Effect of Atogepant for Preventive Migraine Treatment on Patient-Reported Outcomes in the Randomized, Double-blind, Phase 3 ADVANCE Trial

Atogepant; Preventive treatment; MigraineAtogepant; Tractament preventiu; MigranyaAtogepant; Tratamiento preventivo; MigrañaBackground and Objectives The oral calcitonin gene–related peptide receptor antagonist atogepant is indicated for the preventive treatment of episodic migraine. We evaluated changes in patient-reported outcomes with atogepant in adults with migraine. Methods In this phase 3, 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group trial (ADVANCE), adults with 4–14 migraine days per month received atogepant (10, 30, or 60 mg) once daily or placebo. Secondary endpoints included changes from baseline in Migraine-Specific Quality-of-Life Questionnaire (MSQ) version 2.1 Role Function–Restrictive (RFR) domain at week 12 and mean monthly Activity Impairment in Migraine–Diary (AIM-D) Performance of Daily Activities (PDA) and Physical Impairment (PI) domains across the 12-week treatment period. Exploratory endpoints included change in MSQ Role Function–Preventive (RFP) and Emotional Function (EF) domains; AIM-D total scores; and change in Headache Impact Test (HIT)–6 scores. Results Of 910 participants randomized, 873 comprised the modified intent-to-treat population (atogepant: 10 mg [n = 214]; 30 mg [n = 223]; and 60 mg [n = 222]; placebo [n = 214]). All atogepant groups demonstrated significantly greater improvements vs placebo in MSQ RFR that exceeded minimum clinically meaningful between-group difference (3.2 points) at week 12 (least-square mean difference [LSMD] vs placebo: 10 mg [9.9]; 30 mg [10.1]; 60 mg [10.8]; all p < 0.0001). LSMDs in monthly AIM-D PDA and PI scores across the 12-week treatment period improved significantly for the atogepant 30 (PDA: −2.54; p = 0.0003; PI: −1.99; and p = 0.0011) and 60 mg groups (PDA: −3.32; p < 0.0001; PI: −2.46; p < 0.0001), but not for the 10 mg group (PDA: −1.19; p = 0.086; PI: −1.08; p = 0.074). In exploratory analyses, atogepant 30 and 60 mg were associated with nominal improvements in MSQ RFP and EF domains, other AIM-D outcomes, and HIT-6 scores at the earliest time point (week 4) and throughout the 12-week treatment period. Results varied for atogepant 10 mg. Discussion Atogepant 30 and 60 mg produced significant improvements in key patient-reported outcomes including MSQ-RFR scores and both AIM-D domains. Nominal improvements also occurred for other MSQ domains and HIT-6, reinforcing the beneficial effects of atogepant as a new treatment for migraine prevention.Allergan, now AbbVie, sponsored the study

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

Migraine; Atogepant; AdultsMigraña; Atogepant; AdultosMigranya; Atogepant; AdultsImportance 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

The lesbian, gay, bisexual and transgender community online: discussions of bullying and self-disclosure in YouTube videos

Computer-mediated communication has become a popular platform for identity construction and experimentation as well as social interaction for those who identify as lesbian, gay, bisexual or transgender (LGBT). The creation of user-generated videos has allowed content creators to share experiences on LGBT topics. With bullying becoming more common amongst LGBT youth, it is important to obtain a greater understanding of this phenomenon. In our study, we report on the analysis of 151 YouTube videos which were identified as having LGBT- and bullying-related content. The analysis reveals how content creators openly disclose personal information about themselves and their experiences in a non-anonymous rhetoric with an unknown public. These disclosures could indicate a desire to seek friendship, support and provide empathy

Trigger Point Injections for Headache Disorders: Expert Consensus Methodology and Narrative Review

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109332/1/head12442.pd

Lasmiditan mechanism of action – review of a selective 5-HT1F agonist

Migraine is a leading cause of disability worldwide, but it is still underdiagnosed and undertreated. Research on the pathophysiology of this neurological disease led to the discovery that calcitonin gene-related peptide (CGRP) is a key neuropeptide involved in pain signaling during a migraine attack. CGRP-mediated neuronal sensitization and glutamate-based second- and third-order neuronal signaling may be an important component involved in migraine pain. The activation of several serotonergic receptor subtypes can block the release of CGRP, other neuropeptides, and neurotransmitters, and can relieve the symptoms of migraine. Triptans were the first therapeutics developed for the treatment of migraine, working through serotonin 5-HT1B/1D receptors. The discovery that the serotonin 1F (5-HT1F) receptor was expressed in the human trigeminal ganglion suggested that this receptor subtype may have a role in the treatment of migraine. The 5-HT1F receptor is found on terminals and cell bodies of trigeminal ganglion neurons and can modulate the release of CGRP from these nerves. Unlike 5-HT1B receptors, the activation of 5-HT1F receptors does not cause vasoconstriction. The potency of different serotonergic agonists towards 5-HT1F was correlated in an animal model of migraine (dural plasma protein extravasation model) leading to the development of lasmiditan. Lasmiditan is a newly approved acute treatment for migraine in the United States and is a lipophilic, highly selective 5-HT1F agonist that can cross the blood-brain barrier and act at peripheral nervous system (PNS) and central nervous system (CNS) sites. Lasmiditan activation of CNS-located 5-HT1F receptors (e.g., in the trigeminal nucleus caudalis) could potentially block the release of CGRP and the neurotransmitter glutamate, thus preventing and possibly reversing the development of central sensitization. Activation of 5-HT1F receptors in the thalamus can block secondary central sensitization of this region, which is associated with progression of migraine and extracephalic cutaneous allodynia. The 5-HT1F receptors are also elements of descending pain modulation, presenting another site where lasmiditan may alleviate migraine. There is emerging evidence that mitochondrial dysfunction might be implicated in the pathophysiology of migraine, and that 5-HT1F receptors can promote mitochondrial biogenesis. While the exact mechanism is unknown, evidence suggests that lasmiditan can alleviate migraine through 5-HT1F agonist activity that leads to inhibition of neuropeptide and neurotransmitter release and inhibition of PNS trigeminovascular and CNS pain signaling pathways

The Importance of an Early Onset of Migraine Preventive Disease Control: A Roundtable Discussion

Background: Newly approved migraine preventive therapies have allowed for rapid control of migraine activity, offering potential to minimize the burden of migraine. This report summarizes a roundtable discussion convened to analyze evidence for early onset of prevention, ascertain its clinical relevance, and provide guidance for healthcare professionals in crafting goals and treatment expectations for patients with migraine initiating preventive therapy. Methods: A virtual roundtable meeting of migraine clinicians, researchers, and patient advocates convened in October 2020. Participants reviewed and discussed data summarizing patient and healthcare professional perceptions of migraine prevention and evidence from the peer-reviewed and gray literature to develop corresponding recommendations. Summary: Evidence from clinical studies of anti-calcitonin gene-related peptide monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and the chemodenervation agent onabotulinumtoxinA indicate that patients may experience reduction of migraine activity within 7 days of drug administration and early attainment of disease control is associated with improvements in clinically important outcomes. The roundtable of experts proposes that early onset be defined as demonstration of preventive benefits within 1 week of treatment initiation. We recommend focusing discussion with patients around “disease control” and potential benefits of early onset of prevention, so patients can set realistic preventive therapy goals and expectations

Diffractive Dijet Production in Antiproton-Proton Collisions at s\sqrt{s}=1.96 TeV

We report on a study of diffractive dijet production in $\bar{p}p$ collisions at $\sqrt{s}=1.96$ TeV using the CDF II detector at the Fermilab Tevatron $\bar{p}p$ collider. A data sample from 310 pb$^{-1}$ of integrated luminosity collected by triggering on a high transverse energy jet, $E_T^{jet}$, in coincidence with a recoil antiproton detected in a Roman pot spectrometer is used to measure the ratio of single-diffractive to inclusive-dijet event rates as a function of $x^{\bar p}$ of the interacting parton in the antiproton, the Bjorken-$x$, $x^{\bar p}_{Bj}$, and a $Q^2\approx (E_T^{jet})^2$ in the ranges $10^{-3}<x^{\bar p}_{Bj}<10^{-1}$ and $10^2<Q^2 <10^4$ GeV$^2$, respectively. Results are presented for the region of $\bar p$-momentum-loss fraction $0.03-4$ GeV$^2$. The $t_{\bar p}$ dependence is measured as a function of $Q^2$ and $x_{Bj}^{\bar p}$ and compared with that of inclusive single diffraction dissociation. We find weak $x^{\bar p}_{Bj}$ and $Q^2$ dependencies in the ratio of single diffractive to inclusive event rates, and no significant $Q^2$ dependence in the diffractive $t_{\bar p}$ distributions.Comment: 22 pages, 23 figures; published versio

Observation of Charge-Dependent Azimuthal Correlations in p-Pb Collisions and Its Implication for the Search for the Chiral Magnetic Effect

Peer reviewe

Search for anomalous Wtb couplings and flavour-changing neutral currents in t-channel single top quark production in pp collisions at root s=7 and 8 TeV

Peer reviewe