Sustained response to atogepant in episodic migraine: post hoc analyses of a 12-week randomized trial and a 52-week long-term safety trial.

BACKGROUND: Atogepant is an oral calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine in adults. These analyses evaluated the proportions of clinical trial participants who experienced sustained responses to atogepant over 12 or 52 weeks of treatment. METHODS: These were post hoc analyses of ADVANCE, a 12-week, double-blind, randomized trial of atogepant 10, 30, and 60 mg once daily vs. placebo for the preventive treatment of episodic migraine, and a separate open-label long-term safety (LTS) trial of atogepant 60 mg once daily over 52 weeks. The 60 mg dose of atogepant was used to detect safety issues. An initial response was defined as ≥50%, ≥75%, or 100% reduction from baseline in MMDs in month 1 for ADVANCE or quarter 1 for the LTS trial. The proportions of participants who continued to experience a response above each response-defining threshold through each subsequent month (for ADVANCE) or each quarter (for LTS) were calculated. RESULTS: In ADVANCE, sustained response rates during months 2 and 3 varied with dose and were as follows: 70.8-81.1% following an initial ≥50% response, 47.3-61.9% following an initial ≥75% response, and 34.8-41.7% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during month 1, more than 79% continued to experience at least a 50% response during both months 2 and 3. During the LTS trial, sustained response rates through quarters 2, 3, and 4 were 84.7% following an initial ≥50% response, 72.6% following an initial ≥75% response, and 37.8% following an initial 100% response. Of those who experienced an initial ≥75% or 100% response during quarter 1, more than 90% continued to experience at least a 50% response through quarters 2, 3, and 4. CONCLUSION: Over 70% of participants who experienced an initial response with atogepant treatment had a sustained response with continued treatment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03777059 (submitted: December 13, 2018); NCT03700320 (submitted: September 25, 2018).

Comparative efficacy, quality of life, safety, and tolerability of atogepant and rimegepant in migraine prevention: A matching-adjusted indirect comparison analysis.

BACKGROUND: Comparative evaluations of preventive migraine treatments can help inform clinical decision making for managing migraine in clinical practice. METHODS: An anchored matching-adjusted indirect comparison analysis was conducted using pooled participant-level data from two phase 3 atogepant trials (ADVANCE and PROGRESS) and one phase 2/3 rimegepant trial (BHV3000-305) to evaluate the relative efficacy and safety/tolerability of atogepant and rimegepant as preventive migraine treatments. Participants receiving atogepant 60 mg once daily, rimegepant orally disintegrating tablet 75 mg once every other day, and placebo were included. Only participants meeting the BHV3000-305 inclusion/exclusion criteria were analyzed: ≥6 monthly migraine days and ≤18 monthly headache days at baseline. The primary efficacy assessment of interest was change in monthly migraine days across weeks 1-12. RESULTS: There were 252 participants in the atogepant group and 348 in the rimegepant group. Across weeks 1-12, atogepant 60 mg demonstrated a significantly greater reduction in mean monthly migraine days compared with rimegepant 75 mg (mean difference [95% CI]: -1.65 [-2.49, -0.81]; p < 0.001). Both atogepant and rimegepant demonstrated similar safety/tolerability profiles. CONCLUSION: In this matching-adjusted indirect comparison analysis, oral atogepant 60 mg once daily demonstrated a significantly greater reduction in monthly migraine days compared with rimegepant 75 mg orally disintegrating tablet once every other day.

A Novel Virtual-Based Comprehensive Clinical Approach to Headache Care.

One major innovation, a result of the coronavirus pandemic, has been the proliferation of telemedicine. Telehealth can help solve the access problems that plague headache medicine, allowing patients in areas with no headache expertise to consult and work with a headache specialist. This is a retrospective chart review of patients seen by Neura Health, a comprehensive app-based telehealth headache center. Patients are seen by a specialist and, in addition to any medical recommendations, are given care plans individualized to their condition and recommendations at the end of their clinical appointments. The primary outcome of this study is a decrease in monthly headache days after 90 days; secondary outcomes include disability as determined by MIDAS score, depression determined by PHQ-9, patients' utilization of emergency department or urgent care resources, as well as their global impression of improvement. The deidentified outcomes of consecutive patients of Neura Health were evaluated from March 2022-March 2023. Subjects were excluded if they did not complete all forms, or if they did not receive a clinical or coaching follow-up appointment within 90 days. A total of 186 consecutive patients at Neura Health were identified during the review period. The median decrease in monthly headache days was 55.0% after a 90 day period, headache severity was decreased by 16.7%, global impression of improvement increased by 60.9%, disability decreased by 38.7%, depression decreased by 12.5% and ER/urgent care visits were decreased by 66.1%. A comprehensive, telehealth-based virtual headache-care model significantly decreased migraine frequency, severity and disability, and is able to decrease ER or urgent care visits.

The temporal trend of placebo response in migraine prevention from 1990 to 2021: a systematic literature review and meta-analysis with regression.

BACKGROUND: Migraine affects 1.1 billion people globally and is the second leading cause of disability worldwide. In clinical trials, treatment efficacy is evaluated by comparing the differential responses in the treatment and placebo arms. Although placebo response in preventive migraine trials has been studied, there is limited research examining temporal trends. This study evaluates the trend of placebo response over thirty years in migraine prevention trials and investigates the association of potential confounders, such as patient, treatment, and study characteristics on placebo response using meta-analysis with regression. METHODS: We conducted literature searches from January 1990 to August 2021 in bibliographical databases (PubMed, Cochrane Library, and EMBASE). Studies were selected according to PICOS criteria and included randomized, double-blind, placebo-controlled trials evaluating preventive migraine treatments in adult patients diagnosed with episodic or chronic migraine, with or without aura. The protocol was registered with PROSPERO (CRD42021271732). Migraine efficacy outcomes included were either continuous (e.g., monthly migraine days) or dichotomous (e.g., ≥ 50% responder rate (yes/no)). We assessed the correlation of the change in outcome from baseline in the placebo arm, with the year of publication. The relationship between placebo response and year of publication was also assessed after accounting to confounders. RESULTS: A total of 907 studies were identified, and 83 were found eligible. For the continuous outcomes, the change from baseline in mean placebo response showed an increase over the years (rho = 0.32, p = 0.006). The multivariable regression analysis also showed an overall increase in placebo response over the years. The correlation analysis of dichotomous responses showed no significant linear trend between publication year and mean placebo response (rho = 0.08, p = 0.596). Placebo response also varied by route of administration. CONCLUSION: Placebo response increased over the past 30 years in migraine preventive trials. This phenomenon should be considered when designing clinical trials and conducting meta-analyses.

Safety and tolerability results of atogepant for the preventive treatment of episodic migraine from a 40-week, open-label multicenter extension of the phase 3 ADVANCE trial.

BACKGROUND: Atogepant is a United States Food and Drug Administration-approved oral calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. The study objective was to evaluate the long-term safety and tolerability of atogepant in participants who completed the phase 3 ADVANCE trial (NCT03777059). METHODS: This 40-week, open-label extension trial (NCT03939312) monitored safety in participants receiving oral atogepant 60 mg once daily, followed by a four-week safety follow-up period. RESULTS: Of the 685 participants taking at least one dose of atogepant, the treatment period was completed by 74.6% of participants with a mean (standard deviation) treatment duration of 233.6 (89.3) days. Treatment-emergent adverse events occurred in 62.5% of participants, with upper respiratory tract infection (5.5%), urinary tract infection (5.3%), nasopharyngitis (4.8%), sinusitis (3.6%), constipation (3.4%), and nausea (3.4%) occurring at ≥3%. Serious adverse events were observed in 3.4% of participants (none were treatment-related), and there were no deaths. Adverse events leading to discontinuation occurring at >0.1% were nausea (0.4%) and abdominal pain, vomiting, weight decrease, dizziness, and migraine (0.3% each). CONCLUSION: These results are consistent with atogepant's known safety profile and support long-term use of atogepant 60 mg once daily dosing as safe and well tolerated.ClinicalTrials.gov Registration Number: NCT03939312.

Inpatient Constipation Among Migraine Patients Prescribed Anti-calcitonin Gene-Related Peptide Monoclonal Antibodies and Standard of Care Antiepileptic Drugs: A Retrospective Cohort Study in a United States Electronic Health Record Database.

INTRODUCTION: Erenumab, an anti-calcitonin gene-related peptide (CGRP) receptor monoclonal antibody (mAb), was approved by the US Food and Drug Administration in May 2018. Constipation with serious complications was added to the Warning and Precautions section in the erenumab Prescribing Information in October 2019 after events were observed during post-marketing surveillance. We aimed to assess and compare the risk of inpatient constipation, and, separately, inpatient constipation with serious complications, among patients with migraine treated with CGRP mAbs and standard of care antiepileptic drugs (AEDs). METHODS: Within Optum's Electronic Health Record Research Database, patients with migraine who initiated erenumab, other CGRP mAbs, and AEDs were identified from May 2018 through March 2020. Erenumab initiators were propensity score-matched separately to initiators of other CGRP mAbs and AEDs. Incident inpatient constipation events, and serious complications, were identified using multiple risk windows for outcome assessment (30-, 60-, 90-day risk windows, and all available follow-up). Odds ratios (ORs) were calculated comparing inpatient constipation risk among matched erenumab initiators relative to comparators. RESULTS: We identified 17,902 erenumab, 13,404 other CGRP mAb, and 49,497 AED initiators who met study criteria. Among matched initiators, the risk of inpatient constipation was 0.46% (95% confidence interval (CI) 0.35-0.60) for erenumab and 0.44% (95% CI 0.33-0.58) for other CGRP mAbs within the 90-day risk window, with a corresponding OR of 1.06 (95% CI 0.72-1.55). Among matched erenumab and AED initiators, inpatient constipation risk was 0.53% (95% CI 0.42-0.66) and 0.76% (95% CI 0.62-0.92), respectively, and the OR was 0.69 (95% CI 0.51-0.94). Few serious complications were observed. CONCLUSION: Patients initiating erenumab had similar risk of inpatient constipation within 90 days of treatment initiation versus patients initiating other CGRP mAbs, and lower risk versus patients initiating AEDs. These findings provide context to events observed during post-marketing surveillance.

Role of Calcitonin Gene-Related Peptide on the Gastrointestinal Symptoms of Migraine-Clinical Considerations: A Narrative Review.

Calcitonin gene-related peptide (CGRP) is involved in several of the pathophysiological processes underpinning migraine attacks. Therapies that target CGRP or its receptor have shown efficacy as preventive or acute treatments for migraine. Two small-molecule CGRP receptor antagonists (rimegepant and ubrogepant) are approved for the acute treatment of migraine, and four monoclonal antibodies (eptinezumab, erenumab, fremanezumab, and galcanezumab) are approved for migraine prevention; erenumab targets the canonical CGRP receptor, the others CGRP ligand. CGRP plays a role in gastrointestinal nociception, inflammation, gastric acid secretion, and motility. Nausea and vomiting are among the gastrointestinal symptoms associated with migraine, but individuals with migraine may also experience functional upper and lower gastrointestinal comorbidities, such as gastroesophageal reflux disease, gastroparesis, functional diarrhea or constipation, and irritable bowel syndrome. Although gastrointestinal symptoms in migraine can be treatment-related, they may also be attributable to increased CGRP. In this review, we summarize the epidemiological evidence for associations between migraine and gastrointestinal disorders, consider the possible physiological role of CGRP in these associations, and review the clinical occurrence of gastrointestinal events in patients with migraine receiving CGRP-based therapies and other migraine treatments. Because patients with migraine are at an increased risk of comorbid and treatment-related gastrointestinal effects, we also propose a patient-management strategy to mitigate these effects.

Impact of fremanezumab on disability outcomes in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

BACKGROUND: Migraine is the second leading cause of disability worldwide. Although many preventive treatments reduce migraine frequency and severity, it is unclear whether these treatments reduce migraine-related disability in a clinically meaningful way. This pooled analysis evaluated the ability of fremanezumab to reduce migraine-related disability, based on responses and shifts in severity in patient-reported disability outcomes. METHODS: This pooled analysis included 3 double-blind phase 3 trials (HALO EM, HALO CM, FOCUS) in which patients with episodic or chronic migraine were randomly assigned 1:1:1 to quarterly or monthly fremanezumab or matched placebo for 12 weeks. Migraine-related disability was assessed using the 6-item Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) questionnaires. A clinically meaningful improvement in disability was defined per American Headache Society guidelines: for HIT-6, a ≥ 5-point reduction; for MIDAS, a ≥ 5-point reduction when baseline score was 11 to 20 or ≥ 30% reduction when baseline score was > 20. Proportions of patients who demonstrated shifts in severity for each outcome were also evaluated. RESULTS: For patients with baseline MIDAS scores of 11 to 20 (n = 234), significantly higher proportions achieved 5-point reductions from baseline in MIDAS scores with fremanezumab (quarterly, 71%; monthly, 70%) compared with placebo (49%; both P ≤ 0.01). For patients with baseline MIDAS scores of > 20 (n = 1266), proportions achieving ≥30% reduction from baseline in MIDAS scores were also significantly higher with fremanezumab (quarterly, 69%; monthly, 79%) compared with placebo (58%; both P < 0.001). For HIT-6 scores, proportions of patients achieving 5-point reductions from baseline were significantly higher with fremanezumab (quarterly, 53%; monthly, 55%) compared with placebo (39%; both P < 0.0001). Proportions of patients with shifts of 1 to 3 grades down in MIDAS or HIT-6 disability severity were significantly greater with quarterly and monthly fremanezumab compared with placebo (all P < 0.0001). CONCLUSION: Fremanezumab demonstrated clinically meaningful improvements in disability severity in this pooled analysis. TRIAL REGISTRATIONS: HALO CM, NCT02621931 ; HALO EM, NCT02629861 ; FOCUS, NCT03308968 .

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 .

Rates of Response to Atogepant for Migraine Prophylaxis Among Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Some patients with migraine, particularly those in primary care, require effective, well-tolerated, migraine-specific oral preventive treatments. Objective: To examine the efficacy of atogepant, an oral, small-molecule, calcitonin gene-related peptide receptor antagonist, using 4 levels of mean monthly migraine-day (MMD) responder rates. Design, Setting, and Participants: This secondary analysis of a phase 3, double-blind, placebo-controlled randomized clinical trial evaluated the efficacy and safety of atogepant for the preventive treatment of migraine from December 14, 2018, to June 19, 2020, in adults with 4 to 14 migraine-days per month at 128 sites in the US. Interventions: Patients were administered 10 mg of atogepant (n = 222), 30 mg of atogepant (n = 230), 60 mg of atogepant (n = 235), or placebo (n = 223) once daily in a 1:1:1:1 ratio for 12 weeks. Main Outcomes and Measures: These analyses evaluated treatment responder rates, defined as participants achieving 50% or greater (α-controlled, secondary end point) and 25% or greater, 75% or greater, and 100% (prespecified additional end points) reductions in mean MMDs during the 12-week blinded treatment period. Results: Of 902 participants (mean [SD] age, 41.6 [12.3] years; 801 [88.8%] female; 752 [83.4%] White; 825 [91.5%] non-Hispanic), 873 were included in the modified intention-to-treat population (placebo, 214; 10 mg of atogepant, 214; 30 mg of atogepant, 223; and 60 mg of atogepant, 222). For the secondary end point, a 50% or greater reduction in the 12-week mean of MMDs was achieved by 119 of 214 participants (55.6%) treated with 10 mg of atogepant (odds ratio, 3.1; 95% CI, 2.1-4.6), 131 of 223 participants (58.7%) treated with 30 mg atogepant (odds ratio, 3.5; 95% CI, 2.4-5.3), 135 of 222 participants (60.8%) treated with 60 mg of atogepant (odds ratio, 3.8; 95% CI, 2.6-5.7), and 62 of 214 participants (29.0%) given placebo (P < .001). The numbers of participants who reported a 25% or greater reduction in the 12-week mean of MMDs were 157 of 214 (73.4%) for 10 mg of atogepant, 172 of 223 (77.1%) for 30 mg of atogepant, and 180 of 222 (81.1%) for 60 mg of atogepant vs 126 of 214 (58.9%) for placebo (P < .002). The numbers of participants who reported a 75% or greater reduction in mean MMDs were 65 of 214 (30.4%) for 10 mg of atogepant, 66 of 223 (29.6%) for 30 mg of atogepant, and 84 of 222 (37.8%) for 60 mg of atogepant compared with 23 of 214 (10.7%) for placebo (P < .001). The numbers of participants reporting 100% reduction in mean MMDs were 17 of 214 (7.9%) for 10 mg of atogepant (P = .004), 11 of 223 (4.9%) for 30 mg of atogepant (P = .02), and 17 of 222 (7.7%) for 60 mg of atogepant (P = .003) compared with 2 of 214 (0.9%) for placebo. Conclusions and Relevance: At all doses, atogepant was effective during the 12-week double-blind treatment period beginning in the first 4 weeks, as evidenced by significant reductions in mean MMDs at every responder threshold level. Higher atogepant doses appeared to produce the greatest responder rates, which can guide clinicians in individualizing starting doses. Trial Registration: ClinicalTrials.gov Identifier: NCT03777059.

Safety and tolerability of fremanezumab in patients with episodic and chronic migraine: a pooled analysis of phase 3 studies.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab. METHODS: This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans. RESULTS: Two thousand, eight hundred and forty-two patients were included in the study. Overall (58-65%) and serious adverse events (<1-2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2-6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified. CONCLUSION: Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use.Trial Registrations: NCT02629861 (HALO EM, https://clinicaltrials.gov/ct2/show/NCT02629861), NCT02621931 (HALO CM, https://clinicaltrials.gov/ct2/show/NCT02621931), NCT03308968 (FOCUS, https://clinicaltrials.gov/ct2/ show/NCT03308968).

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.

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.

Five-year prospective fistula audit in a single center. TIG training negates consultant learning curve, but surgeons should beware the mid-range palatal defect.

The aim of primary palatoplasty is to achieve optimum speech with minimal morbidity. Symptomatic fistulae are well-recognised complications of palatoplasty and may require additional surgical intervention, increasing the burden of care. Our aims were to better understand fistula experience in our unit and compare fistula rates between an established consultant and a newly appointed training interface group (TIG) trained consultant. Post-operative fistulae were prospectively and independently recorded by Cleft Clinical Nurse Specialists as part of routine 6-week post-operative reviews. Cleft type and intra-operative hard-soft palate junction (HSPJ) width were prospectively recorded by operating surgeons. Data were collated and analysed using Microsoft Excel. Between 1 January 2014 and 31 December 2018, 250 primary palatoplasties were performed. The overall fistula rate was 8% (0% SMCP, ICP 7%, UCLP 8%, BCLP 22%). Fistulae clustered in clefts with a mid-range HSPJ width of 12-16 mm. Numerically, fistula rates remained similar over time despite increased unit activity (doubling of primary surgeries in 2017 and 2018). There was no significant difference in fistulae rates between surgeons (P > 0.05). Overall fistulae rate compared favourably with published data. TIG fellowships were designed in the context of cleft surgery to address issues relating to steep operative learning curves. These data demonstrate that results from a newly appointed TIG-trained surgeon are comparable to that of an established TIG-trained surgeon. Data also suggest surgeons should be aware of the risk of fistulae in the mid-range palatal defect and in HSPJ widths of 12-16 mm.

Real-world impact of fremanezumab on migraine symptoms and resource utilization in the United States.

BACKGROUND: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide (CGRP), is approved for migraine prevention in adults. Real-world data on the effectiveness of fremanezumab are limited. This retrospective, observational cohort study assessed patient-reported migraine symptoms, health care resource utilization (HCRU), and direct medical costs before and after fremanezumab treatment initiation. METHODS: Data were extracted from September 2018 through June 2020 from the Midwest component of EMRClaims+®, an integrated health services database containing > 20 million medical records from national commercial insurance claims, Medicare claims, and regional electronic medical records. Patients included in the cohort analysis were aged ≥ 18 years and were administered fremanezumab, with enrollment or treatment history for ≥ 6 months prior (pre-index) to initiating fremanezumab (index date) and ≥ 1 month after the index date (post-index), and without pregnancy or pregnancy-related encounters during the study period. Patient-reported headache frequency, migraine pain intensity (MPI), composite migraine symptoms, and HCRU were assessed pre-index and ≥ 1 month after fremanezumab initiation. Wilcoxon signed-rank tests were used to compare means of migraine symptoms and outcomes and HCRU before and after fremanezumab initiation. RESULTS: Overall, 172 patients were eligible for analysis. Of patients who self-reported (n = 129), 83.7% reported improvement in headache frequency or symptoms after fremanezumab treatment. Specifically, headache frequency decreased by 63% after fremanezumab initiation: mean (standard deviation) headache frequency was 22.24 (9.29) days per month pre-index versus 8.24 (7.42) days per month post-index (P < 0.0001). Mean MPI also decreased by 18% after fremanezumab initiation: MPI was 5.47 (3.19) pre-index versus 4.51 (3.34) post-index (P = 0.014). Mean emergency room (ER) visits per month decreased from 0.72 to 0.54 (P = 0.003), and mean outpatient visits per month decreased from 1.04 to 0.81 (P < 0.001). Mean hospitalizations per month decreased, but the results did not reach statistical significance (P = 0.095). Hospitalization and ER costs decreased, while outpatient costs increased, from pre-index to post-index, but differences were not statistically significant (P ≥ 0.232). CONCLUSIONS: Significant reductions in headache frequency, MPI, and HCRU were observed after fremanezumab initiation in patients with migraine in a US real-world setting.

Timing and durability of response to erenumab in patients with episodic migraine.

OBJECTIVE: We sought to evaluate temporal response patterns to erenumab treatment in patients with episodic migraine. BACKGROUND: Although many patients treated with erenumab experience onset of efficacy as early as 1 week, clinical benefits of migraine preventive therapies may accrue with continued treatment. Furthermore, details about the maintenance of clinical responses have not been reported. METHODS: This was a post hoc analysis of a 6-month, randomized, double-blind, placebo-controlled, phase 3 study of erenumab for the prevention of episodic migraine. We analyzed temporal responses to erenumab using a threshold of ≥50% reduction from baseline in monthly migraine days (MMDs). RESULTS: During the 6-month treatment period, 73.7% (230/312) and 79.6% (253/318) of patients in the erenumab 70 mg (n = 312) and 140 mg (n = 318) groups, respectively, achieved a response in at least 1 month. In this group of responders, at least half reached first monthly response (first month with ≥50% reduction from baseline in MMDs) by month 2 and at least 75% of them by month 3. The remainder responded in months 4-6. Of patients in the erenumab 70 and 140 mg groups, 35.3% (110/312) and 41.8% (133/318), respectively, responded over months 1-3 (mean response over first 3 months). Of these patients, 81.8% (90/110) and 81.9% (109/133) maintained this response over months 4-6 (mean response over last 3 months) in the 70 and 140 mg groups, respectively. Many patients who did not achieve an initial response (≥50% reduction from baseline in MMDs during month 1) responded later with continued treatment, with approximately one-half or more of initial nonresponders responding by months 4-6. CONCLUSIONS: These results support guidelines recommending at least 3 months following the initiation of erenumab for migraine prevention before the assessment of response.

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

Importance: Intravenous eptinezumab, an anti-calcitonin gene-related peptide antibody, is approved for migraine prevention in adults. It has established onset of preventive efficacy on day 1 after infusion. Objective: To evaluate the efficacy of and adverse events related to eptinezumab when initiated during a migraine attack. Design, Setting, and Participants: Phase 3, multicenter, parallel-group, double-blind, randomized, placebo-controlled trial conducted from November 4, 2019, to July 8, 2020, at 47 sites in the United States and the country of Georgia. Participants (aged 18-75 years) with a greater than 1-year history of migraine and migraine on 4 to 15 days per month in the 3 months prior to screening were treated during a moderate to severe migraine attack. Interventions: Eptinezumab, 100 mg (n = 238), or placebo (n = 242), administered intravenously within 1 to 6 hours of onset of a qualifying moderate to severe migraine. Main Outcomes and Measures: Co-primary efficacy end points were time to headache pain freedom and time to absence of most bothersome symptom (nausea, photophobia, or phonophobia). Key secondary end points were headache pain freedom and absence of most bothersome symptom at 2 hours after start of infusion. Additional secondary end points were headache pain freedom and absence of most bothersome symptom at 4 hours and use of rescue medication within 24 hours. Results: Of 480 randomized and treated patients (mean age, 44 years; 84% female), 476 completed the study. Patients treated with eptinezumab vs placebo, respectively, achieved statistically significantly faster headache pain freedom (median, 4 hours vs 9 hours; hazard ratio, 1.54 [P < .001]) and absence of most bothersome symptom (median, 2 hours vs 3 hours; hazard ratio, 1.75 [P < .001]). At 2 hours after infusion, in the respective eptinezumab and placebo groups, headache pain freedom was achieved by 23.5% and 12.0% (between-group difference, 11.6% [95% CI, 4.78%-18.31%]; odds ratio, 2.27 [95% CI, 1.39-3.72]; P < .001) and absence of most bothersome symptom by 55.5% and 35.8% (between-group difference, 19.6% [95% CI, 10.87%-28.39%]; odds ratio, 2.25 [95% CI, 1.55-3.25]; P < .001). Results remained statistically significant at 4 hours after infusion. Statistically significantly fewer eptinezumab-treated patients used rescue medication within 24 hours than did placebo patients (31.5% vs 59.9%, respectively; between-group difference, -28.4% [95% CI, -36.95% to -19.86%]; odds ratio, 0.31 [95% CI, 0.21-0.45]; P < .001). Treatment-emergent adverse events occurred in 10.9% of the eptinezumab group and 10.3% of the placebo group; the most common was hypersensitivity (eptinezumab, 2.1%; placebo, 0%). No treatment-emergent serious adverse events occurred. Conclusions and Relevance: Among patients eligible for preventive migraine therapy experiencing a moderate to severe migraine attack, treatment with intravenous eptinezumab vs placebo shortened time to headache and symptom resolution. Feasibility of administering eptinezumab treatment during a migraine attack and comparison with alternative treatments remain to be established. Trial Registration: ClinicalTrials.gov Identifier: NCT04152083.

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.