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The Lancet. Neurology Mar 2023Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial.
BACKGROUND
Intranasal formulations can provide treatment options for people with migraine in whom oral drugs are ineffective, slow-acting, or intolerable because of nausea and vomiting. Zavegepant, an intranasally administered small molecule calcitonin gene-related peptide (CGRP) receptor antagonist, was previously assessed in a phase 2/3 trial. This phase 3 trial aimed to compare the efficacy, tolerability, safety, and timecourse of response for zavegepant nasal spray with placebo in the acute treatment of migraine.
METHODS
This double-blind, randomised, placebo-controlled, multicentre phase 3 trial, conducted at 90 academic medical centres, headache clinics, and independent research facilities in the USA, recruited adults (aged ≥18 years) with a history of two to eight moderate or severe migraine attacks per month. Participants were randomly assigned (1:1) to zavegepant 10 mg nasal spray or matching placebo and self-treated a single migraine attack of moderate or severe pain intensity. Randomisation was stratified by the use or non-use of preventive medication. Study centre personnel entered eligible participants into the study using an interactive web response system that was operated and managed by an independent contract research organisation. All participants, investigators, and the funder were masked to group assignment. The coprimary endpoints, freedom from pain and freedom from the most bothersome symptom at 2 h after the treatment dose, were assessed in all randomly assigned participants who took the study medication, had a migraine attack of moderate or severe pain intensity at baseline, and provided at least one evaluable post-baseline efficacy datapoint. Safety was analysed in all randomly assigned participants who received at least one dose. The study is registered with ClinicalTrials.gov, number NCT04571060, and is closed to accrual.
FINDINGS
Between Oct 27, 2020, and Aug 20, 2021, 1978 participants were recruited and assessed for eligibility. 1405 participants were eligible (703 were assigned to zavegepant and 702 to placebo), and 1269 were included in the efficacy analysis set (623 in the zavegepant group and 646 in the placebo group). 2 h after the treatment dose, more participants in the zavegepant group than in the placebo group had pain freedom (147 [24%] of 623 participants vs 96 [15%] of 646 participants, risk difference 8·8 percentage points, 95% CI 4·5-13·1; p<0·0001) and freedom from their most bothersome symptom (247 [40%] vs 201 [31%], risk difference 8·7 percentage points, 3·4-13·9; p=0·0012). The most common adverse events in either treatment group (≥2%) were dysgeusia (129 [21%] of 629 in the zavegepant group vs 31 [5%] of 653 in the placebo group), nasal discomfort (23 [4%] vs five [1%]), and nausea (20 [3%] vs seven [1%]). No signal of hepatotoxicity due to zavegepant was identified.
INTERPRETATION
Zavegepant 10 mg nasal spray was efficacious in the acute treatment of migraine, with favourable tolerability and safety profiles. Additional trials are needed to establish the long-term safety and consistency of effect across attacks.
FUNDING
Biohaven Pharmaceuticals.
Topics: Adult; Humans; Analgesics; Double-Blind Method; Migraine Disorders; Nasal Sprays; Nausea; Treatment Outcome
PubMed: 36804093
DOI: 10.1016/S1474-4422(22)00517-8 -
JAMA Psychiatry Sep 2019Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established. (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.
OBJECTIVE
To assess the efficacy of esketamine nasal spray plus an oral antidepressant compared with an oral antidepressant plus placebo nasal spray in delaying relapse of depressive symptoms in patients with TRD in stable remission after an induction and optimization course of esketamine nasal spray plus an oral antidepressant.
DESIGN, SETTING, AND PARTICIPANTS
In this phase 3, multicenter, double-blind, randomized withdrawal study conducted from October 6, 2015, to February 15, 2018, at outpatient referral centers, 705 adults with prospectively confirmed TRD were enrolled; 455 entered the optimization phase and were treated with esketamine nasal spray (56 or 84 mg) plus an oral antidepressant. After 16 weeks of esketamine treatment, 297 who achieved stable remission or stable response entered the randomized withdrawal phase.
INTERVENTIONS
Patients who achieved stable remission and those who achieved stable response (without remission) were randomized 1:1 to continue esketamine nasal spray or discontinue esketamine treatment and switch to placebo nasal spray, with oral antidepressant treatment continued in each group.
MAIN OUTCOMES AND MEASURES
Time to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.
RESULTS
Among the 297 adults (mean age [SD], 46.3 [11.13] years; 197 [66.3%] female) who entered the randomized maintenance phase, 176 achieved stable remission; 24 (26.7%) in the esketamine and antidepressant group and 39 (45.3%) in the antidepressant and placebo group experienced relapse (log-rank P = .003, number needed to treat [NNT], 6). Among the 121 who achieved stable response, 16 (25.8%) in the esketamine and antidepressant group and 34 (57.6%) in the antidepressant and placebo group experienced relapse (log-rank P < .001, NNT, 4). Esketamine and antidepressant treatment decreased the risk of relapse by 51% (hazard ratio [HR], 0.49; 95% CI, 0.29-0.84) among patients who achieved stable remission and 70% (HR, 0.30; 95% CI, 0.16-0.55) among those who achieved stable response compared with antidepressant and placebo treatment. The most common adverse events reported for esketamine-treated patients after randomization were transient dysgeusia, vertigo, dissociation, somnolence, and dizziness (incidence, 20.4%-27.0%), each reported in fewer patients (<7%) treated with an antidepressant and placebo.
CONCLUSIONS AND RELEVANCE
For patients with TRD who experienced remission or response after esketamine treatment, continuation of esketamine nasal spray in addition to oral antidepressant treatment resulted in clinically meaningful superiority in delaying relapse compared with antidepressant plus placebo.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02493868.
Topics: Administration, Intranasal; Administration, Oral; Adult; Antidepressive Agents; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Remission Induction; Secondary Prevention
PubMed: 31166571
DOI: 10.1001/jamapsychiatry.2019.1189 -
Allergy and Asthma Proceedings Nov 2021The management of chronic rhinosinusitis with nasal polyps (CRSwNP) is evolving, with an emphasis on treating the underlying type 2 inflammation. The objective was to... (Review)
Review
The management of chronic rhinosinusitis with nasal polyps (CRSwNP) is evolving, with an emphasis on treating the underlying type 2 inflammation. The objective was to summarize the updated evidence-based medical and surgical treatment recommendations for CRSwNP, including the position of biologics in the treatment algorithm. This review compared and contrasted the therapeutic recommendations presented by the European Position Paper on Rhinosinusitis and Nasal Polyps 2020 and the International Consensus Statement on Allergy and Rhinology: Rhinosinusitis 2021. The long-term use of intranasal corticosteroids and the short-term use of oral corticosteroids are strongly recommended, whereas corticosteroid-eluting implants are considered an option. Although the use of saline solution rinses is recommended, there is uncertainty as to whether irrigation is more effective than sprays. Oral aspirin (ASA) desensitization, followed by ASA ≥ 300 mg daily for patients with ASA-exacerbated respiratory disease may be considered. In general, the use of antifungal agents offers no benefit and potential harm. Although the use of oral antibiotics for an acute exacerbation is still debated, oral and topical antibiotics are discouraged for subacute or chronic use. Antileukotrienes are inferior to intranasal corticosteroids and are unlikely to provide added benefit when used concomitantly. It is unlikely that the benefit of oral antihistamines and decongestants outweigh the potential harm. Dupilumab is recommended for severe CRSwNP when consensus-determined criteria are met. Omalizumab may be an option with concomitant poorly controlled asthma. Mepolizumab and reslizumab may be used, particularly in patients with concomitant uncontrolled asthma. In allergic fungal rhinosinusitis, oral and topical antifungals, antileukotrienes, allergen immunotherapy, and omalizumab are therapeutic options. Although surgical intervention is recognized to be of benefit for CRSwNP, there are no evidence-based criteria to indicate when maximum medical treatment has failed. An evidence-based CRSwNP treatment algorithm for when to recommend surgery and/or initiate or discontinue biologics to maximize quality of life and cost-effectiveness is still lacking.
Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Aspirin; Asthma; Biological Products; Chronic Disease; Humans; Nasal Polyps; Omalizumab; Quality of Life; Rhinitis; Sinusitis
PubMed: 34871152
DOI: 10.2500/aap.2021.42.210080 -
Journal of Cosmetic Dermatology May 2022Oral finasteride is an FDA-approved treatment for androgenetic alopecia (AGA). Topical finasteride, while not FDA-approved, lacks the systemic adverse effects associated... (Review)
Review
BACKGROUND
Oral finasteride is an FDA-approved treatment for androgenetic alopecia (AGA). Topical finasteride, while not FDA-approved, lacks the systemic adverse effects associated with oral finasteride. The efficacy of topical finasteride has been evaluated.
AIM
To review whether topical finasteride is a safe and effective treatment for male and female pattern hair loss.
METHOD
A structured search in PubMed and Google Scholar identified 864 records, with 32 articles meeting the inclusion criteria for review.
RESULTS AND DISCUSSION
In a phase III, randomized, controlled trial, the efficacies of topical 0.25% w/w finasteride spray (1-4 sprays; 50-200 μl/day) and once-daily finasteride 1 mg oral tablet were similar when administered for 24 weeks (mean change from baseline, 20.2 vs. 21.1 hairs/cm ). Additionally, a double-blind, randomized trial compared the efficacies of twice-daily finasteride 1% topical gel and once-daily finasteride 1 mg oral tablet for 6 months, and found similar results in both groups. Moreover, a combination of topical minoxidil and topical finasteride may enhance efficacy. Topical finasteride reduces both scalp and plasma DHT levels. In an open-label pharmacodynamic study, a 7-day treatment of twice-daily finasteride 0.25% topical solution and once-daily finasteride 1 mg oral tablet provided similar inhibition of plasma DHT. Topical finasteride reduces the potential for systemic side effects, including the risk of sexual dysfunction. The side effects are localized to the application site, for example, scalp pruritus, burning sensation, irritation, contact dermatitis, and erythema.
CONCLUSION
Topical finasteride may be an alternative for those concerned about the oral formulation's systemic side effects.
Topics: Administration, Topical; Alopecia; Clinical Trials, Phase III as Topic; Female; Finasteride; Hair; Humans; Male; Minoxidil; Randomized Controlled Trials as Topic; Tablets; Treatment Outcome
PubMed: 35238144
DOI: 10.1111/jocd.14895 -
The American Journal of Geriatric... Feb 2020Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients,... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Elderly patients with major depression have a poorer prognosis, are less responsive to treatment, and show greater functional decline compared with younger patients, highlighting the need for effective treatment.
METHODS
This phase 3 double-blind study randomized patients with treatment-resistant depression (TRD) ≥65 years (1:1) to flexibly dosed esketamine nasal spray and new oral antidepressant (esketamine/antidepressant) or new oral antidepressant and placebo nasal spray (antidepressant/placebo). The primary endpoint was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to day 28. Analyses included a preplanned analysis by age (65-74 versus ≥75 years) and post-hoc analyses including age at depression onset.
RESULTS
For the primary endpoint, the median-unbiased estimate of the treatment difference (95% CI) was -3.6 (-7.20, 0.07); weighted combination test using MMRM analyses z = 1.89, two-sided p = 0.059. Adjusted mean (95% CI) difference for change in MADRS score between treatment groups was -4.9 (-8.96, -0.89; t = -2.4, df = 127; two-sided nominal p = 0.017) for patients 65 to 74 years versus -0.4 (-10.38, 9.50; t = -0.09, two-sided nominal p = 0.930) for those ≥75 years, and -6.1 (-10.33, -1.81; t = -2.8, df = 127; two-sided nominal p = 0.006) for patients with depression onset <55 years and 3.1 (-4.51, 10.80; t = 0.8, two-sided nominal p = 0.407) for those ≥55 years. Patients who rolled over into the long-term open-label study showed continued improvement with esketamine following 4 additional treatment weeks.
CONCLUSIONS
Esketamine/antidepressant did not achieve statistical significance for the primary endpoint. Greater differences between treatment arms were seen for younger patients (65-74 years) and patients with earlier onset of depression (<55 years).
Topics: Administration, Oral; Age Factors; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Nasal Sprays; Treatment Outcome
PubMed: 31734084
DOI: 10.1016/j.jagp.2019.10.008 -
Clinical Pharmacology and Therapeutics Feb 2021This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with... (Observational Study)
Observational Study Randomized Controlled Trial
This post hoc analysis assessed the benefit-risk profile of esketamine nasal spray + oral antidepressant (AD) induction and maintenance treatment in patients with treatment-resistant depression (TRD). The Benefit-Risk Action Team framework was utilized to assess the benefit-risk profile using data from three induction studies and one maintenance study. Benefits were proportion of remitters or responders in induction studies and proportion of stable remitters or stable responders who remained relapse-free in the maintenance study. Risks were death, suicidal ideation, most common adverse events (AEs), and potential long-term risks. Per 100 patients on esketamine + AD vs. AD + placebo in induction therapy, 5-21 additional patients would remit and 14-17 additional patients would respond. In maintenance therapy, 19-32 fewer relapses would occur with esketamine. In both cases, there was little difference in serious or severe common AEs (primarily dissociation, vertigo, and dizziness). These findings support a positive benefit-risk balance for esketamine + AD as induction and maintenance treatment in patients with TRD.
Topics: Administration, Oral; Adolescent; Adult; Aged; Antidepressive Agents; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Prospective Studies; Risk Assessment; Treatment Outcome; Young Adult
PubMed: 32860422
DOI: 10.1002/cpt.2024