scholarly journals Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Stephanie J. Nahas ◽  
Nada Hindiyeh ◽  
Deborah I. Friedman ◽  
Nada Elbuluk ◽  
Donald J. Kellerman ◽  
...  
Keyword(s):  
Adverse Events ◽  
Migraine Attack ◽  
Acute Treatment ◽  
Application Site ◽  
Tolerability Profile ◽  
Open Label ◽  
Post Dose ◽  
Link Type ◽  
Repeated Use

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

scholarly journals Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study)

Cephalalgia ◽  
2019 ◽  
Vol 39 (11) ◽  
pp. 1343-1357 ◽  
Author(s):  
Jan Lewis Brandes ◽  
Suzanne Klise ◽  
John H Krege ◽  
Michael Case ◽  
Rashna Khanna ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Treatment ◽  
Electronic Diary ◽  
Open Label ◽  
Phase 3 ◽  
Post Dose ◽  
Serious Adverse Events ◽  
Long Term Study ◽  
Open Label Phase

Objectives 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. Methods 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. Results 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. Conclusions The interim results of this long-term study showed intermittent lasmiditan (100 mg and 200 mg) to be generally well tolerated and efficacious for the acute treatment of migraine over a 1-year period. Trial registration number: NCT02565186; https://clinicaltrials.gov/ct2/show/NCT02565186

scholarly journals Long-term safety and efficacy of lasmiditan for acute treatment of migraine: Final results of the GLADIATOR study

2020 ◽  
Vol 3 ◽  
pp. 251581632095817
Author(s):  
Jan Lewis Brandes ◽  
Suzanne Klise ◽  
John H Krege ◽  
Michael Case ◽  
Rashna Khanna ◽  
...  
Keyword(s):  
Adverse Events ◽  
Interim Analysis ◽  
Acute Treatment ◽  
Episodic Migraine ◽  
Migraine Treatment ◽  
Open Label ◽  
Phase 3 ◽  
Post Dose ◽  
Open Label Phase

GLADIATOR was a prospective, randomized, open-label, phase 3 study of lasmiditan 100 mg or 200 mg dosed intermittently for up to 1 year in patients with episodic migraine. Most patients had completed one of two single-attack studies before participation. A total of 2030 patients received ≥1 lasmiditan dose and 19,879 migraine attacks were treated. Safety results were similar to the previously reported interim analysis. The most frequently reported treatment-emergent adverse events (TEAEs) included dizziness (18.5%), somnolence (8.5%), and paresthesia (6.8%), with frequency of adverse events appearing to decrease with subsequently treated attacks. At 2 h post-dose, 26.7% and 32.2% of all attacks treated with lasmiditan 100 mg and 200 mg, respectively, were pain free. This pattern was generally consistent across study quarters and treated attacks. In conclusion, during a 1-year treatment period, intermittent lasmiditan for episodic migraine treatment was associated with generally decreasing TEAEs and consistent efficacy.

Acute treatment of migraine with the selective 5-HT1F receptor agonist lasmiditan – A randomised proof-of-concept trial

Cephalalgia ◽  
2010 ◽  
Vol 30 (10) ◽  
pp. 1170-1178 ◽  
Author(s):  
Michel D Ferrari ◽  
Markus Färkkilä ◽  
Uwe Reuter ◽  
Alison Pilgrim ◽  
Charles Davis ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Treatment ◽  
Neural Mechanism ◽  
Dose Finding ◽  
Stopping Rules ◽  
Tolerability Profile ◽  
Proof Of Concept ◽  
Post Dose ◽  
Double Blind ◽  
Clinical Experiments

Introduction: Lasmiditan (COL-144; LY573144) is a novel, highly selective and potent agonist at 5-HT1F receptors that lacks vasoconstrictor activity. Preclinical and early clinical experiments predict acute antimigraine efficacy of COL-144 that is mediated through a non-vascular, primarily neural, mechanism. Subjects and methods: In a randomised, multicentre, placebo-controlled, double-blind, group-sequential, adaptive treatment-assignment, proof-of-concept and dose-finding study, we treated 130 subjects in-hospital during a migraine attack. Subjects were allocated to an intravenous dose level of lasmiditan or placebo in small cohorts. The starting dose was 2.5 mg. Subsequent doses were adjusted, up or down, according to the safety and efficacy seen in the preceding cohort. The primary outcome measure was headache response defined as improvement from moderate or severe headache at baseline to mild or no headache at 2 h post-dose. The study was designed to explore the overall dose response relationship but was not powered to differentiate individual doses from placebo, nor to detect effect differences for other migraine symptoms. Results: Forty-two subjects received placebo and 88 received lasmiditan in doses of 2.5–45 mg. Subjects were observed in the clinic for 4 h after treatment and used a diary card to record symptoms and adverse events for up to 24 h. The study was terminated when the 20 mg dose met predefined efficacy stopping rules. Of subjects treated in the 10, 20, 30 and 45 mg lasmiditan dose groups, 54–75% showed a 2 h headache response, compared to 45% in the placebo group ( P = 0.0126 for the linear association between response rates and dose levels). Patient global impression at 2 h and lack of need for rescue medication also showed statistically significant linear correlations with dose. Lasmiditan was generally well tolerated. Adverse events were reported by 65% of subjects on lasmiditan and by 43% on placebo and were generally mild. Dizziness, paresthesia and sensations of heaviness (usually limb) were more common on lasmiditan. Conclusions: At intravenous doses of 20 mg and higher, lasmiditan proved effective in the acute treatment of migraine. Further studies to assess the optimal oral dose and full efficacy and tolerability profile are under way. The non-vascular, neural mechanism of action of lasmiditan may offer an alternative means to treat migraine especially in patients who have contra-indications for agents with vasoconstrictor activity. The clinicaltrials.gov identifier for this study is NCT00384774.

One-Year Open-Label Safety and Efficacy Study of Paliperidone Extended-Release Tablets in Patients With Schizophrenia

CNS Spectrums ◽  
2010 ◽  
Vol 15 (8) ◽  
pp. 506-514 ◽  
Author(s):  
Michelle Kramer ◽  
George Simpson ◽  
Valentinas Maciulis ◽  
Stuart Kushner ◽  
Yanning Liu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Extended Release ◽  
Tolerability Profile ◽  
Open Label ◽  
Double Blind ◽  
Safety And Efficacy ◽  
Stabilization Phase ◽  
Open Label Extension ◽  
Paliperidone Extended Release

ABSTRACTIntroduction: This 52-week open-label extension (OLE) to a double-blind placebo-controlled recurrence prevention study examined the long-term safety and efficacy of flexibly-dosed paliperidone extended-release (ER) tablets in patients with schizophrenia.Methods: Patients entering the OLE either entered from the double-blind phase (placebo or paliperidone ER treatment) or entered directly from the run-in or stabilization phase (paliperidone ER) of the earlier study. During the OLE, patients were treated with flexibly-dosed paliperidone ER (3–15 mg/day; 9 mg starting dose). Safety and tolerability assessments included incidence of adverse events and extrapyramidal symptoms. Efficacy was also assessed.Results: The study population (n=235) was predominantly men (66%), 18–58 years of age. Twelve patients (5%) experienced an adverse event requiring treatment discontinuation. One or more serious treatment-emergent adverse events were reported in 13 patients (6%). There was one death. The mean Positive and Negative Syndrome Scale total score decreased from open-label baseline to endpoint for all groups, regardless of previous double-blind treatment (placebo or paliperidone ER).Conclusion: This year-long OLE provides information on the long-term safety and tolerability of paliperidone ER in patients with schizophrenia. The resulting safety and tolerability profile was similar to that seen in earlier short-term studies.

Long-term Effectiveness and Tolerability Profile of Iloperidone in Patients of Psychosis

2017 ◽  
Vol 2 (2) ◽  
pp. 78-84
Author(s):  
Abhinav Kuchhal ◽  
Shivangna Singh ◽  
Hari OK Singh ◽  
Alka Yadav ◽  
Imran Zaheer
Keyword(s):  
Weight Gain ◽  
Adverse Events ◽  
Density Lipoprotein ◽  
Significant Rise ◽  
First Episode ◽  
Tolerability Profile ◽  
Open Label ◽  
Term Efficacy ◽  
End Point

ABSTRACT Aim To evaluate the long-term efficacy, tolerability, and safety profile of iloperidone. Materials and methods A 12 month, prospective, interventional, open label, flexible dose study was conducted on 50 drug naïve, first-episode patients aged 18 to 65 years, fulfilling the International Classification of Diseases-10 criteria for psychosis, for assessing long-term efficacy and adverse events, including biochemical parameters of iloperidone. Detailed clinical examination was carried out. Sociodemographic data and baseline parameters were recorded. Results Two patients dropped out during the course of therapy. M/F ratio was 1.77:1. Mean age of patients was 28.76 ± 10.28 [mean ± standard deviation (SD)] years. Rural/urban ratio was 2.84:1.25. Patients were illiterate, 18 belonged to low socioeconomic class. It was observed that iloperidone was fairly efficacious not only in preventing relapse or aggravation of symptoms but also well restored the patient to almost near-normal till the end point. After 3 months, 20/48 (41.66%) patients showed significant weight gain that was evident. Mean total weight gain from baseline to end point was 2.89 kg and was statistically significant. There was significant rise in body mass index (BMI) but no patient crossed the upper normal limit. Iloperidone did not cause significant rise (p < 0.6955) in fasting blood sugar (FBS), and no significant alterations in total cholesterol (TC), triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol were recorded. Dizziness was one of the earliest adverse events appearing within 2 to 3 days; others were insomnia, weight gain, increased appetite, anxiety, headache, sedation, etc. Conclusion On long-term basis, iloperidone is fairly efficacious and has favorable tolerability profile with modest weight gain and practically no alteration in FBS, and lipid profile as well as absence of extrapyramidal side effects. How to cite this article Singh S, Singh HOK, Kuchhal A, Yadav A, Zaheer I. Long-term Effectiveness and Tolerability Profile of Iloperidone in Patients of Psychosis. Int J Adv Integ Med Sci 2017;2(2):78-84.

Tolerability and Efficacy of Naratriptan Tablets in the Acute Treatment of Migraine Attacks for 1 Year

Cephalalgia ◽  
2000 ◽  
Vol 20 (5) ◽  
pp. 470-474 ◽  
Author(s):  
J Heywood ◽  
MAM Bomhof ◽  
A Pradalier ◽  
L Thaventhiran ◽  
P Winter ◽  
...  
Keyword(s):  
Adverse Event ◽  
Acute Treatment ◽  
Duration Of Treatment ◽  
Open Label ◽  
Post Dose ◽  
Open Label Study ◽  
Frequency Of Use ◽  
Study Results ◽  
Headache Relief ◽  
Repeated Use

Objective and design: This open‐label study was conducted to evaluate the tolerability and efficacy of the 5HT1 agonist naratriptan with repeated use in the acute treatment of migraine attacks for 1 year. Four hundred and seventeen (417) migraine patients treated 15 301 migraine attacks over the course of the study. Results: The results show that 84% of attacks treated with a single 2.5 mg dose of naratriptan were not associated with the occurrence of an adverse event. The percentage of attacks associated with an adverse event did not increase with number of doses used to treat a given attack (1 vs. 2) or duration of use (0–6 months vs. > 6–12 months). The only adverse events experienced in > 2% of attacks throughout the 1‐year study were nausea (3% of attacks), hyposalivation (2% of attacks), and drowsiness/sleepiness (2% of attacks). Headache relief 4 h post‐dose was reported in a median 70% of moderate or severe attacks and a median 86% of mild attacks treated with naratriptan tablets 2.5 mg. The percentages of patients reporting headache relief did not diminish as a function of increased duration of treatment (0–6 months vs. > 6–12 months) or frequency of use (for > 36 vs. < 36 attacks). The mean number of tablets taken per attack was 1.2. A second naratriptan 2.5 mg tablet was taken for headache recurrence in a mean 16% (median 8%) of attacks. Conclusion: The results of this study demonstrate that naratriptan tablets 2.5 mg taken for acute migraine attacks over a 1‐year period are well‐tolerated and effective.

Time-course of treatment-emergent adverse events in a long-term safety study of lisdexamfetamine dimesylate in children and adolescents with ADHD

2016 ◽  
Vol 33 (S1) ◽  
pp. S132-S132
Author(s):  
I. Hernández Otero ◽  
T. Banaschewski ◽  
P. Nagy ◽  
C.A. Soutullo ◽  
A. Zuddas ◽  
...  
Keyword(s):  
Adverse Events ◽  
Children And Adolescents ◽  
Time Course ◽  
Open Label ◽  
Lisdexamfetamine Dimesylate ◽  
Safety Population ◽  
First Onset ◽  
Stimulant Medications ◽  
Competing Interest

IntroductionThe long-term safety and efficacy of lisdexamfetamine dimesylate (LDX) in children and adolescents with attention deficit/hyperactivity disorder (ADHD) was evaluated in a European 2-year, open-label study (SPD489-404).ObjectiveTo evaluate the time-course of treatment-emergent adverse events (TEAEs) in SPD489-404.MethodsParticipants aged 6–17 years received open-label LDX (30, 50 or 70 mg/day) for 104 weeks (4 weeks dose-optimization; 100 weeks dose-maintenance).ResultsAll enrolled participants (n = 314) were included in the safety population and 191 (60.8%) completed the study. TEAEs occurred in 282 (89.8%) participants; most were mild or moderate. TEAEs considered by the investigators as related to LDX were reported by 232 (73.9%) participants with the following reported for ≥ 10% of participants: decreased appetite (49.4%), weight decreased (18.2%), insomnia (13.1%). TEAEs leading to discontinuation and serious TEAEs occurred in 39 (12.4%) and 28 (8.9%) participants, respectively. The median (range) time to first onset and duration, respectively, of TEAEs identified by the sponsor as being of special interest were: insomnia (insomnia, initial insomnia, middle insomnia, terminal insomnia), 17.0 (1–729) and 42.8 (1–739) days; weight decreased, 29.0 (1–677) and 225.0 (26–724) days; decreased appetite, 13.5 (1–653) and 169.0 (1–749) days; headache, 22.0 (1–718) and 2.0 (1–729) days. Reports of insomnia, weight decreased, decreased appetite and headache were highest in the first 4–12 weeks.ConclusionsTEAEs associated with long-term LDX treatment were characteristic of stimulant medications, with the greatest incidence observed during the first 4–12 weeks.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Long-Term, Open-Label Safety Study of Oral Almotriptan 12.5 mg for the Acute Treatment of Migraine in Adolescents

2008 ◽  
Vol 50 (5) ◽  
pp. 795-807 ◽  
Author(s):  
Frank Berenson ◽  
Elza Vasconcellos ◽  
Ann Pakalnis ◽  
Lian Mao ◽  
David M. Biondi ◽  
...  
Keyword(s):  
Acute Treatment ◽  
Open Label ◽  
Safety Study

scholarly journals A phase I study of a dual PI3-kinase/mTOR inhibitor BEZ235 in adult patients with relapsed or refractory acute leukemia

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Fabian Lang ◽  
Lydia Wunderle ◽  
Susanne Badura ◽  
Eberhard Schleyer ◽  
Monika Brüggemann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Acute Leukemia ◽  
Phase I ◽  
Mtor Inhibitor ◽  
Prolonged Treatment ◽  
Small Subset ◽  
Open Label ◽  
Serious Adverse Events ◽  
Efficient Treatment ◽  
Link Type

Abstract Background Combined inhibition of phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) complexes may be an efficient treatment for acute leukemia. The primary objective of this phase I single center open label study was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of the dual pan-class I PI3K and mTOR inhibitor BEZ235 in patients with advanced leukemia. Methods Herein patients > 18 years of age who had relapsed or showed refractory leukemia were treated with BEZ235 (orally at 300–400 mg BID (cohort − 1/1)) to assess safety, tolerability, preliminary efficacy and pharmacokinetic (PK). Adverse events data and serious adverse events were analyzed and haematological and clinical biochemistry toxicities were assessed from laboratory test parameters. Response was assessed for the first time at the end of cycle 1 (day 29) and after every subsequent cycle. Pharmacokinetic and pharmacodynamic analyses of BEZ235 were also included (BEZ235 plasma levels, phosphorylation of AKT, S6 and 4EBP1). On statistics this trial is a multiple ascending dose study in which a following variant of the 3 + 3 rule (“Rolling Six”), a minimum of 6 and a maximum of 12 patients was recruited for the dose escalation and another 5 were planned for the expansion phase. Results Twenty-four patients with ALL (n = 11) or AML (n = 12) or CML-BP (n = 1) were enrolled. All patients had failed one (n = 5) or more lines of therapy (n = 5) and 14 patients were in refractory / refractory relapse. No formal MTD was defined, stomatitis and gastrointestinal toxicity at 400 mg BID dose was considered incompatible with prolonged treatment. The RP2D of BEZ235 was defined as 300 mg BID. Four of 24 patients showed clinical benefit. Twenty-two of 24 patients discontinued because of progression, (median time to progression 27 days (4d-112d). There was no association between PK parameters and efficacy or tolerability. Conclusions Combined inhibition of PI3K and mTOR inhibits a clinically meaningful driver pathway in a small subset of patients with ALL, with no benefit in patients with AML. Trial registration ClinicalTrials.gov, identifier NCT01756118. retrospectively registered 19th December 2012, https://clinicaltrials.gov/ct2/show/NCT01756118.

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