Safety and efficacy of atogepant for the preventive treatment of episodic migraine in adults for whom conventional oral preventive treatments have failed (ELEVATE): a randomised, placebo-controlled, phase 3b trial.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Allergan (now AbbVie).

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Acute Medication Use in Patients With Migraine Treated With Monoclonal Antibodies Acting on the CGRP Pathway: Results From a Multicenter Study and Proposal of a New Index.

Introduction: Assessing the impact of migraine preventive treatments on acute medication consumption is important in clinical evaluation. The number of acute medication intakes per each monthly migraine day (MMD) could provide insights on migraine burden and represent a new proxy of treatment effectiveness in clinical trials and real-life studies. We evaluated the effect of monoclonal antibodies acting on calcitonin gene-related peptide (CGRP) pathway on the consumption of migraine acute medication in real-life. Methods: In two headache centers in Prague (CZ), we included and followed up to 6 months consecutive patients treated with MoAbs acting on CGRP (erenumab or fremanezumab). For each month of treatment, we reported monthly drug intake (MDI) in doses of any medication, migraine-specific (MS), and non-migraine-specific (non-MS) medications, and computed a ratio between MMDs and MDI, i.e., Migraine Medication Index (MMI) for MS and non-MS medications. Results: We included 90 patients (91.1% women) with a median age of 47 [interquartile range (IQR) 42-51] years; 81 (90.0%) treated with erenumab and 9 (10.0%) with fremanezumab. Median MMDs decreased from 11 (IQR 8-14) at baseline to 4 (IQR 2-5) at Month 3 (p < 0.001 vs. baseline) and 3 (IQR 2-6) at Month 6 (p < 0.001 vs. baseline). Median MDI decreased from 15 drug intakes (IQR 11-20) at baseline to four drug intakes (IQR 2-7) at Month 3 (p < 0.001) and four drug intakes (IQR 2-7) at Month 6 (p < 0.001).The corresponding MDIs for MS medications were 10 (IQR 6-14) at baseline, 3 (IQR 1-5, p < 0.001) at Month 3, and 2 (IQR 0-4, p < 0.001) at Month 6. Monthly drug intakes for non-MS medications were 4 (IQR 0-9) at baseline, 1 (IQR 0-3, p < 0.001) at Month 3 and at Month 6.Median MMI decreased from 1.32 (IQR 1.11-1.68) at baseline to 1.00 (IQR 1.00-1.50, p < 0.001) at Month 3 and 1.00 (IQR 1.00-1.34, p < 0.001) at Month 6. Conclusions: We confirmed that MoAbs acting on CGRP pathway decrease acute migraine medication consumption. We proposed a new index that can be easily applied in clinical practice to quantify migraine burden and its response to acute medication. Our index could help optimizing migraine acute treatment in clinical practice.

Comparing the relative and absolute effect of erenumab: is a 50% response enough? Results from the ESTEEMen study.

BACKGROUND: Monoclonal antibodies acting on the calcitonin gene-related peptide (CGRP) or its receptor have changed migraine preventive treatment. Those treatments have led to reconsidering the outcomes of migraine prevention. Available data mostly considered benefits in terms of relative efficacy (percent or absolute decrease in monthly migraine days [MMDs] or headache days compared with baseline). However, not enough attention has been paid to residual MMDs and/or migraine-related disability in treated patients. In the present study, we aimed at comparing the relative and absolute efficacy of erenumab. METHODS: ESTEEMen was a collaborative project among 16 European headache centers which already performed real-life data collections on patients treated with erenumab for at least 12 weeks. For the present study, we performed a subgroup analysis on patients with complete data on MMDs at baseline and at weeks 9-12 of treatment. Starting from efficacy thresholds proposed by previous literature, we classified patients into 0-29%, 30-49%, 50-74%, and ≥75% responders according to MMD decrease from baseline to weeks 9-12 of treatment. For each response category, we reported the median MMDs and Headache Impact test-6 (HIT-6) scores at baseline and at weeks 9-12. We categorized the number of residual MMDs at weeks 9-12 as follows: 0-3, 4-7, 8-14, ≥15. We classified HIT-6 score into four categories: ≤49, 50-55, 56-59, and ≥60. To keep in line with the original scope of the ESTEEMen study, calculations were performed in men and women. RESULTS: Out of 1215 patients, at weeks 9-12, 381 (31.4%) had a 0-29% response, 186 (15.3%) a 30-49% response, 396 (32.6%) a 50-74% response, and 252 (20.7%) a ≥75% response; 246 patients (20.2%) had 0-3 residual MMDs, 443 (36.5%) had 4-7 MMDs, 299 (24.6%) had 8-14 MMDs, and 227 (18.7%) had ≥15 MMDs. Among patients with 50-74% response, 246 (62.1%) had 4-7 and 94 (23.7%) 8-14 residual MMDs, while among patients with ≥75% response 187 (74.2%) had 0-3 and 65 (25.8%) had 4-7 residual MMDs. CONCLUSIONS: The present study shows that even patients with good relative response to erenumab may have a clinically non-negligible residual migraine burden. Relative measures of efficacy cannot be enough to thoroughly consider the efficacy of migraine prevention.

Gender Differences in 3-Month Outcomes of Erenumab Treatment-Study on Efficacy and Safety of Treatment With Erenumab in Men.

Objective: We reported gender-specific data on the efficacy and safety of erenumab, a monoclonal antibody antagonizing the calcitonin gene-related peptide (CGRP) receptor. Methods: Our pooled patient-level analysis of real-world data included patients treated with erenumab and followed up for 12 weeks. We considered the following outcomes at weeks 9-12 of treatment compared with baseline: 0-29%, 30-49%, 50-75%, and ≥75% responder rates, according to the decrease in monthly headache days (MHDs), rate of treatment stopping, change in MHDs, monthly migraine days (MMDs), monthly days of acute medication and triptan use, and Headache Impact Test-6 (HIT-6) score from baseline to weeks 9-12. Outcomes were compared between men and women by the chi-squared test or t-test, as appropriate. An analysis of covariance (ANCOVA) was performed to identify factors influencing the efficacy outcomes. Results: We included 1,410 patients from 16 centers, of which 256 (18.2%) were men. Men were older than women and had a lower number of MHDs at baseline. At weeks 9-12, compared with baseline, 46 (18.0%) men had a ≥75% response, 75 (29.3%) had a 50-74% response, 35 (13.7%) had a 30-49% response, and 86 (33.6%) had a 0-29% response, while 14 (5.5%) stopped the treatment. The corresponding numbers for women were 220 (19.1%), 314 (27.2%), 139 (12.0%), 402 (34.8%), and 79 (6.8%). No gender difference was found in any of the outcomes. The ANCOVA showed that gender did not influence the efficacy of outcomes. Conclusion: We found that erenumab is equally safe and effective in men compared with women after 12 weeks.

Psychogenic non-epileptic seizures: our video-EEG experience.

OBJECTIVE: The aim of our study was to assess the number of psychogenic non-epileptic seizures (PNES) in our patients with a refractory seizure disorder, to determine the 'typical' PNES semiology using video-EEG monitoring and describe other PNES parameters. METHODS: We evaluated prospectively 596 patients with pharmacoresistant seizures. All these patients underwent continuous video-EEG monitoring. In consenting patients, we used suggestive seizure provocation. We assessed seizure semiology, interictal EEG, brain MRI, psychiatric co-morbidities, personality profiles, and seizure outcome. RESULTS: In the sample of 596 monitored patients, we detected 111 (19.3%) patients with PNES. Of the 111 patients with PNES, 86.5% had spontaneous and 76.5% had provoked seizures. The five most typical symptoms were: initially closed eyelids (67.6%), rapid tremor (47.7%), asynchronous limb movement (37.8%), preictal pseudosleep (33.3%), and side-to-side head movement (32.4%). Interictal EEG was rated as abnormal in 46.2% and with epileptiform abnormality in 9%. Brain MRI was abnormal in 32 (28.8%) patients. Personality disorders (46.8%), anxiety (39.6%), and depression (12.6%) were the most frequent additional psychiatric co-morbidities. PNES outcome after at least 2 years is reported; 22.5% patients was seizure-free; one-third had markedly reduced seizure frequency. We have not seen any negative impact of the provocative testing on the seizure outcome. DISCUSSION: Video-EEG monitoring with suggestive seizure provocation supported by clinical psychiatric and psychological evaluation significantly contributes to the correct PNES diagnosis, while interictal EEG and brain MRI are frequently abnormal. Symptoms typical for PNES, as opposed to epileptic seizures, could be distinguished.

Is pseudo-intractability in population of patients with epilepsy still alive in the 21st century? Audit of 100 seizure-free patients, referred with the diagnosis of pharmacoresistant epilepsy.

OBJECTIVE: There is no universally accepted definition of pseudo-intractable epilepsy. Pseudo-intractability means that the resistance to treatment is, in fact, caused by clinical errors. The purpose of our study was to identify the reasons for intractability and subsequent effective therapeutic management approaches in a group of patients with established pseudo-intractable epilepsy. METHODS: The study was designed as a retrospective audit of 100 adult patients who, in their past medical history, were diagnosed as having intractable epilepsy but, following adjustments to their medical management, were seizure free for at least 2 years. Patients underwent standard clinical evaluation, including EEG and/or video-EEG monitoring. We re-evaluated past medical, family, seizure and pharmacological history and morphological findings. Epilepsy was re-classified according to the ILAE classification. RESULTS: We identified possible errors including incorrect diagnosis and/or inappropriate previous epilepsy management in all 100 patients. Incorrect diagnosis (seizure type and/or syndrome) was observed in 47 patients (47%). Thirty two patients (32%) with idiopathic generalized epilepsy were treated for complex focal seizures with inappropriate choice of medication. Therapeutic errors were identified in 48 patients (48%). Issues with medication compliance were found in 20 patients (20%). Potential seizure precipitating factors were detected in 23 patients (23%). CONCLUSIONS: Our study of 100 patients confirmed that the problem of pseudo-intractability still exists. Every case of pharmacoresistance in epilepsy could potentially be caused by one or more clinical errors.

Vagus nerve stimulation: longitudinal follow-up of patients treated for 5 years.

We performed a retrospective, multicenter, open-label study to evaluate the efficacy of vagus nerve stimulation (VNS) in all patients in the Czech Republic who have received this treatment for at least 5 years (n=90). The mean last follow-up was 6.6+/-1.1 years (79+/-13 months). The median number of seizures among all patients decreased from 41.2 seizures/month in the prestimulation period to 14.9 seizures/month at 5 years follow-up visit. The mean percentage of seizure reduction was 55.9%. The responder rate in these patients is in concordance with the decrease of overall seizure frequency. At 1 year after beginning the stimulation, 44.4% of patients were responders; this percentage increased to 58.7% after 2 years. At the 5 years last follow-up 64.4% of patients were responders, 15.5% experienced > or = 90% seizure reduction, and 5.5% were seizure-free. A separate analysis of patients younger than 16 years of age showed lower efficacy rates of VNS in comparison to the whole group. Complications and chronic adverse effects occurred in 13.3% of patients. VNS is an effective and safe method to refractory epilepsy in common clinical practice.

Psychogenic non-epileptic seizures, prospective clinical experience: diagnosis, clinical features, risk factors, psychiatric comorbidity, treatment outcome.

In our study, we evaluated 249 patients with refractory seizures using video-EEG monitoring. In this sample, we identified 56 (22.5%) patients with psychogenic non-epileptic seizures - PNES only. Spontaneous seizures were recorded in 49 (87%) patients with PNES. Suggestive seizure induction using intravenous saline placebo was successful in 77.1% of induced PNES cases. Disease duration prior to PNES diagnosis was quite long. Prolonged past and current intake of high number of different antiepileptic drugs was also typical for these patients. We evaluated ictal PNES semiology. Whereas ictal EEG was normal in all PNES patients, interictal EEG was abnormal in 46.4%. Brain MRI was abnormal in 30.4%. Personality disorders were the most frequent psychiatric co-morbidity (in 44.6% of PNES patients), emotionally unstable (borderline) personality disorder was predominant (in 32.1% of PNES patients). Risk factors for epilepsy misdiagnosis and PNES manifestation are discussed. Therapeutic outcome after two years of combined treatment (psychopharmacotherapy and/or psychotherapy) is presented; approximately one third of patients were seizure-free following two years of treatment, one third of patients were responders (>or= 50% reduction in seizure frequency) and one third did not respond to treatment.