(#17) Early Dose Management and Up-Titration of Esketamine to 84 mg in the Double-Blind Induction Phase of the Randomized, Active-Controlled, Phase 3 TRANSFORM-2 Study

Abstract: Background: The Phase 3 TRANSFORM-2 study (NCT02418585/Popova et al.Am J Psychiatry.2019;176[6]:428-438) evaluated the efficacy and safety of esketamine nasal spray and supported its approval for adults with treatment-resistant depression (TRD) in conjunction with an oral antidepressant (OAD). This post-hoc analysis explored early-dose management and up-titration of esketamine. Methods: TRANSFORM-2 included adults with major depressive disorder and nonresponse to ?2 OADs in the current episode. Eligible participants (Nf227) were randomized 1:1 to esketamine (56mg on Day 1 followed by flexible dosing with 84 or 56mg thereafter [twice/week for 4 weeks]) plus a new OAD, or to placebo plus a new OAD. The primary endpoint was change from baseline to Day 28 in Montgomery-≈sberg Depression Rating Scale (MADRS) total score. Results: On Day 1, 113/114 (99.1%) participants received 56mg esketamine+OAD. On Day 4, 58/107 (54.2%) received 56mg and 49/107 (45.8%) received 84mg. On Day 8, 40/108 (37%) received 56mg and 68/108 (63%) received 84mg; this ratio was approximately maintained through the rest of the double-blind induction phase. The mean (SD) change from baseline in MADRS total score at Day 28 was -19.6 (12.62) for mode dose 56mg (n=34) and -22.4 (12.16) for mode dose 84mg (n=67). The proportion of participants who experienced ?1 treatment-emergent adverse event was 94.6% (35/37) for mode dose 56mg and 80.6% (58/72) for mode dose 84mg. Conclusion: Most participants up-titrated to 84mg of esketamine by Day 8. Numerically greater decreases in MADRS total score were observed with 84mg vs 56mg of esketamine, with a similar safety profile.Short Description: This post-hoc analysis explored early-dose management and up-titration of esketamine nasal spray in the Phase 3 TRANSFORM-2 study in treatment-resistant depression. Eligible participants were randomized 1:1: flexibly dosed esketamine plus a new oral antidepressant or placebo plus a new oral antidepressant. Most participants up-titrated to 84 mg of esketamine by Day 8. Numerically greater decreases in MADRS total score were observed with 84 mg vs 56 mg of esketamine, with a similar safety profile.Name of Sponsoring Organization(s): Johnson & Johnson. PMS: Research grants from the Ministry of Education (Spain), the Government of Navarra (Spain), the Spanish Foundation of Psychiatry and Mental Health, and AstraZeneca; Clinical consultant for MedAvante-ProPhase and Worldwide Clinical Trials Limited; Lecture honoraria from/consultant for AB-Biotics, Adept Field Solutions, Dialectica, Guidepoint, Janssen, Novumed, Roland Berger, and Scienta; Received travel support for taking part in scientific meetings in the last 3 years (air/ground tickets + hotel) from Boston Scientific and Janssen; Principal investigator of several studies supported by Janssen and Novartis about the efficacy and safety of novel pharmacological treatments for depression. TCL, AL, DJF, CB, BB (presenter): Employees of Johnson & Johnson and may hold stock/stock options in Johnson & Johnson.