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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)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02422186
First Posted: April 21, 2015
Last Update Posted: September 27, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Janssen Research & Development, LLC
  Purpose
The purpose of this study is to evaluate the efficacy and safety of switching elderly participants with treatment-resistant depression (TRD) from a prior antidepressant treatment (to which they have not responded) to either intranasal esketamine plus a new oral antidepressant or switching to a new oral antidepressant plus intranasal placebo.

Condition Intervention Phase
Depressive Disorder, Treatment-Resistant Drug: Esketamine Drug: Placebo Drug: Duloxetine (Oral Antidepressant) Drug: Escitalopram (Oral Antidepressant) Drug: Sertraline (Oral Antidepressant) Drug: Venlafaxine Extended Release (XR) (New Antidepressant) Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-blind, Multicenter, Active-controlled Study to Evaluate the Efficacy, Safety, and Tolerability of Intranasal Esketamine Plus an Oral Antidepressant in Elderly Subjects With Treatment-resistant Depression

Resource links provided by NLM:


Further study details as provided by Janssen Research & Development, LLC:

Primary Outcome Measures:
  • Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at end of Double-Blind Induction Phase [ Time Frame: Baseline and End of Double-blind Induction Phase (Week 4) ]
    The MADRS is a clinician-rated scale designed to measure depression severity and detects changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. The MADRS evaluates apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, inability to feel (interest level), pessimistic thoughts, and suicidal thoughts.


Secondary Outcome Measures:
  • Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score at end of Double-Blind Induction Phase [ Time Frame: Baseline and End of Double-blind Induction Phase (Week 4) ]
    The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7. Considering total clinical experience, a participant is assessed on severity of mental illness at the time of rating according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill participants. The CGI-S permits a global evaluation of the participant's condition at a given time.

  • 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 [ Time Frame: Baseline and End of Double-blind Induction Phase (Week 4) ]
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It consists of the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ-VAS). The EQ-5D-5L descriptive system comprises the following 5 dimensions: Mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each of the 5 dimensions is divided into 5 levels of perceived problems (Level 1 indicating no problem, Level 2 indicating slight problems, Level 3 indicating moderate problems, Level 4 indicating severe problems, and Level 5 indicating extreme problems). The participant selects an answer for each of the 5 dimensions considering the response that best matches his or her health "today." The descriptive system can be represented as a health state. The EQ-VAS self-rating records the respondent's own assessment of his or her overall health status at the time of completion, on a scale of 0 to 100.

  • Number of Participants with Adverse Events (AEs) and Serious AEs [ Time Frame: Screening up to end of Follow-up Phase (approximately up to 13 Weeks) ]
    An adverse event (AE) is any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (at risk of death at the time of the event); persistent or significant disability/incapacity (is a suspected transmission of any infectious agent via a medicinal product); congenital anomaly (is medically important based on medical and scientific judgment).

  • Percentage of participants with Response (>=50% reduction from baseline in MADRS total score) at the end of Double-Blind induction phase [ Time Frame: Baseline and End of Double-blind Induction Phase (Week 4) ]
    Percentage of participants with response which is defined as 50% reduction from baseline in MADRS total score at the end of Double-Blind induction phase will be reported.

  • Percentage of participants in remission (MADRS <=12) at the end of Double-Blind induction phase [ Time Frame: Baseline and End of Double-blind Induction Phase (Week 4) ]
    Percentage of participants in remission which is defined as MADRS total score <=12 at the end of Double-Blind induction phase.


Enrollment: 139
Actual Study Start Date: August 25, 2015
Study Completion Date: August 10, 2017
Primary Completion Date: August 10, 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Intranasal Esketamine plus Oral Antidepressant
Participants will self-administer esketamine intranasally twice per week for 4 weeks as a flexible dose regimen in the Double-Blind Induction Phase. All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine extended release [XR]) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Drug: Esketamine
All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability.
Drug: Duloxetine (Oral Antidepressant)
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).
Drug: Escitalopram (Oral Antidepressant)
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.
Drug: Sertraline (Oral Antidepressant)
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.
Drug: Venlafaxine Extended Release (XR) (New Antidepressant)
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.
Active Comparator: Placebo plus Oral Antidepressant
Participants will self-administer matching placebo, intranasally, twice per week for 4 weeks as a flexible dose regimen in Double-Blind Induction Phase using the same titration as Esketamine. In addition participants will simultaneously initiate a new, open-label oral antidepressant (Duloxetine, Escitalopram, Sertraline, or Venlafaxine XR) on Day 1 that will be continued for the duration of Double-Blind Induction Phase.
Drug: Placebo
Participants will self-administer matching placebo, intranasally, twice per week for 4-weeks as a flexible dose regimen in the Double-Blind Induction Phase.
Drug: Duloxetine (Oral Antidepressant)
Duloxetine could be selected as the oral antidepressant medication by the investigator based on review of Massachusetts General Hospital -Antidepressant Treatment Response Questionnaire (MGH-ATRQ) and relevant prior antidepressant medication information. The minimum therapeutic dose is 60 milligram per day (mg/day).
Drug: Escitalopram (Oral Antidepressant)
Escitalopram could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Escitalopram will be given at a dose of 10 mg/day throughout the Double-Blind Induction Phase. This dose (10 mg/day) is the also the minimum therapeutic dose.
Drug: Sertraline (Oral Antidepressant)
Sertraline could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Sertraline may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 50 mg/day.
Drug: Venlafaxine Extended Release (XR) (New Antidepressant)
Venlafaxine Extended Release could be selected as the oral antidepressant medication by the investigator based on review of MGH-ATRQ and relevant prior antidepressant medication information. Venlafaxine Extended Release may be titrated up to a dose of 150 mg/day, but if not tolerated the dose can be reduced to the minimum therapeutic dose of 75 mg/day.

Detailed Description:
This is a randomized, double-blind (neither the researchers nor the participants know what treatment the participant is receiving), active-controlled, multicenter study (more than 1 study site) in elderly participants with TRD to assess the efficacy, safety, and tolerability of flexible doses of intranasal esketamine plus a newly initiated oral antidepressant compared with a newly initiated oral antidepressant (active comparator) plus intranasal placebo. The study will consist of 3 phases: Screening/Prospective Observational Phase (4 to 7 weeks), Double-blind induction Phase (4 weeks), Follow up Phase (2 weeks). Participants who rollover into a long-term open-label safety study will not participate in the Follow-up Phase. At the start of the Screening/Prospective observational Phase, participant must have had documented nonresponse to at least one antidepressant treatment (based on Massachusetts General Hospital - Antidepressant Treatment Response Questionnaire [MGH-ATRQ] criteria) in the current episode of depression, and the participant is taking a different oral antidepressant treatment on the MGH-ATRQ for at least the previous 2 weeks at or above the minimum therapeutic dose. This antidepressant treatment will be discontinued prior to the double-blind induction Phase. Participants taking benzodiazepines (at dosages equal to or less than the equivalent of 6 mg/day of lorazepam) and/or permitted non-benzodiazepine sleep medications (example, zolpidem, zaleplon) during the screening/prospective observational phase can continue these medications. All participants will start with first dose (Day 1 as 28 milligram [mg]); second dose (Day 4) is either 28 or 56 mg. All subsequent doses may be 28, 56 or 84 mg. After the first dose, all dosing decisions are determined by the investigator based on efficacy and tolerability. In addition, each participant will be assigned to receive 1 of 4 oral antidepressant medications from 2 different classes of antidepressant treatments, a Selective Serotonin Reuptake Inhibitor (SSRI) (escitalopram or sertraline) or a Serotonin and Norepinephrine Reuptake Inhibitor (SNRI) [duloxetine or venlafaxine extended release (XR)], initiated on Day 1 and continued through the double-blind induction Phase. Participants will be primarily evaluated for improvement in depressive symptoms as assessed by change in Montgomery Asberg Depression Rating Scale (MADRS) total score at Week 4. Participants' safety will be monitored throughout the study.
  Eligibility

Information from the National Library of Medicine

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Ages Eligible for Study:   65 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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 (>=) 31
  • At the start of the Screening/Prospective observational Phase, participants must have had nonresponse (less than or equal to 25% improvement) to >=1 but less than or equal to (<=) 8 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 records by medical and pharmacy/prescription records, or a letter from the treating physician, for the current episode of depression
  • Participant must be taking one of the oral antidepressant treatment with nonresponse that is documented on the MGH-ATRQ at the start of the screening/prospective observational phase
  • The participant's current major depressive episode, depression symptom severity (Week 1 MADRS total score greater than or equal to 24 required) and treatment response to antidepressant treatments used in the current depressive episode (retrospectively assessed) must be confirmed for participation in a clinical study based on a Site-Independent Qualification Assessment
  • Participant must be medically stable on the basis of clinical laboratory tests performed in the screening/prospective observational phase

Exclusion Criteria:

  • The participant's depressive symptoms have previously demonstrated nonresponse to: Esketamine or ketamine in the current major depressive episode per clinical judgment, or all of the 4 oral antidepressant treatment options available for the double-blind induction Phase (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
  • Participants who has received vagal nerve stimulation (VNS) or who 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), obsessive compulsive disorder (current episode only), intellectual disability ( intellectual disability [DSM-5 diagnostic codes 317, 318.0, 318.1, 318.2, 315.8, and 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) and also includes history of suicidal behavior within the past year prior to start of the screening/prospective observational phase
  • Participant has a history (lifetime) of ketamine, phencyclidine (PCP), lysergic acid diethylamide (LSD), or 3, 4-methylenedioxy-methamphetamine (MDMA) hallucinogen-related use disorder\
  • Participant has a Mini Mental State Examination (MMSE) < 25 or <22 for those participants with less than an equivalent of high school education
  • Participant has neurodegenerative disorder (eg, Alzheimer's Disease, Vascular dementia, Parkinson's disease with clinical evidence of cognitive impairment) or evidence of mild cognitive impairment (MCI)
  • Participant has a history of uncontrolled hypertension; current or past history of significant pulmonary insufficiency/condition;clinically significant ECG abnormalities; current or past history of seizures; clinically significant cardiovascular disorders including cerebral and cardiac vascular disease
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02422186


  Show 68 Study Locations
Sponsors and Collaborators
Janssen Research & Development, LLC
Investigators
Study Director: Janssen Research & Development, LLC Clinical Trial Janssen Research & Development, LLC
  More Information

Responsible Party: Janssen Research & Development, LLC
ClinicalTrials.gov Identifier: NCT02422186     History of Changes
Other Study ID Numbers: CR107129
ESKETINTRD3005 ( Other Identifier: Janssen Research & Development, LLC )
2014-004588-19 ( EudraCT Number )
First Submitted: April 16, 2015
First Posted: April 21, 2015
Last Update Posted: September 27, 2017
Last Verified: September 2017

Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Janssen Research & Development, LLC:
Depressive Disorder, Treatment-Resistant
Esketamine
Oral Antidepressant
Elderly Participants

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mood Disorders
Mental Disorders
Antidepressive Agents
Citalopram
Duloxetine Hydrochloride
Sertraline
Venlafaxine Hydrochloride
Dexetimide
Psychotropic Drugs
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Parasympatholytics
Autonomic Agents
Peripheral Nervous System Agents
Muscarinic Antagonists
Cholinergic Antagonists
Cholinergic Agents
Serotonin and Noradrenaline Reuptake Inhibitors