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MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments.

ABSTRACT: To evaluate the efficacy of MAP0004, an orally inhaled dihydroergotamine, for acute treatment of migraine when administered at various time points from within 1 hour to more than 8 hours after migraine onset.This post hoc subanalysis was conducted using data from 902 patients enrolled in a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study conducted from July 14, 2008, through March 23, 2009. End points were 2-hour pain relief and pain-free rates in patients who treated a migraine in ?1 hour, from >1 hour to ?4 hours, from >4 to ?8 hours, or in >8 hours after onset of migraine, given that patients may be unwilling or unable to initiate treatment at headache inception.Treatment with MAP0004 was significantly more effective than placebo in relieving pain at all treatment points (?1 hour after start of migraine: 66% [74/112] for MAP0004 vs 41% [48/118] for placebo, P<.001; >1 to ?4 hours: 60% [91/153] vs 35% [58/168], P<.001; >4 to ?8 hours: 53% [36/68] vs 30% [16/54], P=.008; and >8 hours: 48% [25/52] vs 24% [11/46], P=.007). Pain-free rates were also significantly higher with MAP0004 than placebo for treatment within 8 hours after migraine onset (?1 hour: 38% [43/112] for MAP0004 vs 13% [15/118] for placebo, P<.001; >1 to ?4 hours: 28% [43/153] vs 10% [17/168], P<.001; >4 to ?8 hours: 22% [15/68] vs 7% [4/54], P<.025) but not at >8 hours (19% [10/52] vs 9% [4/46], P=.106).This post hoc subanalysis shows that MAP0004 was effective in treating migraine irrespective of the time of treatment, even more than 8 hours after onset of migraine pain.

SUBMITTER: Tepper SJ

PROVIDER: S-EPMC3184024 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments.

Tepper Stewart J SJ Kori Shashidhar H SH Goadsby Peter J PJ Winner Paul K PK Wang Min H MH Silberstein Stephen D SD Cutrer F Michael FM

Mayo Clinic proceedings 20111001 10

<h4>Objective</h4>To evaluate the efficacy of MAP0004, an orally inhaled dihydroergotamine, for acute treatment of migraine when administered at various time points from within 1 hour to more than 8 hours after migraine onset.<h4>Patients and methods</h4>This post hoc subanalysis was conducted using data from 902 patients enrolled in a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study conducted from July 14, 2008, through March 23, 2009. End points were 2-hour pain ...[more]

PMID: 21964172

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Project description:ObjectiveThe objective of this study was to ascertain to what extent adults with migraine value an early onset of efficacy for preventive migraine treatments.BackgroundIn placebo-controlled clinical trials, treatment with eptinezumab resulted in a lower proportion of adults with migraine on the first day following infusion (day 1; 14% point-reduction for chronic migraine [CM] in PROMISE-2 and 8% point-reduction for episodic migraine [EM] in PROMISE-1).MethodsAdults with migraine completed an online preference-elicitation thresholding exercise to ascertain to what extent they value not having a migraine on day 1 postdosing relative to a clinically relevant reduction in number of migraine days during the first month postdosing (≥2 migraine-free days for CM and ≥1 migraine-free days for EM).ResultsOne hundred and one participants (mean age, 50.6 ± 12.4 years; 81 [80%] women) were included. In participants with CM, 29 of 50 (58%) considered the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in number of migraine days the first month postdosing, whereas 37 of 50 (74%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing. In participants with EM, 18 of 35 (51%) considered the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing, whereas 24 of 35 (69%) considered a clinically relevant reduction of migraine days the first month postdosing to have a value equivalent to the eptinezumab-generated reduction in the likelihood of migraine on day 1 postdosing.ConclusionMost participants considered the reduction in the likelihood of migraine offered by eptinezumab on day 1 postdosing to be at least as important as a clinically relevant reduction in migraine days the first month postdosing.

Project description:BackgroundIn the absence of head-to-head trials, comprehensive evidence comparing onset of efficacy of novel agents for acute treatment of migraine is lacking. This study aimed to explore the relative efficacy of lasmiditan (serotonin [5-hydroxytryptamine] 1F receptor agonist) versus rimegepant and ubrogepant (calcitonin gene-related peptide antagonists) for the acute oral treatment of migraine through network meta-analysis (NMA).MethodsData included in the NMA were identified through a systematic literature search (conducted April 2018, updated May/December 2020) of phase II-IV, randomised controlled trials (RCTs) in adults with chronic/episodic migraine with/without aura. Treatments included: lasmiditan 50, 100, 200 mg; rimegepant 75 mg; ubrogepant 25, 50, 100 mg. Pairwise treatment comparisons from Bayesian fixed-effect/random-effects NMA, adjusted by baseline risk where appropriate, were conducted. Comparisons were reported as odds ratios with 95% credible intervals. Early-onset efficacy endpoints included: pain freedom at 2 hours and pain relief at 1 and 2 hours. Adverse drug reaction (ADR) profiles were summarised. Heterogeneity and inconsistency in the network were explored; sensitivity analyses investigated robustness of findings.ResultsAcross 12 RCTs included in the base case, females represented >80% of included patients (mean age 37.9-45.7 years). Odds of achieving both pain freedom and pain relief at 2 hours were higher with lasmiditan 100 and 200 mg versus rimegepant 75 mg and ubrogepant 25 and 50 mg. Results for pain relief at 1 hour were consistent with those at 2 hours, but fewer comparisons were available. There were no statistically significant differences between lasmiditan 50 mg and ubrogepant or rimegepant for any outcome. Sensitivity analyses were in the same direction as base case analyses. Most commonly reported ADRs (incidence ≥2%) were: dizziness, fatigue, paraesthesia, sedation, nausea/vomiting and muscle weakness with lasmiditan; nausea with rimegepant; and nausea, somnolence and dry mouth with ubrogepant.ConclusionsThe efficacy findings of this indirect comparison indicate that lasmiditan 100 mg or 200 mg might be an appropriate acute treatment option for patients with migraine seeking a fast onset of action. Differently from rimegepant and ubrogepant, lasmiditan use is associated with mainly neurological events, which are mostly mild or moderate in severity and self-limiting. 350/350 words.

Project description:OBJECTIVE:To understand the efficacy of zolmitriptan applied with Adhesive Dermally Applied Microarray (ADAM) in treating types of migraine (those with severe headache pain, the presence of nausea, treatment ≥2 hours after migraine onset, or migraine present upon awakening) that are historically considered to be less responsive to oral medications. BACKGROUND:ADAM is an investigational system for intracutaneous drug administration. In a pivotal Phase 2b/3 study (ZOTRIP, N = 321 in the modified intention-to-treat population), ADAM zolmitriptan 3.8 mg provided superior pain freedom and freedom from patients' usual most bothersome associated symptom (MBS), compared with placebo at 2 hours post-dose. We undertook a post hoc analysis of data from the ZOTRIP trial to examine these same outcomes in subsets of patients whose migraine characteristics have been associated with poorer outcomes when treated with oral medications. METHODS:The ZOTRIP trial was a multicenter, randomized, double-blind, placebo-controlled, parallel group Phase 2b/3 study conducted at 36 sites in the United States. Presented here are post hoc subgroup analyses of patients with nausea (n = 110) or severe pain (n = 72) at baseline, those whose treatment was delayed 2 or more hours after onset (n = 75), and those who awoke with migraine (n = 80). The Cochran-Mantel-Haenszel test was used to assess whether patients in the ADAM zolmitriptan 3.8 mg group had superior treatment outcomes compared with placebo. RESULTS:In patients with nausea, 2-hour pain freedom was achieved in 44% (26/59) in the ADAM zolmitriptan 3.8 mg group and 14% (7/51) in the placebo group (P = .005) (odds ratio = 5.11, 95% CI: 1.96-13.30), and 2-hour MBS freedom was achieved in 68% (40/59) in the active treatment group and 45% (23/51) of those receiving placebo (P = .009) (odds ratio = 2.86, 95% CI: 1.28-6.43). For those with severe pain, corresponding pain-free values were 26% (10/39) and 15% (5/33) (P = .249) (odds ratio = 2.14, 95% CI: 0.60-7.62), and MBS-free values were 64% (25/39) and 42% (14/33) (P = .038) (odds ratio = 2.86, 95% CI: 1.05-7.79). Among participants who awoke with migraine, 44% (16/36) and 16% (7/44) were pain-free in the ADAM zolmitriptan 3.8 mg and placebo groups, respectively (P = .006) (odds ratio = 4.29, 95% CI: 1.50-12.31), and 72% (26/36) vs 39% (17/44) were MBS-free, respectively (P = .003) (odds ratio = 4.40, 95% CI: 1.61-12.05). In those whose treatment was delayed ≥2 hours, pain freedom in the active treatment group and placebo group were 33% (12/36) and 10% (4/39), respectively (P = .017) (odds ratio = 4.33, 95% CI: 1.24-15.10), and MBS freedom was achieved in 69% (25/36) and 41% (16/39), respectively, in the delayed treatment group (P = .014) (odds ratio = 3.37, 95% CI: 1.27-8.95). No significant effects (overall interaction P = .353) were observed in logistical regression models of treatment by subgroup interaction. CONCLUSION:Severe pain, delayed treatment, awakening with a headache, and the presence of nausea are factors that predict a poorer response to acute migraine treatment. In these post hoc analyses of subgroups of patients with each of these characteristics in the ZOTRIP trial, participants receiving ADAM zolmitriptan 3.8 mg displayed nearly uniformly better headache responses (2-hour headache freedom and 2-hour MBS freedom) compared with those who received placebo.

Project description:ObjectiveTo determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine.BackgroundM207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks.MethodsIn this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months.ResultsAmong 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks.ConclusionsThe majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial.Trial registrationClinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

Project description:ImportanceMigraine is common and can be associated with significant morbidity, and several treatment options exist for acute therapy.ObjectiveTo evaluate the benefits and harms associated with acute treatments for episodic migraine in adults.Data sourcesMultiple databases from database inception to February 24, 2021.Study selectionRandomized clinical trials and systematic reviews that assessed effectiveness or harms of acute therapy for migraine attacks.Data extraction and synthesisIndependent reviewers selected studies and extracted data. Meta-analysis was performed with the DerSimonian-Laird random-effects model with Hartung-Knapp-Sidik-Jonkman variance correction or by using a fixed-effect model based on the Mantel-Haenszel method if the number of studies was small.Main outcomes and measuresThe main outcomes included pain freedom, pain relief, sustained pain freedom, sustained pain relief, and adverse events. The strength of evidence (SOE) was graded with the Agency for Healthcare Research and Quality Methods Guide for Effectiveness and Comparative Effectiveness Reviews.FindingsEvidence on triptans and nonsteroidal anti-inflammatory drugs was summarized from 15 systematic reviews. For other interventions, 115 randomized clinical trials with 28 803 patients were included. Compared with placebo, triptans and nonsteroidal anti-inflammatory drugs used individually were significantly associated with reduced pain at 2 hours and 1 day (moderate to high SOE) and increased risk of mild and transient adverse events. Compared with placebo, calcitonin gene-related peptide receptor antagonists (low to high SOE), lasmiditan (5-HT1F receptor agonist; high SOE), dihydroergotamine (moderate to high SOE), ergotamine plus caffeine (moderate SOE), acetaminophen (moderate SOE), antiemetics (low SOE), butorphanol (low SOE), and tramadol in combination with acetaminophen (low SOE) were significantly associated with pain reduction and increase in mild adverse events. The findings for opioids were based on low or insufficient SOE. Several nonpharmacologic treatments were significantly associated with improved pain, including remote electrical neuromodulation (moderate SOE), transcranial magnetic stimulation (low SOE), external trigeminal nerve stimulation (low SOE), and noninvasive vagus nerve stimulation (moderate SOE). No significant difference in adverse events was found between nonpharmacologic treatments and sham.Conclusions and relevanceThere are several acute treatments for migraine, with varying strength of supporting evidence. Use of triptans, nonsteroidal anti-inflammatory drugs, acetaminophen, dihydroergotamine, calcitonin gene-related peptide antagonists, lasmiditan, and some nonpharmacologic treatments was associated with improved pain and function. The evidence for many other interventions, including opioids, was limited.

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MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments.

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MAP0004, orally inhaled dihydroergotamine for acute treatment of migraine: efficacy of early and late treatments.

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