col-144 and Migraine-Disorders

Treatment of migraine in the setting of either renal or hepatic disease can be daunting for clinicians. Not only does the method of metabolism have to be considered, but also the method of elimination/excretion of the parent drug and any active or toxic metabolites. Furthermore, it is difficult to think about liver or kidney disease in isolation, as liver disease can sometimes contribute to impaired renal function and renal disease can sometimes impair hepatic metabolism, through the cytochrome P450 system.. A detailed search for terms related to liver disease, renal disease, and migraine management was performed in PubMed, Ovid Medline, Embase, and the Cochrane Library.For each medication, product labels were retrieved and reviewed using the US FDA website, with additional review of IBM Micromedex, LiverTox, and the Renal Drug Handbook.. This manuscript provides an overview of migraine drug metabolism and how it can be affected by liver and renal impairment. It reviews the standard terminology recommended by the US Food and Drug Administration for the different stages of hepatic and renal failure. The available evidence regarding the use of abortive and preventative medicines in the setting of organ failure is discussed in detail, including more recent therapies such as lasmiditan, gepants, and calcitonin gene-related peptide antibodies.. For acute therapy, the use of NSAIDS should be limited, as these carry risk for both severe hepatic and renal disease. Triptans can be selectively used, often with dose guideline adjustments. Ubrogepant may be used in severe hepatic disease with dose adjustment and lasmiditan can be used in end stage renal disease. Though non-medicine strategies may be the most reasonable initial approach, many preventative medications can be used in the setting of hepatic and renal disease, often with dose adjustment. This review provides tables of guidelines, including reduced dosing recommendations, for the use of abortive and preventative migraine medications in hepatic and renal failure.

Topics: Drug Elimination Routes; Humans; Liver Diseases; Migraine Disorders; Renal Insufficiency

Long-term data helps assess the consistency of efficacy, tolerability, and safety of acute treatment over repeated use for different attacks. Real-world studies help assess tolerability, safety, and efficacy in patients with possibly refractory chronic migraine, more comorbidities, other diseases such as cardiovascular diseases, and polypharmacy.. This is a narrative review of the long-term open-label and real-world studies of lasmiditan, ubrogepant, and rimegepant for the acute treatment of migraine. Both manuscripts and abstracts were reviewed.. The efficacy and tolerability of lasmiditan, ubrogepant, and rimegepant are maintained over time. No significant cardiovascular adverse events were thought to be related to any of these medications. The rare instances of palpitations and/or tachycardia occurred within 48 hours of lasmiditan. One participant with a history of supraventricular tachycardia had sinus tachycardia thought to be related to ubrogepant which did not recur despite continued use. One case of thrombocytopenia and two cases of increased aspartate aminotransferase and alanine transaminase were thought to be possibly related, but the alanine transaminase and aspartate aminotransferase levels normalized despite continued use of ubrogepant. A case of first-degree atrioventricular block was considered possibly related to rimegepant. Acute use of rimegepant was associated with a decrease in monthly migraine days over time. The three medications were associated with improvement in function and/or productivity.. Long-term and real-world data of tolerability, safety and efficacy of lasmiditan, ubrogepant, and rimegepant is thus far consistent with prior studies, but more longitudinal data that clarifies long-term safety as well as consistency and predictors of response is needed.

Topics: Alanine Transaminase; Aspartate Aminotransferases; Humans; Migraine Disorders

Topics: Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Contraindications; Humans; Migraine Disorders; Tryptamines

We performed a random-effects network meta-analysis to study the efficacy and safety of newly developed drugs for the acute treatment of migraine attacks.. MEDLINE via PubMed, Embase and The Cochrane Register of Controlled Trials were searched from inception to 11 February 2022. Phase 3 randomized controlled trials examining all formulations of lasmiditan, rimegepant and ubrogepant for the acute treatment of adults with migraine, were included. Data were extracted following the PRISMA guidelines.. Seven studies (SAMURAI, SPARTAN, CENTURION, Study 302, Study 303, ACHIEVE I and II) involving. Lasmiditan 200 mg was the most effective intervention in the treatment of migraine attacks, although it was associated with high degrees of dizziness, nausea and somnolence. Rimegepant showed slightly lower, but similar efficacy rates to lasmiditan. Ubrogepant had overall the best tolerability profile. These conclusions are limited by the absence of head-to-head comparisons, limitations of individual trials and of the meta-analysis methodology itself.

Topics: Adult; Double-Blind Method; Humans; Migraine Disorders; Network Meta-Analysis; Treatment Outcome

Migraine is a common neurological disorder that is present in a large proportion of the global population. It is estimated to occur in around 20.7% of women and 10.7% of men in the United States. The pathophysiology of migraine is a major focus of research, and medications have been developed to interrupt the processes that generate headache and other bothersome symptoms of migraine attacks. The triptan class of medications acts as a direct agonist at the 5-HT1B/D receptor but its use is limited by contraindications for those with coronary or cerebrovascular disease. Lasmiditan is a first-in-class agonist at the 5-HT1F serotonin receptor that does not appear to generate vasoconstriction. This article reviews the design, development, and place in therapy for lasmiditan. A narrative review of the literature using the Ovid MEDLINE database was performed. The rationale behind the development of lasmiditan and pre-clinical, proof-of-concept, Phase II, pivotal, Phase III trials and post-hoc data is covered. Additionally, the efficacy and safety of lasmiditan when compared to other acute treatments in migraine is described, including lasmiditan's side effect profile and status as a Schedule V substance. Further, head-to-head studies of lasmiditan compared with other acute treatments are required.

Topics: Adult; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

In 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).. Data 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.. Across 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.. The 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.

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Middle Aged; Migraine Disorders; Network Meta-Analysis; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic

To develop and compare benefit-risk profiles for rimegepant, ubrogepant, and lasmiditan based on a network meta-analysis (NMA) of published clinical trials.. A fixed-effects Bayesian NMA of randomized controlled trials of lasmiditan, rimegepant, and ubrogepant for the acute treatment of adults with migraine were used to determine risk differences for efficacy and safety outcomes of the 3 treatments compared with pooled placebo. Risk differences were used to calculate number needed to treat (NNT) for pain relief and pain freedom at 2 and 2 to 24 hours and freedom from most bothersome symptoms at 2 hours; and number needed to harm (NNH) for dizziness and nausea, relative to placebo.. Results were based on 5 randomized controlled trials (NCT03461757, NCT02828020, NCT02867709, NCT02439320, and NCT02605174). NNT to achieve sustained pain relief at 2 to 24 hours was lowest for rimegepant 75 mg (5; 95% credible interval [Crl]: 4, 7) and ubrogepant 100 mg (5; 95% Crl: 4, 8) and highest for ubrogepant 25 mg (8; 95% Crl: 5, 16). Rimegepant had the lowest NNT to achieve sustained pain freedom at 2 to 24 hours and lasmiditan 50 mg had the highest (7; 95% Crl: 5, 12 vs. 26; 95% Crl: 13, 95). NNH for dizziness and nausea was highest for ubrogepant 25 mg (28; 95% Crl: 15, 62 and 99; 95% Crl: -2580, 2378, respectively). Lasmiditan 200 mg had the lowest NNH for dizziness and rimegepant 75 mg had the lowest NNH for nausea.. The benefit-risk profiles of lasmiditan, rimegepant, and ubrogepant may improve clinical decision-making.

Topics: Adult; Bayes Theorem; Benzamides; Dizziness; Double-Blind Method; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Pyrroles; Serotonin Receptor Agonists; Treatment Outcome

In the absence of head-to-head comparisons, the objective of this study was to conduct a network meta-analysis (NMA) to indirectly compare the relative efficacy and safety of rimegepant, ubrogepant, and lasmiditan for the acute treatment of migraine.. A systematic literature review was conducted to identify randomized controlled trials (RCTs) of rimegepant, ubrogepant, and lasmiditan in adults with acute migraine. Outcomes included sustained pain freedom and -relief 2-48 hours post-dose, and adverse events. No RCTs were identified that directly compared these interventions. Therefore, a fixed-effects Bayesian NMA was conducted by identifying a connected (via comparison to placebo) network of RCTs.. Five RCTs were identified as follows: rimegepant study 303 (n = 1,466), ubrogepant ACHIEVE I and II (n = 1,672 and n = 1,686, respectively), and lasmiditan SAMURAI and SPARTAN (n = 2,231 and n = 3,005, respectively). Efficacy outcomes (pain freedom and relief at 2, 24, 48 hours) tended to be highest for lasmiditan 200 mg and rimegepant followed lower doses of lasmiditan and all doses of ubrogepant. However, lasmiditan 200 mg was also associated with higher rates of adverse events, particularly somnolence and dizziness.. Lasmiditan, rimegepant, and ubrogepant all performed significantly better than placebo with respect to pain freedom and pain relief. Efficacy results were similar for rimegepant and lasmiditan with rimegepant having higher rates of pain freedom and relief than lower doses of lasmiditan, while somnolence and dizziness outcomes were lower for rimegepant than higher doses of lasmiditan.

Topics: Adult; Benzamides; Humans; Migraine Disorders; Network Meta-Analysis; Piperidines; Pyridines; Pyrroles; Randomized Controlled Trials as Topic; Treatment Outcome

Monotherapy with triptans in acute migraine is ineffective in many patients and contraindicated in certain cardiovascular diseases where alternative therapeutic options are necessary to explore. This meta-analysis has evaluated the efficacy and safety of lasmiditan for the treatment of acute migraine in adults. After performing a literature search on MEDLINE/PubMed, Scopus, Cochrane databases, and International Clinical Trial Registry Platform, reviewers assessed eligibility and extracted data from 4 relevant articles. Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines were followed in the selection, analysis, and reporting of findings. A random-effects model was used to estimate effect size. Quality assessment was done using the risk of bias assessment tool and meta-regression for probable variables affecting effect size. Subgroup analysis was done depending on the dose of lasmiditan. Lasmiditan use was associated with a significantly higher percentage of patients with pain freedom (odds ratio [OR], 2.02; 95% confidence interval [CI], 1.72-2.39; P < .00001), sustained pain freedom (OR, 1.93; 95%CI, 1.55-2.39; P <.00001), headache response (OR, 2.05; 95%CI, 1.77-2.36; P < .00001), clinical disability level (OR, 1.36; 95%CI, 1.20-1.55; P < .00001), patients' global impression (OR, 1.88; 95%CI, 1.69-2.10; P < .00001), and significantly lower use of rescue medication (OR, 0.49; 95%CI, 0.38-0.63; P < .00001) compared to placebo. Lasmiditan use was also associated with a higher likelihood of adverse effects like dizziness (OR, 6.54; 95%CI, 4.24-10.07; P < .00001), paresthesia (OR, 4.28; 95%CI, 2.97-6.17; P < .00001), and fatigue (OR, 5.67; 95%CI, 3.78-8.52; P < .00001) compared to placebo. Subgroup analysis showed a dose-dependent effect of lasmiditan on pain freedom, sustained pain freedom, patient's global impression, and occurrence of adverse drug reactions. Prediction probability for effect estimate favoring placebo was calculated to be 0.0017%. Lasmiditan has shown a favorable effect in terms of efficacy and safety in the treatment of an acute attack of migraine in comparison to placebo. Further studies are needed to evaluate long-term safety, efficacy, and use in specific subgroups of patients. PROSPERO Registration Number: CRD42020177838.

Topics: Benzamides; Disability Evaluation; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Pain Measurement; Patient Satisfaction; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Time Factors

Migraine has a great impact on public health. Current acute therapies do not satisfy all migraineurs. The novel serotonin 5-HT. To evaluate the clinical efficacy and safety of lasmiditan in treating acute migraine attacks.. The literature search was performed in PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) which assessed the effect and safety of lasmiditan on migraine. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool. Results were extracted and pooled as risk ratios (RRs) with a fixed or random-effects model.. Based on the four included RCTs, pooled estimates showed that lasmiditan with the 50 mg, 100 mg, and 200 mg doses was superior to placebo at 2 h after the first dose in terms of pain freedom, absence of migraine-associated symptoms, headache relief, no/mild disability, and global impression of change (very much/much better) (RRs ranged from 1.13 to 1.96), except for nausea-free and vomiting-free. Both lasmiditan 100 mg and 200 mg resulted in significantly fewer patients using rescue medication (100 mg: RR = 0.75, 95% CI (0.61, 0.92),. Lasmiditan with the 50 mg, 100 mg, and 200 mg doses are effective and safe in acute migraine treatment. Lasmiditan 200 mg is more effective than lasmiditan 100 mg in pain freedom, while lasmiditan 100 mg is better tolerated in the short-term follow-up. Further larger sample-size RCTs are required to verify the applicability and tolerability in the long term.

Topics: Adult; Benzamides; Cardiovascular Diseases; Confidence Intervals; Disability Evaluation; Female; Humans; Male; Migraine Disorders; Piperidines; Publication Bias; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk; Serotonin Receptor Agonists; Treatment Outcome

This narrative review provides an update on the research that led to the development of ditans and lasmiditan for the acute treatment of migraine in adults and discusses the potential advantages and disadvantages of lasmiditan in clinical use.. The electronic databases PubMed, Scopus, and ClinicalTrials.gov were searched from database inception through January 9, 2021, to identify relevant studies. Search results were assessed for their overall relevance to this review.. Because part of the effect of the triptans is mediated by the serotonin 1F receptors, which are not present in the smooth muscle, a pure agonist of these receptors, lasmiditan, was developed. Lasmiditan is hypothesized to act on antinociceptive pathways and inhibit the calcitonin gene-related peptide release. Lasmiditan was approved by the US Food and Drug Administration in 2019 based on the results of 2 pivotal trials that found a significant difference from placebo in the percentage of patients who achieved freedom from pain and most bothersome symptom at 2 h. The main concern of lasmiditan derives from its central nervous system-related adverse effects, mainly dizziness and paraesthesia, probably attributable to its high blood brain barrier penetration. These central nervous system adverse effects impair driving performance for hours and might be suboptimal for individuals with migraine who want to quickly stop the migraine attack to resume their activities as soon as possible.. Despite the advantage of being beneficial in the acute treatment of migraine without vasocostrictive action, lasmiditan also presents limitations, in particular the central nervous system adverse effects. Moreover, head-to-head trials against triptans and gepants are indispensable to determine the better option for patients.

Topics: Adult; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan, a selective 5-HT1F receptor agonist, is a harbinger for the novel ditan class of medications for acute migraine treatment. Lasmiditan activates 5-HT1F receptors on presynaptic trigeminal nerve terminals, which impedes the release of calcitonin gene-related peptide (CGRP) from trigeminal nerve endings and thereby suppresses activation of the trigeminovascular system. Notably, lasmiditan does not result in vasoconstriction, making lasmiditan a migraine-specific acute treatment option for those with cardiovascular risk factors. However, lasmiditan does have centrally mediated side effects. This review will discuss the background of lasmiditan development, its preclinical pharmacology, safety, drug interactions and indications for use.

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists

Migraine is a leading cause of morbidity and disability worldwide. Triptans were the first migraine-specific drug class developed and have proven efficacy in treatment of this neurological disease. They are however contraindicated in patients with cardiovascular disease and possibly others, owning to their vasoconstrictive properties. This review will focus on lasmiditan, which has been called the first 'ditan' and 'neurally acting anti-migraine agent', designed to selectively agonize the serotonin 5-HT. Lay abstract Migraine is a leading cause of pain and disability worldwide. Triptans (e.g., sumatriptan) were the first migraine-specific drug class developed and have proven to be effective treatments. Triptans are however contraindicated in patients with heart disease and possibly in some subsets of migraine, due to vasoconstriction concerns. This review will focus on lasmiditan, the first 5-HT

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists

Topics: Benzamides; Disability-Adjusted Life Years; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Vestibular System

Migraine has been recognized as one of common diseases in the world whose current treatment options are not ideal. Lasmiditan, an oral 5-hydroxytryptamine (HT). PubMed, Cochrane Library, Embase were searched on lasmiditan for the acute treatment of migraine from inception of the databases to Feb 1, 2020. Pain free and pain relief, global impression (very much/much better), and no/mild disability at 2 h in efficacy; total treatment-emergent adverse events (TEAEs), dizziness, nausea, fatigue, paraesthesia and somnolence in safety were extracted from the included studies. A systematic review and meta-analysis was performed using Review Manager Software version 5.3 (RevMan 5.3).. Four RCTs with a total of 4960 subjects met our inclusion criteria. The overall effect estimate showed that lasmiditan was significantly superior to placebo in terms of pain free (RR 1.71, 95% CI 1.55-1.87), pain relief (RR 1.40, 95% CI 1.33-1.47), global impression (very much/much better) (RR 1.55, 95% CI 1.44-1.67), and no/mild disability (RR 1.15, 95% CI 1.10-1.20) at 2 h. For the safety, significant number of patients experienced TEAEs with lasmiditan than with placebo (RR 2.77, 95% CI 2.53-3.03), most TEAEs were central nervous system (CNS)-related and included dizziness (RR 5.81, 95% CI 4.72-7.14), nausea (RR 2.58, 95% CI 1.87-3.57), fatigue (RR 5.38, 95% CI 3.78-7.66), paraesthesia (RR 4.48, 95% CI 3.33-6.02), and somnolence (RR 2.82, 95% CI 2.18-3.66).. This meta-analysis suggests that lasmiditan is effective for the acute treatment of migraine with a higher incidence of CNS-related adverse reactions compared with placebo. Long-term, open-label, multi-dose trials are required to verify the current findings.

Topics: Benzamides; Dizziness; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Vertigo

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-HT

Topics: Animals; Benzamides; Calcitonin Gene-Related Peptide; Humans; Migraine Disorders; Neurons; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Trigeminal Ganglion; Tryptamines; Vasoconstriction

The US Food and Drug Administration has approved orally administered 100-mg and 200-mg doses of lasmiditan for the acute treatment of migraine, with or without aura. Having a unique mechanism of action, lasmiditan is the first and only Food and Drug Administration-approved serotonin 5-HT. The objective of this study was to systematically evaluate the efficacy and safety of lasmiditan for the acute treatment of migraine in adult patients.. We systematically searched PUBMED, EMBASE, and Cochrane Library databases. Any relevant articles published before 3 March, 2020 were collected. Inclusion criteria were: (1) randomized clinical trials; (2) enrolled adult participants diagnosed with migraine; (3) compared lasmiditan at 100 mg or 200 mg with placebo; (4) enrolled more than 100 participants; and (5) provided any available data for predefined primary or secondary outcomes.. In this meta-analysis, the use of lasmiditan as an acute treatment for episodic migraine in adults led to a greater percentage of freedom of pain and the absence of the most bothersome symptoms at 2 h post-dose. Lasmiditan 200 mg had superior efficacy to 100-mg dose without a significantly increased risk for adverse events.

Topics: Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Topics: Administration, Oral; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Migraines are a common form of primary headache, affecting women more than men (17.4% and 5.7% of US population, respectively, a total of 12%) that carry significant morbidity and disability, as well as a hefty healthcare price tag. They are most prevalent in women of reproductive ages and are estimated to be the 6th disease in order of causing global burden. They are estimated to cause 45.1 million years lived with disability, or 2.9% of global years lost to disability. Migraine treatment divides into acute, abortive treatment for relief of an ongoing migraine attack, and prophylactic therapy to reduce the occurrence of migraines, specifically for patients suffering from chronic and frequent episodic migraines. Traditional abortive treatment usually begins with NSAID and non-specific analgesics that are effective in curbing mild to moderate attacks. 5HT

Topics: Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Disability-Adjusted Life Years; Epilepsy; Humans; Migraine Disorders; Piperidines; Pyridines

To describe the new classes of medication for headache management and their roles in clinical practice.. Calcitonin gene-related peptide (CGRP) is a key component in the underlying pathophysiology of migraine. Research focused on targeting CGRP for headache treatment has led to the development of entirely new classes of medications - the gepants and the CGRP monoclonal antibodies (mAbs) - for both acute and preventive treatment. A third class, the ditans, is being developed to target the 5-HT. This article reviews the pathophysiology of migraine that has led to these new pharmacologic developments. Available information from randomized controlled trials, abstracts, press releases, and relevant preclinical studies is summarized for each class of medications.. At the time of this writing, one ditan has been submitted to the U.S. Food and Drug Administration (FDA) for approval. One gepant is anticipated to be submitted within the first quarter of 2019, and others are in clinical trials. Three CGRP mAbs have been FDA approved and are now available in clinical practice, and a fourth was submitted in the first quarter of 2019.. The development of new migraine-specific classes of medications provides more treatment options for both acute and preventive treatment of migraine.

Topics: Analgesics; Antibodies, Monoclonal; Benzamides; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Clinical Trials as Topic; Contraindications, Drug; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Calcitonin Gene-Related Peptide; Receptors, Serotonin; Serotonin Receptor Agonists; United States; United States Food and Drug Administration; Vasoconstriction; Vasoconstrictor Agents

Lasmiditan (REYVOW™; Eli Lilly and Company) is an orally available serotonin (5-HT)

Topics: Benzamides; Clinical Trials, Phase III as Topic; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists

Migraine is the most common of all neurological disorders. A breakthrough in migraine treatment emerged in the early nineties with the introduction of 5-HT1B/D receptor agonists called triptans. Triptans are used as the standard of care for acute migraine; however, they have significant limitations such as incomplete and inconsistent pain relief, high rates of headache recurrence, class- specific side effects and cardiovascular contraindications. First- and second-generation calcitonin gene-related peptide (CGRP) receptor antagonists, namely gepants, is a class of drugs primarily developed for the acute treatment of migraine. CGRP is the most evaluated target for migraine treatments that are in development.. This article reviews the available data for first- and second-generation CGRP receptor antagonists, the role of CGRPs in human physiology and migraine pathophysiology and the possible mechanism of action and safety of CGRP-targeted drugs.. Available data suggest that second generation of gepants has clinical efficacy similar to triptans and lasmiditan (5-HT1F receptor agonist) and has improved tolerability. Future studies will assess their safety, especially in specific populations such as patients with cardiovascular disease and pregnant women.

Topics: Acute Disease; Animals; Benzamides; Calcitonin Gene-Related Peptide Receptor Antagonists; Drug Development; Humans; Migraine Disorders; Piperidines; Pyridines; Tryptamines

Migraine is a recurrent, disabling, complex and highly prevalent neurological disorder. The mystery behind the cause of migraine is continuously evolving, according to the scientific understanding of the disease. This growing understanding helps to identify novel therapeutic targets for the management of migraine to treat the ailing migraineurs. The role of serotonin (5HT) in migraine is recognized to be the cornerstone for the currently available therapeutic options namely ergot alkaloids and triptans. The role of mediators such as Calcitonin Gene-Related Peptide (CGRP), nitric oxide and excitatory neurotransmitter glutamate, has been realized and ignited the development of drugs targeting these factors. Lasmiditan, known as a Neurally Active Anti- Migraine Agent (NAAMA) is a specific 5HT1F agonist, developed as a new group named as 'ditans'. The drug was designed and developed to meet the unmet needs of currently available medications to circumvent the vascular adverse effects. Having a group of drugs with a nonvascular mechanism of action, devoid of unwanted effects with a different spectrum of indication and contraindications, is the need of the hour to expand the armamentarium available to tackle acute migraine attack.

Topics: Animals; Benzamides; Drug Design; Humans; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin 5-HT1 Receptor Agonists; Signal Transduction; Structure-Activity Relationship; Treatment Outcome

Migraine is among the most disabling disorders worldwide, with a significant therapeutic need. Triptans are drugs of choice in the acute attack treatment, but they are contraindicated in patients with vascular conditions due to their potential vasoconstrictive properties. Further limitations include side effects, inconsistency in therapeutic action and possible non-response. Lasmiditan, a highly selective 5-HT1F receptor agonist, is a novel acute anti-migraine substance devoid of vasoconstriction. Areas covered: This article reviews the clinical efficacy and safety of oral and intravenous lasmiditan as a possible acute migraine treatment. We analyze all currently available results in Phase I to III studies. Expert opinion: Lasmiditan is a promising acute migraine therapy, in particular for patients at cardiovascular risk. Phase II and the first Phase III clinical trials show a significant better headache response in comparison to placebo. The efficacy of lasmiditan proves that vasoconstriction is not essential for acute migraine therapy and thereby points, in addition to a well-established trigeminal contribution, to central neuronal mechanisms in migraine pathophysiology. Lasmiditan penetrates the blood-brain barrier and CNS associated adverse events are common, but mostly in mild to moderate severity. The results of long-term Phase III studies will determine if these adverse events represent a limitation in clinical practice.

Topics: Benzamides; Cardiovascular Diseases; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Risk Factors; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Migraine is a highly prevalent neurovascular disorder.. Of the many factors that have been implicated over the years, 5-hydroxytryptamine (5-HT; serotonin) has long been involved in the pathophysiology of migraine. Certainly, some lines of evidence suggest: (i) a 5-HT depletion from blood platelets resulting in cranial extracerebral vasodilatation; and (ii) the effectiveness of an intravenous (i.v.) infusion of 5-HT to abort migraine in some patients. More direct evidence comes from some drugs that influence 5-HT release and/or interact (as agonists or antagonists) with 5-HT receptors to treat this disorder. Indeed, the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors). Although the triptans represent the current mainstay of acute antimigraine treatment, a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies.. This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors, including selective agonists at 5-HT1D and 5-HT1F receptors, agonists at 5-HT1B/1D receptors combined with other properties as well as antagonists at 5-HT2B/2C, 5-HT3 and 5-HT7 receptors. It also touches upon the recent development of antagonists and antibodies at calcitonin gene-related peptide (CGRP) and its receptors, which produce a direct blockade of the CGRPergic vasodilator mechanisms involved in migraine. These alternative pharmacological approaches will hopefully lead to less side-effects.

Topics: Benzamides; Drug Design; Humans; Indoles; Migraine Disorders; Piperidines; Protein Binding; Pyridines; Receptor, Serotonin, 5-HT1D; Serotonin; Serotonin 5-HT1 Receptor Agonists

Migraine is one of the most common diseases in the world, with high economical and subjective burden. Migraine acute therapy is nowadays based on specific and non-specific drugs but up to 40% of episodic migraineurs still have unmet treatment needs and over 35% do not benefit from triptans administration. Serotonin-1F receptors have been identified in trigeminal system and became an ideal target for anti-migraine drug development as potential trigeminal neural inhibitors. Lasmiditan, a novel serotonin1F receptor agonist, showed specific affinity in vitro for the receptor without any vasoconstrictive action and inhibited markers associated with electrical stimulation of trigeminal ganglion in migraine animal models. Areas covered: This article reviews both preclinical and clinical studies on lasmiditan as a potential acute therapy for migraine, as well as pharmacokinetic and pharmacodynamic features. It also summarizes safety and tolerability data gathered in the various human studies. Expert opinion: The absence of vasoconstrictive effects makes lasmiditan a promising novel migraine acute therapy. Although preclinical and Phase I and II studies established a significant efficacy, the limited knowledge about pharmacokinetics and metabolism, the high rate of non-serious central nervous system side effects and the lack of larger studies remain still a matter of concern that should be addressed in future studies.

Topics: Animals; Benzamides; Disease Models, Animal; Drug Design; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists

The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines.. This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE).. Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.

Topics: Animals; Benzamides; Drug Administration Routes; Humans; Migraine Disorders; Piperidines; Pyridines; Receptors, Serotonin; Serotonin Receptor Agonists; Tryptamines

Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans.

Topics: Animals; Benzamides; Clinical Trials, Phase II as Topic; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists

The effective anti-migraine drugs triptans, all bind with high affinity to three serotonin (5-HT) subtypes, the 5-HT1B, 5-HT1D and 5-HT1F. 5-HT1B mRNA is densely localized within smooth muscle, and less in the endothelium of cerebral blood vessels. This vascular distribution of 5-HT1B receptor has been shown to mediate the vasoconstrictive properties of the triptans, responsible for potential cardiac adverse events. Activation of 5-HT1D subtype, although effective in animal models of migraine, was not enough efficient to attenuate migraine attacks in clinical trials. The 5-HT1F receptor is located both in vessels and within the trigeminal ganglion (TG) and the trigeminal nucleus caudalis (Sp5C), but with the difference that the 5-HT1F receptor lack vasoconstrictive properties, making it an attractive target for new anti-migraine drugs. Selective activation of 5-HT1F receptor potently inhibited markers associated with electrical stimulation of the TG. Thus 5-HT1F receptor represents an ideal target for anti-migraine drugs. So far two selective 5-HT1F agonists have been tested in human trials for migraine: LY334370 and lasmiditan. Both molecules were efficient in attenuating migraine attacks with efficacy in the same range as oral sumatriptan 100mg, the gold standard for triptans. The LY334370 project withdrew because of toxicity in animals, while lasmiditan is still testing. In this review we present all the available preclinical and clinical data on the 5-HT1F agonists as a potential new class of anti-migraine drugs lacking vascular activity and we discuss related issues on the vascular and neuronal aspects of migraine pathogenesis.

Topics: Animals; Benzamides; Carbazoles; Clinical Trials as Topic; Disease Models, Animal; Drug Evaluation, Preclinical; Fatigue; Fluorobenzenes; Humans; Indoles; Migraine Disorders; Models, Neurological; Molecular Targeted Therapy; Nausea; Paresthesia; Pilot Projects; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Treatment Outcome; Vertigo

MONONOFU, a multicenter, randomized, double-blind, placebo-controlled phase 2 study of Japanese patients with migraine, was pivotal for lasmiditan approval in Japan. However, treatment-emergent adverse events (TEAEs) were more common than in global studies. A detailed safety profile would assist patient management.. Safety assessments in MONONOFU included specific terms reported, frequency, severity, time to onset, duration, TEAE management, common TEAE risk factors, and TEAE-efficacy associations.. Of 846 participants, 691 were assessed for safety. The proportion of participants reporting ≥1 TEAE was 23.4% with placebo and 70.9% with lasmiditan; 87.3% of TEAEs with lasmiditan were mild. The most frequent TEAEs with lasmiditan, dizziness (39.4%) and somnolence (19.3%), started ≤1 hour postdose (median durations: 2.5 and 3.3 hours, respectively). Higher lasmiditan dose, but not patient factors including body size, was identified as a clinically meaningful predictor of dizziness and somnolence. There were no adverse consequences of neurological TEAEs, which did not appear to adversely affect lasmiditan efficacy.. In the MONONOFU study, TEAEs appeared typically mild, transient, and self-limiting. Lasmiditan may represent a useful and well-tolerated acute treatment option for smaller (body mass index <30 kg/m

Topics: Dizziness; Double-Blind Method; Humans; Migraine Disorders; Serotonin Receptor Agonists; Sleepiness; Treatment Outcome

Following the CENTURION phase 3 randomized controlled trial's four-month double-blind phase, this 12-month open-label extension collected data for up to one year about dose optimization, patterns of use, migraine-related disability, and quality of life during lasmiditan treatment.. Migraine patients ≥18 years completing the double-blind phase and treating ≥3 migraine attacks could continue into the 12-month open-label extension. The initial oral lasmiditan dose was 100 mg; the dose could subsequently be adjusted to 50 mg or 200 mg at the investigator's discretion.. 477 patients entered and 321 (72.1%) completed the extension; 445 (93.3%) treated ≥1 attack with lasmiditan. Of 11,327 attacks, 8654 (76.4%) were lasmiditan-treated (84.9% of these involved moderate or severe pain). By study end, 17.8%, 58.7%, and 23.4% of patients were taking lasmiditan 50, 100, and 200 mg, respectively. Mean improvements were observed in disability and quality of life. The most common treatment-emergent adverse event was dizziness (35.7% of patients, 9.5% of attacks).. During this 12-month extension, lasmiditan was associated with a high rate of study completion, most attacks were treated with lasmiditan, and patients reported improvements in migraine-related disability and quality of life. No new safety findings were observed with longer exposure.

Topics: Double-Blind Method; Humans; Migraine Disorders; Quality of Life; Serotonin Receptor Agonists; Treatment Outcome

A significant proportion of triptan users exhibit an insufficient response or inadequate tolerability to a triptan, and some may develop a contraindication. Lasmiditan, a selective 5-HT. Patients were randomized to lasmiditan 200 mg for four attacks, lasmiditan 100 mg for four attacks, or placebo for three and lasmiditan 50 mg for one attack. Triptan insufficient responders were pre-defined as patients with insufficient efficacy or tolerability, or who developed a contraindication.. Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

The robust enrollment in SPARTAN and SAMURAI provided the opportunity to present post-hoc descriptive details on migraine disease characteristics and treatment outcomes after treatment with lasmiditan, a selective serotonin (5-HT. Descriptive data from racial (White [W](. Clinical characteristics were generally similar across populations. W participants had longer migraine history than AA participants, and Non-HL participants had more migraine disability than HL participants. In the lasmiditan single-attack studies, AA participants waited longer than W participants to take study drug. A higher proportion of HL participants rated baseline migraine severity as severe compared to Non-HL participants. Response to lasmiditan was similar across racial and ethnic groups, including pain response, freedom from most bothersome symptom and migraine-related disability, and safety and tolerability. Across multiple outcomes, AA and HL participants tended to report more positive outcomes.. There were few differences in demographic and clinical characteristics across racial and ethnic groups. Similar lasmiditan efficacy and safety outcomes were observed in AA versus W participants, and in HL versus Non-HL participants. Small observed differences may be driven by a tendency toward a more positive response observed across all treatment groups by AA and HL participants.

Topics: Benzamides; Double-Blind Method; Ethnicity; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Some migraine treatments are contraindicated for patients with cardiovascular disease (CVD) or risk factors (CVRFs). We report safety and efficacy of lasmiditan, a new oral acute migraine treatment with no cardiovascular contraindication, in Japanese patients with CVRFs.. MONONOFU was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study of Japanese patients with migraine (met International Headache Society criteria, Migraine Disability Assessment score ≥11, disabling migraine for ≥1 year). Eligible patients were randomized (7:3:7:6) to placebo or lasmiditan 50, 100, 200 mg. This prespecified analysis described CVDs, CVRFs, and cardiovascular treatment-emergent adverse events (TEAEs). Efficacy (proportion pain-free, experienced pain relief, most bothersome symptom-free, or disability-free 2 hours post-dose) was evaluated within CVRF subgroups (≤1, ≥2).. Of 846 randomized patients, 691 were analyzed (CVRF≤1: 375; CVRF≥2: 316). The proportion of lasmiditan-treated patients with ≥1 TEAE was not related to CVRF numbers. Eighteen (3.8%) lasmiditan-treated and three (1.4%) placebo-treated patients reported likely cardiovascular TEAEs. Lasmiditan was more effective than placebo at relieving pain, symptoms, and disability in both CVRF subgroups. There was no consistent relationship between CVRF subgroups and efficacy.. Lasmiditan was well tolerated and effective in Japanese patients with migraine and CVRFs.. ClinicalTrials.gov: NCT03962738.

Topics: Cardiovascular Diseases; Double-Blind Method; East Asian People; Humans; Migraine Disorders; Serotonin Receptor Agonists; Treatment Outcome

In controlled clinical trials, compared with placebo, a significantly greater proportion of participants using lasmiditan to treat a migraine attack achieved 2-h pain freedom (PF) and experienced ≥ 1 treatment-emergent adverse event (TEAE).. To better inform clinicians about treatment expectations by evaluating the association between TEAEs and efficacy outcomes after lasmiditan treatment.. Pooled data from SAMURAI, SPARTAN, MONONOFU, and CENTURION were analyzed. A common TEAE (CTEAE) was defined as occurring in ≥ 2% in the overall population. Central nervous system (CNS)-CTEAEs were based on Medical Dictionary for Regulatory Activities.. At 2 h, a significantly higher percentage of lasmiditan 200 mg-treated participants who achieved PF experienced ≥ 1 CTEAE than non-responders who continued to experience moderate/severe pain (48.2% vs. 28.7%, respectively). Correspondingly, a significantly higher percentage of lasmiditan 200 mg-treated participants who experienced ≥ 1 CTEAE achieved PF at 2 h than those who did not (39.0% vs. 30.2%, respectively). Similar results were generally observed with individual CNS-CTEAEs, but for non-CNS-CTEAEs, this pattern was less evident or in the opposite direction. No consistent differences were observed for migraine-related functional disability freedom. The percentage of participants with improved patient global impression of change (PGIC) was greater with a CNS-CTEAE versus no CNS-CTEAE.. Those who had PF at 2 h were more likely to experience a CNS-CTEAE, and those with CNS-CTEAEs were more likely to experience PF. The occurrence of CTEAEs did not seem to negatively affect disability freedom or PGIC.. SAMURAI (NCT02439320), SPARTAN (NCT02605174), MONONOFU (NCT03962738), CENTURION (NCT03670810), ClinicalTrials.gov: NCT02439320, NCT02605174, NCT03962738, NCT03670810.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; Treatment Outcome

Perimenstrual migraine attacks in women with menstrual migraine is difficult to treat. This post-hoc analysis evaluated the efficacy of lasmiditan, a high affinity and selective 5-HT. Patients from two randomized, double-blind, placebo-controlled clinical trials (MONONOFU and CENTURION) were instructed to treat an attack with a single dose of study medication within four hours of pain onset. After dosing, the proportion of patients who achieved freedom from migraine-related head pain, most bothersome symptom, and disability was reported at baseline up to 48 hours after dose and pooled data were evaluated.. A total of 303 patients (MONONOFU N = 78; CENTURION N = 225) treated perimenstrual migraine attacks with lasmiditan 50 mg (N = 24), 100 mg (N = 90), 200 mg (N = 110), and placebo (N = 79). More patients achieved migraine-related head pain freedom with lasmiditan 200 mg versus placebo at all time points assessed. At 2 hours, 33.6% of patients in the 200-mg group (p < 0.001), and 16.7% of patients in the 100-mg (p = 0.11) and 50-mg (p = 0.19) groups were pain free, compared with 7.6% in the placebo group.. Lasmiditan treatment of perimenstrual migraine attacks was associated with freedom from migraine-related head pain at two hours, early onset of efficacy, and sustained efficacy.

Topics: Benzamides; Double-Blind Method; Female; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

Lasmiditan is the first 5-HT. Patients were randomized 1:1:1 to lasmiditan 200 mg lasmiditan 100 mg, or a control group. The incidence of treatment-emergent adverse events (TEAEs), their severity, and incidence by treated attacks for frequently reported TEAEs (≥ 5%) were evaluated. The duration, onset, and relationship of efficacy with very common TEAEs (≥ 10%) was analyzed.. A total of 281 Chinese patients were included in this post hoc analysis. No deaths and no study drug-related treatment emergent serious adverse events (TESAEs) were reported. The incidence of at least one TEAE was higher in patients receiving lasmiditan 200 mg (73.9%) and 100 mg (66.3%) versus placebo (26.6%). TEAEs were generally mild or moderate in severity, and the incidence of frequently reported TEAEs was generally highest during the first attack. Very common TEAEs with lasmiditan included dizziness, asthenia, somnolence, muscular weakness, fatigue, and nausea. The duration of dizziness was longest during the first attack. There were no cardio-cerebrovascular ischemic events and serotonin syndrome. The presence of very common TEAEs (except nausea), and severe dizziness, did not appear to have a negative influence on the efficacy.. In the Chinese population of the CENTURION study, most of the TEAEs were neurologic, of mild or moderate severity, and self-limiting. The distribution of frequently reported TEAEs at the first attack differed from the primary cohort, while the overall safety profile of lasmiditan in the Chinese population was generally consistent with the CENTURION primary cohort. No new safety concerns were observed in the Chinese population.. NCT03670810.. Although there is significant unmet medical need among patients with migraine, there has been no novel compound for treatment of migraine over past two decades in China. These unmet medical needs persist because the current available medications for the acute treatment of migraine are reported to have safety and tolerability issues. Lasmiditan is a new class of acute migraine medication (5-HT receptor agonist with high selectivity for the 5-HT

Topics: Benzamides; Dizziness; Double-Blind Method; Humans; Migraine Disorders; Nausea; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

This MONONOFU trial subgroup analysis evaluates the efficacy of lasmiditan across patient and migraine characteristics in Japanese patients with migraine.. MONONOFU trial was a multicenter, randomized, double-blind, placebo-controlled study. The patients were randomly assigned in a 3:7:6:7 ratio to receive lasmiditan 50 mg, 100 mg, 200 mg, or placebo for a single migraine attack within 4 h of pain onset. Efficacy of lasmiditan vs placebo was evaluated at 2 h post dose for proportion of patients with headache pain freedom. Efficacy was assessed across patient characteristics (age, sex, body weight, cardiovascular risk factors (CVRF), and comorbidity of tension-type headache), migraine disease characteristics (history of migraine with aura, migraine prevention therapy, triptan response, and triptan use or nonuse), and migraine attack characteristics (headache severity, aggressive headache, attack during perimenstrual period, time to dosing, time of dosing, experienced treatment-emergent adverse event (TEAE) of dizziness, and experienced TEAE of somnolence). Logistic regression was used; all subgroup analyses were not analyzed with multiplicity-adjusted statistical tests.. Treatment-by-subgroup interactions (by each arm) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups and lasmiditan doses, except for CVRF (100 mg and 200 mg), migraine with aura (50 mg), triptan response (50 mg), and time to dosing (200 mg). Treatment-by-subgroup interactions (by overall) were not significant (p ≥ 0.05) for pain freedom at 2 h post dose across all patient subgroups, except for CVRFs. Higher proportions of patients were pain free at 2 h post dose when treated with lasmiditan (50 mg, 100 mg, and 200 mg) versus placebo, irrespective of most patient characteristics, migraine disease characteristics, and migraine attack characteristics.. Although few interactions were observed, lasmiditan could be a promising acute treatment option in a wide range of Japanese patients with migraine, as efficacy is not generally influenced by patient and migraine characteristics.

Topics: Benzamides; Double-Blind Method; Headache; Humans; Japan; Migraine Disorders; Migraine with Aura; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Lasmiditan (LTN) is a selective 5-HT. Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses.. Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents.. In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks.. NCT03670810.

Topics: Adult; Benzamides; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks.. Patients were randomized 1:1:1 to one of three treatment groups - lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity.. Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg (. These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks.

Topics: Benzamides; Double-Blind Method; Humans; Migraine Disorders; Pain; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan is a selective serotonin (5-HT1F) receptor agonist approved in the US for the acute treatment ofmigraine in adults. This phase I, open-label, two-cohort study assessed the pharmacokinetics (PK), safety, and tolerability of lasmiditan in patients with migraine aged 6 to < 18 years.. Cohort 1 (15 to ≤ 40 kg) and Cohort 2 (> 40 to ≤ 55 kg) received single oral doses of lasmiditan (100 mg and 200 mg, respectively).Blood samples for the assessment of PK and safety parameters were collected over a 24-h period. Follow-up was approximately 14 days after dosing.. Eighteen patients received lasmiditan (11 in Cohort 1, 7 in Cohort 2) and 17 patients completed the study. One patient in Cohort 2 discontinued due to adverse events. Plasma concentrations peaked at 1.5-2 h post dose and then declined, with a terminal half-life of approximately 4 h in both cohorts. While the exposure to lasmiditan was generally similar between cohorts, PK parameters, such as apparent total body clearance and volume of distribution, were greater for the 200 mg cohort relative to the 100 mg cohort. No deaths or serious adverse events were reported. The frequency and severity of adverse events (including somnolence, dizziness, and fatigue) were generally mild and similar to those in adult studies.. The PK results support weight-based dosing of lasmiditan in pediatric patients with migraine and no new safety or tolerability issues were identified. These findings support further investigation of lasmiditan as a potential treatment in pediatric patients with migraine. Clinical Trial Registration Numbers NCT03988088 and EMEA-002166-PIP01-17M02.

Topics: Adolescent; Benzamides; Child; Cohort Studies; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity.. Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain.. In SAMURAI and SPARTAN, most treated attacks were of moderate (. Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Topics: Benzamides; Double-Blind Method; Headache; Humans; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine.. Global clinical studies have demonstrated the efficacy and safety of lasmiditan in the acute treatment of migraine.. This was a multicenter, randomized, double-blind, placebo-controlled, phase 2 study in Japan (NCT03962738), which enrolled adults with migraine with or without aura. Participants were randomized 7:3:7:6 to placebo, lasmiditan 50 mg, 100 mg, or 200 mg to be self-administered orally within 4 h of onset of a single moderate-to-severe migraine attack. Participants recorded their response to treatment prior to dosing and for 48 h postdose. The primary endpoint was headache pain freedom at 2 h postdose.. Participants (N = 846) were randomized and treated (N = 691, safety; N = 682, modified intent-to-treat). At 2 h postdose, a significantly higher proportion of participants were headache pain-free in the lasmiditan 200 mg (40.8%, 73/179; odds ratio 3.46 [95% confidence interval 2.17 to 5.54]; p < 0.001; primary objective) and 100 mg groups (32.4%, 67/207; odds ratio 2.41 [1.51 to 3.83]; p < 0.001) compared with the placebo group (16.6%, 35/211), whereas the lasmiditan 50 mg group had a numerically higher proportion of participants headache pain-free (23.5%, 20/85; odds ratio 1.55 [0.83 to 2.87]; p = 0.167) compared with placebo. A statistically significant linear dose-response relationship for pain freedom was achieved at 2 h by a Cochran-Armitage trend test (p < 0.001). Lasmiditan treatment was also associated with headache pain relief, most bothersome symptom freedom, and improvement on disability and Patient Global Impression of Change outcomes. The majority of treatment-emergent adverse events were mild and of short duration, the most common of which were dizziness (39.4%; 188/477), somnolence (19.3%; 92/477), and malaise (10.5%; 50/477) in all lasmiditan groups, with no serious adverse events reported.. Lasmiditan was well tolerated and effective for the acute treatment of Japanese patients with migraine, consistent with global phase 3 studies.

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Japan; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Limited information is available on acute treatments for migraine in elderly patients. Our objective was to evaluate the tolerability and safety of lasmiditan, a serotonin 1F agonist, for the acute treatment of migraine in elderly compared with nonelderly patients, with special emphasis on cardiovascular-related issues because cardiovascular comorbidities are more common in the elderly population.. These post hoc analyses evaluated the incidence of treatment-emergent adverse events (TEAEs) in elderly (≥65 years of age) versus nonelderly (<65 years of age) lasmiditan-treated patients. Two clinical trials entitled A Study of Two Doses of LAsMiditan (100 mg and 200 mg) Compared to Placebo in the AcUte Treatment of MigRAIne (SAMURAI) and A Study of Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute TReaTment of MigrAiNe (SPARTAN) were randomized, double-blind, placebo-controlled, Phase III studies in adults (no upper age limit) who took placebo or lasmiditan 50 (SPARTAN only), 100, or 200 mg for a single migraine attack within 4 hours of the onset of moderate or severe pain. Patients who completed SAMURAI or SPARTAN were eligible to enroll in An Open-label, LonG-term, Safety Study of LAsmiDItan (100 mg and 200 mg) in the Acute Treatment Of MigRaine (GLADIATOR), a Phase III, randomized, open-label, multiattack study of lasmiditan 100 or 200 mg. For pooled SAMURAI+SPARTAN data, treatment × age subgroup interactions were examined using logistic regression analyses. In addition, common cardiovascular event rates were assessed from GLADIATOR during 3 periods: treatment-emergent (<48 hours after dosing), intermediate (48 hours to 1 week after dosing), and remote (>1 week after dosing).. Of 3177 lasmiditan-treated patients in SAMURAI or SPARTAN, 132 (4.2%) were elderly, and of 1262 placebo-treated patients, 54 (4.3%) were elderly. Of 2030 lasmiditan-treated patients in GLADIATOR, 85 (4.2%) were elderly. The incidences of at least 1 TEAE with lasmiditan in nonelderly and elderly patients with migraine were 36% and 35% in pooled SAMURAI+SPARTAN, respectively, and 49% and 38% in GLADIATOR, respectively. No significant treatment × age subgroup interactions were observed in patients with ≥1 TEAE overall or for any individual TEAE in pooled SPARTAN+SAMURAI; however, numerical differences in the incidence of some specific TEAEs were seen. No treatment × age subgroup interactions and no tolerability concerns for individual TEAEs were detected. Cardiovascular TEAEs were much more frequent in the nonelderly population than the elderly population. Cardiovascular events were not reported in the elderly population during the treatment-emergent period or intermediate period. There were 2 cases of increased blood pressure in elderly patients during the remote period.. The incidence of TEAEs was similar for elderly and nonelderly patients, and cardiovascular safety of lasmiditan was generally consistent with that in single-attack studies. No safety signals were observed with the limited number of patients in the elderly population. ClinicalTrials.gov identifiers: NCT02565186 (GLADIATOR), NCT02439320 (SAMURAI), and NCT02605174 (SPARTAN).

Topics: Adult; Aged; Benzamides; Double-Blind Method; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

Lasmiditan demonstrated superiority to placebo in the acute treatment of migraine in adults with moderate/severe migraine disability in two similarly designed Phase 3 trials, SAMURAI and SPARTAN. Post-hoc integrated analyses evaluated the efficacy of lasmiditan in patients who reported a good or insufficient response to triptans and in those who were triptan naïve.. Subgroups of patients reporting an overall response of "good" or "poor/none" to the most recent use of a triptan at baseline (defined as good or insufficient responders, respectively) and a triptan-naïve subpopulation were derived from combined study participants randomized to receive lasmiditan 50 mg (SPARTAN only), 100 mg or 200 mg, or placebo, as the first dose. Outcomes including headache pain-freedom, most bothersome symptom-freedom, and headache pain relief 2 hours post-first dose of lasmiditan were compared with placebo. Treatment-by-subgroup analyses additionally investigated whether therapeutic benefit varied according to prior triptan response (good or insufficient).. Regardless of triptan response, lasmiditan showed higher efficacy than placebo (most comparisons were statistically significant). Treatment-by-subgroup analyses found that the benefit over placebo of lasmiditan did not vary significantly between patients with a good response and those with an insufficient response to triptans. Lasmiditan also showed higher efficacy than placebo in triptan-naïve patients.. Lasmiditan demonstrated comparable efficacy in patients who reported a good or insufficient response to prior triptan use. Lasmiditan also showed efficacy in those who were triptan naïve. Lasmiditan may be a useful therapeutic option for patients with migraine.. SAMURAI (NCT02439320); SPARTAN (NCT02605174).

Topics: Adult; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Tryptamines

Lasmiditan (LY573144/COL-144) is a high-affinity, centrally penetrant, selective 5-HT

Topics: Administration, Oral; Adrenergic beta-Antagonists; Adult; Aged; Benzamides; Blood Pressure; Cardiovascular System; Drug Interactions; Drug Therapy, Combination; Fasting; Female; Healthy Volunteers; Heart Rate; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Propranolol; Pyridines; Serotonin Receptor Agonists

Migraine is recognized as the second leading cause of disability globally. Lasmiditan is a novel, selective serotonin 5-HT. Completers of two single-attack parent studies were offered participation in the 1 year GLADIATOR study, that randomized participants to treatment with lasmiditan 100 mg or 200 mg taken as needed for migraine attacks of at least moderate severity. Changes in MIDAS were modeled using a mixed model repeated measures analysis.. The sample included 1978 patients who received ≥1 lasmiditan dose and were followed for a median of 288 days. Baseline mean MIDAS scores for the lasmiditan 100-mg and 200-mg groups were 29.4 and 28.9, respectively, indicating severe migraine-related disability. Relative to baseline, MIDAS total scores were significantly lower at 3, 6, 9, and 12 months for both dose groups. At 12 months, changes in MIDAS scores were - 12.5 and - 12.2 for lasmiditan 100 mg and 200 mg, respectively, with 49% and 53% of patients, respectively, achieving at least a 50% decrease in MIDAS total score. Statistically significant improvements were also seen for work and/or school absenteeism and presenteeism, monthly headache days, and mean headache pain intensity at all time points up to 1 year. Findings for patients who completed all visits versus those dropping out early were similar. Responses were generally similar for the lasmiditan 100 mg or 200 mg doses, between subgroups defined based on the number of baseline monthly migraine attacks (≤5 vs. >5), and also between subgroups defined by pain-free response (yes/no) during initial attacks.. Long-term treatment with lasmiditan was associated with significant reductions in migraine-related disability, including both work or school absenteeism and presenteeism. The similarity of responses in completers and those who dropped out suggests that selective attrition does not account for the improvements. Benefits were significant at 3 months and maintained through 12 months.. clinicaltrials.govNCT02565186; first posted October 1, 2015.

Topics: Absenteeism; Adult; Benzamides; Disability Evaluation; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Young Adult

To identify factors predicting response (2-hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult-to-treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed.. Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine.. Pooled analyses were completed from 2 Phase 3 double-blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent-to-treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom.. Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post-treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult-to-treat subgroups, patients receiving lasmiditan achieved greater responses (2-hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients.

Topics: Adolescent; Adult; Aged; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Outcome Assessment, Health Care; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Time Factors; Young Adult

We studied the efficacy and safety of a second dose of lasmiditan for acute treatment of migraine.. SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies in which individuals with migraine were randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Study drug was to be taken within 4 h (h) of onset of a migraine attack (moderate or severe pain). A second dose of study drug was provided for rescue (patient not pain-free at 2 h and took a second dose 2-24 h post-first dose) or recurrence (patient pain-free at 2 h, but experienced recurrence of mild, moderate, or severe migraine pain and took a second dose 2-24 h after first dose). Randomization to second dose occurred at baseline; patients originally assigned lasmiditan were randomized to the same lasmiditan dose or placebo (2:1 ratio), and those originally assigned placebo received placebo. Data from SAMURAI and SPARTAN were pooled for efficacy and safety assessment of a second dose of lasmiditan.. The proportion of patients taking a second dose was lower with lasmiditan versus placebo, and decreased with increasing lasmiditan dose; the majority who took a second dose did so for rescue. In patients taking lasmiditan as first dose, outcomes (pain free, most bothersome symptom [MBS] free) at 2 h after a second dose for rescue were similar whether the second dose was lasmiditan or placebo (p > 0.05 in all cases). In patients taking lasmiditan for first dose, outcomes at 2 h after a second dose for recurrence were as follows: lasmiditan pooled versus placebo - pain free, 50% vs 32% (p > 0.05); MBS free, 71% vs 41% (p = 0.02); pain relief, 77% vs 52% (p = 0.03). In patients whose first dose was lasmiditan, the incidence of treatment emergent adverse events (TEAEs) reported after the second dose was similar whether second dose was lasmiditan or placebo.. A second dose of lasmiditan showed some evidence of efficacy when taken for headache recurrence. There was no clear benefit of a second dose of lasmiditan for rescue treatment. The incidences of TEAEs were similar whether the second dose was lasmiditan or placebo.. SAMURAI ( NCT02439320 ) [April 2015]. SPARTAN ( NCT02605174 ) [May 2016].

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Recurrence; Serotonin Receptor Agonists

To address the need for long-term lasmiditan data, the GLADIATOR study evaluated the safety (primary) and efficacy (secondary) of lasmiditan for the intermittent, acute treatment of migraine attacks for up to 1 year.. In this prospective, randomized, open-label, Phase 3 study, patients who had completed either of two single-attack studies were offered the opportunity to be randomized 1:1 to lasmiditan 100 mg or 200 mg. Patients were asked to use lasmiditan as the first treatment for each new migraine attack of at least moderate severity. Assessments occurred at baseline and at prespecified time increments up to 48 hours after each dose of study drug using an electronic diary, and safety was assessed throughout the study. Migraine Disability Assessment (MIDAS) was assessed at each visit.. As of the cut-off date for this interim analysis (6 March 2018), 1978 patients had received ≥ 1 lasmiditan dose and treated 19,058 migraine attacks. Overall, treatment-emergent adverse events (TEAEs) were similar to those in the single-attack studies and included dizziness (18.6%), somnolence (8.5%), and paresthesia (6.8%). The frequency of TEAEs generally decreased with subsequent attacks. No treatment-related serious adverse events and no cardiovascular TEAEs potentially due to vasoconstriction were observed. For both lasmiditan doses, efficacy measures were generally consistent over study quarters and treated attacks. Overall, across all treated attacks at 2 hours post-dose, pain freedom was observed in 26.9% of the attacks treated with lasmiditan 100 mg and 32.4% of the attacks treated with lasmiditan 200 mg. MIDAS total scores decreased over time.

Topics: Adolescent; Adult; Aged; Benzamides; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Prospective Studies; Pyridines; Serotonin Receptor Agonists; Treatment Outcome; Young Adult

In addition to the increased risk for cardiovascular (CV) disease and CV events associated with migraine, patients with migraine can also present with a number of CV risk factors (CVRFs). Existing treatment options can be limited due to contraindications, increased burden associated with monitoring, or patient avoidance of side effects. Safe and effective migraine treatment options are needed for patients with migraine and a history of CV or cerebrovascular disease or with increased risk for CV events. This analysis was designed to evaluate the safety and efficacy of oral lasmiditan, a selective serotonin 5-hydroxytryptamine 1F receptor agonist, in acute treatment of migraine attacks in patients with CVRFs.. SAMURAI and SPARTAN were similarly designed, Phase 3, randomized, double-blind, placebo-controlled trials in adults treating a single migraine attack with lasmiditan 50, 100, or 200 mg. Both studies included patients with CVRFs, and SPARTAN allowed patients with coronary artery disease, clinically significant arrhythmia, or uncontrolled hypertension. Efficacy and safety of lasmiditan in subgroups of patients with differing levels of CVRFs are reported. For efficacy analyses, logistic regression was used to assess treatment-by-subgroup interactions. For safety analyses, Cochran-Mantel-Haenszel test of general association evaluated treatment comparisons; Mantel-Haenszel odds ratio assessed significant treatment effects.. In this pooled analysis, a total of 4439 patients received ≥1 dose of study drug. A total of 3500 patients (78.8%) had ≥1 CVRF, and 1833 patients (41.3%) had ≥2 CVRFs at baseline. Both trials met the primary endpoints of headache pain freedom and most bothersome symptom freedom at 2 h. The presence of CVRFs did not affect efficacy results. There was a low frequency of likely CV treatment-emergent adverse events (TEAEs) overall (lasmiditan, 30 [0.9%]; placebo, 5 [0.4%]). There was no statistical difference in the frequency of likely CV TEAEs in either the absence or presence of any CVRFs. The only likely CV TEAE seen across patients with ≥1, ≥ 2, ≥ 3, or ≥ 4 CVRFs was palpitations.. When analyzed by the presence of CVRFs, there was no statistical difference in lasmiditan efficacy or the frequency of likely CV TEAEs. Despite the analysis being limited by a single-migraine-attack design, the lack of differences in efficacy and safety with increasing numbers of CVRFs indicates that lasmiditan might be considered in the treatment algorithm for patients with CVRFs. Future studies are needed to assess long-term efficacy and safety.. ClinicalTrials.gov NCT02439320 (SAMURAI), registered 18 March 2015 and ClinicalTrials.gov NCT02605174 (SPARTAN), registered 11 November 2015.

Topics: Adult; Benzamides; Cardiovascular Diseases; Double-Blind Method; Female; Headache; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin Receptor Agonists; Treatment Outcome

To expand on available information on the efficacy of oral lasmiditan for the acute treatment of migraine with particular focus on the timing of the effect and on its impact on migraine-associated symptoms.. Lasmiditan is a novel selective 5-hydroxytryptamine 1F receptor agonist that lacks vasoconstrictive activity. In 2 phase 3 studies, SAMURAI and SPARTAN, lasmiditan met primary and key secondary efficacy endpoints at 2 hours following initial dose.. Integrated analyses were completed from 2 phase 3 clinical trials, SPARTAN and SAMURAI. Baseline data and data collected every 30 minutes up to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to determine the onset of efficacy. A total of 5236 patients were randomized to be treated with placebo (N = 1493), lasmiditan 50 mg (N = 750), lasmiditan 100 mg (N = 1498), or lasmiditan 200 mg (N = 1495). Data were analyzed to determine the onset of improvement for the following efficacy measures: pain freedom, most bothersome symptom freedom, pain relief, freedom from associated individual symptoms (photophobia, phonophobia, or nausea), total migraine freedom (defined as pain freedom and freedom from associated symptoms), and freedom from migraine-related functional disability. Time to meaningful headache relief and time to first become pain free were also analyzed.. Significantly higher rates of pain freedom (100 mg, 10.0%, P = .012; 200 mg, 15.5%, P < .001; Placebo, 7.0%) and total migraine freedom (100 mg, 8.9%, P = .017; 200 mg, 12.4%, P < .001; Placebo, 6.1%) were achieved starting at 60 minutes in 100- and 200-mg lasmiditan-treated groups compared with placebo group. Rates of freedom from most bothersome symptom (100 mg, 11.1%, P = .015; 200 mg, 13.0%, P < .001; Placebo, 7.9%), and pain relief (100 mg, 17.5%, P = .007; 200 mg, 19.1%, P < .001; Placebo, 13.4%) were significantly higher starting as early as 30 minutes in lasmiditan 100- and 200-mg lasmiditan-treated groups. A significantly higher percentage of patients in the 200-mg lasmiditan-treated group achieved freedom from photophobia (13.7%, P = .005; Placebo, 9.2%) and phonophobia (17.4%, P = .042; Placebo, 13.4%) starting at 30 minutes. A significantly greater proportion of patients in the 200-mg lasmiditan-treated group achieved freedom from migraine-related functional disability starting at 60 minutes (16.4%, P < .001; Placebo, 11.1%). All efficacy measures, except for freedom from nausea, were statistically significant after lasmiditan treatment (50, 100, or 200 mg) compared with placebo at 90 and 120 minutes. Finally, patients taking lasmiditan had a higher likelihood of achieving meaningful headache relief and becoming headache pain free within 24 hours compared with those taking placebo (P < .001).. Patients treated with lasmiditan for a migraine attack reported an earlier onset of efficacy compared with those treated with placebo. Some of the efficacy measures such as pain relief demonstrated improvement as early as the first assessment at 30 minutes after 100- or 200-mg lasmiditan treatment.

Topics: Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Lasmiditan, a serotonin 5-HT1F receptor agonist, was effective for acute treatment of patients with migraine in a phase 3 double-blind randomized controlled study. The current study was designed to replicate these findings in a generalizable population of patients with migraine, including those with a cardiovascular medical history. This prospective, double-blind, phase 3 multicentre study randomly assigned patients with migraine with and without aura (1:1:1:1 ratio) to oral lasmiditan 200 mg, 100 mg, 50 mg, or placebo. Patients were instructed to dose at home within 4 h of onset of migraine attack of at least moderate intensity and not improving. The primary objective was to assess the proportion of patients' headache pain-free and most bothersome symptom-free at 2 h post-dose for each dose of lasmiditan versus placebo (NCT02605174). Patients (n = 3005) were assigned and treated (n = 2583, safety population): 1938 lasmiditan (200 mg n = 528, 100 mg n = 532, and 50 mg n = 556 included in primary analysis) and 645 placebo (540 included in primary analysis). Most patients (79.2%) had ≥1 cardiovascular risk factor at baseline, in addition to migraine. Lasmiditan was associated with significantly more pain freedom at 2 h (lasmiditan 200 mg: 38.8%, odds ratio 2.3, 95% confidence interval 1.8-3.1, P < 0.001; 100 mg: 31.4%, odds ratio 1.7, 1.3-2.2, P < 0.001; 50 mg: 28.6%, odds ratio 1.5, 1.1-1.9, P = 0.003 versus placebo 21.3%) and freedom from most bothersome symptom at 2 h (lasmiditan 200 mg: 48.7%, odds ratio 1.9, 95% confidence interval 1.4-2.4, P < 0.001; 100 mg: 44.2%, odds ratio 1.6, 1.2-2.0, P < 0.001; 50 mg: 40.8%, odds ratio 1.4, 1.1-1.8, P = 0.009 versus placebo 33.5%). Treatment-emergent adverse events were reported in 253 of 649 (39.0%), 229 of 635 (36.1%), and 166 of 654 (25.4%) of patients on lasmiditan 200, 100, and 50 mg, respectively, versus 75 of 645 (11.6%) on placebo. Most adverse events were CNS-related and included dizziness, somnolence and paraesthesia. Lasmiditan was effective at 2 h post-dose for acute treatment of migraine at all oral doses tested. Efficacy and safety were consistent with the previous phase 3 study.

Topics: Adult; Benzamides; Cardiovascular Diseases; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Migraine Disorders; Piperidines; Pyridines; Risk Factors; Serotonin Receptor Agonists; Time Factors; Young Adult

SAMURAI and SPARTAN were double-blind, placebo-controlled Phase 3 studies conducted in the United States, as well as the United Kingdom and Germany (SPARTAN only). Individuals with migraine were randomized to receive oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo within 4 hours of onset of a migraine attack. The aim of this analysis was to characterize dizziness reported with lasmiditan treatment.. Data from SAMURAI and SPARTAN were pooled for the current post hoc analyses. Onset time and duration of dizziness were analyzed using descriptive statistics. Subgroup analyses based on presence/absence of dizziness were performed for the endpoints of interference with daily activity, patient global impression of change (PGIC), pain at 2 hours, and most bothersome symptom (MBS) at 2 hours based on adverse events occurring within 2 hours of taking study drug.. Dizziness incidence was as follows: Placebo (N = 1262), 2.9% (0.1% severe); lasmiditan 50 mg (N = 654), 8.6% (0.3% severe); lasmiditan 100 mg (N = 1265), 14.9% (0.7% severe); and lasmiditan 200 mg (N = 1258), 16.8% (1.4% severe). Among participants who received lasmiditan as their first dose, risk factors for dizziness were higher lasmiditan dosage, being non-Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. The median time to onset of dizziness was generally 30-40 minutes, and the median duration was 1.5-2 hours. The presence of dizziness did not appear to have a negative influence on lasmiditan's effect on daily activity, PGIC, freedom from pain, or MBS. Overall, 21 participants experienced vertigo: Lasmiditan 50 mg, n = 2 (0.3%); 100 mg, n = 11 (0.9%); 200 mg, n = 7 (0.6%); and placebo, n = 1 (<0.1%).. The incidence of dizziness with lasmiditan increased with dose. Dizziness was generally mild or moderate in severity and of quick onset and short duration. The presence of dizziness did not influence drug efficacy.

Topics: Acute Disease; Adult; Benzamides; Dizziness; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Outcome Assessment, Health Care; Piperidines; Pyridines; Severity of Illness Index; Vertigo

We assessed the safety profile of lasmiditan, a selective 5-HT. SAMURAI and SPARTAN were Phase 3 double-blind studies of patients with migraine, randomized to oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo to be taken within 4 hours of onset of migraine pain. Safety data from the studies were integrated. Treatment-emergent adverse events (occurring within 48 hours of first dose) were considered in the analyses.. The safety population comprised 1262 patients assigned placebo, and 654, 1265, and 1258 assigned lasmiditan 50 mg, 100 mg, and 200 mg, respectively. There were no deaths; serious adverse events were reported for seven patients (placebo, n = 2 [0.2%]; lasmiditan 50 mg, n = 1 [0.2%]; lasmiditan 100 mg, n = 1 [0.2%]; lasmiditan 200 mg, n = 3 [0.2%]). Patients reporting ≥ 1 treatment-emergent adverse events were: Placebo, n = 174 (13.5%); lasmiditan 50 mg, n = 166 (25.4%); lasmiditan 100 mg, n = 458 (36.2%); and lasmiditan 200 mg, n = 510 (40.6%). Treatment-emergent adverse events were generally mild or moderate in severity. The most common treatment-emergent adverse events with lasmiditan were dizziness, paresthesia, somnolence, fatigue, nausea, muscular weakness and hypoesthesia. There were no ischemic events.. As a centrally-penetrant drug, lasmiditan use was associated with neurologic treatment-emergent adverse events; most were mild or moderate in severity and self-limiting.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174).

Topics: Administration, Oral; Adult; Benzamides; Double-Blind Method; Fatigue; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Time Factors; Treatment Outcome; Vertigo

Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT. Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3-8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications.. Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all. Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses.. SAMURAI: NCT02439320; SPARTAN: NCT02605174.

Topics: Adult; Benzamides; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

To study the efficacy and safety of lasmiditan for acute treatment of migraine in patients using migraine preventive medications.. While lasmiditan has been proven to be an effective acute treatment for migraine, its effectiveness has not been examined when used concurrently with migraine preventives.. SAMURAI and SPARTAN were similarly designed, double-blind, phase 3, placebo-controlled studies of patients 18 years or older with 3 to 8 migraine attacks per month. Patients were randomized to treat a migraine attack with oral lasmiditan 50 mg (SPARTAN only), 100 mg, 200 mg, or placebo. Migraine preventives were allowed as long as doses were stable for 3 months prior to screening and were unchanged during the study. Preventive medications with established or probable efficacy, as recommended by the American Academy of Neurology, the American Headache Society, and the European Headache Federation, plus botulinum toxin type A and candesartan, were included. Within the subgroups of patients using and not using preventive therapies, lasmiditan and placebo groups were analyzed for the outcome of pain-free at 2 h and other efficacy outcomes. The subgroups of patients using and not using preventive therapies were compared and interaction p-values were calculated for safety and efficacy outcomes.. In these trials, 698 of 3981 patients (17.5%) used migraine preventive treatments. Among patients using preventives, all lasmiditan doses resulted in significantly more patients being pain-free at 2 h, compared to placebo (p < 0.05). Primary efficacy outcome (pain-free at 2 h), key secondary outcome (most bothersome symptom-free at 2 h) and all other efficacy outcomes were not significantly different between patients using or not using migraine preventives (all interaction p-values ≥0.1). Rates of adverse events were similar for patients using and not using preventive medications.. Lasmiditan was more effective than placebo for the acute treatment of migraine in patients concurrently using migraine preventive medications. Lasmiditan efficacy and safety measures were similar for patients using and not using preventive medications.. SAMURAI (NCT02439320) and SPARTAN (NCT02605174). Registered 18 March 2015.

Topics: Adult; Benzamides; Benzimidazoles; Biphenyl Compounds; Botulinum Toxins, Type A; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Tetrazoles; Treatment Outcome

To assess the efficacy and safety of lasmiditan in the acute treatment of migraine.. Adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo and were asked to treat their next migraine attack within 4 hours of onset. Over 48 hours after dosing, patients used an electronic diary to record headache pain and the presence of nausea, phonophobia, and photophobia, one of which was designated their most bothersome symptom (MBS).. Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared with placebo, more patients dosed with lasmiditan 200 mg were free of headache pain at 2 hours after dosing (32.2% vs 15.3%; odds ratio [OR] 2.6, 95% confidence interval [CI] 2.0-3.6,. Lasmiditan dosed at 200 and 100 mg was efficacious and well tolerated in the treatment of acute migraine among patients with a high level of cardiovascular risk factors.. NCT02439320.. This study provides Class I evidence that for adult patients with migraine, lasmiditan increases the proportion of subjects who are headache pain free at 2 hours after treating a migraine attack.

Topics: Acute Disease; Administration, Oral; Adult; Benzamides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

Migraine constitutes the world's second-leading cause of disability. Triptans, as serotonin 5-HT

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Migraine Disorders; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists; Serotonin Syndrome; Tryptamines

New acute and preventive migraine medications are available, but data on current treatment patterns are limited. This study describes migraine treatment patterns among patients initiating novel acute migraine specific medications (nAMSMs), overall and by prior use of anti-calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies (mAbs).. In this retrospective cohort study using IQVIA open-source pharmacy and medical claims data, we identified patients with ≥ 1 claim for a nAMSM (ubrogepant, rimegepant, lasmiditan) between 01/01/2020 and 09/30/2020 (index period). Patients were indexed on their first nAMSM claim and stratified into 2 cohorts: patients with prior mAb use (≥ 1 claim for erenumab, fremanezumab, galcanezumab in the 6-month pre-index period) or patients without prior mAb use. Treatment patterns were assessed during the 6-month post-index period.. Overall, 78,574 patients were identified (63% indexed on ubrogepant, 34% on rimegepant, and 3% on lasmiditan) with 26,656 patients (34%) having had prior mAb use. In the pre-index period, 79% of patients used non-mAb preventive medications and 75% of patients used acute medications. Following the index nAMSM claim, 65% of patients had ≥ 1 refill and 21% had ≥ 4 refills of their index nAMSM; 10% of patients switched to another nAMSM. Post-index mAb use was observed in 82% of patients with a prior mAb and 15% of patients without. Among patients with pre- and post-index use of acute medications, 38% discontinued ≥ 1 acute medication class in the post-index period. Among patients with concomitant use of traditional preventive medications at index, 30% discontinued ≥ 1 concomitant preventive anti-migraine medication in the post-index period.. Most patients initiating nAMSMs had prior treatment with acute and preventive medications. Approximately one-third of patients had prior treatment with anti-CGRP pathway mAbs. After starting nAMSMs, more than one-third of patients discontinued at least one traditional acute medication and one-third of patients discontinued at least one traditional preventive medication. Despite nAMSM initiation, most patients with prior anti-CGRP pathway mAb use continued mAb use. Around 15% of patients without a prior mAb newly started a mAb. These results provide insight into how nAMSMs and mAbs have been integrated into clinical management of migraine in the real-world.

Topics: Antibodies, Monoclonal; Calcitonin Gene-Related Peptide; Calcitonin Gene-Related Peptide Receptor Antagonists; Humans; Migraine Disorders; Retrospective Studies

Lasmiditan is a novel selective 5-HT. Electrical stimulation of the dura mater or the superior salivatory nucleus in anaesthetised rats evoked trigeminovascular or trigeminal-autonomic reflex activation at the level of the trigeminocervical complex. Additionally, cranial autonomic manifestations in response to trigeminal-autonomic reflex activation were measured, via anterior choroidal blood flow alterations. These responses were then challenged with lasmiditan. We explored the tissue distribution of mRNA for 5-HT. Lasmiditan dose-dependently reduced trigeminovascular activation in a preclinical model of migraine. Lasmiditan also reduced superior salivatory nucleus-evoked activation of the trigeminal-autonomic reflex, but had no effect on cranial autonomic activation. mRNA profiling in human tissue showed expression of the 5-HT. Our data suggest that lasmiditan acts, at least in part, as an anti-migraine agent by reducing trigeminovascular activation. Furthermore, our results highlight a clear action for lasmiditan in a preclinical model of cluster headache. Given the proven translational efficacy of this model, our data support the potential utility of lasmiditan as a therapeutic option for the acute treatment of cluster headache attacks.. This article is part of a themed issue on Advances in Migraine and Headache Therapy (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.3/issuetoc.

Topics: Animals; Benzamides; Cluster Headache; Migraine Disorders; Nociception; Piperidines; Pyridines; Rats; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; RNA, Messenger; Serotonin

In four large controlled trials with lasmiditan and ubrogepant placebo was administered in the first step to demonstrate an effect on migraine attack. In the same trials the investigators also asked the question: is a second dose of the drug effective in non-responders to the first dose? In this phase patients who received placebo in the first phase of the trial again after 2 hours received another dose of placebo.. To be ethical, clinical research requires balancing rigorous science with the protection of human subjects; and it is, in our view, questionable whether placebo was used with "scientific rigor" in the second step of these trials, and this design is not recommended.

Topics: Benzamides; Controlled Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Migraine is a common neurovascular disease which has been classified as the sixth most disabling disorder. Current migraine therapy was triptans, however, riptans can cause contraction of blood vessels. Therefore, novel drugs without cardiovascular effects emerged, such as CGRP and selective 5-HT

Topics: Animals; Body Weight; Dose-Response Relationship, Drug; Drug Design; Eating; Female; Haplorhini; HEK293 Cells; Humans; Inflammation; Male; Migraine Disorders; Molecular Structure; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Structure-Activity Relationship

Topics: Benzamides; Budgets; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Surveys and Questionnaires; United States

While pain freedom at 2 h is a key primary outcome for current trials for acute treatment of migraine, the relationship between the degree of head pain and other efficacy measures at 2 h has rarely been explored. Following lasmiditan treatment of a migraine attack with moderate or severe head pain, we contrast those who achieve pain freedom with those who achieve mild pain but not pain freedom 2 h post dosing.. Patient-level data were pooled across studies and treatment arms from two Phase 3 trials comparing lasmiditan and placebo, SAMURAI and SPARTAN. This post hoc analysis assessed freedom from the most bothersome symptom (MBS), freedom from migraine-related functional disability (disability), and improved patient global impression of change (PGIC) in patients who achieved 2 h pain freedom compared to those who experienced 2 h mild pain. Mild pain differs from pain relief which is defined as either mild pain or pain freedom.. Patients who achieved 2 h pain freedom (N = 913), in comparison with those with 2 h mild pain (N = 864), were significantly more likely to experience MBS freedom (91.9% vs. 44.9%), disability freedom (87.1% and 13.4%), and improved PGIC (86.5% and 31.5%) (p < 0.001 for all combinations). In addition, more patients who were pain free experienced both 2 h MBS freedom and 2 h functional disability freedom (83.6%) compared to those with mild pain (10.8%; p < 0.001). The proportion of patients with pain freedom who did not achieve either MBS or disability freedom (4.6%) was lower than in patients with mild pain (52.4%). Lastly, 55.2% of patients experienced mild pain before disability freedom compared to 72.1% who experienced pain freedom and disability freedom at the same time.. This study demonstrated that, at 2 h post treatment, patients who were pain free were more likely to achieve other outcomes including freedom from their MBS, freedom from migraine-related functional disability, and improved PGIC compared to those with mild pain, confirming that 2 h pain freedom is more robustly associated with other clinical outcomes than the 2 h mild pain endpoint.. SAMURAI ( NCT02439320 ); SPARTAN ( NCT02605174 ).

Topics: Benzamides; Double-Blind Method; Freedom; Headache; Humans; Migraine Disorders; Piperidines; Pyridines; Treatment Outcome

We explore factors that may have contributed to differences in treatment-emergent adverse events in the phase 2 and phase 3 lasmiditan clinical trials.. Phase 2 and phase 3 trials showed that the centrally penetrant 5-HT. This work represents a hybrid of a review of primary documents and study reports with additional post hoc analyses. Protocols, informed consents, data collection forms, and methodologies were reviewed. This information was supplemented by results from the clinical study reports and post hoc analyses of individual patient data from each trial.. For lasmiditan 100 and 200 mg, in phase 2, the incidence of ≥1 AE was 72-86% (26% severe), while in phase 3 was 36-43% (2% severe). The most common AEs in all studies were CNS-related. The phase 2 consent form was more descriptive of AEs than phase 3. In phase 2, patients recorded AEs and severity in a paper diary that warned about drowsiness and dizziness. In phase 3, patients recorded in electronic diaries whether they experienced unusual feelings after dosing with lasmiditan that they had not felt with a migraine before, and were contacted to determine if an AE had occurred. In phase 2, the AE Schwindel was variably translated from German as "vertigo" or "dizziness," while phase 3 vertigo cases were queried to ensure there was a sensation of rotation or movement. History of recurrent dizziness and/or vertigo was exclusionary in phase 3.. This work illustrates how informed consent wording, AE collection methods, translation, exclusion criteria, and other factors may be important determinants for reporting of the frequency and severity of AEs in clinical trials.

Topics: Adult; Benzamides; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug-Related Side Effects and Adverse Reactions; Female; Forms as Topic; Humans; Informed Consent; Male; Middle Aged; Migraine Disorders; Patient Reported Outcome Measures; Piperidines; Pyridines; Serotonin Receptor Agonists; Translating

Topics: Benzamides; Drug Approval; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; United States; United States Food and Drug Administration

Topics: Animals; Benzamides; Drug Development; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists

Topics: Acute Disease; Adult; Benzamides; Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Serotonin Receptor Agonists; Treatment Outcome

Topics: Animals; Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Lasmiditan is a new oral medication for treatment of acute migraine. It was approved by the U.S. Food and Drug Administration in October 2019 and is marketed under the brand name Reyvow (Eli Lilly and Company, Indianapolis, IN). It is the first of its kind in a new drug class called ditans. Lasmiditan has been studied as monotherapy for acute migraine treatment and as an abortive therapy for adults taking chronic migraine preventive medication. Lasmiditan may be an option for individuals who have had no relief with triptans or other acute migraine treatment agents or who are unable to use other migraine treatments because of contraindications.

Topics: Adult; Benzamides; Dose-Response Relationship, Drug; Humans; Migraine Disorders; Piperidines; Pyridines; Randomized Controlled Trials as Topic; Serotonin Receptor Agonists; United States

Topics: Benzamides; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles

Topics: Analgesics; Benzamides; Calcitonin Gene-Related Peptide; Cost-Benefit Analysis; Drug Costs; Humans; Migraine Disorders; Piperidines; Pyridines; Pyrroles; Quality-Adjusted Life Years; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin 5-HT1 Receptor Agonists; Signal Transduction; Systematic Reviews as Topic; Time Factors; Treatment Outcome

Topics: Benzamides; Clinical Trials as Topic; Humans; Migraine Disorders; Piperidines; Pyridines; Receptor, Serotonin, 5-HT1F; Receptors, Serotonin; Serotonin; Serotonin Receptor Agonists