A Randomized, Double-blind, Multicenter, Active-Controlled Study of Intranasal Esketamine Plus an Oral Antidepressant for Relapse Prevention in Treatment-resistant Depression
- UT Southwestern-Other
Madhukar Trivedi, M.D.
This is a randomized, double-blind, parallel-group, active-controlled, multicenter study to evaluate the efficacy, safety, and tolerability of intranasal esketamine plus an oral antidepressant compared with an oral antidepressant (active comparator) plus intranasal placebo in delaying relapse of depressive symptoms in adult men and women with TRD who are in stable remission after an induction and optimization course with intranasal esketamine plus an oral antidepressant.
approximately 211 subjects in stable remission (see Definition of Terms below) at the end of the optimization phase will be randomized in a 1:1 ratio to either continue intranasal esketamine (same dose)or be switched to intranasal placebo; all subjects will continue the same oral antidepressant at the same dose.
an independent Data Monitoring Committee (iDMC) will be commissioned for this study.
Subjects will enter the study either directly (referred to as direct-entry subjects) or after completing the double-blind induction phase of a short-term study (eSKeTinTRD3001 or eSKeTinTRD3002)(referred to as transferred-entry subjects).
The study has 5 phases (but uTSW will only be involved in the last 3, as this site will only be enrolling transfer entry subjects):
a 4-week screening/prospective observational phase, with an optional taper of up to 3 weeks for oral antidepressant medication(s) (direct-entry subjects only)
a 4-week open-label induction phase (direct-entry subjects only)
a 12-week optimization phase (open-label for direct-entry subjects and double-blind for transferredentry subjects)
a maintenance phase (variable duration)
a 2-week follow-up phase
The maximum duration of a subject's participation will be variable, depending on whether he or she enters the study directly or is transferred from one of the double-blind short-term studies, and whether he or she meets phase-specific criteria for (e.g., meets criteria for response at the end of the induction phase, is in stable remission/response at the end of the optimization phase, and when and if he or she relapses in the maintenance phase). Direct-entry subjects may participate in up to 5 phases and transferred-entry subjects may participate in up to 3 phases.
The study will be stopped once 84 relapses (in the subjects with stable remission) occur during the maintenance phase, or earlier based on the results of the interim analysis for efficacy or futility. at the time the study is stopped (for efficacy), subjects in the induction phase or optimization phase will be able to complete the respective phase. after completing the respective phase, these subjects and subjects who are in the maintenance phase at the time the study is terminated will proceed directly to the follow-up phase.
Only the following criteria apply at this site (enrolling transfer entry subjects only):
The following criterion applies to subjects who enter this study after participation in a short-term study, ESKETINTRD3002. Each potential subject must satisfy the following criterion to be enrolled in the study:
1. The subject must have completed the open-label induction phase in ESKETINTRD3002 and must hae demonstrated response at the end of the phase (greater than or equal to 50% reduction in the MADRS total score from baseline [Day 1 pre-randomization] at the end of the 4-week double-blind induction phase).
2. Each subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol:
-A woman must be either:
-Not of childbearing potential: Postmenopausal (>45 years of age with amenorrhea for at least 12 months or any age with amenorrhea for at least 6 months and a serum follicle stimulating hormone (FSH) level >40 IU/L or mIU/mL); permanently sterilized (eg, tubal occlusion, hysterectomy, bilateral salpingectomy); or otherwise be incapable of pregnancy.
-Of childbearing potential and practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies, eg, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); barrier methods (eg, condom with spermicidal foam/gel/film/cream/suppository or occlusive cap [diaphragm or cervical/vault caps] with spermicidal foam/gel/film/cream/suppository); male partner sterilization (the vasectomized partner should be the sole partner for that subject); or true abstinence (when this is in line with the preferred and usual lifestyle of the subject).
Note: If the childbearing potential changes after start of the study (eg, woman who is not heterosexually active becomes active), a woman must begin a highly effective method of birth control, as described above.
-Women must agree to continue using these methods of contraception throughout the study and for at least 6 weeks after the last dose of intranasal study drug.
-A woman of childbearing potential must have a negative serum (beta-human chorionic gonadotropin [beta-hCG]) at the start of the screening/prospective observational phase and a negative urine pregnancy test on Day 1 of the open-label induction phase prior to the first intranasal treatment session.
-A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control eg, either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository from Day 1 of the open-label induction phase (prior to the first intranasal treatment session) through 3 months after the last dose of intranasal study medication. Alternatively female partners of childbearing potential may be practicing a highly effective method of birth control, eg, established use of oral, injected, or implanted hormonal methods of contraception; placement of an intrauterine device (IUD) or intrauterine system (IUS); or male partner sterilization. Note: If the childbearing potential changes after start of the study, a female partner of a male study subject, must begin a highly effective method of birth control, as described above.
-Concomitant therapies must be recorded throughout the study, beginning with signing of the informed consent and continuing up to the last follow-up visit. Information on concomitant therapies should also be obtained beyond this time only in conjunction with new or worsening adverse events until resolution of the event. Subjects should continue to take their permitted concomitant medications (eg, antihypertensive medications) at their regular schedule. Of note, if oral antihypertensive medications are taken in the morning, the morning dose should be taken on intranasal dosing days.
-A positive urine drug screen for use of phencyclidine (PCP), 3, 4-methylenedioxymethamphetamine (MDMA), or cocaine from Day 1 of the induction phase through the final visit in the final treatment phase (open-label induction, optimization, or maintenance phase) will lead to discontinuation.
- Subjects must abstain from using alcohol within 24 hours before and after each intranasal treatment session. If a subject appears intoxicated, dosing should not occur (delayed per the permitted visit window).
- On all intranasal study drug dosing days, all subjects must remain at the clinical study site until study procedures have been completed and the subject is ready for discharge, and should be accompanied by a responsible adult when released from the clinical study site. Subjects must not drive a car or work with machines for 24 hours after study drug dosing.
- Subjects should not ingest grapefruit juice, Seville oranges, or quinine for 24 hours before an intranasal dose of study medication is to be administered.
- Electroconvulsive therapy, DBS, transcranial magnetic stimulation (TMS), and VNS are prohibited from study entry through the end of the last treatment phase (open-label induction, optimization, or maintenance phase).
- Subjects receiving psychotherapy can continue receiving psychotherapy provided this therapy has been stable in terms of frequency for the last 6 months prior to the screening/prospective observational phase and will remain unchanged until the end of the last treatment phase (open-label induction, optimization, or maintenance phase).
3. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and is willing to participate in the study.