A Study to Evaluate the Efficacy, Safety, and Tolerability of Fixed Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression (TRANSFORM-1)
Randomized, double-blind, active-controlled Phase III study (n=346) comparing fixed-dose intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant versus intranasal placebo plus a newly initiated oral antidepressant in adults with treatment-resistant depression.
This multicenter, randomized, double-blind, active-controlled study enrolled adults with treatment-resistant major depressive disorder to assess efficacy and safety of fixed doses of intranasal esketamine (56 mg or 84 mg) administered twice weekly plus a newly initiated oral antidepressant versus matching intranasal placebo plus a newly initiated oral antidepressant.
The trial included a screening/prospective observational phase (4–7 weeks), a 4-week double-blind induction phase (twice-weekly dosing), and a 24-week follow-up; primary outcome was change in MADRS total score at Week 4. Safety monitoring included adverse events, vital signs, and assessments per protocol.
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 — Orange, California, United States
Unknown facility — San Diego, California, United States
Unknown facility — San Marcos, California, United States
Unknown facility — San Rafael, California, United States
Unknown facility — Bradenton, Florida, United States
Unknown facility — Miami, Florida, United States
Unknown facility — Orlando, Florida, United States
Unknown facility — Chicago, Illinois, United States
Unknown facility — Hoffman Estates, Illinois, United States
Unknown facility — Maywood, Illinois, United States
Unknown facility — Schaumburg, Illinois, United States
Unknown facility — Wichita, Kansas, United States
Unknown facility — Gaithersburg, Maryland, United States
Unknown facility — Boston, Massachusetts, United States
Intranasal esketamine 84 mg administered twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
Esketamine84 mg
via Other• twice per week• 8 doses total
Day 1 56 mg then 84 mg from Day 4 onwards per protocol titration.
Compound
• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Esketamine 56 mg
experimental
Intranasal esketamine 56 mg administered twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
Esketamine56 mg
via Other• twice per week• 8 doses total
Fixed 56 mg dosing twice weekly.
Compound
• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Placebo plus oral antidepressant
active comparator
Matching intranasal placebo twice weekly plus a newly initiated oral antidepressant during 4-week double-blind induction.
Interventions
Placebo
• twice per week• 8 doses total
Matching intranasal placebo.
Compound
• daily
Open-label oral antidepressant (duloxetine 60 mg/day; escitalopram up to 20 mg/day; sertraline up to 200 mg/day; venlafaxine XR up to 225 mg/day).
Participants
Ages
18 – 64
Sexes
Male & Female
BMI
-
Psychosis History
-
Inclusion Criteria
Inclusion Criteria:
At the time of signing the informed consent form (ICF), participant must be a man or woman 18 to 64 years of age, inclusive
At the start of the screening/prospective observational phase, participant must meet DSM-5 diagnostic criteria for single-episode MDD (if single-episode MDD, duration must be >= 2 years) or recurrent MDD, without psychotic features, confirmed by MINI
At the start of the screening/prospective observational phase, participant must have an IDS-C30 total score >= 34
At the start of the screening/prospective observational phase, participants must have had non-response (<=25% improvement) to >=1 and <=5 oral antidepressant treatments taken at adequate dosage and duration in the current episode, as assessed by MGH-ATRQ
Participant is taking a different oral antidepressant on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose
Current major depressive episode and Week 1 MADRS total score >=28 must be confirmed using a Site Independent Qualification Assessment
Exclusion Criteria
Exclusion Criteria:
Prior nonresponse of depressive symptoms to esketamine or ketamine in the current episode, to all 4 oral antidepressant options available for induction (duloxetine, escitalopram, sertraline, venlafaxine XR) in the current episode, or an adequate course of ECT (>=7 treatments) in the current episode
Participant has received VNS or DBS in the current episode of depression
Current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychotic features, bipolar or related disorders, current OCD, intellectual disability, autism spectrum disorder, borderline personality disorder, antisocial, histrionic, or narcissistic personality disorder
Participant has homicidal ideation/intent per investigator judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of screening/prospective observational phase (per investigator judgment or C-SSRS)
Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria
Unknown facility — Quincy, Massachusetts, United States
Unknown facility — Watertown, Massachusetts, United States
Unknown facility — Worcester, Massachusetts, United States
Unknown facility — Minneapolis, Minnesota, United States
Unknown facility — O'Fallon, Missouri, United States
Unknown facility — Saint Charles, Missouri, United States
Unknown facility — Omaha, Nebraska, United States
Unknown facility — New York, New York, United States
Unknown facility — Durham, North Carolina, United States
Unknown facility — Dayton, Ohio, United States
Unknown facility — Oklahoma City, Oklahoma, United States
Unknown facility — Media, Pennsylvania, United States
Unknown facility — Philadelphia, Pennsylvania, United States
Unknown facility — Lincoln, Rhode Island, United States
Unknown facility — Austin, Texas, United States
Unknown facility — Dallas, Texas, United States
Unknown facility — Houston, Texas, United States
Unknown facility — Woodstock, Vermont, United States
Unknown facility — Bothell, Washington, United States
Unknown facility — Middleton, Wisconsin, United States
Unknown facility — Aalst, Belgium
Unknown facility — Bruges, Belgium
Unknown facility — Brussels, Belgium
Unknown facility — Ghent, Belgium
Unknown facility — Hasselt, Belgium
Unknown facility — Heusden-Zolder, Belgium
Unknown facility — Liège, Belgium
Unknown facility — Spa, Belgium
Unknown facility — Yvoir, Belgium
Unknown facility — Belo Horizonte, Brazil
Unknown facility — Curitiba, Brazil
Unknown facility — Fortaleza, Brazil
Unknown facility — Passo Fundo, Brazil
Unknown facility — Porto Alegre, Brazil
Unknown facility — Rio de Janeiro, Brazil
Unknown facility — Santo André, Brazil
Unknown facility — Calgary, Alberta, Canada
Unknown facility — Vancouver, British Columbia, Canada
Unknown facility — Kingston, Ontario, Canada
Unknown facility — Ottawa, Ontario, Canada
Unknown facility — Toronto, Ontario, Canada
Unknown facility — Montreal, Quebec, Canada
Unknown facility — Pärnu, Estonia
Unknown facility — Tallinn, Estonia
Unknown facility — Tartu, Estonia
Unknown facility — Besançon, France
Unknown facility — Clermont-Ferrand, France
Unknown facility — Douai, France
Unknown facility — Issy-les-Moulineaux, France
Unknown facility — La Tronche, France
Unknown facility — Lille, France
Unknown facility — Limoges, France
Unknown facility — Montpellier, France
Unknown facility — Nantes, France
Unknown facility — Neuilly-sur-Marne, France
Unknown facility — Nîmes, France
Unknown facility — Paris, France
Unknown facility — Poitiers, France
Unknown facility — Toulon, France
Unknown facility — Tours, France
Unknown facility — Budapest, Hungary
Unknown facility — Vác, Hungary
Unknown facility — Guadalajara, Mexico
Unknown facility — León, Mexico
Unknown facility — Mazatlán, Mexico
Unknown facility — Mexico City, Mexico
Unknown facility — Monterrey, Mexico
Unknown facility — San Luis Potosí City, Mexico
Unknown facility — Bratislava, Slovakia
Unknown facility — Liptovský Mikuláš, Slovakia
Unknown facility — Rimavská Sobota, Slovakia
Unknown facility — Rožňava, Slovakia
Unknown facility — Svidník, Slovakia
Open AccessindividualPooled analysis
Efficacy and safety of esketamine nasal spray by sex in patients with treatment-resistant depression: findings from short-term randomized, controlled trials
Pooled analyses of three short-term randomised controlled trials found that esketamine nasal spray plus a newly initiated oral antidepressant produced greater reductions in MADRS total score than antidepressant plus placebo in both women and men with treatment‑resistant depression, with no significant sex effect or treatment-by-sex interaction. Overall safety was similar between sexes, although nausea, dissociation, dizziness and vertigo were reported more frequently in women.
Published
Journal
Archives of Women's Mental Health
Authors
Jones, R. R., Freeman, M. P., Kornstein, S. G., Cooper, K., Daly, E. J., Canuso, C. M., Nicholson, S.