Lasmiditan for the acute treatment of migraine: Subgroup analyses by prior response to triptans

Background 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. Methods 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). Results 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. Conclusions 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. Trial Registration SAMURAI (NCT02439320); SPARTAN (NCT02605174).

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Lasmiditan efficacy in the acute treatment of migraine was independent of prior response to triptans: Findings from the CENTURION study

Cephalalgia ◽

10.1177/03331024211048507 ◽

2021 ◽

pp. 033310242110485

Author(s):

Uwe Reuter ◽

John H Krege ◽

Louise Lombard ◽

Elisa Gomez Valderas ◽

Judith Krikke-Workel ◽

...

Keyword(s):

Pain Relief ◽

Acute Treatment ◽

Receptor Agonist ◽

Rescue Medication ◽

Significant Proportion ◽

Phase 3 ◽

Patient Global Impression ◽

Insufficient Response ◽

Bothersome Symptom ◽

Global Impression Of Change

Background 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-HT1F receptor agonist, may be an option for these individuals. We assessed lasmiditan efficacy in a subgroup of patients in CENTURION (Phase 3 migraine consistency study) who exhibited an insufficient response to triptans, including a subgroup with insufficient response due to efficacy only. Methods 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. Results In triptan insufficient responders, lasmiditan was superior to placebo ( p < 0.05) for pain freedom beginning at 1 h (both doses); pain relief beginning at 0.5 (200 mg) or 1 h (100 mg); migraine-related disability freedom, much/very much better on the Patient Global Impression of Change, and most bothersome symptom freedom at 2 h; sustained pain freedom; and need for rescue medication. Lasmiditan showed benefit for consistency of effect across attacks for 2-h pain freedom and pain relief. Findings were similar in triptan responders and triptan naïve patients and when the triptan insufficient response definition was based on efficacy only. Conclusions Lasmiditan was efficacious across multiple clinically relevant endpoints in the acute treatment of migraine independent of prior response to triptans. Trial Registration: CENTURION (NCT03670810); SAMURAI (NCT02439320); SPARTAN (NCT02605174)

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Lasmiditan is an effective acute treatment for migraine

Neurology ◽

10.1212/wnl.0000000000006641 ◽

2018 ◽

Vol 91 (24) ◽

pp. e2222-e2232 ◽

Cited By ~ 92

Author(s):

Bernice Kuca ◽

Stephen D. Silberstein ◽

Linda Wietecha ◽

Paul H. Berg ◽

Gregory Dozier ◽

...

Keyword(s):

Risk Factors ◽

Cardiovascular Risk ◽

Cardiovascular Risk Factors ◽

Migraine Attack ◽

Acute Treatment ◽

Adult Patients ◽

Electronic Diary ◽

Double Blind ◽

Bothersome Symptom ◽

Headache Pain

ObjectiveTo assess the efficacy and safety of lasmiditan in the acute treatment of migraine.MethodsAdult 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).ResultsOf 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, p< 0.001), similar to those dosed with lasmiditan 100 mg (28.2%; OR 2.2, 95% CI 1.6–3.0, p< 0.001). Furthermore, compared with those dosed with placebo, more patients dosed with lasmiditan 200 mg (40.7% vs 29.5%; OR 1.6, 95% CI 1.3–2.1, p< 0.001) and lasmiditan 100 mg (40.9%; OR 1.7, 95% CI, 1.3–2.2, p< 0.001) were free of their MBS at 2 hours after dosing. Adverse events were mostly mild or moderate in intensity.ConclusionsLasmiditan 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.ClinicalTrials.gov identifierNCT02439320.Classification of evidenceThis 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.

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Development of a novel zolmitriptan intracutaneous microneedle system (Qtrypta™) for the acute treatment of migraine

Pain Management ◽

10.2217/pmt-2020-0041 ◽

2020 ◽

Vol 10 (6) ◽

pp. 359-366 ◽

Cited By ~ 1

Author(s):

Alan M Rapoport ◽

Mahmoud Ameri ◽

Hayley Lewis ◽

Donald J Kellerman

Keyword(s):

Acute Treatment ◽

Application Site ◽

Therapeutic System ◽

Pivotal Trial ◽

Post Dose ◽

Migraine Headaches ◽

Bothersome Symptom ◽

Headache Pain ◽

Post Hoc ◽

Severe Migraine

M207 is an investigational intracutaneous microneedle therapeutic system for nonoral zolmitriptan delivery. In a Phase I trial, M207 provided faster absorption with a higher 2 h exposure than oral zolmitriptan. In the pivotal trial evaluating efficacy, tolerability and safety in moderate-to-severe migraine attacks, M207 3.8 mg was superior to placebo in providing freedom from headache pain (42 vs 14%) and freedom from most bothersome symptom (68 vs 43%) 2 h post-dose. Treatment-emergent adverse events were mild and transient and most commonly concerned the application site. In post hoc analyses: pain freedom was sustained in approximately 1/3 of patients; efficacy was observed in migraine headaches that are typically more difficult to treat.

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The Autophagy Pathway: A Critical Route in the Disposal of Alpha 1-Antitrypsin Aggregates That Holds Many Mysteries

International Journal of Molecular Sciences ◽

10.3390/ijms22041875 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1875

Author(s):

Celine Leon ◽

Marion Bouchecareilh

Keyword(s):

Liver Transplantation ◽

Liver Disease ◽

Therapeutic Option ◽

Ubiquitin Proteasome System ◽

Therapeutic Benefit ◽

Cellular Functions ◽

Precise Control ◽

New Therapeutic Approaches ◽

Alpha 1 Antitrypsin Deficiency ◽

Alpha 1 Antitrypsin

The maintenance of proteome homeostasis, or proteostasis, is crucial for preserving cellular functions and for cellular adaptation to environmental challenges and changes in physiological conditions. The capacity of cells to maintain proteostasis requires precise control and coordination of protein synthesis, folding, conformational maintenance, and clearance. Thus, protein degradation by the ubiquitin–proteasome system (UPS) or the autophagy–lysosomal system plays an essential role in cellular functions. However, failure of the UPS or the autophagic process can lead to the development of various diseases (aging-associated diseases, cancer), thus both these pathways have become attractive targets in the treatment of protein conformational diseases, such as alpha 1-antitrypsin deficiency (AATD). The Z alpha 1-antitrypsin (Z-AAT) misfolded variant of the serine protease alpha 1-antitrypsin (AAT) is caused by a structural change that predisposes it to protein aggregation and dramatic accumulation in the form of inclusion bodies within liver hepatocytes. This can lead to clinically significant liver disease requiring liver transplantation in childhood or adulthood. Treatment of mice with autophagy enhancers was found to reduce hepatic Z-AAT aggregate levels and protect them from AATD hepatotoxicity. To date, liver transplantation is the only curative therapeutic option for patients with AATD-mediated liver disease. Therefore, the development and discovery of new therapeutic approaches to delay or overcome disease progression is a top priority. Herein, we review AATD-mediated liver disease and the overall process of autophagy. We highlight the role of this system in the regulation of Z-variant degradation and its implication in AATD-medicated liver disease, including some open questions that remain challenges in the field and require further elucidation. Finally, we discuss how manipulation of autophagy could provide multiple routes of therapeutic benefit in AATD-mediated liver disease.

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A.07 Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: a single-attack phase 3 study, ACHIEVE I

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.89 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S9-S10 ◽

Cited By ~ 1

Author(s):

DW Dodick ◽

RB Lipton ◽

J Ailani ◽

K Lu ◽

H Lakkis ◽

...

Keyword(s):

Migraine Attack ◽

Initial Dose ◽

Acute Treatment ◽

Phase 3 ◽

Double Blind ◽

Safety Population ◽

Parallel Group ◽

Attack Phase ◽

Headache Pain ◽

Cgrp Receptor Antagonist

Background: To evaluate efficacy, safety, and tolerability of ubrogepant, an oral CGRP receptor antagonist, for acute treatment of a single migraine attack. Methods: Multicenter, randomized, double-blind, placebo-controlled, parallel-group, single-attack, phase 3 study (NCT02828020). Patients randomized 1:1:1 to placebo, ubrogepant 50mg, or ubrogepant 100mg had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints: pain freedom 2 hours post initial dose and absence of most bothersome migraine-associated symptom (MBS). Results: 1672 patients were randomized (safety population: n=1436; mITT population: n=1327). Mean age: 40.7 years; white (82.4%); female (87.5%). A significantly greater percentage of ubrogepant- than placebo-treated patients achieved pain freedom 2 hours post initial dose (50mg: 19.2%, adjusted P=0.0023; 100mg: 21.2%, adjusted P=0.0003; placebo: 11.8%). A significantly greater percentage of ubrogepant patients achieved absence of MBS (50mg: 38.6%, adjusted P=0.0023, 100mg: 37.7%, adjusted P=0.0023; placebo: 27.8%). The adverse event (AE) profile of ubrogepant was similar to placebo. The most common AEs (incidence ≥2% in any treatment group) within 48 hours of initial or optional second dose were nausea, somnolence, and dry mouth (all with incidence <5%). Conclusions: Both co-primary endpoints were met, with clinically meaningful effects on migraine headache pain and MBS. Ubrogepant was well tolerated, with no identified safety concerns.

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P.010 Efficacy, safety, and tolerability of ubrogepant for the acute treatment of migraine: a single-attack phase 3 study, ACHIEVE II

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2019.111 ◽

2019 ◽

Vol 46 (s1) ◽

pp. S16 ◽

Cited By ~ 1

Author(s):

RB Lipton ◽

DW Dodick ◽

J Ailani ◽

K Lu ◽

H Lakkis ◽

...

Keyword(s):

Pain Relief ◽

Acute Treatment ◽

Statistical Significance ◽

Phase 3 ◽

Double Blind ◽

Primary Endpoints ◽

Safety Population ◽

Secondary Endpoints ◽

Attack Phase ◽

Headache Pain

Background: To evaluate efficacy, safety, and tolerability of ubrogepant for acute treatment of migraine attacks. Methods: Multicenter, double-blind, phase 3 study (NCT02867709). Randomized patients (1:1:1, placebo or ubrogepant 25mg or 50mg) had 60 days to treat one migraine attack (moderate/severe pain intensity). Co-primary efficacy endpoints (2 hours post initial dose): headache pain freedom and absence of most bothersome migraine-associated symptom (MBS). Secondary endpoints: pain relief, sustained pain relief, sustained pain freedom, and absence of migraine-associated symptoms. Results: 1686 patients were randomized (safety population: n=1465; mITT population: n=1355). Mean age: 41 years; white: 81%; female: 89%. Significantly greater proportions of ubrogepant- than placebo-treated patients achieved 2-hour pain freedom (placebo: 14.3%; 25mg: 20.7%, adjusted P=0.0285; 50mg: 21.8%, adjusted P=0.0129) and absence of MBS for 50mg (placebo: 27.4%; 50mg: 38.9%, adjusted P=0.0129). Secondary endpoints (except absence of nausea at 2h) met statistical significance versus placebo for ubrogepant 50mg. Absence of MBS and secondary outcomes were not significant for 25mg after multiplicity adjustment. Ubrogepant’s and placebo’s AE profiles were similar. Conclusions: Co-primary endpoints were met for ubrogepant 50mg. Ubrogepant 25mg was significantly superior to placebo for 2h pain freedom. Ubrogepant was well tolerated. Results support the efficacy, tolerability, and safety of ubrogepant for acute treatment of migraine attacks.

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Intranasal Civamide for the Acute Treatment of Migraine Headache

Cephalalgia ◽

10.1046/j.1468-2982.2000.00088.x ◽

2000 ◽

Vol 20 (6) ◽

pp. 597-602 ◽

Cited By ~ 43

Author(s):

S Diamond ◽

F Freitag ◽

SB Phillips ◽

JE Bernstein ◽

JR Saper

Keyword(s):

Migraine Headache ◽

Acute Treatment ◽

Serotonin Release ◽

Pain Severity ◽

Double Blind Study ◽

Plasma Extravasation ◽

Post Dose ◽

Double Blind ◽

Excitatory Neurotransmitters ◽

Headache Pain

The objective of this study was to investigate the safety and efficacy of intranasal civamide for the acute treatment of migraine headache with or without aura. Civamide is a vanilloid receptor agonist and neuronal calcium channel blocker that inhibits the neuronal release of excitatory neurotransmitters (e.g. calcitonin gene-related peptide (CGRP) and substance P (SP)) and depletes the neurones of the trigeminal plexus of their neurotransmitter content. Applied intranasally, the release of neurotransmitters to meningeal and dural blood vessels should be decreased, along with the resultant vasodilatation, plasma extravasation, and histamine/serotonin release. Subsequent migraine headache pain may also be diminished. Thirty-four patients were enrolled into a double-blind study of intranasal civamide, and randomized to receive a single dose of either 20 μg or 150 μg of civamide, for the treatment of a single migraine headache, with or without aura, of moderate to severe pain. At 2 h post-dose, 55.6% of patients treated with either dose had a decrease in pain severity, with 22.2% of patients being pain-free. At 4 h post-dose, 72.7% of patients treated with either dose had a decrease in pain severity, with 33.0% of patients being pain-free. Adverse events were similar for both dosages, with 91.2% of patients experiencing nasal burning and 44.1% of patients experiencing lacrimation. No systemic side-effects were observed. Based upon the results of this study, intranasal civamide may be effective in the acute treatment of migraine headache. Given civamide's proposed mechanism of action, intranasal civamide should be substantially more effective for prophylaxis than acute treatment of migraine. A study evaluating its efficacy in prophylaxis of migraine is currently planned.

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An Open Study of Sertraline in Acute and Continuation Treatment of Depressed Out-Patients

Journal of International Medical Research ◽

10.1177/030006059702500604 ◽

1997 ◽

Vol 25 (6) ◽

pp. 340-353 ◽

Cited By ~ 3

Author(s):

B Van Houdenhove ◽

P Onghena ◽

M Flows ◽

F Janssen ◽

AR De Nayer ◽

...

Keyword(s):

Major Depression ◽

Open Study ◽

Acute Treatment ◽

Rating Scale ◽

Severity Of Illness ◽

Final Visit ◽

Clinical Global Impression Scale ◽

Scale Scores ◽

Insufficient Response ◽

Continuation Treatment

The efficacy and tolerability of sertraline in 422 out-patients with major depression (DSM-III-R) was evaluated in an open multicentre 8-month study. Patients received sertraline 50 mg/day; if there was insufficient response at week 4, the dose was increased to 100 mg/day. After 8 weeks, 68.6% of patients had responded (≥ 50% reduction in Montgomery Åsberg depression rating scale and clinical global impression scale scores of two or less (improvement of illness) and three or less (severity of illness); of patients receiving continuation treatment, 87.9% maintained at least a partial response at the final visit. The clinical response to the 50 mg/day dose was maintained throughout the acute treatment in 64% of patients. In all, 23% of the patients had mild or moderate drug-related gastrointestinal disturbances, which generally disappeared after 2 weeks. Only 8% of the patients withdrew because of side-effects. Just over half of the patients were taking other psychotropic drugs. Nevertheless the results of this open study are consistent with those of controlled studies in which sertraline was effective and well tolerated, in acute and continuation treatment for major depression, at 50 mg/day in most patients.

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Visual Function and Structure Outcomes in a Patient with Diabetic Macular Oedema Insufficiently Responsive to Available Therapies – Treatment with Fluocinolone Acetonide Implant

European Ophthalmic Review ◽

10.17925/eor.2014.08.02.137 ◽

2014 ◽

Vol 08 (02) ◽

pp. 137

Author(s):

Érica ABC Guerreiro Paulo ◽

Claus Eckardt ◽

◽

Keyword(s):

Visual Function ◽

Macular Oedema ◽

Therapeutic Option ◽

Diabetic Macular Oedema ◽

Fluocinolone Acetonide ◽

Eye Drops ◽

Short Term ◽

Patient Reported ◽

Before And After ◽

Insufficient Response

Importance:Early experience with intraocular, non-biodegradable fluocinolone acetonide (FAc) (0.2 μg/day) implant (ILUVIEN®), comparing visual function before and after treatment in an insufficiently responsive diabetic macular oedema (DMO) patient.Observations:This 62-yearold male patient with type 2 diabetes mellitus was first treated for DMO in 2004, when best corrected visual acuity (BCVA) was 0.8 for his right eye. He did not visit an ophthalmologist again until 2011 when BCVA had declined to 0.2. Three separate, monthly intravitreal (IV) ranibizumab injections and additional laser photocoagulation resulted in no improvement. Subsequently, 0.7 mg IV dexamethasone was administered, giving short-term DMO improvement. However, six further IV ranibizumab injections produced no effect and a combined injection of IV ranibizumab with 0.7 mg IV dexamethasone provided only short-term improvements. Following phacoemulsification, a 0.2 μg/day FAc implant was administered. Optical coherence tomography (OCT) indicated complete DMO regression after 3 weeks, sustained 6 months post-implant. BCVA improved to 0.25 and the patient reported greater vision-related quality of life. Intraocular pressure increased gradually but resolved with daily timolol/dorzolamide and tafluoprost eye drops.Conclusions and relevance:In a DMO patient showing insufficient response to IV ranibizumab and dexamethasone injections, FAc implant provided an effective therapeutic option with manageable side effects.

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Rituximab for the Treatment of Graves’ Orbitopathy

US Endocrinology ◽

10.17925/use.2011.07.02.130 ◽

2011 ◽

Vol 07 (02) ◽

pp. 130

Author(s):

Mario Salvi ◽

Guia Vannucchi ◽

Paolo Beck-Peccoz ◽

◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

T Cell Activation ◽

Cell Activation ◽

Plasma Cells ◽

Cell Function ◽

Therapeutic Option ◽

Therapeutic Benefit ◽

Graves Orbitopathy

The contribution of B-cells to human autoimmune disease has recently been underscored because of the therapeutic benefit of B-cell depleting therapies. B-cells are involved in the production of autoantibodies, and in CD4+ T-cell activation, control of T-cell function, and inflammation through cytokine production. B-cells are also important antigen-presenting cells. Rituximab (RTX) has been used off-label in various autoimmune disorders and has been shown to effectively deplete mature and memory CD20+ B-cells, but not long-lived plasma cells. The rationale behind the use of RTX in Graves’ disease (GD) and Graves’ orbitopathy (GO) relies on its putative effect on pathogenic autoantibodies causing hyperthyroidism. RTX in patients with active GO has been shown to have a significant effect on the inflammatory activity and severity of GO. However, caution is suggested before proposing RTX as a novel therapeutic tool in this disease until randomized controlled trials are available. Should preliminary observations be confirmed, an optimal strategy for controlling the progression of GO would be to pursue B-cell depletion shortly after diagnosis, rather than only as an alternative therapeutic option when standard immunosuppression has failed.

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