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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 -
Assay and Drug Development Technologies Oct 2021(Review)
Review
Topics: Administration, Oral; Drug Delivery Systems; Humans; Nanoparticles; Pharmaceutical Preparations; Powders; Technology, Pharmaceutical
PubMed: 34550790
DOI: 10.1089/adt.2021.053 -
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 -
The Journal of Clinical Psychiatry Apr 2020To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD).
Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).
OBJECTIVE
To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD).
METHODS
This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase.
RESULTS
Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]).
CONCLUSIONS
Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02497287.
Topics: Administration, Intranasal; Administration, Oral; Adolescent; Adult; Aged; Antidepressive Agents; Cognition; Depressive Disorder, Treatment-Resistant; Drug Therapy, Combination; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Young Adult
PubMed: 32316080
DOI: 10.4088/JCP.19m12891 -
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 -
Journal of Affective Disorders Feb 2021Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have... (Randomized Controlled Trial)
Randomized Controlled Trial
Meaningful Change in Depression Symptoms Assessed with the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) Among Patients with Treatment Resistant Depression in Two, Randomized, Double-blind, Active-controlled Trials of Esketamine Nasal Spray Combined...
BACKGROUND
Patients with major depressive disorder who do not respond to ≥2 different pharmacological treatments within the current depressive episode are considered to have treatment resistant depression (TRD). This analysis determined meaningful change thresholds (MCT) of the Patient Health Questionnaire (PHQ-9) and Montgomery-Åsberg Depression Rating Scale (MADRS) using anchor-based methods and compared proportions of meaningful changes in patients with TRD across treatment groups from two Phase 3 trials for esketamine nasal spray (SPRAVATO).
METHODS
Data from two Phase 3 trials in patients with TRD, TRANSFORM-1 and -2, were used in this analysis. The MCTs for the PHQ-9 and MADRS were derived using a clinician global impression of severity anchor. Blinded probability density functions displayed score distributions between anchor categories. Proportions of meaningful response were compared between treatment groups using chi-square tests supported by unblinded cumulative distribution functions of change scores.
RESULTS
Baseline scores were similar for the PHQ-9 and MADRS between the esketamine/antidepressant (AD) and AD/placebo groups. The most appropriate MCT on the PHQ-9 was -6 points. By Day 28, 86.5% of patients reached or exceeded the PHQ-9 MCT in the esketamine/AD group compared to 70% in the placebo/AD group. The most appropriate MCT for the MADRS was -10 points. By Day 28, 78.2% of patients reached or exceeded the MADRS MCT in the esketamine/AD group compared to 65.0% in the placebo/AD group.
CONCLUSIONS
Individual-level meaningful change for the PHQ-9 and MADRS was effectively quantified using a clinical anchor to interpret efficacy from patients with TRD and their treating clinicians.
Topics: Antidepressive Agents; Depression; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Double-Blind Method; Humans; Ketamine; Nasal Sprays; Patient Health Questionnaire; Treatment Outcome
PubMed: 33261932
DOI: 10.1016/j.jad.2020.11.066 -
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 -
European Archives of... Nov 2016The purpose of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the symptomatic management of... (Meta-Analysis)
Meta-Analysis Review
The purpose of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the symptomatic management of corticosteroid nasal spray plus antihistamine (oral or local spray) with that of either therapy given alone, or placebo in patients with allergic rhinitis (AR). The PRISMA guidelines for meta-analysis reporting were followed. Total nasal symptom scores and individual nasal symptom scores were pooled after assessing heterogeneity among studies. The pooled estimates were expressed as weighted mean differences (WMD) between treatments. A total of ten studies fulfilled eligibility. Three trials studied the combination therapy of corticosteroid nasal spray and oral antihistamine. Pooled results of two trials failed to show significant difference on total nasal symptoms between combination therapy and intranasal corticosteroid alone (WMD = -0.20, 95 % CI -0.38 to -0.01, P = 0.04). The qualitative analysis showed that combination therapy has greater efficacy than oral antihistamines alone or placebo in improving symptoms. Seven trials investigated corticosteroid nasal spray plus antihistamine nasal spray. The cumulative meta-analysis of six RCTs revealed that combination therapy was superior to solo intranasal corticosteroid (WMD = -1.16, 95 % CI -1.49 to -0.83, P < 0.00001), solo intranasal antihistamine (WMD = -1.73, 95 % CI -2.08 to -1.38, P < 0.00001), and placebo (WMD = -2.81, 95 % CI -3.16 to -2.47, P < 0.00001) in improving total nasal symptom scores. Intranasal corticosteroid plus oral antihistamine have similar efficacy to intranasal corticosteroid alone, greater efficacy than oral antihistamines alone or placebo in reducing nasal symptoms for AR patients. Intranasal corticosteroid plus intranasal antihistamine are significantly superior to either therapy given alone, or placebo.
Topics: Administration, Intranasal; Adrenal Cortex Hormones; Aerosols; Double-Blind Method; Drug Therapy, Combination; Female; Histamine Antagonists; Histamine H1 Antagonists; Humans; Male; Nasal Sprays; Randomized Controlled Trials as Topic; Rhinitis, Allergic; Rhinitis, Allergic, Seasonal
PubMed: 26545381
DOI: 10.1007/s00405-015-3832-1 -
Future Science OA Apr 2022To assess the efficacy of vitamin E oral spray in pregnancy.
AIM
To assess the efficacy of vitamin E oral spray in pregnancy.
MATERIALS & METHODS
This was a retrospective study aimed to evaluate efficacy of vitamin E oral spray (vitamin E acetate in a medium chain tryglicerides vehicle - patented formulation) starting from the first trimester of pregnancy, with a control group.
RESULTS
A total of 100 women were included in the study and were compared with a matched control group. Only 25/200 women reported to have at least one teeth cleaning during pregnancy. Women who received the oral spray had a significantly lower risk of preterm birth compared with the control group, and lower risk of periodontal diseases.
CONCLUSION
Use of oil-based vitamin E oral spray in pregnancy is associated with a decreased risk of periodontal diseases and therefore preterm birth.
PubMed: 35369278
DOI: 10.2144/fsoa-2021-0095 -
The International Journal of... Jan 2021Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment. (Randomized Controlled Trial)
Randomized Controlled Trial
Esketamine Nasal Spray for Rapid Reduction of Depressive Symptoms in Patients With Major Depressive Disorder Who Have Active Suicide Ideation With Intent: Results of a Phase 3, Double-Blind, Randomized Study (ASPIRE II).
BACKGROUND
Patients with major depressive disorder (MDD) having active suicidal ideation with intent require immediate treatment.
METHODS
This double-blind study (ASPIRE II) randomized adults (aged 18-64 years) with MDD having active suicidal ideation with intent to esketamine 84 mg or placebo nasal spray twice weekly for 4 weeks, given with comprehensive standard of care (hospitalization ≥5 days and newly initiated or optimized oral antidepressant[s]). Change from baseline to 24 hours post-first dose in Montgomery-Asberg Depression Rating Scale total score (primary efficacy endpoint) was analyzed using ANCOVA. Clinical Global Impression-Severity of Suicidality-revised (key secondary endpoint) was analyzed using ANCOVA on ranks of change.
RESULTS
Of 230 patients who were randomized (115 per arm), 227 received study drug and were included in efficacy/safety analyses; 184 (80.0%) completed double-blind treatment. Greater improvement in Montgomery-Asberg Depression Rating Scale total score was observed with esketamine (mean [SD]: -15.7 [11.56]) vs placebo (-12.4 [10.43]), each with standard of care, at 24 hours (least-squares mean difference [SE]: -3.9 [1.39], 95% CI: -6.60, -1.11; 2-sided P = .006). This was also noted at the earlier (4-hour) timepoint (least-squares mean difference -4.2, 95% CI: -6.38, -1.94). Patients in both treatment groups experienced rapid reduction in Clinical Global Impression-Severity of Suicidality-revised score; the between-group difference was not statistically significant. The most common adverse events among esketamine-treated patients were dizziness, dissociation, nausea, dysgeusia, somnolence, headache, and paresthesia.
CONCLUSION
This study confirmed rapid and robust reduction of depressive symptoms with esketamine nasal spray in severely ill patients with MDD who have active suicidal ideation with intent. Trial Registration: Clinical Trials.gov identifier: NCT03097133.
Topics: Administration, Intranasal; Adolescent; Adult; Antidepressive Agents; Depressive Disorder, Major; Double-Blind Method; Female; Humans; Ketamine; Male; Middle Aged; Nasal Sprays; Outcome Assessment, Health Care; Patient Acuity; Suicidal Ideation; Young Adult
PubMed: 32861217
DOI: 10.1093/ijnp/pyaa068