A Long-term Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression (SUSTAIN-3)
Open-label, long-term extension Phase III safety study (n≈1148) of esketamine nasal spray (flexible 28–84 mg dosing) in participants with treatment-resistant depression, induction twice weekly for 4 weeks then individualised maintenance.
This open-label extension evaluates the long-term safety and tolerability of esketamine nasal spray in participants with treatment-resistant depression who rolled over from prior phase trials.
Design includes a 4-week induction phase with twice-weekly flexible dosing (28, 56 or 84 mg depending on age and prior dosing), followed by an optimisation/maintenance phase with weekly or biweekly dosing determined by clinical judgement.
Primary assessments are safety and tolerability measures including adverse events, vital signs, ECG and laboratory monitoring; study enrolled participants from multinational sites.
Study Protocol
Preparation
sessions
Dosing
Locations
Unknown facility — Birmingham, Alabama, United States
Unknown facility — Little Rock, Arkansas, United States
Unknown facility — Garden Grove, California, United States
Unknown facility — Glendale, California, United States
Unknown facility — Oakland, California, United States
Unknown facility — Orange, California, United States
Unknown facility — San Diego, California, United States
Unknown facility — San Rafael, California, United States
Unknown facility — Hartford, Connecticut, United States
Unknown facility — New Haven, Connecticut, United States
Unknown facility — Gainesville, Florida, United States
Unknown facility — Miami, Florida, United States
Unknown facility — Orlando, Florida, United States
Unknown facility — Atlanta, Georgia, United States
Unknown facility — Chicago, Illinois, United States
Unknown facility — Hoffman Estates, Illinois, United States
Unknown facility — Joliet, Illinois, United States
Open-label induction (twice weekly for 4 weeks, flexible dosing) followed by optimisation/maintenance (weekly or every-other-week dosing based on clinical judgement).
Interventions
Esketamine28 - 84 mg
via Inhalation• twice per week (induction) then weekly or every other week (maintenance)
Flexible dosing: 28, 56 or 84 mg depending on age and prior study dosing; participants <65 typically 56 or 84 mg, ≥65 start at 28 mg. Induction = twice weekly for 4 weeks (≈8 sessions); maintenance individualised after Week 4.
Participants
Ages
18 – 99
Sexes
Male & Female
BMI
-
Psychosis History
-
Inclusion Criteria
Inclusion Criteria:
Based on the prior study the participant is entering 54135419TRD3008 from: a) From ESKETINTRD3001 (NCT02417064) or ESKETINTRD3002 (NCT02418585) study: Participant has completed the induction phase and the 2-weeks follow up phase visit; or Participants completed the induction phase and was a responder and study ESKETINTRD3003 is terminated.; b) From ESKETINTRD3003 (NCT02493868) study: (1) Participant relapsed during the maintenance phase; or (2) Participant was in the induction phase of the ESKETINTRD3003 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization or maintenance phases at the time the study was terminated; or (4) or (5) Participants was in the induction phase and after completion of induction phase was determined to not meet response criteria (1) Participant completed ESKETINTRD3004 study (optimization/maintenance phase); or (2) Participant was in the induction phase of the ESKETINTRD3004 study when the study was terminated and, after completion of the induction phase, was determined to be a responder; or (3) Participant was in the optimization/maintenance phase at the time the study was terminated; (4) Participant was in the induction phase and did not meet criteria for response may be eligible for to be rolled over into 54135419TRD3008. d) From ESKETINTRD3005 (NCT02422186) study: Participant was in the induction phase of the ESKETINTRD3005 study at the time enrollment into the ESKETINTRD3004 study was closed and, after completion of the induction phase, was determined to be a responder or did not meet the criteria for response. e) From ESKETINTRD3006 study (US Study sites only) (1) Participant completed the induction phase and was a responder.
Participant must be medically stable on the basis of physical examination, vital signs, pulse oximetry, and 12-lead Electrocardiogram (ECG) performed predose on the day of the first intranasal treatment session. If there are any abnormalities that are not specified in the inclusion and exclusion criteria, their clinical significance must be determined by the investigator and recorded in the participant's source documents and initialed by the investigator
Participant must be medically stable according to the investigator's judgment and knowledge of the subject's medical stability in the parent study. This determination must be documented.
A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [b-hCG]) predose on the day of the first intranasal treatment session
During the study (that is, from the first intranasal treatment session) and for a minimum of 1 spermatogenesis cycle (defined as approximately 90 days) after receiving the last dose of intranasal study medication, a man who is sexually active with a woman of childbearing potential must be practicing a highly effective method of contraception with his female partner c) must agree not to donate sperm.
Exclusion Criteria
Exclusion Criteria:
The evaluation of the benefit versus risk of continued esketamine nasal spray treatment is not favorable for the participant in the opinion of the investigator
Since the last study visit in the participant's prior study, participant has suicidal ideation with intent to act per the investigator's clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS) [corresponding to a response of "Yes" on Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) in the suicidal ideation module of the C-SSRS] or suicidal behavior per the investigator's clinical judgment or based on the C-SSRS (corresponding to any score higher than 0 in the suicidal behavior module of the C-SSRS)
Participant has positive test result(s) for drugs of abuse (including barbiturates, methadone, opiates, cocaine, phencyclidine, and amphetamine/methamphetamine) predose on the day of the first intranasal treatment session
Participant has any anatomical or medical condition that, per the investigator's clinical judgment based on assessment, may impede delivery or absorption of intranasal study drug
Participant has taken any prohibited therapies that would not permit administration of the first intranasal treatment session
Safety and Efficacy with Esketamine in Treatment-Resistant Depression: Long-Term Extension Study
In the phase 3 SUSTAIN-3 long-term extension (1,148 patients, 3,777 patient‑years), intermittent intranasal esketamine plus an oral antidepressant showed no new safety signals and an adverse event profile consistent with earlier studies. Depression severity improved during induction and was generally maintained during optimisation/maintenance, with remission in 35.6% at induction and about 48–50% at week 112/maintenance endpoint.
Published
Journal
International Journal of Neuropsychopharmacology
Authors
Zaki, N., Chen, N. )., Lane, R., Doherty, T., Drevets, W. C., Morrison, R. L., Sanacora, G., Wilkinson, S. T., Young, A. H., Chb, M. B., Lacerda, A. L. T., Paik, J. W., Popova, V., Fu, D. J.