We updated the design of this site on September 25th. Learn more.
Show more
ClinicalTrials.gov
ClinicalTrials.gov Menu

A Study to Evaluate the Safety and Efficacy of Intranasal Esketamine in Treatment-resistant Depression (SYNAPSE)

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT01998958
First Posted: December 3, 2013
Last Update Posted: June 8, 2016
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 assess the efficacy and dose response of intranasal esketamine (Panel A: 28 mg, 56 mg, and 84 mg and Panel B: 14 mg and 56 mg) compared with placebo in improving depressive symptoms in participants with treatment-resistant depression (TRD).

Condition Intervention Phase
Treatment Resistant Depressive Disorder Drug: Esketamine 14 mg Drug: Esketamine 28 mg Drug: Esketamine 56 mg Drug: Esketamine 84 mg Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression (SYNAPSE)

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

Primary Outcome Measures:
  • Change from baseline to the 1-week endpoint in Montgomery Asberg Depression Rating Scale (MADRS) total score [ Time Frame: (Day 1 predose, Day 8 predose) to (Day 8 predose, Day 15) ]
    The MADRS is a clinician-rated scale designed to measure depression severity and to detect 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.


Secondary Outcome Measures:
  • Percentage of participants with sustained response (>=50% reduction from baseline in MADRS total score) with onset by Day 2 through the end of the double-blind phase (Day 15) [ Time Frame: Day 2 to Day 15 ]
  • Percentage of responders (>=50% reduction from baseline in MADRS total score) at each visit [ Time Frame: Days 1, 2, 4, 8, 9, 11, 15, and in the optional open-label treatment period, if applicable on Days 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 18, 22, 25 (Panel B) and up to 8 weeks after the last dose ]
  • Percentage of participants in remission (MADRS <=10) at each visit [ Time Frame: Days 2 to 15 ]
  • Change from baseline in patient-reported depressive symptoms using the 16-item quick inventory of depressive symptoms - self report (QIDS-SR16) scale [ Time Frame: Days 1 to 15, and in the optional open-label treatment period, if applicable on Days 18 to 74 (Panel A), Days 18 to 25 (Panel B) and up to 2 weeks after the last dose ]
    The QIDS-SR16 is a patient reported measure designed to assess the severity of depressive symptoms. The QIDS-SR16 assesses all the criterion symptom domains designated by the DSM-IV to diagnose a major depressive episode. This assessment can be used to screen for depression, although it has been used predominantly as a measure of symptom severity

  • Change from baseline in severity of illness using the Clinical Global Impression Severity (CGI-S) scale [ Time Frame: Day 1 to Day 15, and in the optional open-label treatment period, if applicable on Days 18 to 74 (Panel A), Days 18 to 25 (Panel B) and up to 8 weeks after the last dose ]
    The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill participants". Higher scores indicate worsening.

  • Change from baseline in severity of illness using the patient global impression - severity (PGI-S) scale [ Time Frame: Days 1 to 15 and in the optional open-label treatment period, if applicable on Days 18 to 74 (Panel A), Days 18 to 25 (Panel B) and up to 2 weeks after the last dose ]
    The PGI-S is a 4-point scale that requires the participant to rate the severity of their illness at the time of assessment, relative to the participant's past experience. Considering their total experience, the patient assesses the severity of their depression illness at the time of rating as none, mild, moderate, or severe. Paper and pen format will be used for this study.

  • Change from baseline in anxiety symptoms, as measured by the generalized anxiety disorder 7-item (GAD-7) scale [ Time Frame: Days 1, 8, 15, and in the optional open-label treatment period, if applicable on Days 22, 32, 46 and 74 (Panel A) and Day 22 (Panel B) and up to 2 weeks after the last dose ]
    The GAD-7 is a 7-item self-report assessment of severity of anxiety. Each item is scored on a 4-point scale (0-3), with a total score range of 0-30. The standard recall period used is 2 weeks, but in the current study we plan to use a 7-day recall.

  • Change from baseline in local nasal tolerability scores obtained using a nasal tolerability questionnaire [ Time Frame: Days 1, 4, 8, 11, and in the optional open-label treatment period, if applicable on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
    Changes from baseline in nasal tolerability scores obtained from a nasal tolerability questionnaire will be assessed.

  • Change from baseline in local nasal tolerability ratings obtained from nasal examinations [ Time Frame: Days 1 to 74 (Panel A) and Days 1 to 25 (Panel B) ]
    Changes from baseline in local nasal tolerability will be measured by nasal examinations that will provide ratings (none, mild, moderate, or severe) that are based on a visual inspection of the nostrils, nasal mucosa, and throat for nasal erythema, rhinorrhea, rhinitis, capillary/blood vessel disruption and epistaxis.

  • Changes from baseline in heart rate, blood pressure, and blood oxygen saturation (SpO2) [ Time Frame: Day 1, 4, 8, 11, and in the optional open-label treatment period, if applicable on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
  • Effects on suicidal ideation/behavior will be measured using the Columbia Suicide Severity Rating Scale (C-SSRS) [ Time Frame: Days 1, 4, 8, 11, 15, and in the optional open-label treatment period, if applicable on Days 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) and up to 2 weeks after the last dose ]
  • Treatment-emergent sedation will be measured using the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) [ Time Frame: Every 5 minutes pre- and postdose up to 1 hour postdose on Days 1, 4, 8, 11 and in the optional open label treatment period, if applicable on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
  • The level of alertness will be measured using the Clinical Global Assessment of Alertness [ Time Frame: Days 1, 4, 8, and 11, and in the optional open-label treatment period, if applicable on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
  • Psychosis-like side effects will be assessed using a four-item positive symptom subscale of the Brief Psychiatric Rating Scale (BPRS+) [ Time Frame: Days 1, 4, 8, 11 and in the optional open-label treatment period, if applicable, on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
  • Effects on dissociative symptoms using the Clinician Administered Dissociative States Scale (CADSS) [ Time Frame: Days 1, 4, 8, 11 and in the optional open-label treatment period, if applicable, on Days 15, 18, 22, 25, 32, 39, 46, 60, 74 (Panel A) and Days 15, 18, 22, 25 (Panel B) ]
  • Potential withdrawal symptoms following cessation of intranasal esketamine treatment, as measured by the clinician-administered 20-item Physician Withdrawal Checklist (PWC-20) [ Time Frame: Conducted on Day 15 in the double-blind treatment period for subjects not entering open-label treatment or at the last visit of the open-label period for those participating in open label phase and up to 2 weeks after the last dose. ]
  • Potential treatment-emergent symptoms of cystitis using the Bladder Pain/ Interstitial Cystitis Symptom Score (BPIC-SS) [ Time Frame: Day 1, 15, 25, 46, 74 (Panel A only), and the 2nd follow up visit (performed 2 weeks after the last dose). ]
    The Bladder Pain/Interstitial Cystitis Symptom Score (BPIC-SS), a patient-reported assessment contains 8 questions. The range of scores for the scale is 0 to 38 (0 = no pain).

  • Changes from baseline in cognitive domain scores using the Cogstate computerized test battery [ Time Frame: Day 1,25,46,74, and at the 2nd follow up visit (performed 2 weeks after the last dose) (Panel A only). ]
    The Cogstate computerized test battery provides assessment of multiple cognitive domains Including attention, visual learning and memory, and executive function. Each test is scored on a scale as follows: Detection (lower score=better performance); Identification (lower score=better performance); One Card learning (higher score=better performance); One Back (higher score=better performance); Groton Maze Learning Test (lower score=better performance).

  • Changes from baseline in cognitive domain scores using the Hopkins Verbal Learning Test-Revised (HVLT-Revised) [ Time Frame: Day 1,25,46,74, and at the 2nd follow up visit (performed 2 weeks after the last dose). (Panel A only). ]
    The HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. Administration includes 3 learning trials, a 24-word recognition list including 12 target and 12 foil words, and a delayed recall (20 minute) trial. Scores for learning, short-term, and delayed recall are generated via the test software.


Enrollment: 108
Study Start Date: January 2014
Study Completion Date: September 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Esketamine 14 mg
Participants in Panel B will self-administer intranasal esketamine 14 milligram or placebo on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, and 25 during the optional open-label phase. During the optional open-label phase, participants will start with treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine can be adjusted if desired based on the Investigator's clinical judgment of efficacy and tolerability).
Drug: Esketamine 14 mg
1 to 6 sprays of esketamine 14 mg self-administered as an intranasal formulation for 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable during the optional open-label phase for up to 4 days
Drug: Esketamine 56 mg
1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Placebo
1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase
Experimental: Esketamine 28 mg
Participants in Panel A will self-administer intranasal esketamine 28 mg or placebo on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74 during the optional open-label phase. During the optional open-label phase, all participants will start treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine can be adjusted if desired based on the Investigator's clinical judgment of efficacy and tolerability).
Drug: Esketamine 28 mg
1 to 6 sprays of esketamine 28 mg self-administered as an intranasal formulation for 4 days (Days 1,4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Esketamine 56 mg
1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Placebo
1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase
Experimental: Esketamine 56 mg
Participants in Panel A and Panel B will self-administer intranasal esketamine 56 mg or placebo on Days 1, 4, 8, and 11 during the double-blind phase. During the optional open-label phase, participants in Panel A will self-administer intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74 and participants in Panel B will self-administer intranasal esketamine on Days 15, 18, 22, and 25. During the optional open-label phase, all participants will start treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine can be adjusted if desired based on the Investigator's clinical judgment of efficacy and tolerability).
Drug: Esketamine 56 mg
1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Placebo
1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase
Experimental: Esketamine 84 mg
Participants in Panel A will self-administer intranasal esketamine 84 mg or placebo on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74 during the optional open-label phase. During the optional open-label phase, all participants will start treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine can be adjusted if desired based on the Investigator's clinical judgment of efficacy and tolerability).
Drug: Esketamine 56 mg
1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Esketamine 84 mg
1 to 6 sprays of esketamine 84 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Placebo
1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase
Placebo Comparator: Placebo
Participants in Panel A and B will self-administer intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants will receive intranasal placebo on Days 8 and 11 or be re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.
Drug: Esketamine 14 mg
1 to 6 sprays of esketamine 14 mg self-administered as an intranasal formulation for 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable during the optional open-label phase for up to 4 days
Drug: Esketamine 28 mg
1 to 6 sprays of esketamine 28 mg self-administered as an intranasal formulation for 4 days (Days 1,4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Esketamine 56 mg
1 to 6 sprays of esketamine 56 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Esketamine 84 mg
1 to 6 sprays of esketamine 84 mg self-administered as an intranasal formulation for up to 4 days (Days 1, 4, 8, 11) during the double-blind phase and if applicable, during the optional open-label phase for up to 9 days
Drug: Placebo
1 to 6 sprays of placebo self-administered as an intranasal formulation for 2 days (Days 1 and 4) or depending on response on Day 8, for 4 days (Days 1,4, 8, 11) during the double-blind phase

Detailed Description:
This will be a 2-panel, randomized ( participants are assigned different treatments based on chance), double-blind (neither investigator nor participant knows which treatment the participant receives), placebo-controlled (placebo is an inactive substance that is compared with a drug to test whether the drug has a real effect in a clinical trial), multicenter study. Approximately 100 male and female adult participants diagnosed with TRD will participate in this study. For participants in both panels (Panel A and Panel B), there will be 4 study phases: a 4-week screening phase, a double-blind treatment phase (Day 1 to Day 15), an optional open-label treatment phase (Panel A: Day 15 to 74; Panel B: Day 15 to 25), and an 8-week post-treatment (follow-up) phase. Depending on the treatment Panel, patients will be assigned to intranasal placebo or intranasal esketamine 14 mg, 28 mg, 56 mg, or 84 mg. Safety assessments will be performed throughout the study. The maximum study duration for a participant will be 23 weeks for Panel A and 16 weeks for Panel B.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   20 Years to 64 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

--Participant must meet Diagnostic and Statistical Manual of Mental Disorders -Fourth Edition -Text Revised (DSM-IV-TR) diagnostic criteria for Major Depressive Disorder (MDD), without psychotic features, based upon clinical assessment, and confirmed by the Mini International Neuropsychiatric Interview (MINI)-Participant's major depressive episode and treatment response must be deemed "valid" by remote independent raters-Participant must have had an inadequate response to at least 2 antidepressants, at least one of which is in the current episode of depression; the antidepressant treatment response questionnaire (ATRQ) will be used to assess antidepressant treatment response during the current episode; prior medication history will be used to determine antidepressant treatment response in prior episode(s) -Have an Inventory of Depressive Symptoms-Clinician rated, 30-item (IDS-C30) total score >=34 at Screening and predose at Day 1

Exclusion Criteria:

-Participant has a current DSM-IV-TR diagnosis of bipolar and related disorders, intellectual disability, or cluster b personality disorder (e.g., borderline personality disorder, antisocial personality disorder, histrionic personality disorder, and narcissistic personality disorder) -Participant has a current or prior DSM-IV-TR diagnosis of a psychotic disorder, MDD with psychosis, post-traumatic stress disorder (PTSD), or obsessive compulsive disorder (OCD) -Anatomical or medical conditions that may impede delivery or absorption of study medication (e.g., undergone facial reconstruction, rhinoplasty, significant structural or functional abnormalities of the nose or upper airway; obstructions or mucosal lesions of the nostrils or nasal passages; undergone sinus surgery in the previous 2 years; signs and symptoms of rhinitis) -Has an abnormal or deviated nasal septum with any 1 or more of the following symptoms: blockage of 1 or both nostrils, nasal congestion (especially 1-sided), frequent nosebleeds, frequent sinus infections, and at times has facial pain, headaches, and postnasal drip -Has a history of substance abuse (drug or alcohol) or dependence (except nicotine or caffeine) within the previous 1 year of the screening visit -Participant has known allergies, hypersensitivity, intolerance, or contraindication to esketamine/ketamine or its excipients

  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): NCT01998958


Locations
United States, Alabama
Birmingham, Alabama, United States
United States, California
Garden Grove, California, United States
United States, Connecticut
Hartford, Connecticut, United States
United States, Florida
Jacksonville, Florida, United States
Tampa, Florida, United States
United States, Georgia
Atlanta, Georgia, United States
United States, Illinois
Chicago, Illinois, United States
Hoffman Estates, Illinois, United States
United States, Maryland
Rockville, Maryland, United States
United States, New York
Cedarhurst, New York, United States
New York, New York, United States
United States, Pennsylvania
Allentown, Pennsylvania, United States
Philadelphia, Pennsylvania, United States
United States, Tennessee
Memphis, Tennessee, United States
Belgium
Lede, Belgium
Japan
Akita, Japan
Hiroshima, Japan
Ichikawa, Japan
Kanzaki, Japan
Kashihara, Japan
Kitakyushu, Japan
Kodaira, Japan
Kumamoto, Japan
Nagano, Japan
Shibukawa, Japan
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: NCT01998958     History of Changes
Other Study ID Numbers: CR102968
2013-004005-11 ( EudraCT Number )
JNJ-54135419 ( Other Identifier: Janssen Research & Development, LLC )
ESKETINTRD2003 ( Other Identifier: Janssen Research & Development, LLC )
First Submitted: November 25, 2013
First Posted: December 3, 2013
Last Update Posted: June 8, 2016
Last Verified: June 2016

Keywords provided by Janssen Research & Development, LLC:
Treatment resistant depressive disorder
Intranasal esketamine
Efficacy
SYNAPSE
JNJ-54135419

Additional relevant MeSH terms:
Depression
Depressive Disorder
Depressive Disorder, Treatment-Resistant
Behavioral Symptoms
Mood Disorders
Mental Disorders