Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1).

Abstract

BACKGROUND:

About one-third of patients with depression fail to achieve remission despite treatment with multiple antidepressants and are considered to have treatment-resistant depression.

METHODS:

This Phase 3, double-blind, multicenter study enrolled adults with moderate-to-severe depression and nonresponse to ≥2 antidepressants in the current depression episode. Eligible patients (N = 346) were randomized (1:1:1) to twice-weekly nasal spray treatment (esketamine [56 or 84 mg] or placebo) plus a newly initiated, open-label, oral antidepressant taken daily for 4 weeks. The primary efficacy endpoint was change from baseline to day 28 in the Montgomery-Asberg Depression Rating Scale total score, performed by blinded, remote raters. Based on the predefined statistical testing sequence, esketamine 84 mg/antidepressant had to be significant for esketamine 56 mg/antidepressant to be formally tested.

RESULTS:

Statistical significance was not achieved with esketamine 84 mg/antidepressant compared with antidepressant/placebo (least squares [LS] means difference [95% CI]: -3.2 [-6.88, 0.45]; 2-sided P value = .088). Although esketamine 56 mg/antidepressant could not be formally tested, the LS means difference was -4.1 [-7.67, -0.49] (nominal 2-sided P value = .027). The most common (>20%) adverse events reported for esketamine/antidepressant were nausea, dissociation, dizziness, vertigo, and headache.

CONCLUSIONS:

Statistical significance was not achieved for the primary endpoint; nevertheless, the treatment effect (Montgomery-Asberg Depression Rating Scale) for both esketamine/antidepressant groups exceeded what has been considered clinically meaningful for approved antidepressants vs placebo. Safety was similar between esketamine/antidepressant groups and no new dose-related safety concerns were identified. This study provides supportive evidence for the safety and efficacy of esketamine nasal spray as a new, rapid-acting antidepressant for patients with treatment-resistant depression.

TRIAL REGISTRATION:

ClinicalTrials.gov identifier: NCT02417064.

• Authors: Maggie Fedgchin, Madhukar Trivedi, Ella J Daly, Rama Melkote, Rosanne Lane, Pilar Lim, Dawn Vitagliano, Pierre Blier, Maurizio Fava, Michael Liebowitz, Arun Ravindran, Raphael Gaillard, Hans Van Den Ameele, Sheldon Preskorn, Husseini Manji, David Hough, Wayne C Drevets, Jaskaran B Singh
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 22 Issue 10 Pg. 616-630 (10 01 2019) ISSN: 1469-5111 [Electronic] England
• PMID: 31290965 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2019. Published by Oxford University Press on behalf of CINP.

Chemical References

• Antidepressive Agents
• Delayed-Action Preparations
• Citalopram
• Esketamine
• Ketamine
• Venlafaxine Hydrochloride
• Duloxetine Hydrochloride
• Sertraline

Topics

• Administration, Intranasal
• Administration, Oral
• Adolescent
• Adult
• Antidepressive Agents (administration & dosage, adverse effects, therapeutic use)
• Citalopram (therapeutic use)
• Delayed-Action Preparations (therapeutic use)
• Depressive Disorder, Treatment-Resistant (drug therapy)
• Double-Blind Method
• Drug Therapy, Combination (adverse effects)
• Duloxetine Hydrochloride (therapeutic use)
• Female
• Humans
• Ketamine (administration & dosage, adverse effects, therapeutic use)
• Male
• Middle Aged
• Sertraline (therapeutic use)
• Treatment Outcome
• Venlafaxine Hydrochloride (therapeutic use)
• Young Adult