A Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Participants With Treatment-resistant Depression (TRANSFORM-3)
Randomized, double-blind, active-controlled Phase III study (n=139) in elderly participants with TRD testing intranasal esketamine (flexible 28–84 mg, twice weekly for 4 weeks) plus a new oral antidepressant versus intranasal placebo plus a new oral antidepressant.
Detailed Description
This multicentre, randomized, double-blind, active-controlled trial evaluated efficacy, safety, and tolerability of flexible-dose intranasal esketamine administered twice weekly for 4 weeks in elderly participants (>=65 years) with treatment-resistant depression, each initiating a new oral antidepressant.
Participants started Day 1 with 28 mg intranasal esketamine; Day 4 dose was 28 or 56 mg and subsequent doses could be 28, 56 or 84 mg per investigator judgement. Oral antidepressant options (duloxetine, escitalopram, sertraline, venlafaxine XR) were started on Day 1 and continued through the double-blind induction phase.
Primary efficacy was change in MADRS total score at Week 4; safety monitoring included vital signs, labs, and protocol-specified cardiac and cognitive assessments.
Study Protocol
Preparation
Dosing
Integration
Study Arms & Interventions
Esketamine + AD
experimentalIntranasal esketamine administered twice weekly for 4 weeks (flexible dosing) plus newly initiated oral antidepressant.
Interventions
- Esketamine28 - 84 mgvia Intranasal• twice per week• 8 doses total
Day 1 = 28 mg; Day 4 = 28 or 56 mg; subsequent doses 28, 56 or 84 mg per investigator titration based on efficacy/tolerability.
- Compoundvia Oral• daily
New oral antidepressant initiated Day 1: duloxetine (min 60 mg/day), escitalopram (10 mg/day), sertraline (50–150 mg/day), or venlafaxine XR (75–150 mg/day).
Placebo + AD
active comparatorIntranasal placebo administered twice weekly for 4 weeks plus newly initiated oral antidepressant.
Interventions
- Placebovia Intranasal• twice per week• 8 doses total
Matching intranasal placebo using same titration schedule as esketamine.
- Compoundvia Oral• daily
New oral antidepressant initiated Day 1: duloxetine, escitalopram, sertraline, or venlafaxine XR (dosing per protocol).
Participants
Inclusion Criteria
- Inclusion Criteria:
- At the time of signing the informed consent form (ICF), participant must be a man or woman 65 years of age or older
- At the start of the Screening/prospective observational Phase, participant must meet DSM-5 diagnostic criteria for single-episode major depressive disorder (MDD) [if single-episode MDD, the duration must be >= 2 years] or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the MINI
- At the start of the Screening/Prospective observational Phase, participant must have an IDS-C30 total score >= 31
- At the start of the Screening/Prospective observational Phase, participants must have had nonresponse (<=25% improvement) to >=1 but <=8 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the MGH-ATRQ and documented records
- Participant must be taking one of the oral antidepressant treatments with nonresponse that is documented on the MGH-ATRQ at the start of the screening/prospective observational phase
- Current major depressive episode, symptom severity (Week 1 MADRS total score >=24) and treatment response must be confirmed by Site-Independent Qualification Assessment
- Participant must be medically stable based on screening clinical laboratory tests
Exclusion Criteria
- Exclusion Criteria:
- Prior nonresponse in current episode to esketamine or ketamine, or to all 4 oral antidepressant options available for induction (duloxetine, escitalopram, sertraline, venlafaxine XR), or an adequate course of ECT (>=7 unilateral treatments)
- Prior vagal nerve stimulation (VNS) or deep brain stimulation (DBS) in the current episode
- Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, bipolar or related disorders, current OCD episode, intellectual disability, borderline/antisocial/histrionic/narcissistic personality disorder
- Homicidal ideation/intent or suicidal ideation with some intent to act within 6 months prior to screening, or history of suicidal behaviour within the past year prior to screening
- Lifetime history of ketamine, PCP, LSD, or MDMA hallucinogen-related use disorder
- MMSE <25 (<22 for those with less than equivalent of high school education)
- Neurodegenerative disorder or evidence of mild cognitive impairment
- History of uncontrolled hypertension; significant pulmonary insufficiency; clinically significant ECG abnormalities; history of seizures; clinically significant cardiovascular disorders including cerebral and cardiac vascular disease
Study Details
- StatusCompleted
- PhasePhase III
- Typeinterventional
- DesignRandomizeddouble Blind
- Target Enrollment139 participants
- TimelineStart: 2015-08-20End: 2017-08-10
- Compounds
- Topic