Clinical Trial Results:
An Open-label, Long-term, Safety and Efficacy Study of Intranasal Esketamine in Treatment-resistant Depression. Safety and Sustenance of Esketamine Treatment Response with Repeated Doses at Intervals Determined by Symptom Severity (SUSTAIN-2)
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Summary
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EudraCT number |
2014-004587-38 |
Trial protocol |
SE BE DE ES GB AT PL BG LT FI IT |
Global end of trial date |
28 Oct 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
10 Nov 2018
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First version publication date |
10 Nov 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
ESKETINTRD3004
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02497287 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Janssen-Cilag International NV
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Sponsor organisation address |
Turnhoutseweg 30, Beerse, Belgium, 2340
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Public contact |
Janssen-Cilag International NV, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Janssen-Cilag International NV, Clinical Registry Group, ClinicalTrialsEU@its.jnj.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
28 Oct 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
28 Oct 2017
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The primary objective of this study was to assess the long-term safety and tolerability of intranasal esketamine plus a newly initiated oral antidepressant in subjects with treatment resistant depression (TRD), with special attention to the following: potential effects on cognitive function; potential treatment-emergent symptoms of cystitis and/or lower urinary tract symptoms; potential withdrawal and/or rebound symptoms following cessation of intranasal esketamine treatment.
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Protection of trial subjects |
This study was conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki and that are consistent with good clinical practices and applicable regulatory
requirements. Screening safety evaluation included the following clinical laboratory tests: hematology, serum chemistry, urinalysis, lipid panel, serum and urine pregnancy testing (for women of childbearing potential only), urine drug screen, alcohol breath test, thyroid-stimulating hormone (TSH), free thyroxine (FT4), creatinine clearance, glycated hemoglobin (HbA1c) test, serum follicle stimulating hormone (FSH) level test. Safety assessments in the study included single, 12-lead electrocardiogram (ECG), vital signs, pulse oximetry, physical examination, height, body weight and neck circumference, nasal examinations, nasal symptom questionnaire, columbia suicide severity rating scale (C-SSRS), clinician administered dissociative states scale (CADSS), positive-symptom subscale of the brief psychiatric rating scale (BPRS+), modified observer's assessment of alertness/sedation (MOAA/S), clinical global assessment of discharge readiness (CGADR), physician withdrawal checklist, 20-item (PWC-20), bladder pain/interstitial cystitis symptom score (BPIC-SS), cognition testing.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
12 Oct 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Argentina: 106
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Country: Number of subjects enrolled |
Australia: 23
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Country: Number of subjects enrolled |
Austria: 16
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Country: Number of subjects enrolled |
Belgium: 5
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Country: Number of subjects enrolled |
Bulgaria: 94
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Country: Number of subjects enrolled |
Brazil: 52
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Spain: 42
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Country: Number of subjects enrolled |
Finland: 2
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Country: Number of subjects enrolled |
France: 4
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Country: Number of subjects enrolled |
United Kingdom: 12
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Country: Number of subjects enrolled |
Italy: 7
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Country: Number of subjects enrolled |
Korea, Republic of: 26
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Country: Number of subjects enrolled |
Mexico: 10
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Country: Number of subjects enrolled |
Malaysia: 19
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Country: Number of subjects enrolled |
Poland: 6
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Country: Number of subjects enrolled |
Sweden: 90
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Country: Number of subjects enrolled |
Turkey: 31
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Country: Number of subjects enrolled |
Taiwan: 33
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Country: Number of subjects enrolled |
United States: 147
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Country: Number of subjects enrolled |
South Africa: 64
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Worldwide total number of subjects |
802
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EEA total number of subjects |
291
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
624
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From 65 to 84 years |
176
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85 years and over |
2
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 802 subjects were enrolled in this study. Direct-entry subjects (691) and transferred-entry subjects (111) from study ESKETINTRD3005 were assigned to esketamine plus oral antidepressant. | ||||||||||||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||||||||||||||||||||||||
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Arms
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Arm title
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Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD) | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Esketamine Intranasal Solution
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Nasal spray, solution
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Routes of administration |
Intranasal use
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Dosage and administration details |
In the Induction phase, direct-entry subjects and non-responders from the TRD3005 study self-administered Esk twice per week for 4 weeks as a flexible dose regimen (56 or 84 mg for those less than [<]65 years; 28 mg, 56 mg or 84 mg for those greater than or equal to [>]=65 years old until Day 11 and 15, respectively, after which the dose remained to be stable for the remainder of the study. The transfer-entry responder subjects from TRD3005 joined the study in the OP/MA phase and received Esk at the starting dose of 28 mg which could be further up-titrated until week 8; from week 9, the dose remained stable until the end of the study. Subjects in OP/MA Phase received the weekly sessions of intranasal Esk for week 5 to 8 and received either weekly or every other week dosing depending on the MADRS score which was assessed monthly from week 9 to 52.
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Investigational medicinal product name |
Duloxetine
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Gastro-resistant capsule, hard
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Routes of administration |
Oral use
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Dosage and administration details |
Direct entry subjects who were < 65 years old, administered duloxetine at a dose of 60mg/day during of the study period. Subjects >=65 years old administered duloxetine at a dose of 30 mg/day with a maximum dose of 60mg/day.
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Investigational medicinal product name |
Escitalopram
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Direct entry subjects who were < 65 years old, administered Escitalopram at a dose of 10 mg/day during Week 1 of the Induction Phase, and from Week 2 to Week 52 of the study administered Escitalopram at a dose of 20 mg/day. Subjects >=65 years old administered Escitalopram at a dose of 10 mg/day during the entire Induction and Optimization/Maintenance phase.
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Investigational medicinal product name |
Sertraline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Film-coated tablet
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Routes of administration |
Oral use
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Dosage and administration details |
Direct entry subjects <65 years old received 50 mg during week 1, 100 mg during Week 2 and 150 mg during Week 3 and 4 of the Induction Phase and during Optimization/Maintenance phase. Transferred entry subjects received 150 mg dose during their entire participation in the study. The dose could be reduced due to tolerability.
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Investigational medicinal product name |
Venlafaxine XR Extended Release
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Prolonged-release capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Direct entry subjects who were < 65 years old received AD Venlafaxine XR at increasing doses during the Induction Phase (75 mg/day during Week 1, 150 mg/day during week 2, and 225 mg/day during week 3 and 4 of the Induction phase) and continued to administer 225 mg/day during the Optimization/Maintenance phase. Subjects who were >=65 years old received AD Venlafaxine XR (37.5 mg/day during Week 1, 75 mg/day during Week 2 and 150 mg/day during weeks 3 and 4) during open-label Induction Phase. All subjects continued to administer Venlafaxine XR at a dose of 225 mg/day during the OP/MA phase.
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Baseline characteristics reporting groups
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Reporting group title |
Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
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Reporting group description |
Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
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Reporting group description |
Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study. | ||
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End point title |
Percentage of Subjects With Treatment-Emergent Adverse Events (TEAEs) [1] | ||||||||
End point description |
An adverse event is any untoward medical occurrence in a clinical study which subject administered a medicinal (investigational or non-investigational) product and does not necessarily have a causal relationship with the treatment. A TEAE defined as an event that was new in onset or increased in severity following treatment initiation. The TEAEs for the induction (IND) phase were those events with an onset date/time on or after the start of study medication, which occurred on or before the end of the IND phase and for the optimization/maintenance (OP/MA) phase were those events with an onset date/time on or after the start of OP/MA study medication, which occurred on or before the end of the optimization/maintenance phase. All enrolled analysis set include all transferred-entry and direct-entry subjects who were not screen failures and received at least one dose of intranasal study medication or 1 dose of oral antidepressant.
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End point type |
Primary
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End point timeframe |
Screening up to Follow up period (Maximum 60 Weeks)
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Percentage of Subjects With Cystitis, Urinary Tract Infections, Urinary Tract Symptom, Renal and Urinary Disorders [2] | ||||||||||||||||
End point description |
Percentage of subjects with cystitis, urinary tract infections, urinary tract symptom, renal and urinary disorders was evaluated. Cystitis and urinary tract infections are selected MedDRA preferred terms, "urinary tract symptoms" refers to any preferred term (PT) in the group of selected PTs; and "renal and urinary disorders" refers to a MedDRA System Organ Class (SOC). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication.
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End point type |
Primary
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End point timeframe |
Screening to follow up phase (Maximum 60 Weeks)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||||||||||
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End point title |
Change From Baseline in Cognitive Test Battery: Detection Test (DET) Score [3] | ||||||||
End point description |
The DET is a measure of psychomotor function and uses a well-validated simple reaction time. Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of Optimization/Maintenance [OP/MA] period)
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| Notes [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Cognitive Test Battery: Identification Test (IDN) Score [4] | ||||||||
End point description |
IDN test is a measure of visual attention, uses a validated choice reaction time and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Cognitive Test Battery: One Card Learning Test (OCL) Score [5] | ||||||||
End point description |
OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses. Higher score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
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| Notes [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Cognitive Test Battery: One Back Test (ONB) Score [6] | ||||||||
End point description |
The ONB is a measure of working memory and scored for speed of correct response (mean of the log10-transformed reaction times for correct responses). Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
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| Notes [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Cognitive Test Battery: Groton Maze Learning Test (GMLT) Score [7] | ||||||||
End point description |
GMLT measures executive function; maze/sequencing test, scored for total number of errors. Lower score indicates better performance. Higher change from baseline indicates better performance. All enrolled analysis set: all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005and received at least 1 dose of oral AD medication. 'N' (number of subjects analysed); subjects evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Total Recall [8] | ||||||||
End point description |
HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), and a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, and recognition scores. HVLT-R is a well-validated and widely used measure of verbal episodic memory. HVLT-R Score (Total Recall) is used to measure the verbal learning. Higher score indicate better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
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| Notes [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Delayed Recall [9] | ||||||||
End point description |
HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. HVLT-R is a well-validated and widely used measure of verbal episodic memory. The test measure total number of words recalled after a 20 minute delay. Higher score indicate better performance. Higher change from baseline indicates better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
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End point type |
Primary
|
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End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
| Notes [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: True Positives [10] | ||||||||
End point description |
HVLT-R, a measure of verbal learning and memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (including 12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions and word lists aloud, and recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. The HVLT-R is a well-validated and widely used measure of verbal episodic memory. The test measures total number of true positives (words recognized) after a 20 minute delay. Higher score indicate better performance. Higher change from baseline is better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral AD medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
| Notes [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score: Recognition Discrimination Index [11] | ||||||||
End point description |
HVLT-R, a measure of verbal learning, memory, is a 12-item word list recall test. It includes 3 learning trials, a 24-word recognition list (12 target and 12 foil words), a delayed recall trial (20-minute). Test administrator read instructions, word lists aloud, recorded words recalled/ recognized by the subject. Scores included learning, delayed recall, recognition scores. HVLT-R is a well-validated and measures verbal episodic memory. Test measures total number of true positives (words recognized) minus total number of false positives after a 20 minute delay. Higher score indicates better performance. Higher change from baseline is better performance. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral AD medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Primary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
| Notes [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: This study was an open-label, single-arm study. There were no pre-planned inferential statistical analyses. |
|||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score During Induction (IND) Phase | ||||||||
End point description |
MADRS measures depression severity, detects changes due to AD treatment. It consists 10 items (evaluate apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts), scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), total possible score of 60. Mean change (standard deviation [SD]) in MADRS total score from baseline to endpoint was evaluated. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in open-label IND phase (for direct-entry and transferred-entry non-responder subjects). 'N' (number of subjects analysed); subjects evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in MADRS Total Score During Optimization/Maintenance (OP/MA) Phase | ||||||||
End point description |
MADRS measure depression severity, detects changes due to AD treatment. It evaluates 10 items: apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, suicidal thoughts, each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of the symptoms), a total possible score of 60. The mean change (SD) in MADRS total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Higher scores represent a more severe condition. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in Patient Health Questionnaire - 9 (PHQ-9) Total Score During IND Phase | ||||||||
End point description |
PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item was rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The mean change (SD) in PHQ-9 total score from baseline (IND) to the endpoint (4 weeks) was evaluated. A higher score indicates greater severity of depression. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in PHQ-9 Total Score During OP/MA Phase | ||||||||
End point description |
PHQ-9 is a 9-item, self-report scale assessing depressive symptoms. Each item is rated on a 4-point scale (0 = Not at all, 1 = Several Days, 2 = More than half the days, and 3 = Nearly every day), with a total score range of 0-27. The mean change (SD) in PHQ-9 total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. A higher score indicates greater severity of depression. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (OP/MA) analysis set include all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in Clinical Global Impression of Severity (CGI-S) Scale Score During IND Phase | ||||||||
End point description |
CGI-S measures severity of subject’s illness that include knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on subject’s ability to function. Scale ranges from 0 - 7, were 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 patients. Median change (range) in CGI-S score from baseline (IND) to endpoint (4 weeks) was evaluated. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in CGI-S Scale Score During OP/MA Phase | ||||||||
End point description |
The CGI-S measures the severity of the subject’s illness that include knowledge of the subject’s history, psychosocial circumstances, symptoms, behavior, and the impact of the symptoms on the subject’s ability to function. The CGI-S evaluates the severity of psychopathology on a scale of 0 to 7, where 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 patients. The median change (range) in CGI-S score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Negative change in score indicates improvement. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in Generalized Anxiety Disorder (GAD-7) Total Score During IND Phase | ||||||||
End point description |
GAD-7 is brief, validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield total score ranges from 0-21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of GAD-7 is categorized as: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Mean change (SD) in GAD-7 total score from baseline (IND) to endpoint (4 weeks) was evaluated. Missing data was imputed using LOCF method, last post baseline observation during the phase was carried forward as “End Point”. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed): subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline to Endpoint in GAD-7 Total Score During OP/MA Phase | ||||||||
End point description |
GAD-7 is brief and validated 7-item self-report assessment of overall anxiety. Subjects respond to each item using a 4 point scale with response categories: 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score ranges from 0-21, higher scores indicate more anxiety. Negative change in score indicates improvement. Severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14), Severe (15 -21). Mean change (SD) in GAD-7 total score from baseline (OP/MA) to endpoint (52 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||
End point title |
Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as European Quality of Life (EuroQol) Group, 5-Dimension, 5-Level (EQ 5D-5L) During IND Phase | ||||||||||||||
End point description |
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ visual analogue scale (EQ VAS), EQ-5D-5L descriptive system. It comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health), EQ-VAS score from 0 (worst health you can imagine) to 100 (best health you can imagine), Sum score from 0 - 100, Sum score=(sum of scores from 5 dimensions minus 5)*5”. Mean change (SD) in EQ-5D health status index score from baseline (IND) to endpoint (4 weeks) was evaluated. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in the open-label IND phase (direct-entry, transferred-entry non-responder subjects). 'n' signifies those subjects who were evaluable for each category.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||||||||
End point title |
Change From Baseline to Endpoint in Health-Related Quality of Life and Health Status as EQ 5D-5L During OP/MA Phase | ||||||||||||||
End point description |
EQ-5D-5L measures health outcome self-completed by respondents. It consists of EQ visual analogue scale (EQ VAS), EQ-5D-5L descriptive system. It comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort, anxiety/depression. Each has 5 levels (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Health Status Index range is -0.148 - 0.949, is anchored at 0 (dead) and 1 (full health), EQ-VAS score from 0 (worst health) to 100 (best health), Sum score from 0-100, Sum score=(sum of the scores from the 5 dimensions minus 5)*5”. Mean change (SD) in EQ-5D health status index score from baseline (OP/MA) to endpoint (52 weeks) was evaluated. Full (OP/MA) analysis set: all subjects who received at least 1 dose of intranasal study drug or 1 dose of oral AD in OP/MA phase. 'N' (number of subjects analysed) signifies: subjects who were evaluable for this endpoint, 'n' signifies those subjects who were evaluable for each category.
|
||||||||||||||
End point type |
Secondary
|
||||||||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||||||||
|
|||||||||||||||
| No statistical analyses for this end point | |||||||||||||||
|
|||||||||
End point title |
Change From Baseline in Sheehan Disability Scale (SDS) Total Score During IND Phase | ||||||||
End point description |
SDS was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, (3) family life/home responsibilities using a 0-10 rating scale. Score for the first three items are summed to create a total score of 0-30, higher score indicates greater impairment and a negative change in score indicates improvement. Mean change (SD) in SDS total score from baseline (IND) to the endpoint (4 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set: all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Change From Baseline in Functional Impairment and Associated Disability Using Sheehan Disability Scale Total Score During OP/MA Phase | ||||||||
End point description |
SDS was a subject-reported outcome measure and was a 5 item questionnaire used for assessment of functional impairment and associated disability. The first three items assess disruption of (1) work/school, (2) social life, and (3) family life/home responsibilities using a 0-10 rating scale. The score for the first three items are summed to create a total score of 0-30 where a higher score indicates greater impairment and a negative change in score indicates improvement. The mean change (SD) in SDS total score from baseline (OP/MA) to the endpoint (52 weeks) was evaluated. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (OP/MA) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the OP/MA phase. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline (OP/MA) up to the End-point (last post-baseline assessment value during 52 weeks of OP/MA period)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects With Response Rate Over Time Who Achieved Greater Than or Equal to (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score During IND Phase | ||||||||||||||||
End point description |
Response rate over time is defined as percentage of subjects with >= 50 % reduction from baseline (IND phase) in the MADRS total score. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. Full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 8, 15, 22 and End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Response Rate Over Time Who Achieved >= 50 % Reduction From Baseline in PHQ-9 Total Score During IND Phase | ||||||||||||
End point description |
Response rate over time is defined as percentage of subjects with >= 50 % reduction from baseline (IND phase) in PHQ-9 total score. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set include all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline up to the End-point (last post-baseline assessment value during 4 Week IND period)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||
End point title |
Percentage of Subjects With Remission Rate Over Time With MADRS Total Score Less Than or Equal to (<=) 12 During IND Phase | ||||||||||||||||
End point description |
Remission rate over time is defined as percentage of subjects with MADRS total score <= 12. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
|
||||||||||||||||
End point type |
Secondary
|
||||||||||||||||
End point timeframe |
Day 8, 15, 22 and End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||||||||||
|
|||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Remission Rate Over Time With PHQ-9 Total Score <= 4 During IND Phase | ||||||||||||
End point description |
Remission rate over time is defined as percentage of subjects with PHQ-9 total score less than or equals to 4. Missing data was imputed using LOCF method and the last post baseline observation during the phase was carried forward as the “End Point”. The full (IND) analysis set included all subjects who received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant in the open-label IND phase (for direct-entry and transferred-entry non-responder subjects). Here, 'n' signifies those subjects who were evaluable at specific time point for this endpoint.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Day 15 and End-point (last post-baseline assessment value during 4 weeks of IND period)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||
End point title |
Percentage of Subjects With an Increase Score From Predose at Any Time in Clinician-Administered Dissociative States Scale (CADSS) During IND Phase | ||||||||
End point description |
The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization, derealization, and amnesia. Subjects responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline of each dosing session (predose) , up to the last post-dose measurement (1.5 hours) from the start of Induction Phase to End of Induction phase (week 4)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||
End point title |
Percentage of Subjects With an Increase Score From Predose at Any Time in CADSS During OP/MA Phase | ||||||||
End point description |
The CADSS used to measure present-state dissociative symptoms, and to assess treatment-emergent dissociative symptoms. It comprises 23 subjective items divided into 3 components: depersonalization, derealization, and amnesia. Subjects responses are coded on a 5-point scale (0 = “Not at all”, 1 = “Mild”, 2 = “Moderate”, 3 = ‘Severe” and 4 = “Extreme”). All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication. Here, 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
|
||||||||
End point type |
Secondary
|
||||||||
End point timeframe |
Baseline of each dosing session (predose) , up to the last post-dose measurement (1.5 hours) from the start of Induction Phase to End of Optimization/Maintenance Phase (week 52)
|
||||||||
|
|||||||||
| No statistical analyses for this end point | |||||||||
|
|||||||||||||
End point title |
Percentage of Subjects With Treatment-Emergent Acute Hypertension (Systolic and Diastolic) During IND and OP/MA Phases | ||||||||||||
End point description |
Percentage of subjects with treatment-emergent acute hypertension (Systolic Blood Pressure >= 180 mm Hg or Diastolic Blood Pressure >= 110 mm Hg) during IND and OP/MA Phases was evaluated. All enrolled analysis set include all subjects enrolled into the study, including transferred-entry subjects from study ESKETINTRD3005 and received at least 1 dose of intranasal study medication or 1 dose of oral antidepressant medication.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Screening up to OP/MA phase (Week 52)
|
||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
Screening up to follow up phase (Week 60)
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Adverse event reporting additional description |
There were 2 deaths resulting from adverse events.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
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Reporting groups
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Reporting group title |
Intranasal Esketamine (Esk) Plus Oral Antidepressant (AD)
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Reporting group description |
Subjects enrolled directly or were non-responders in the double blind, placebo-controlled study in elderly (TRD3005) self-administered Esk in induction (IND) phase twice per week for 4 weeks as flexible dose regimen. Subjects who met the response criteria at the end of IND phase, entered Optimization/Maintenance (OP/MA) phase and received Esk nasal spray at the same dose as in the end of IND phase from week 5 to 52 in OP/MA phase. Subjects who responded in the TRD3005 study joined the OP/MA phase and received intranasal Esk at a dose of 28 mg, flexible dose until week 8. Direct entry subjects initiated new oral antidepressant (O.A) (duloxetine, escitalopram, sertraline, or venlafaxine extended release [XR]) on Day 1 of IND Phase and continued during IND and OP/MA phase. The dose of O.A was increased according to titration schedule provided in the protocol. Transfer entry subjects continued to administer the same O.A which was initiated during the TRD3005 study. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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11 Jun 2015 |
The overall reason for the amendment was to allow for the use of a 28 milligram (mg) dose throughout the study, based on pharmacokinetic data from study ESKETINTRD1012 in elderly subjects. |
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17 Feb 2016 |
The overall reason for this amendment was to update and/or clarify protocol content based on ongoing feedback received during the study initiation activities. In addition, key protocol entry criteria for direct entry subjects have been added for transferred entry subjects, in order to confirm that subject’s, who completed ESKETINTRD3005, continue to meet the criteria at entry to the ESKETINTRD3004 study. |
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06 Jun 2016 |
The overall reason for the amendment was to modify entry criteria with respect to PR interval based on Phase 1 and Phase 2 data, to add the information about the long-term safety study 54135419TRD3008; to implement changes and align language being applied across all Phase 3 studies in the esketamine development program; to correct errors and make minor clarifications in the text of the inclusion and exclusion criteria. |
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06 Jul 2016 |
The overall reason for the amendment was to remove the exclusion criteria for subjects aged ≥ 65 years with first degree AV block. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The treatment was open-label with no comparator group. Based on predefined criteria related to achieving the required number of exposures at 6 and 12 months, not all enrolled subjects completed the full planned duration of the study. | |||
