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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

ABSTRACT: BACKGROUND:Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes. METHODS:This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a new oral antidepressant daily. In responders (?50% reduction in Montgomery-Åsberg Depression Rating Scale total score from baseline), esketamine treatment frequency was thereafter decreased during an optimization/maintenance phase to weekly for 4 weeks and then adjusted to the lowest frequency (weekly or every other week) that maintained remission (Montgomery-Åsberg Depression Rating Scale???12) based on a study-defined algorithm. The relationship between treatment frequency and symptom response, based on clinically meaningful change in Clinical Global Impression-Severity score, was subsequently evaluated 4 weeks after treatment frequency adjustments in the optimization/maintenance phase. RESULTS:Among 580 responders treated with weekly esketamine for the first 4 weeks in the optimization/maintenance phase (per protocol), 26% continued to improve, 50% maintained clinical benefit, and 24% worsened. Thereafter, when treatment frequency could be reduced from weekly to every other week, 19% further improved, 49% maintained benefit, and 32% worsened. For patients no longer in remission after treatment frequency reduction, an increase (every other week to weekly) resulted in 47% improved, 43% remained unchanged, and 10% worsened. CONCLUSIONS:These findings support individualization of esketamine nasal spray treatment frequency to optimize treatment response in real-world clinical practice. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT02497287.

SUBMITTER: Nijs M

PROVIDER: S-EPMC7387766 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

Nijs Michel M Wajs Ewa E Aluisio Leah L Turkoz Ibrahim I Daly Ella E Janik Adam A Borentain Stephane S Singh Jaskaran B JB DiBernardo Allitia A Wiegand Frank F

The international journal of neuropsychopharmacology 20200701 7

<h4>Background</h4>Esketamine nasal spray was recently approved for treatment-resistant depression. The current analysis evaluated the impact of symptom-based treatment frequency changes during esketamine treatment on clinical outcomes.<h4>Methods</h4>This is a post-hoc analysis of an open-label, long-term (up to 1 year) study of esketamine in patients with treatment-resistant depression (SUSTAIN 2). During a 4-week induction phase, 778 patients self-administered esketamine twice weekly plus a n ...[more]

PMID: 32270176

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Project description:BACKGROUND:Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. METHODS:In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. FINDINGS:Of 12?030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (-0·20, -0·23 to -0·16), levofloxacin (-0·06, -0·09 to -0·04), moxifloxacin (-0·07, -0·10 to -0·04), or bedaquiline (-0·14, -0·19 to -0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. INTERPRETATION:Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. FUNDING:American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Project description:AimMajor depressive disorder is considered one of the most frequent diseases in the general population, and treatment-resistant depression (TRD) represents the subset with more significant clinical and social impact. Large, robust phase III studies have shown safety and efficacy of esketamine nasal spray plus SSRI/SNRI antidepressants (ADs) compared with SSRI/SNRI plus placebo nasal spray in patients with TRD. The main aim of this study was to perform a cost-utility analysis comparing esketamine plus ADs with ADs alone in TRD patients, from the societal perspective in Italy. A secondary analysis focused on the National Healthcare Service (NHS) perspective.MethodsA Markov multistate model has been developed to estimate quality-adjusted life years and economic outcomes of both treatment strategies over 5 years considering the initiation of esketamine in the different treatment lines, from 3 to 5 (3L-5L). The model has been populated with data from literature and real-world evidence. The analysis from the societal perspective considered direct healthcare costs and patients' productivity losses. In addition to the incremental cost-utility ratio (ICUR), the incremental net monetary benefit (INMB) has been calculated as (incremental benefit × WTP) - incremental cost and by applying a willingness-to-pay (WTP) of 50,000€/QALY. Deterministic and probabilistic sensitivity analyses have been performed to assess the robustness of the model results.ResultsFrom the societal perspective, the ICUR ranged between 16,314€ and 22,133€ per QALY according to the different treatment lines, while it was over the threshold of 100,000€/QALY for the NHS perspective. The INMB was positive and ranged from 2259€ to 2744€ across treatment lines in the societal perspective; the INMB begins to occur earlier when moving towards subsequent lines of treatment (3.9 years for 3L, 3.6 years for 4L and 3.5 years for 5L). The analyses showed also that the advantage in terms of INMB is maintained for a wide range of societal preferences expressed by WTP thresholds, and in particular for values above 22,200€, 16,400€ and 17,100€ for 3L, 4L and 5L, respectively.ConclusionThe study showed that esketamine may be a cost-effective opportunity from the societal perspective for the management of patients with treatment-resistant depression. In the future, data collected from observational studies or registries, which can include the collection of productivity losses and also costs sustained by the patients, will be able to provide further evidence in order to improve the reliability of the model results.

Project description:RationaleKetamine is the first widely used substance with rapid-onset antidepressant action. However, there are uncertainties regarding its potential urothelial toxicity, particularly after repeated application. In the context of rising recreational ketamine use, severe side effects affecting the human urinary tract have been reported. It is assumed that ketamine interacts with bladder urothelial cells and induces apoptosis.ObjectivesThis study aimed to assess whether single or repeated doses of esketamine used in an antidepressant indication are associated with urinary toxicity.MethodsWe included male and female inpatients with a current episode of depression and a diagnosis of recurrent depressive disorder, bipolar disorder or schizoaffective disorder according to ICD-10 criteria (n = 25). The esketamine treatment schedule involved a maximum of 3× weekly dosing at 0.25-0.5 mg/kg i.v. or s.c. The primary outcome was the change in urine toxicity markers (leukocytes, erythrocytes, protein and free haemoglobin). Description of demographic, clinical and laboratory data was conducted using means, standard deviations, frequencies and percentages. Changes in urinary toxicity markers over time were evaluated using linear mixed models with gender as a covariate.ResultsThe participants received an average of 11.4 (SD 8) esketamine treatments, and an average number of 11.2 (SD 8) urine samples were analysed over the course of treatment. Neither urinary leukocyte concentration (F(20; 3.0) = 3.1; p = 0.2) nor erythrocyte concentration (F(20;2.2) = 4.1; p = 0.2) showed a significant trend towards increase during the course of esketamine treatment. Similarly, free haemoglobin and protein concentrations, which were analysed descriptively, did not display a rise during treatment. There was a significant improvement in depression ratings after esketamine treatment (p < 0.001).ConclusionsThis study is, to the best of our knowledge, the first to focus on urothelial toxicity of esketamine used in antidepressant indication and dose. The results indicate that the use of single or repeated doses of esketamine is unlikely to cause urothelial toxicity. The results are in need of confirmation as sample size was small.

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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

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Managing Esketamine Treatment Frequency Toward Successful Outcomes: Analysis of Phase 3 Data.

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