reported opioid use. About one‐third of respondents with primary care or neurology consults in the prior 6 months reported receiving an opioid, and more than half of respondents (209/391, 53.5%) with a pain clinic consultation did so. Models compared those using opioids ≤3 days/month (879/4701, 18.7%), 4‒9 days/month (304/4701, 6.5%), ≥10 days/month (345/4701, 7.3%) to non‐opioid users (3173/4701, 67.5%). Compared to non‐opioid users, infrequent users (≤3 days/month) were more likely to be male and less likely to have chronic migraine or to screen positive for anxiety and depression; and frequent opioid users (the 4‒9 days/month and the ≥10 days/month groups) were more likely to be male, to smoke, to be obese, to report greater pain interference, to have moderate to severe disability, to have symptoms of anxiety and depression, to use fewer triptans and nonsteroidal anti‐inflammatory drugs, and to have poor acute treatment optimization. Conclusion Among prescription medication users, this cross‐sectional analysis shows that increasing use of prescription opioids is associated with male gender, chronic migraine, more severe disability, anxiety and depression, poor acute treatment optimization, and treatment in a pain clinic.

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 full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated. Methods ACHIEVE-I and -II were double-blind, single-attack, Phase 3 trials. Adults with migraine were randomised 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25 mg or 50 mg, ACHIEVE-II). Pain freedom, absence of most bothersome symptom, and pain relief were assessed at various timepoints. Samples were collected for pharmacokinetic analysis. Data were pooled for this post-hoc analysis. Results Participants’ (n = 912 placebo, n = 887 ubrogepant 50 mg, pooled analysis population) mean age was 41 years, with a majority female and white. Pain relief separated from placebo by 1 h (43% versus 37% [OR, 95% CI: 1.30, 1.0–1.59]), absence of most bothersome symptom by 1.5 h (28% versus 22% [1.42, 1.14–1.77]), and pain freedom by 2 h (20% vs. 13% [1.72, 1.33–2.22]). Efficacy was sustained from 2–24 h (pain relief: 1.71, 1.1–2.6; pain freedom: 1.71, 1.3–2.3) and remained separated at 48 h (pain relief: 1.7, 1.1–2.6; pain freedom: 1.31, 1.0–1.7). Pharmacokinetic analysis demonstrated maximum plasma concentrations were achieved at 1 h, with pharmacologically active concentrations reached within 11 min and remaining above the EC 90 for nearly 12 h. Conclusions Evaluation of the time course of effect of ubrogepant showed pain relief as the most sensitive and earliest measure of clinical effect, followed by absence of most bothersome symptom, and pain freedom. Efficacy was demonstrated out to 48 h, providing evidence of the long-lasting effect of ubrogepant. This evaluation supports the role of examining the entire time course of effect to understand fully the utility of an acute treatment for migraine. Trial registration: ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (ClinicalTrials.gov, NCT02867709)

Objective To determine the onset of preventive efficacy with eptinezumab in patients with migraine. Background Eptinezumab is a monoclonal antibody inhibiting calcitonin gene‐related peptide approved as an intravenously administered treatment for the prevention of migraine. Methods Patients who received eptinezumab 100 mg, eptinezumab 300 mg, or placebo in PROMISE7‐1 (episodic migraine; 100 mg, n = 221; 300 mg, n = 222; placebo, n = 222) or PROMISE7‐2 (chronic migraine; 100 mg, n = 356; 300 mg, n = 350; placebo, n = 366) were included. Testing of the percentage of patients with a migraine on day 1 after dosing was prespecified and alpha‐controlled. In further exploration of this prespecified endpoint, a post hoc closed testing procedure, which controlled the false‐positive (type 1) error rate, provided a statistically rigorous evaluation of migraine prevention onset. The procedure involved up to 84 tests of significance, all of which were performed in sequence until the first nonsignificant result. Results For both studies, all tests for significance for eptinezumab 100 and 300 mg, from days 1‐84 through day 1 alone, achieved nominal significance ( P < .05), indicating that eptinezumab was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1‐12. Mean changes from baseline in monthly migraine days for the primary endpoint period ranged from −3.9 to −4.9, −4.1 to −4.9, and −2.2 to −3.2 for eptinezumab 100, 300 mg, and placebo, respectively, in PROMISE7‐1 and from −7.2 to −8.0, −7.9 to −8.2, and −4.3 to −5.6, respectively, in PROMISE7‐2. The difference from placebo (95% confidence interval) in day 1 treatment effect was −2.2 (−4.1, −0.3) and −2.5 (−4.4, −0.6) days/month for eptinezumab 100 and 300 mg, respectively, in PROMISE7‐1, and was −3.8 (−5.6, −2.0) and −4.0 (−5.8, −2.1) days/month for 100 and 300 mg, respectively, in PROMISE7‐2. Conclusions The migraine preventive effect of eptinezumab is rapid and sustained in patients with episodic or chronic migraine, with onset of optimal preventive efficacy observed on the day following the initial dose.

Introduction Acute medication overuse is prevalent in patients with migraine. Methods In three phase 3, double-blind, randomized, placebo-controlled studies, patients with episodic migraine (EVOLVE-1 and EVOLVE-2) or chronic migraine (REGAIN) were randomized 2:1:1 to monthly subcutaneous injections of placebo or galcanezumab 120 or 240 mg for 3 or 6 months. This subgroup analysis evaluated mean changes in the number of monthly migraine headache days in each treatment among patients with versus without baseline acute medication overuse via mixing modelling with repeated measures. Results The percentages of patients with baseline medication overuse in placebo, galcanezumab 120-mg and 240-mg groups, respectively, were 19.4%, 17.3%, and 19.3% for EVOLVE-1/-2 (pooled; post hoc), and 63.4%, 64.3%, and 64.1% for REGAIN ( a priori). Both galcanezumab doses demonstrated significant improvement compared with placebo for overall least squares mean change in monthly migraine headache days in patients with baseline medication overuse in both the episodic and chronic migraine studies ( p ≤ 0.001). Furthermore, both galcanezumab doses reduced average monthly medication overuse rates compared to placebo ( p < 0.001) in both patient populations with medication overuse at baseline. Conclusions Galcanezumab appears to be effective for the preventive treatment of episodic and chronic migraine in patients who overuse acute medications. Trial registration: ClinicalTrials.gov Identifiers: NCT02614183, NCT02614196, and NCT02614261