Dataset Information

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression.

ABSTRACT: 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.

SUBMITTER: Katz EG

PROVIDER: S-EPMC7894501 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression.

Katz Eva G EG Hough David D Doherty Teodora T Lane Rosanne R Singh Jaskaran J Levitan Bennett B

Clinical pharmacology and therapeutics 20201013 2

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 rel ...[more]

PMID: 32860422

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Project description:BackgroundIntranasal drug delivery offers a non-invasive and convenient dosing option for patients and physicians, especially for conditions requiring chronic/repeated-treatment administration. However, in some cases such delivery may be harmful to nasal and olfactory epithelia.ObjectiveThe aim of this study was to assess the potential impact of long-term intermittent treatment with esketamine nasal spray, taken in conjunction with an oral antidepressant (AD), on olfactory function and nasal tolerability in patients with treatment-resistant depression (TRD).MethodsA total of 1142 patients with TRD participated from four multicenter, randomized, double-blind, phase III studies: three short-term studies (two in patients aged 18-64 years, one in patients ≥65 years), and one long-term maintenance study of esketamine nasal spray + AD versus placebo nasal spray + AD. Across the four studies, assessments were performed at 208 sites in 21 countries. Olfactory function was measured using the 40-item University of Pennsylvania Smell Identification Test (UPSIT®) and the single-staircase Snap & Sniff® Odor Detection Threshold Test (S&S-T). Nasal tolerability, including nasal examinations and a quantitative, self-administered nasal symptom questionnaire (NSQ), was also assessed. Data were analyzed using analyses of covariance.ResultsOf 1142 participants, 734 were women (64.3%). The mean age of all participants ranged from 45.7 to 70.0 years across the studies. Overall, 855 patients received esketamine nasal spray + AD and 432 received placebo nasal spray + AD. Objective evaluation of nasal function showed no evidence of an adverse impact following esketamine administration. Based on the UPSIT® and S&S-T results, intranasal administration of esketamine had no effect on the odor identification or threshold test scores compared with placebo nasal spray + oral AD. Similarly, repeated administration with esketamine nasal spray had no meaningful impact on assessments of nasal function. No dose-response relationship was observed between esketamine doses and the olfactory test scores. Esketamine nasal spray was well tolerated, as indicated by responses on the NSQ and negative nasal examination findings.ConclusionFindings from this analysis indicate that there was no evidence of adverse effect on either olfactory or nasal health measures with repeated intermittent administration of esketamine nasal spray at any dose over the course of short-term (4 weeks) or long-term (16-100 weeks) studies.Clinical trial registrationTRANSFORM-1: NCT02417064, date of registration: 15/04/2015; TRANSFORM-2: NCT02418585, date of registration: 16/04/2015; TRANSFORM-3: NCT02422186, date of registration: 21/04/2015; SUSTAIN-1: NCT02493868, date of registration: 10/07/2015.

Project description:BackgroundPatients with treatment-resistant depression (TRD) report significant deficits in physical and mental health, as well as severely impaired health-related quality of life (HRQoL) and functioning. Esketamine effectively enhances the daily functioning in these patients while also improving their depressive symptoms. This study assessed HRQoL and health status of patients with TRD, who were treated with esketamine nasal spray and an oral antidepressant (ESK + AD) vs. placebo nasal spray and an AD (AD + PBO).MethodsData from TRANSFORM-2, a phase 3, randomized, double-blind, short-term flexibly dosed study, were analyzed. Patients (aged 18-64 years) with TRD were included. The outcome assessments included the European Quality of Life Group, Five Dimension, Five Level (EQ-5D-5L), EQ-Visual Analogue Scale (EQ-VAS), and Sheehan Disability Scale (SDS). The health status index (HSI) was calculated using EQ-5D-5L scores.ResultsThe full analysis set included 223 patients (ESK + AD: 114; AD + PBO: 109; mean [SD] age: 45.7 [11.89]). At Day 28, a lower percentage of patients reported impairment in the ESK + AD vs. AD + PBO group in all five EQ-5D-5L dimensions: mobility (10.6% vs. 25.0%), self-care (13.5% vs. 32.0%), usual activities (51.9% vs. 72.0%), pain/discomfort (35.6% vs. 54.0%), and anxiety/depression (69.2% vs. 78.0%). The mean (SD) change from baseline in HSI at Day 28 was 0.310 (0.219) for ESK + AD and 0.235 (0.252) for AD + PBO, with a higher score reflecting better levels of health. The mean (SD) change from baseline in EQ-VAS score at Day 28 was greater in ESK + AD (31.1 [25.67]) vs. AD + PBO (22.1 [26.43]). The mean (SD) change in the SDS total score from baseline to Day 28 also favored ESK + AD (-13.6 [8.31]) vs. AD + PBO (-9.4 [8.43]).ConclusionsGreater improvements in HRQoL and health status were observed among patients with TRD treated with ESK + AD vs. AD + PBO.Trial registrationClinicalTrials.gov Identifier: NCT02418585.

Project description:ImportanceControlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.ObjectiveTo 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 participantsIn 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.InterventionsPatients 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 measuresTime to relapse was examined in patients who achieved stable remission, as assessed using a weighted combination log-rank test.ResultsAmong 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 relevanceFor 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 registrationClinicalTrials.gov identifier: NCT02493868.

Project description:Patients with treatment-resistant depression (TRD) have higher rates of relapse and pronounced decreases in daily functioning and health-related quality of life compared to patients with major depressive disorder who are not treatment-resistant, underscoring the need for treatment choices with sustained efficacy and long-term tolerability. Adults with TRD who participated in ≥1 of 6 phase 3 "parent" studies could continue esketamine treatment, combined with an oral antidepressant, by enrolling in phase 3, open-label, long-term extension study, SUSTAIN-3. Based on their status at parent-study end, eligible participants entered a 4-week induction phase followed by an optimization/maintenance phase, or directly entered the optimization/maintenance phase of SUSTAIN-3. Intranasal esketamine dosing was flexible, twice-weekly during induction and individualized to depression severity during optimization/maintenance. At the interim data cutoff (01 December 2020), 1148 participants were enrolled, 458 at induction and 690 at optimization/maintenance. Mean (median) cumulative duration of maintenance esketamine treatment was 31.5 (37.7) months (totaling 2769 cumulative patient-years). Common treatment-emergent adverse events (≥20%) were headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Mean Montgomery-Åsberg Depression Rating Scale (MADRS) total score decreased during induction, and this reduction persisted during optimization/maintenance (mean [SD] change from the baseline to the endpoint of each phase: induction -12.8 [9.73]; optimization/maintenance +1.1 [9.93]), with 35.6% and 46.1% of participants in remission (MADRS total score ≤12) at induction and optimization/maintenance endpoints, respectively. Improvement in depression ratings generally persisted among participants who remained in maintenance treatment, and no new safety signal was identified during long-term treatment (up to 4.5 years) using intermittent-dosed esketamine in conjunction with daily antidepressant.

Project description:BackgroundThe efficacy of esketamine nasal spray (NS) as a rapid-acting agent for treatment resistant depression (TRD) was demonstrated in comparisons with placebo, when both were given in addition to a newly initiated selective serotonin reuptake inhibitor (SSRI)/serotonin norepinephrine reuptake inhibitor (SNRI). How esketamine NS compares with commonly used real-world (RW) polypharmacy treatment strategies is not known.MethodICEBERG was an adjusted indirect treatment comparison that analysed data from SUSTAIN-2 (NCT02497287; clinicaltrials.gov), a long-term, open-label study of esketamine NS plus SSRI/SNRI, and the European Observational TRD Cohort (EOTC; NCT03373253; clinicaltrials.gov), an observational study of routine clinical practice. Data were compared between patients receiving esketamine NS (SUSTAIN-2) and those from the EOTC treated with polypharmacy treatment strategies, either combination or augmentation. Analyses were adjusted for potential confounders, using rescaled average treatment effect among treated estimates. Threshold analyses were conducted to assess potential impact of unmeasured confounders on the robustness of analyses where esketamine NS was found to be significantly superior. Sensitivity analyses were used to understand the impact of analysis method selection and data handling.ResultsEsketamine NS treatment resulted in a higher probability of 6-month response (49.7% [95% confidence interval (CI) 45.6-53.9]) and remission (33.6% [95% CI 29.7-37.6]) versus RW polypharmacy (26.8% [95% CI 21.0-32.5] and 19.4%, [95% CI 14.2-24.6], respectively). Relative risk calculations showed esketamine NS was 1.859 (95% CI 1.474-2.345; p < 0.0001) times as likely to result in response and 1.735 (1.297-2.322; p = 0.0002) times as likely to result in remission versus RW polypharmacy at 6 months. Threshold and extensive sensitivity analyses supported that analyses of esketamine NS superiority were robust.ConclusionICEBERG supports esketamine NS being superior to current RW individualized polypharmacy strategies, including augmentation, with benefits extending beyond acute use, to improved chance of 6-month response and remission. While unobserved confounding factors may certainly impact results of an indirect comparison, threshold analysis supported a low likelihood of this affecting the conclusions.To view an animated summary of this publication, please click on the Supplementary video.

Project description:To compare the efficacy of ketorolac nasal spray (NS) vs. placebo and sumatriptan NS for the acute treatment of migraine.This was a randomized, double-blind, placebo and active-comparator, crossover study. Adult migraineurs were randomized to ketorolac NS 31.5 mg, sumatriptan NS 20 mg, or placebo to treat three moderate to severe migraine attacks and switched treatments with each attack. Patients seeking headache care at a headache center or in response to community advertisement were recruited. Adult participants with episodic migraine who experienced ?2 migraine attacks per month were eligible for the Ketorolac vs. Sumatriptan vs. Placebo Nasal Spray migraine study. Participants were randomized to treatment arms by a research pharmacist, in a 1:1:1 ratio using computer-generated lists. The primary outcome was 2-hour pain relief. Secondary outcomes included 2-hour pain freedom and absence of migraine associated symptoms, and 24-hour sustained pain relief and pain freedom.Of the 72 randomized participants, 54 (75%) treated at least one attack and 49 (68%) completed all three treatments, for a total of 152 treated migraine attacks. Both ketorolac NS (72.5%, P?<?.001) and sumatriptan NS (69.4%, P?=?.001) were more effective than placebo (38.3%) for 2-hour pain relief and 2-hour pain freedom (ketorolac: 43.1%, P?=?.004; sumatriptan: 36.7%, P?=?.046; placebo: 18.4%). Ketorolac NS, but not sumatriptan NS, was more effective than placebo in 2-hour absence of nausea. Both ketorolac NS and sumatriptan NS were more effective than placebo for 24-hour sustained pain relief (ketorolac: 49%, P?<?.001; sumatriptan: 31%, P?=?.01, placebo: 20%). Only ketorolac NS was superior to placebo for 24-hour (ketorolac: 35.3%, P?=?.003; sumatriptan: 22.4%, P?=?.18, placebo: 12.2%) sustained pain freedom. Nasal burning and dysgeusia were the most common adverse effects for active treatments.This study supports that ketorolac NS is superior to placebo and that it is non-inferior to sumatriptan NS for the acute abortive treatment of migraine.

Dataset Information

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression.

Publications

Benefit-Risk Assessment of Esketamine Nasal Spray vs. Placebo in Treatment-Resistant Depression.

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