Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Plus a Newly Initiated Oral Antidepressant in Adult Patients with Treatment-Resistant Depression: A Randomized, Double-Blind, Multicenter, Active-Controlled Study Conducted in China and USA

Abstract

Xu Chen,1,2,* Xuan Hou,3,* Daisy Bai,4 Rosanne Lane,5 Chong Zhang,6 Carla Canuso,7 Gang Wang,1,2 Dong-Jing Fu7 1The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Advanced Innovation Center for Human Brain Protection, Capital Medical University, Beijing, People’s Republic of China; 3Clinical Development, Janssen China Research & Development, Shanghai, People’s Republic of China; 4Statistics, Janssen China Research & Development, Shanghai, People’s Republic of China; 5Statistics, Janssen US Research & Development, Titusville, NJ, USA; 6Clinical Pharmacology, Janssen China Research & Development, Shanghai, People’s Republic of China; 7Neuroscience, Janssen US Research & Development, Titusville, NJ, USA*These authors contributed equally to this workCorrespondence: Gang Wang, The National Clinical Research Center for Mental Disorders and Beijing Key Laboratory of Mental Disorders, Beijing Anding Hospital and Advanced Innovation Center for Human Brain Protection, Capital Medical University, 5 Ankang Hu Tong, Beitaipingzhuang, Xicheng District, Beijing, 100035, People’s Republic of China, Tel [phone], Email [email protected] Dong-Jing Fu, Neuroscience, Janssen US Research & Development, 1125 Trenton-Harbourton Road, Titusville, NJ, 08560, USA, Tel [phone], Email [email protected]: This Phase 3, multicenter study (NCT03434041) was conducted in primarily Chinese patients with treatment-resistant depression (TRD) to support the registration of esketamine nasal spray in China.Patients and Methods: This randomized, double-blind, active-controlled study was conducted in China and the United States (US) in patients with TRD (single or recurrent episode). Eligible patients were randomized 1:1 to receive intranasal esketamine or matching placebo, each in conjunction with a newly initiated oral antidepressant (AD; duloxetine, escitalopram, sertraline, and venlafaxine extended release) (ie, esketamine plus AD or AD plus placebo). The primary endpoint, change from baseline in Montgomery-Åsberg Depression Rating Scale (MADRS) total score at Day 28, was analyzed using a mixed-effects model for repeated measures. Secondary endpoints including safety were also evaluated.Results: Of 252 randomized patients (China, 224; US, 28), 214 completed the double-blind treatment phase. The difference between treatment groups at Day 28 was not statistically significant (difference in least-square means [95% CI]: − 2.0 [− 4.64, 0.55]; 2-sided p = 0.123). However, esketamine plus AD demonstrated a clinically meaningful treatment difference compared with AD plus placebo in MADRS total score at 24 hours after first dose for the study overall population and China sub-population (difference in least-square mean [95% CI]: − 3.3 [− 5.33, − 1.33] and − 2.6 [− 4.64, − 0.60], respectively). No new safety signals were observed.Conclusion: Esketamine plus AD was not statistically superior to AD plus placebo in improving depressive symptoms in TRD patients at Day 28. Rapid reduction in depressive symptoms within 24 hours was observed for TRD patients treated with esketamine plus AD in the overall population and China sub-population. Safety was consistent with the established safety profile of esketamine.Keywords: intranasal, major depressive disorder, MDD, TRD

Keywords

• intranasal
• major depressive disorder
• mdd
• trd