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)

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

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)616-630
Number of pages15
JournalThe international journal of neuropsychopharmacology
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2019

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Treatment-Resistant Depressive Disorder
Nasal Sprays
Antidepressive Agents
Safety
Depression
Placebos
Least-Squares Analysis
Dissociative Disorders
Vertigo
Dizziness
Double-Blind Method
Nausea
Multicenter Studies
Headache

Keywords

  • esketamine
  • ketamine
  • s-ketamine
  • treatment-resistant depression

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)

Cite this

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). / Fedgchin, Maggie; Trivedi, Madhukar; Daly, Ella J.; Melkote, Rama; Lane, Rosanne; Lim, Pilar; Vitagliano, Dawn; Blier, Pierre; Fava, Maurizio; Liebowitz, Michael; Ravindran, Arun; Gaillard, Raphael; Ameele, Hans Van Den; Preskorn, Sheldon; Manji, Husseini; Hough, David; Drevets, Wayne C.; Singh, Jaskaran B.

In: The international journal of neuropsychopharmacology, Vol. 22, No. 10, 01.10.2019, p. 616-630.

Research output: Contribution to journalArticle

Fedgchin, M, Trivedi, M, Daly, EJ, Melkote, R, Lane, R, Lim, P, Vitagliano, D, Blier, P, Fava, M, Liebowitz, M, Ravindran, A, Gaillard, R, Ameele, HVD, Preskorn, S, Manji, H, Hough, D, Drevets, WC & Singh, JB 2019, '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)', The international journal of neuropsychopharmacology, vol. 22, no. 10, pp. 616-630. https://doi.org/10.1093/ijnp/pyz039
Fedgchin, Maggie ; Trivedi, Madhukar ; Daly, Ella J. ; Melkote, Rama ; Lane, Rosanne ; Lim, Pilar ; Vitagliano, Dawn ; Blier, Pierre ; Fava, Maurizio ; Liebowitz, Michael ; Ravindran, Arun ; Gaillard, Raphael ; Ameele, Hans Van Den ; Preskorn, Sheldon ; Manji, Husseini ; Hough, David ; Drevets, Wayne C. ; Singh, Jaskaran B. / 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). In: The international journal of neuropsychopharmacology. 2019 ; Vol. 22, No. 10. pp. 616-630.
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T1 - Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression

T2 - Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1)

AU - Fedgchin, Maggie

AU - Trivedi, Madhukar

AU - Daly, Ella J.

AU - Melkote, Rama

AU - Lane, Rosanne

AU - Lim, Pilar

AU - Vitagliano, Dawn

AU - Blier, Pierre

AU - Fava, Maurizio

AU - Liebowitz, Michael

AU - Ravindran, Arun

AU - Gaillard, Raphael

AU - Ameele, Hans Van Den

AU - Preskorn, Sheldon

AU - Manji, Husseini

AU - Hough, David

AU - Drevets, Wayne C.

AU - Singh, Jaskaran B.

PY - 2019/10/1

Y1 - 2019/10/1

N2 - 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.

AB - 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.

KW - esketamine

KW - ketamine

KW - s-ketamine

KW - treatment-resistant depression

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