A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression

• Register: EUCTR
• Last refreshed on: 11 December 2017
• Main ID: EUCTR2014-004585-22-ES
• Date of registration: 05/10/2015
• Prospective Registration: No
• Primary sponsor: Janssen-Cilag International NV
• Public title: A Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Participants With Treatment-resistant Depression
• Scientific title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Flexible Doses of Intranasal Esketamine Plus an Oral Antidepressant in Adult Subjects with Treatment-resistant Depression - TRANSFORM-2
• Date of first enrolment: 24/09/2015
• Target sample size: 196
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-004585-22
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: yes Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Brazil, Czech Republic, Germany, Poland, Spain, United States

Contacts

• Name: Global Clinical Operations Spain
• Affiliation: Janssen-Cilag, S.A.

• Name: Global Clinical Operations Spain
• Affiliation: Janssen-Cilag, S.A.

Key inclusion & exclusion criteria

Inclusion criteria:
At the time of signing the informed consent form (ICF), participant must be a man or woman 18 (or older if the minimum legal age of consent in the country in which the study is taking place is greater than [>]18) to 64 years of age, inclusive
- At the start of the screening/prospective observational phase, participant must meet the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for single-episode major depressive disorder (MDD) (if single-episode MDD, the duration must be greater than or equal to [>=] 2 years) or recurrent MDD, without psychotic features, based upon clinical assessment and confirmed by the Mini-International Neuropsychiatric Interview (MINI)
- At the start of the screening/prospective observational phase, participant must have an Inventory of Depressive Symptomatology-Clinician rated ( IDS-C30) total score of greater than or equal to (>=) 34
- At the start of the screening/prospective observational phase, participants must have had nonresponse to >=2 but less than or equal to (<=) 5 oral antidepressant treatments taken at adequate dosage and for adequate duration, as assessed using the Massachusetts General Hospital
- Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and documented by medical history and pharmacy/prescription records, for
the current episode of depression: Subject must be taking an oral antidepressant treatment with nonresponse at the start of the screening/prospective observational phase
- The participant?s current major depressive episode and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be deemed valid for participation in a clinical study based on a Site-Independent Qualification Assessment
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 196
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range 0

Exclusion criteria:
- Participants who have previously demonstrated nonresponse of depressive symptoms to esketamine or ketamine in the current major depressive episode, to all 4 of the oral antidepressant treatment options available for the double-blind induction phase (ie, duloxetine, escitalopram, sertraline, and venlafaxine extended release [XR]) in the current major depressive episode (based on MGH-ATRQ), or an adequate course of treatment with
electroconvulsive therapy (ECT) in the current major depressive episode, defined as at least 7 treatments with unilateral ECT
- Participant currently has an implant for vagal nerve stimulation (VNS) or has received deep brain stimulation (DBS) in the current episode of depressIon
- Participant has a current or prior DSM-5 diagnosis of a psychotic disorder or MDD with psychosis, bipolar or related disorders (confirmed by the
MINI), comorbid obsessive compulsive disorder, intellectual disability (only DSM-5 diagnostic code 319), borderline personality disorder, antisocial personality disorder, histrionic personality disorder, or narcissistic personality disorder
- Participant has homicidal ideation/intent, per the investigator?s clinical judgment, or has suicidal ideation with some intent to act within 6 months prior to the start of the screening/prospective observational phase, per the investigator?s clinical judgment or based on the Columbia Suicide Severity Rating Scale (C-SSRS)
- Participants with history of moderate or severe substance or alcohol use disorder according to DSM-5 criteria


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Treatment-resistant Major Depression
MedDRA version: 18.0 Level: PT Classification code 10057840 Term: Major depression System Organ Class: 10037175 - Psychiatric disorders

Therapeutic area: Psychiatry and Psychology [F] - Mental Disorders [F03]

Intervention(s)

Product Name: Esketamine - Nasal Solution - eq 140mg/mL esketamine base (eq 161.4 mg/mL esketamine HCl)
Pharmaceutical Form: Nasal spray, solution
INN or Proposed INN: ESKETAMINE Esketamine (for (S)-2-(o-chlorophenyl)-2-(methylamino)cyclohexanone)
Other descriptive name: ESKETAMINE HYDROCHLORIDE
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 161.4-
Pharmaceutical form of the placebo: Nasal spray
Route of administration of the placebo: Nasal use

Trade Name: Cymbalta 30 mg hard gastro-resistant capsules
Pharmaceutical Form: Gastro-resistant capsule, hard
INN or Proposed INN: DULOXETINE HYDROCHLORIDE
CAS Number: 136434-34-9
Other descriptive name: DULOXETINE HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 30-

Trade Name: CIPRALEX® 10 mg film-coated tablets
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: ESCITALOPRAM
Other descriptive name: ESCITALOPRAM
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 10-

Trade Name: ZOLOFT
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: SERTRALINE HYDROCHLORIDE
Other descriptive name: SERTRALINE HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 50-

Trade Name: Trevilor® retard 75 mg hard, prolonged-release capsules
Pharmaceutical Form: Prolonged-release capsule, hard
INN or Proposed INN: VENLAFAXINE HYDROCHLORIDE
Other descriptive name: VENLAFAXINE HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 75-

Primary Outcome(s)

Timepoint(s) of evaluation of this end point: Baseline and End of Doubleblind Induction Phase (Week 4)

Main Objective: The primary objective of this study is to evaluate the efficacy of switching adult subjects with TRD from a prior antidepressant treatment (to which they have not responded) to flexibly dosed intranasal esketamine (56 mg or 84 mg) plus a newly initiated oral antidepressant compared with switching to a newly initiated oral antidepressant (active comparator) plus intranasal placebo, in improving depressive symptoms, as assessed by the change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score from Day 1 (pre-randomization) to the end of the 4-week double-blind induction phase.

Primary end point(s): Change From Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score at End of Double-blind Induction Phase

Secondary Objective: The key secondary objectives are to assess the effect of intranasal esketamine plus a newly initiated oral antidepressant (AD) compared with a newly initiated oral AD plus intranasal placebo on the following parameters in adult subjects with TRD:
- Depressive symptoms (subject-reported)
- Onset of clinical response by Day 2
- Functioning and associated disability

Other Secondary Objectives
To assess the effect of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo on additional parameters in adult subjects with TRD (see protocol for details)

To investigate the safety and tolerability of intranasal esketamine plus a newly initiated oral AD compared with a newly initiated oral AD plus intranasal placebo in adult subjects with TRD (see protocol for details)

To assess the pharmacokinetics (PK) of intranasal esketamine in adult subjects with TRD receiving intranasal esketamine plus a newly-initiated oral AD

Secondary Outcome(s)

Secondary end point(s): 1) Change from Baseline in Subject-reported Depressive Symptoms Using the Patient Health Questionnaire-9 (PHQ-9) Total Score at End of Double-blind
Induction Phase
2) Change From Baseline in Subject-reported Functioning and Associated Disability as assessed by the Sheehan Disability Scale (SDS) Total Score at End of
Double-blind Induction Phase
3) Change From Baseline in Clinical Global Impression ? Severity (CGI-S) Score at End of Double-blind Induction Phase
4) Change From Baseline in Subject-reported Generalized Anxiety Disorder (GAD-7) Total Score at End of Double-blind Induction Phase
5) Change From Baseline in Subject-reported Health-related Quality of Life and Health Status as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) at
End of Double-blind Induction Phase
6) Number of Participants with Adverse Events (AEs) and Serious AEs
7) Onset of Clinical Response That Continued Through the End of the 4-Week Double-blind Induction Phase

Timepoint(s) of evaluation of this end point: 1) Baseline and End of Double-blind Induction Phase (Week 4)
2) Baseline and End of Double-blind Induction Phase (Week 4)
3) Baseline and End of Double-blind Induction Phase (Week 4)
4) Baseline and End of Double-blind Induction Phase (Week 4)
5) Baseline and End of Double-blind Induction Phase (Week 4)
6) Screening up to End of Follow-up Phase (approximately up to 32 - 35 weeks)
7) Day 2 through the End of Double-Blind Induction Phase (Week 4)

Secondary ID(s)

2014-004585-22-DE

ESKETINTRD3002

Source(s) of Monetary Support

Janssen Research & Development