Intranasal esketamine (Spravato™), the S-enantiomer of ketamine, targets the glutamatergic system via non-competitive antagonism of the N-methyl-D-aspartate receptor, thereby providing a novel approach to traditional antidepressants that target modulation of the monoaminergic system. Another phase III trial, the SUSTAIN-2 trial, was conducted to evaluate the long-term (up to 1 year of exposure) therapeutic and safety characteristics of esketamine. Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. The Sustain 1 trial provides comparative evidence that stopping esketamine results in a higher rate of relapse than continuing esketamine. Esketamine clinical trials: Reply to Maju et al. SUSTAIN-2 (Phase 3, long-term, open label safety trial) 55; female: Died as a result of suicide (i.e., overdosed with zolpidem and oxazepam) on day 188, 12 days after receiving the last dose of SPRAVATO 84 mg. Of note, there were psychosocial stressors that were subsequently reported to have preceded the suicide. Data as of May 20, 2019 CME/KAL Page 2 of 4 SUSTAIN-2. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Full results from TRANSFORM-2, a phase 3 trial that led to the FDA approval in March for esketamine (Spravato), appear Tuesday in the American Journal of Psychiatry. 9-20. 1, pp. 0''lv d 6hulrxv 'lvhdvh zlwk )du 5hdfklqj ,psdfw *oredo khdowk sureohp ! Download Prime PubMed App to iPhone, iPad, or Android 2020;81(3):19m12891. Esketamine, the S-enantiomer of ketamine racemate, has a three- to four-fold higher affinity to N-methyl-D-aspartate receptors than the R-enantiomer. The estimated hazard ratio of esketamine nasal spray plus an oral antidepressant relative to an oral antidepressant plus placebo nasal spray based on the Cox proportional hazards model was 0.30 (95% Confidence Interval: 0.16, 0.55), indicating that patients treated with esketamine plus an oral antidepressant had a 70% reduced risk of relapse. (2020). The committee understood that the TRANSFORM-2 and SUSTAIN-1 results showed an improvement in response, remission and relapse rates for esketamine plus oral antidepressant compared with … We appreciate the questions raised by Gastaldon et al. 21, No. Expert Opinion on Pharmacotherapy: Vol. The trial aimed to assess the short-term efficacy and safety of esketamine, and therefore it does not inform on maintenance of effect and long-term safety, which are being evaluated in other studies (36, 37). J Clin Psychiatry (in press). Esketamine’s adverse effects include dizziness, dysgeusia, somnolence, dissociation, suicidal thoughts and behaviors, and increased heart rate and blood pressure. The safety profile observed was consistent across the two Phase 3 studies in patients with major depressive disorder who have active suicidal ideation with intent, as well as previous studies of esketamine in patients with treatment-resistant depression. The Sustain 2 trial, though assessing outcomes of esketamine Efficacy and safety of intranasal esketamine for the treatment of major depressive disorder. 66 Using the minimal data from two phase III trials (TRANSFORM 1 and 2), a meta-analysis was performed and the findings favoured greater improvement in MADRS score for esketamine … 9, 10 A nasal spray, versus intravenous administration, … The clinical trial development program for esketamine in TRD consisted of 3 unpublished, Phase 3, short-term, double-blind (DB), randomized studies (fixed dose [TRANSFORM-1], ... open-label, long-term safety study (SUSTAIN-2) (FDA Advisory Committee Spravato briefing document 2019). 16 This open-label, multicenter trial included direct-entry patients and transfer-entry patients from the TRANSFORM-3 trial. Wajs E, Aluisio L, Holder R, et al. ploolrq lq 86 2yhu ploolrq 86 sdwlhqwv kdyh wuhdwphqw uhvlvwdqw ghsuhvvlrq stopping esketamine treatment is implausible. In this trial, esketamine efficacy was evaluated when combined with a newly initiated antidepressant. 7, 8 Two phase 2 randomized clinical trials of esketamine (intravenous and nasal spray) in TRD patients under 65 years, demonstrated rapid-onset, dose-related antidepressant effects. The findings from SUSTAIN-2 support the benefits of continued individualization of esketamine nasal spray treatment frequency to optimize treatment response in real world clinical practice. April 2020; Epidemiology and Psychiatric Sciences 29; DOI: 10.1017/S204579602000027X NCT02493868 (SUSTAIN-1) is a 104-week RCT evaluating esketamine + oral antidepressant in relapse prevention and NCT02497287 (SUSTAIN-2) is an open-label study of esketamine of 56 weeks duration. Findings In this randomized, double-blind clinical trial of 67 adults with treatment-resistant depression, significant improvement of depressive symptoms, assessed by the Montgomery-Åsberg Depression Rating Scale total score, was observed after 1 week with intranasal esketamine, 28 to 84 mg administered twice weekly, with a significant ascending dose-response relationship. These studies are due to complete by Q3 2017. ploolrq zruogzlgh ! Semaglutide journal club 1. JOURNAL CLUB Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes 2. J Clin Psychiatry. PubMed journal article: 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). They are due to complete in 2017/8 [4]. The SUSTAIN 8 trial – reported in The Lancet Diabetes & Endocrinology – demonstrated a significantly greater reduction in HbA1c levels with semaglutide versus the sodium-glucose cotransporter (SGLT)-2 inhibitor canagliflozin at 1 year, with mean decreases of 1.5% and 1.0%, respectively. esketamine nasal spray + oral AD (n=705) SUSTAIN 2 (3004)5 A long-term (up to 1 year), open-label safety trial. (Reference Gastaldon, Papola, Ostuzzi and Barbui 2020) in Epidemiology and Psychiatric Services about esketamine's efficacy and the study designs within the clinical development programme for treatment-resistant depression (TRD), and provide clarification herein.Dr Gastaldon and associates acknowledged that the TRANSFORM-2 study … Wajs E, Aluisio L, Holder R, et al. An intranasal formulation of esketamine, combined with an oral antidepressant, is approved in the USA and the European Union for adults with treatment-resistant depression (TRD). A larger proportion of older patients in the esketamine arm of the TRANSFORM-3 trial also achieved clinical response (23.6% versus 12.3%) and clinical remission (15.3% versus 6.2%) compared with placebo. The aim was to evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant in patients with TRD. Transform-2 • Patients with TRD (2 or more failed AD trials) The least biased estimate would not include discontinuation of esketamine for reasons other than lack of efficacy 3.12 Mortality Exclusion of people with acute suicide risk in the trials and lack of data means it … Patients either entered directly or after completing the double-blind induction phase of TRANSFORM 3 (n=802) Comparing the efficacy and safety of fixed-dose esketamine nasal spray + oral AD vs vertigo, headache, somnolence, 6 56mg or 84mg IN. A third short-term acute induction trial TRANSFORM-3 TRD 3005 was a phase three flexible-dose randomized trial in the 65 + age group.This study had three phases, the 4 weeks screening phase, followed by 4 weeks of double-blind phase in which patients were administered flexible-dose esketamine/oral antidepressant (28, 56 or 84 mg) or placebo/antidepressant twice weekly. 12, 16: Not related The company also provided supporting evidence from esketamine trials with different doses and populations (TRANSFORM-1 and TRANSFORM-3) and from a long-term safety study (SUSTAIN-2). Two long-term trials (SUSTAIN-1 and -2) suggested maintenance of response with continued use. Transient cardiovascular stimulatory effects have been reported with ketamine. Intranasal Esketamine Phase 3 trials • Short term outcome RCTs in TRD (2 failed ADs) – 28 day outcomes on MADRS, 2 weekly tx esketamine + new AD. 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). ... – Sustain-2-> long term safety. The Transform 1 and 2 trials provide comparative evidence of the short-term benefit of esketamine compared to another antidepressant. 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). A Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression (SUSTAIN-2) Brief Summary: The purpose of this open-label, multicenter study is to assess the long term safety and efficacy of intranasal esketamine plus an oral antidepressant in participants with treatment-resistant depression (TRD). In the ASPIRE I & II trials, esketamine nasal spray plus SOC was well-tolerated with no new safety signals. Importance: Controlled studies have shown short-term efficacy of esketamine for treatment-resistant depression (TRD), but long-term effects remain to be established.

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