Table 3.

Published trials on esketamine nasal spray.

Author, year, country	Design and sample size	Age and study duration, randomisation	Gender (% female)	Inclusion criteria	Phases	Intervention(s)	Comparator(s)	Key outcome measures/findings	Study type and comments
van de Loo et al.,75 2017, Netherlands	Phase I, double-blind, placebo-controlled, randomised, three-way crossover study, N = 24	21–60 years, 100-km on-road driving test 8 h after administration, double-dummy technique	50.0	Valid driving license for more than 3 years. Have driven at least 5000 km in the past year. Normal visual acuity. Body mass index 18–30 kg/m2 Bodyweight: ⩾45kg	• Subjects were trained once to obtain baseline performance on the driving test	Intranasal esketamine (84 mg)	Intranasal placebo	SDLP that is, the weaving of the car. No significant difference in driving performance was observed 8 h after administering intranasal esketamine (84 mg) or placebo.	Safety and efficacy of on-road driving performance
Morrison et al.,60 2018, Netherlands [ClinicalTrials.gov identifier: NCT02094378]	Phase I, randomised, double-blind, placebo-controlled, 2-way crossover study, N = 24	19–49 years June 2014 to August 2014 Computer-generated randomisation	50.0	Body mass index 18–30 kg/m2 Body weight: ⩾45kg	• Screening phase (up to 3 weeks), • Double-blind treatment phase (2 weeks) • Post treatment (follow-up) phase (1-week)	Treatment sequence 1 (n = 12): intranasal esketamine 84 mg Treatment sequence 2 (n = 12): intranasal placebo	Treatment sequence 1: intranasal placebo Treatment sequence 2: intranasal esketamine 84 mg	Primary: five tests of Cogstate® computerised test battery assessed at 1 h pre-dose and 40 min, 2, 4, and 6-hour post-dose. Secondary: Mental Effort Scale, KSS, and safety and tolerability (TEAEs, C-SSRS, MOAA/S, BPRS+, and CADSS)	Safety and efficacy of intranasal esketamine on cognitive functioning in healthy participants. Esketamine was associated with cognitive performance decline
Targum et al.,30 2019, United States. Results from SYNAPSE trial10	Phase II, double-blind, two-panel, placebo-controlled, delayed-start pilot study, N = 14	20–64 years 28 January 2014 to 25 September 2015 Blinded computer-generated randomisation algorithm selected seven patients at the three participating trial sites who were randomly assigned to placebo nasal spray and seven patients assigned to one of three different esketamine doses for the MADRS recordings.	NR	MDD TRD, defined as an inadequate response to at least two adequate AD treatments of which at least one documented failure. The AD that participants had been receiving immediately before study entry was continued unchanged	• Screening phase • Double-blind treatment phase (days 1–15) composed of two 1-week periods (Period 1, Period 2) • Optional open-label treatment (days 15–74) with tapering of intranasal dosing frequency • Post-treatment follow-up phase (8 weeks)	Esketamine 28, 56, or 84 mg (n = 7)	Placebo nasal spray (n = 7)	TEAEs Site-based MADRS CADSS Blinded remote ratings (without the likelihood of functional unblinding) were comparable with site-based ratings of the efficacy of esketamine nasal spray.	Safety and efficacy Comparison of site-based MADRS scores to remote, site-independent scores by blinded raters. Change in baseline MADRS score was significantly higher in all three esketamine-assigned treatment groups compared with the placebo group after one week of treatment and revealed a significant ascending dose-response relationship.
Popova et al.,76 2019. Six sites in the Czech Republic, nine in Germany, seven in Poland, seven in Spain, and 10 in the United States. Results from TRANSFORM-2 trial54–56	Phase III, randomised, double-blind, active-controlled, multicentre study, N = 223	18–64 years Between August 2015 and November 2017 Computer-generated randomisation	61.9	Single-episode (⩾2 years) or recurrent MDD without psychotic features. TRD, defined as a nonresponse to an adequate trial of at least two ADs in the current episode.	4-week screening and prospective observation phase 4-week treatment phase during which participants received a new oral AD combined with either esketamine nasal spray or placebo nasal spray. Post-treatment follow-up phase of up to 24 weeks.	Esketamine (56 mg or 84 mg) nasal spray administered twice weekly, each combined with a newly initiated open-label oral AD administered daily. (n = 114)	Placebo nasal spray administered twice weekly, each combined with a newly initiated open-label oral AD administered daily. (n = 109)	Change in MADRS score Clinical response (defined as a ⩾50% reduction in MADRS). Clinical response (MADRS score ⩽12). Changes in the Sheehan Disability Scale and PHQ-9 scores. Change in MADRS score with esketamine plus AD was significantly higher (difference of least square means −4.0, SE 1.69, 95% CI 27.31–20.64) than with AD plus placebo at day 28, and clinically meaningful improvement was observed in the esketamine plus AD arm at earlier time points.	Compared the efficacy and safety of switching patients with TRD from an ineffective AD to flexible dosed esketamine nasal spray plus a newly initiated AD versus placebo nasal spray plus a newly initiated AD. SSRI (escitalopram or sertraline) or an SNRI (duloxetine or venlafaxine extended-release) was provided as open-label AD.
Daly et al.,4 2018, 13 sites in the United States, one site in Belgium. Results from SYNAPSE trial10	Phase II, double-blind, doubly randomised, delayed-start, placebo-controlled study (14 sites), N = 67	20–64 years 28 January 2014, to 25 September 2015 Computer-generated randomisation	NR	Diagnosis of MDD TRD, defined as an inadequate response to 2 or more AD with at least one inadequate response in the current depression episode	Screening Double-blind treatment (days 1–15), composed of two 1-week periods. Optional open-label treatment (days 15–74). Post-treatment follow-up (8 weeks).	Period 1: Esketamine 28 mg ((n = 11) Esketamine 56 mg (n = 11) Esketamine 84 mg (n = 12) Period 2: Esketamine 28 mg (n = 8) Esketamine 56 mg (n = 9) Esketamine 84 mg (n = 5)	Period 1: Placebo (n = 33) Period 2: Placebo (n = 6)	Change in MADRS score from baseline to day 8 CADSS BPRS Change from baseline in the MADRS total score was significantly higher in all three esketamine groups than in the placebo group after 1-week of treatment; the ascending dose-response relationship also was significant.	Assessed the efficacy, safety, and dose-response of esketamine in patients with TRD. AD effect was rapid in onset and dose-related. The response appeared to persist for more than two months with a lower dosing frequency.
Canuso et al.,62 2018, United States. Results from SUI2001 trial62,63	Double-blind, randomised, placebo-controlled, multicentre study (2 sites), N = 66	19–64 years June 2014 to February 2016 Computer-generated randomisation	65.2	Diagnosis of MDD	24- to 48-hour screening 4 weeks of double-blind treatment (days 1–25) eight weeks of posttreatment follow-up (days 26–81).	Esketamine 84 mg administered twice weekly (n = 35)	Matching placebo administered twice weekly (n = 31)	Change in MADRS score from baseline to 4 h after the initial dose. CADSS Remission of depressive symptoms (MADRS score ⩽12). Significantly greater improvement in MADRS score was observed in the esketamine group compared with the placebo group at 4 h and at∼24 h but not at day 25. Significant improvement was also observed in the esketamine group on the MADRS suicidal thoughts item score at 4 h but not at 24 h or at day 25.	Compared the efficacy of standard-of-care treatment plus intranasal esketamine or placebo for rapid reduction of symptoms of MDD, including suicidality, among individuals at imminent suicide risk. Standard-of-care AD medication was initiated or optimised for all participants on day 1.
Daly et al.,31 2019, United States, Canada, and Europe. Results from SUSTAIN-1 trial67	Phase III, multicentre, double-blind, randomised withdrawal study in an outpatient setting (99 sites), N = 297	18–64 years 6 October 2015, to 15 February 2018	66.3	Recurrent or single episode (⩾2 years) MDD A total score of 34 or higher on the Clinician-Rated Inventory of Depressive Symptomatology A total MADRS score of 28 or higher, indicating moderate to severe depression	4-week screening and prospective observation phase (direct-entry patients only) 4-week open-label induction phase (direct-entry patients only); 12-week optimisation phase (open-label, direct entry patients or double-blind, transfer-entry patients) Maintenance phase (double-blind, randomised withdrawal, event-driven, variable duration) 2-week posttreatment follow-up phase	Stable remission: Esketamine nasal spray (56 or 84 mg) twice weekly plus an oral AD administered daily (n = 90) Stable response: Esketamine nasal spray (56 or 84 mg) twice weekly plus an oral AD (n = 62)	Stable remission: Matched placebo plus an oral AD administered daily (n = 86) Stable response: Matched placebo plus an oral AD (n = 59)	Time to relapse C-SSRS CADSS BPRS Adverse events Stable remission, defined as MADRS score ⩽12 for ⩾3 of the last 4 weeks Stable response defined as ⩾50% reduction in MADRS score from baseline in the last 2-weeks of the optimisation phase.	Efficacy of esketamine nasal spray plus an oral AD compared with an oral AD plus placebo nasal spray in delaying relapse of depressive symptoms. Continued treatment with esketamine and an AD demonstrated clinically meaningful and statistically significant superiority compared with AD and placebo in delaying relapse.
Fedgchin et al.,65 2019, Belgium, Brazil, Canada, Estonia, France, Hungary, Mexico, Slovakia, and the United States. Results from TRANSFORM-1 trial64,65	Phase III, randomised, double-blind, active-controlled, multicentre study, N = 342	18–64 years September 2015 and February 2018 Computer-generated randomisation	70.5	Recurrent MDD or single-episode MDD (⩾2 years). A total MADRS score of 34 or higher, indicating moderate to severe depression. One AD with non-response (⩽25% improvement) in the current depressive episode.	Three phases: 4-week screening/ prospective observation phase 4-week double-blind treatment phase Up to 24-week follow-up phase	Esketamine 56 mg/oral AD (n = 115) Esketamine 84 mg/oral AD (n = 114)	Oral AD/ placebo (n = 113)	Change in MADRS total score from baseline to day 28.	Efficacy of esketamine 84 mg/ AD compared with AD/ placebo did not achieve statistical significance and as a result, the study did not formally evaluate esketamine 56 mg/AD dosing. No new safety-related concerns were identified across the treatment groups.
Ochs-Ross et al.,77 2020, includes 13 countries. Results from TRANSFORM-3 trial66	Phase III, randomised, double-blind, active-controlled, multicentre study	⩾65 years (mean age 70.0 (4.52)), August 2015 and August 2017, Computer-generated randomisation	62.0	Patients ⩾65 years old and diagnosed (DSM-5) with recurrent moderate to severe MDD without psychotic features. TRD, defined as no clinically meaningful improvement following treatment with ⩾2 different ADs. IDS-C30 total score of ⩾31	Three phases: 4-week screening/ prospective observational phase 4-week double-blind induction phase 2-week post-treatment follow-up phase assessing safety and tolerability, including potential withdrawal symptoms	Flexibly-dosed esketamine nasal spray (28 mg, 56 mg, or 84 mg) dosed twice-weekly for 4 weeks and oral AD	Oral AD and placebo nasal spray	Changes in MADRS total score	Efficacy: Change in MADRS total score from baseline to day 28 did not achieve statistical significance Safety: TEAEs developed in 70.8% of intervention patients, and 60.0% of control group. Common TEAEs in the intervention group were dizziness (20.8%) and nausea (18.1%).
Wajs et al.,68 2020, includes 21 countries and 114 sites. Results from SUSTAIN-2 trial69	Phase III, open-label, multicentre study, N = 802	18 Years and older Direct-entry, 18–64 years Transfer-entry, ⩾65 years; mean age (SD), 52.2 (13.7) October 2015 and October 2017	62.6	DSM-5 diagnosis of recurrent MDD or single episode (⩾2 years) MDD without psychotic features, nonresponse to ⩾2 oral AD and MADRS total score ⩾22 at screening	Four phases: 4-week screening phase 4-week induction phase Up to 48 weeks optimisation/ maintenance phase, 4-week follow-up phase	Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new oral AD (administered twice a week in a 4-week induction phase and weekly or every-other-week for patients who were responders and entered a 48-week optimisation/ maintenance phase)	No comparator (single group assignment)	TEAEs C-SSRS assessment Changes in MADRS total score	Safety assessments of esketamine for TEAEs (common TEAEs were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%)) Efficacy: MADRS total score reduced during the induction phase, and this reduction continued during the maintenance phase.

AD, antidepressant; BPRS, Brief Psychiatric Rating Scale; CADSS, Clinician-Administered Dissociative States Scale; C-SSRS, Columbia Suicide Severity Rating Scale; DSM, Diagnostic and Statistical Manual of Mental Disorders; IDS-C30, Inventory of Depressive Symptoms-Clinician rated-30-item; KSS, Karolinska Sleepiness Scale; MADRS, Montgomery-Åsberg depression rating scale; MDD, major depressive disorder; MOAA/S, Modified Observer’s Assessment of Alertness/Sedation; NR, not reported; SDLP, standard deviation of lateral position; TEAEs, treatment-emergent adverse events; TRD, treatment-resistant depression.