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Emerging evidence suggest migraine is a response to cerebral energy deficiency or oxidative stress in the brain. Beta-hydroxybutyrate (BHB) is likely able to circumvent some of the meta-bolic abnormalities reported in migraine. Exogenous BHB was given to test this assumption and, in this post-hoc analysis, multiple metabolic biomarkers were identified to predict  clinical improvements. A randomized clinical trial, involving 41 patients with episodic migraine. Each treatment period was 12 weeks long, followed by eight weeks of washout phase / second run-in phase before entering the corresponding second treatment period. The primary endpoint was the number of migraine days in the last 4 weeks of treatment adjusted for baseline. BHB re-sponders were identified (those with at least a 3-day reduction in migraine days over placebo) and its predictors were evaluated using Akaike’s Information Criterion (AIC) stepwise boot-strapped analysis and logistic regression. Responder analysis showed that metabolic markers could identify a “metabolic migraine” subgroup, which responded to BHB with a 5.7 migraine days reduction compared to the placebo. This analysis provides further support for a “metabolic migraine” subtype. Additionally, these analyses identified low-cost and easily accessible biomarkers that could guide recruitment in future research on this subgroup of patients. This study is part of the trial registration: ClinicalTrials.gov: NCT03132233, registered on 27.04.2017, https://clinicaltrials.gov/ct2/show/NCT03132233

A higher percentage of participants who received the calcitonin gene–related peptide receptor antagonist ubrogepant had freedom from migraine pain and absence of the most bothersome migraine-associated symptom at 2 hours than participants who received placebo.

Rimegepant is a calcitonin gene-related peptide receptor antagonist that has shown efficacy and safety in the acute treatment of migraine. We aimed to compare the efficacy of rimegepant with placebo for preventive treatment of migraine. We did a multicentre, phase 2/3, randomised, double-blind, placebo-controlled trial at 92 sites in the USA. Adults with at least a 1-year history of migraine were recruited. After a 4-week observation period, eligible participants were randomised using an interactive web response system to oral rimegepant 75 mg or matching placebo every other day for 12 weeks (double-blind treatment phase). The primary efficacy endpoint was change from the 4-week observation period in the mean number of migraine days per month in the last 4 weeks of the double-blind treatment phase (weeks 9–12). Participants who received at least one dose of their assigned study medication and who had 14 days or more of data in the observation period and 14 days or more of data for at least one 4-week interval during the double-blind treatment phase were analysed for efficacy. Those who received at least one dose of study medication were analysed for safety. This study is registered with ClinicalTrials.gov, NCT03732638. Between Nov 14, 2018, and Aug 30, 2019, 1591 participants were recruited and assessed for eligibility, of whom 747 were randomly allocated either rimegepant (n=373) or placebo (n=374). 695 participants were included in the analysis for efficacy, of whom 348 were assigned rimegepant and 347 were allocated placebo. Rimegepant was superior to placebo on the primary endpoint of change in the mean number of migraine days per month during weeks 9–12. The change from the observation period in mean number of migraine days per month during weeks 9–12 was −4·3 days (95% CI –4·8 to –3·9) with rimegepant and −3·5 days (–4·0 to –3·0) with placebo (least squares mean difference −0·8 days, 95% CI −1·46 to −0·20; p=0·0099). 741 participants received study medication and were included in the safety analysis. 133 (36%) of 370 patients who received rimegepant reported an adverse event, compared with 133 (36%) of 371 who received placebo. Seven (2%) participants who received rimegepant and four (1%) who received placebo discontinued the study due to an adverse event; no patients died. Taken every other day, rimegepant was effective for preventive treatment of migraine. Tolerability was similar to that of placebo, and no unexpected or serious safety issues were noted. Biohaven Pharmaceuticals.

In adults with migraine and previous preventive treatment failures, a single infusion of a monoclonal antibody to pituitary adenylate cyclase–activating polypeptide led to fewer migraine days per month than placebo over the next 4 weeks.

Treatment with the oral calcitonin gene–related peptide receptor antagonist rimegepant resulted in freedom from migraine pain 2 hours after the dose in 20% of patients; 12% of the patients who received placebo were pain-free. Freedom from the most bothersome migraine symptom aside from pain 2 hours after the dose was reported in 38% of patients who received rimegepant and 25% who received placebo.

(1) Background: OnabotulinumtoxinA (BoNT-A) is a commonly used prophylactic treatment for chronic migraine (CM). Although randomized placebo studies have shown its clinical efficacy, the mechanisms by which it exerts its therapeutic effect are still incompletely understood and debated. (2) Methods: We studied in 15 CM patients the cephalic and extracephalic nociceptive and lemniscal sensory systems using electrophysiological techniques before and 1 and 3 months after one session of pericranial BoNT-A injections according to the PREEMPT protocol. We recorded the nociceptive blink reflex (nBR), the trigemino-cervical reflex (nTCR), the pain-related cortical evoked potential (PREP), and the upper limb somatosensory evoked potential (SSEP). (3) Results: Three months after a single session of prophylactic therapy with BoNT-A in CM patients, we found (a) an increase in the homolateral and contralateral nBR AUC, (b) an enhancement of the contralateral nBR AUC habituation slope and the nTCR habituation slope, (c) a decrease in PREP N-P 1st and 2nd amplitude block, and (d) no effect on SSEPs. (4) Conclusions: Our study provides electrophysiological evidence for the ability of a single session of BoNT-A injections to exert a neuromodulatory effect at the level of trigeminal system through a reduction in input from meningeal and other trigeminovascular nociceptors. Moreover, by reducing activity in cortical pain processing areas, BoNT-A restores normal functioning of the descending pain modulation systems.

Atogepant, an oral calcitonin gene-related peptide receptor antagonist, has been approved for the preventive treatment of migraine, but its efficacy and safety in people who have been failed by conventional oral preventive migraine treatments has not yet been evaluated in a dedicated clinical trial. The ELEVATE trial evaluated the safety, tolerability, and efficacy of atogepant for the preventive treatment of episodic migraine in participants for whom two to four classes of conventional oral preventive treatments have failed. ELEVATE was a randomised, double-blind, placebo-controlled, parallel-group, phase 3b trial done at 73 sites in Canada, the Czech Republic, Denmark, France, Germany, Hungary, Italy, the Netherlands, Poland, Russia, Spain, the UK, and the USA. Adults (18–80 years) with episodic migraine who had previously been failed by two to four classes of conventional oral treatments for migraine prevention were randomly assigned (1:1) using interactive web response technology to oral atogepant 60 mg once a day or placebo, stratified by baseline monthly migraine days, number of treatment classes participants have been failed by, and region. The primary endpoint was change from baseline in mean monthly migraine days across the 12-week treatment period in the off-treatment hypothetical estimand (OTHE) population, which included participants in the safety population (all participants who received ≥1 dose of study intervention) who had evaluable data available for the baseline period and for one or more of the 4-week post-baseline periods (whether on treatment or off treatment). The primary endpoint was analysed using a mixed model for repeated measures and a fixed-sequence procedure was used to control for multiple comparisons. The trial is registered with ClinicalTrials.gov (NCT04740827) and EudraCT (2019-003448-58), and is completed. Between March 5, 2021, and Aug 4, 2022, 540 participants were screened, 315 were randomly assigned, and 313 participants (280 [89%] female, 33 [11%] male, and 300 [96%] White) received at least one dose of study intervention. In the OTHE population, which comprised 309 participants (155 assigned to placebo and 154 to atogepant), least squares mean changes from baseline in monthly migraine days across 12 weeks were −1·9 (SE 0·4) with placebo and −4·2 (0·4) with atogepant (least squares mean difference −2·4, 95% CI −3·2 to −1·5; adjusted p<0·0001). The most common treatment-emergent adverse event with atogepant was constipation in 16 (10%) of 156 participants (vs four [3%] of 157 for placebo). Serious adverse events occurred in four [3%] of 156 participants in the atogepant group vs none in the placebo group, and treatment-emergent adverse events resulting in treatment discontinuation occurred in three [2%] in the atogepant group vs two [1%] in the placebo group. Atogepant 60 mg once a day was safe, well tolerated, and showed significant and clinically relevant reductions in mean monthly migraine days compared with placebo across 12 weeks in patients with episodic migraine who had previously been failed by two to four classes of conventional oral preventive treatments. Atogepant might be an effective preventive treatment option for patients in this difficult-to-treat population. Allergan (now AbbVie).

A substantial proportion of patients with migraine does not respond to, or cannot tolerate, oral preventive treatments. Erenumab is a novel CGRP-receptor antibody with preventive efficacy in migraine. We assessed its efficacy and tolerability in patients with episodic migraine in whom previous treatment with two-to-four migraine preventives had been unsuccessful. LIBERTY was a 12-week, double-blind, placebo-controlled randomised study at 59 sites in 16 countries. Eligible patients were aged 18–65 years and had a history of episodic migraine with or without aura for at least 12 months, had migraine for an average of 4–14 days per month during the 3 months before screening, and had been treated unsuccessfully (in terms of either efficacy or tolerability, or both) with between two and four preventive treatments. Eligible participants were randomly assigned (1:1) to receive either erenumab 140 mg (via two 70 mg injections) or placebo every 4 weeks subcutaneously for 12 weeks. Randomisation was by interactive response technology and was stratified by monthly frequency of migraine headache (4–7 vs 8–14 migraine days per month) during the baseline phase. Cenduit generated the randomisation list and assigned participants to groups. Participants, investigators, people doing various assessments, and the study sponsor were masked to treatment assignment. The primary endpoint was the proportion of patients achieving a 50% or greater reduction in the mean number of monthly migraine days during weeks 9–12. Efficacy was measured in the full analysis set, which included all randomly assigned patients who started their assigned treatment and completed at least one post-baseline monthly migraine day measurement. Safety and tolerability were assessed by recording adverse events and by physical examination, assessment of vital signs, clinical laboratory assessments, and electrocardiography. Safety was assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT03096834. The trial is closed to new participants, but the open-label extension phase is ongoing. Between March 20, 2017, and Oct 27, 2017, 246 participants were randomly assigned, 121 to the erenumab group and 125 to the placebo group. 95 of 246 (39%) participants had previously unsuccessfully tried two preventive drugs, 93 (38%) had tried three, and 56 (23%) had tried four. At week 12, 36 (30%) patients in the erenumab had a 50% or greater reduction from baseline in the mean number of monthly migraine days, compared with 17 (14%) in the placebo group (odds ratio 2·7 [95% CI 1·4–5·2]; p=0·002). The tolerability and safety profiles of erenumab and placebo were similar. The most frequent treatment-emergent adverse event was injection site pain, which occurred in seven (6%) participants in both groups. Compared with placebo, erenumab was efficacious in patients with episodic migraine who previously did not respond to or tolerate between two and four previous migraine preventive treatments. Erenumab might be an option for patients with difficult-to-treat migraine who have high unmet needs and few treatment options. Novartis Pharma.

Rimegepant, a small molecule calcitonin gene-related peptide receptor antagonist, has shown efficacy in the acute treatment of migraine using a standard tablet formulation. The objective of this trial was to compare the efficacy, safety, and tolerability of a novel orally disintegrating tablet formulation of rimegepant at 75 mg with placebo in the acute treatment of migraine. In this double-blind, randomised, placebo-controlled, multicentre phase 3 trial, adults aged 18 years or older with history of migraine of at least 1 year were recruited to 69 study centres in the USA. Participants were randomly assigned to receive rimegepant (75 mg orally disintegrating tablet) or placebo and instructed to treat a single migraine attack of moderate or severe pain intensity. The randomisation was stratified by the use of prophylactic medication (yes or no), and was carried out using an interactive web response system that was accessed by each clinical site. All participants, investigators, and the sponsor were masked to treatment group assignment. The coprimary endpoints were freedom from pain and freedom from the most bothersome symptom at 2 h postdose. The efficacy analyses used the modified intention-to-treat population, which included all patients who were randomly assigned, had a migraine attack with pain of moderate or severe intensity, took a dose of rimegepant or placebo, and had at least one efficacy assessment after administration of the dose. The safety analyses included all randomly assigned participants who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, number NCT03461757, and is closed to accrual. Between Feb 27 and Aug 28, 2018, 1811 participants were recruited and assessed for eligibility. 1466 participants were randomly assigned to the rimegepant (n=732) or placebo (n=734) groups, of whom 1375 received treatment with rimegepant (n=682) or placebo (n=693), and 1351 were evaluated for efficacy (rimegepant n=669, placebo n=682). At 2 h postdose, rimegepant orally disintegrating tablet was superior to placebo for freedom from pain (21% vs 11%, p<0·0001; risk difference 10, 95% CI 6–14) and freedom from the most bothersome symptom (35% vs 27%, p=0·0009; risk difference 8, 95% CI 3–13). The most common adverse events were nausea (rimegepant n=11 [2%]; placebo n=3 [<1%]) and urinary tract infection (rimegepant n=10 [1%]; placebo n=4 [1%]). One participant in each treatment group had a transaminase concentration of more than 3 × the upper limit of normal; neither was related to study medication, and no elevations in bilirubin greater than 2 × the upper limit of normal were reported. Treated participants reported no serious adverse events. In the acute treatment of migraine, a single 75 mg dose of rimegepant in an orally disintegrating tablet formulation was more effective than placebo. Tolerability was similar to placebo, with no safety concerns. Biohaven Pharmaceuticals.

BackgroundClinical trials have shown the safety and clinical superiority of erenumab compared to placebo in chronic migraine (CM). The aim of this analysis is to evaluate the effectiveness and tolerability of erenumab in a real-world setting in patients with refractory CM.MethodsThis is a prospective single centre real-world audit conducted in patients with CM with and without medication overuse, refractory to established preventive medications, who received monthly erenumab for 6 months.ResultsOf 164 patients treated, 162 patients (female = 135, mean age 46 ± 14.3 years old) were included in the audit. Patients had failed a mean of 8.4 preventive treatments at baseline and 91% of patients failed Botulinum toxin type A at baseline. The mean reduction in monthly migraine days was 6.0 days at month 3 (P = 0.002) and 7.5 days at month 6 (P < 0.001) compared to baseline. The mean reduction in monthly headache days was 6.3 days (P < 0.001) at month 3 and 6.8 days (P < 0.001) at month 6. At month 3, 49%, 35% and 13% and at month 6, 60%, 38% and 22% of patients obtained at least a 30%, 50% and 75% reduction in migraine days, respectively. The percentage of patients with medication overuse was reduced from 54% at baseline to 20% at month 3 and to 25% at month 6. Compared to baseline, the mean reduction of Headache Impact Test-6 score was 7.7 points at month 3 (from 67.6 ± 0.4 to 59.9 ± 0.9) (P < 0.001) and of 7.5 points at month 6 (60.1 ± 1.3) (P = 0.01). The percentage of patients with severe headache-related disability (HIT-6: 60–78) was reduced from 96% at baseline to 68% after three monthly treatments and to 59% after six treatments. At least one side effect was reported by 48% of patients at month 1, 22% at month 3 and 15% at month 6. Constipation (20%) and cold/flu-like symptoms (15%) were the most frequent adverse events reported.ConclusionErenumab may be an effective and well tolerated therapy for medically refractory CM patients with and without medication overuse.