Table 2.

Major randomised trials on esketamine from https://www.clinicaltrials.gov.

Trial name, year	Esketamine strength	Age and population	Design and study focus	Treatment duration	Intervention(s) and comparator(s)	Sample size/ characteristics	Key outcomes
Phase I
DriveSaFe261 [ClinicalTrials.gov identifier: NCT02228239], 2014	Fixed esketamine dose 84 mg	Adults (21– 60 years) Healthy participants Body mass index 18–30 Bodyweight ⩾45 kg Normal cardiac function Valid driving license for more than 3 years	Safety focus Randomised, double-blind placebo-controlled, 3-way crossover study	7-week study • Screening phase (between 21 days and 1 day prior to the first dose administration) • 3-way crossover double-blind, single-dose treatment phase (45 days) • Follow-up phase (7–10 days after last dose administration)	• Treatment A (esketamine 84 mg intranasal and 1 placebo capsule) • Treatment B (placebo intranasal and 1 mirtazapine 30 mg capsule) • Treatment C (placebo intranasal and placebo capsule)	N = 26	SDLP
Phase II
SYNAPSE10 [ClinicalTrials.gov identifier: NCT01998958], 2014–2015	Flexible esketamine doses (14 mg, 28 mg, 56 mg, 84 mg)	Adults (20–64 years) MDD, failed ⩾2ADs, IDS-C30 ⩾ 34	Safety focus Randomised, 2-panel, double-blind placebo-controlled study	Four phases for Panel A and Panel B • 4-week screening phase • 1–15 days double-blind treatment phase • Optional open-label treatment phase (panel A: Day 15–74; Panel B: Day 15–25) • 8-week post-treatment (follow-up) phase	• Esketamine 14 mg • Esketamine 28 mg • Esketamine 56 mg • Esketamine 84 mg • Placebo (comparator)	N = 108	MADRS change
SUI200162,63 [ClinicalTrials.gov identifier: NCT02133001], 2014–2016	Fixed esketamine dose 84 mg	Adult 18–64 Years MDD with suicidal ideation	Safety focus Randomised, double-blind placebo-controlled study	Approximately 81 days per participant • Screening phase (1-day before the study commences) • Double-blind treatment phase (day 1–25) • Follow-up phase (Day 26–81)	• Esketamine 84 mg • Placebo	N = 66	MADRS change
Phase III
TRANSFORM-164,65 [ClinicalTrials.gov identifier: NCT02417064], 2015–2018	Fixed esketamine dose (56 mg or 84 mg)	Adult 18–64 Years MDD IDS-C30 ⩾ 34	Efficacy and safety focus Randomised, double-blind, active-controlled, multicentre study	• 4–7 weeks screening/prospective observation phase • 4-weeks double-blind induction phase • 24 weeks follow-up	• Intervention: esketamine 56 mg (n = 115) or 84 mg (n = 116) intranasally twice per week • Comparator: Matching placebo given intranasally twice per week (n = 113)	N = 344 Mean age: 47 Current episode duration (years): 3.9 MADRS mean: 37.5 Past failures of ⩾ 3 ADs: 40%	MADRS change Clinical remission Clinical response
TRANSFORM-254–56 [ClinicalTrials.gov identifier: NCT02418585], 2015–2017	Flexible esketamine dose (56 mg or 84 mg)	Adult 18–64 Years MDD IDS-C30 ⩾ 34	Efficacy and safety focus Randomised, double-blind, active-controlled, multicentre study	• 4–7 weeks screening/prospective observation phase • 4-weeks double-blind induction phase • 24 weeks follow-up	• Intervention: esketamine 56 mg or 84 mg intranasally twice per week (n = 114) • Comparator: matching intranasal placebo (n = 109)	N = 224 Mean age: 46 Current episode duration (years): 2.2 MADRS mean: 37 Past failures of ⩾ 3 ADs: 36%	MADRS change Clinical remission Clinical response
TRANSFORM-366 [ClinicalTrials.gov identifier: NCT02422186], 2015–2017	Flexible esketamine dose (28 mg or 56 mg or 84 mg)	Adult ⩾65 Years MDD IDS-C30 ⩾ 31	Efficacy and safety focus Randomised, double-blind, active-controlled, multicentre study	• 4–7 weeks screening/prospective observation phase • 4-weeks double-blind induction phase • 2-week follow-up	• Intervention: esketamine 28 mg, 54 mg, or 84 mg intranasally twice per week (n = 72) • Comparator: matching intranasal placebo (n = 65)	N = 137 Mean age: 70 Current episode duration (years): 4.1 MADRS mean: 35 Past failures of ⩾3 ADs: 39%	MADRS change Clinical remission Clinical response
SUSTAIN-167 [ClinicalTrials.gov identifier: NCT02493868], 2015–2018	Flexible esketamine dose (56 mg or 84 mg)	Adult 18–64 Years MDD Response to esketamine MADRS ⩾28 at original screening IDS-C30 ⩾ 34	Efficacy focus Randomised withdrawal double-blinded, relapse prevention study	• 4–7 weeks screening/prospective observation phase for direct-entry participants • 4-week open-label induction phase for direct-entry participants • 12 weeks optimisation phase (open-label for direct-entry participants and double-blind for transferred-entry participants) • Maintenance phase (double-blind, variable duration) • 2-week follow-up phase	• Intervention: Induction: esketamine 56 mg or 84 mg intranasally twice per week for 4 weeks • Optimisation: intranasal esketamine 56 mg or 84 mg once every week for 4 weeks, then once every week or every other week • Maintenance: intranasal esketamine once every week or every other week (n = 152) • Comparator: matching intranasal placebo (n = 145)	N=705 Mean age: 48 Current episode duration: NR Past AD failures: NR Stable remitters, MADRS mean: 37.5 Stable responders, MADRS mean: 39.5	Time to relapse
SUSTAIN-268,69 [ClinicalTrials.gov identifier: NCT02497287], 2015–2017	For 18 to 64 years old: Flexible esketamine dose (56 mg or 84 mg) For ⩾65 years old: Flexible esketamine dose (28 mg, 56 mg or 84 mg)	18 Years and older Direct-entry, 18–64 years (n = 691) Transfer-entry, ⩾65 years (n = 111) MDD MADRS ⩾22	Long-term safety and efficacy focus Open-label, 52-week safety study	• 4-week screening phase • 4-week induction phase (open-label) • 48-week optimisation/ maintenance phase (open-label) • 4-week follow-up phase	• Intervention: Induction: esketamine 28 (for ⩾ 65 years), 56 mg or 84 mg intranasally twice per week • Optimisation and maintenance: intranasal esketamine once every week or every other week	N = 802 MADRS mean: 16.4 Stable remitters 58.2% Stable responders (76.5%) 55 (6.9%) patients experienced serious TEAEs	TEAEs, nasal tolerability and cognitive tests, MADRS total score, response rate and remission rate over time
SUSTAIN 370 [ClinicalTrials.gov identifier: NCT02782104], 2016–2022*	Flexible dosing	Adult 18 years and older MDD Patients entered from other esketamine studies	Long-term safety and tolerability focus Uncontrolled, open-label, long-term extension study	Up to 63 months • 4-week Induction phase (if applicable) • Variable, open-label optimisation/maintenance phase	• Intervention: Induction: esketamine 24 mg, 56 mg, or 84 mg intranasally twice per week for 4 weeks • Optimisation: esketamine intranasally once weekly (same dose as induction) for 4 weeks • Maintenance: esketamine intranasally once weekly or once every other week	N = 1,150	TEAE Safety outcome up to ~5 years
Aspire I71 [ClinicalTrials.gov identifier: NCT03039192), 2017–2018	Fixed esketamine dose 84 mg	Adults (18–64 years) MDD MADRS > 28	Efficacy and safety focus Randomised, double-blind placebo-controlled study	• Screening phase (48 h prior to day 1 of dose administration) • Double-blind treatment phase for 25 days • Follow-up phase for 65 days	• Intervention: esketamine 84 mg intranasally twice per week • Comparator: matching placebo given intranasally twice per week	N = 226	MADRS change CGI-SS-R change
Aspire II72 [ClinicalTrials.gov identifier: NCT03097133), 2017–2019*	Fixed esketamine dose 84 mg	Adults (18–64 years) MDD MADRS > 28	Efficacy and safety focus Randomised, double-blind placebo-controlled study	4-week	• Intervention: esketamine 84 mg intranasally twice per week • Comparator: matching placebo given intranasally twice per week	N = 230	MADRS change CGI-SS-R change
ESKETINTRD300673 [ClinicalTrials.gov identifier: NCT03434041), 2018–2021*	Flexible dosing esketamine 56 mg or 84 mg	Adults (18–64 years) MDD MADRS ⩾28	Efficacy focus Randomised, double-blind, active-controlled, multicentre study	4-week	• Intervention: esketamine 56 mg or 84 mg intranasally twice per week • Comparator: matching placebo given intranasally twice per week	N = 234	MADRS Onset of clinical response; response rate at week 4; remission rate at week 4; sustained remission at week 8
[ClinicalTrials.gov identifier: NCT02918318]74 2016–2020*	Fixed esketamine dose (28 mg, 56 mg and 84 mg)	Adult 20–64 years MDD MADRS ⩾28	Efficacy focus Randomised, double-blind placebo-controlled study	4-week	• Esketamine 28 mg versus 56 mg versus 84 mg versus placebo	N = 183	Change from baseline MADRS at 4 weeks

AD, antidepressant; CGI-SS-R, Clinical Global Impression - Severity of Suicidality – Revised; IDS-C30, Inventory of Depressive Symptoms-Clinician rated, 30-item total score; MADRS, Montgomery-Asberg depression rating scale; MDD, major depressive disorder; NR, not reported; RCT, randomised controlled trial; SDLP, standard deviation of lateral position; TEAEs, treatment emergent adverse events.

^*ongoing trial.