Clinical Trial Results:
An Open-label Long-term Extension Safety Study of Esketamine Nasal Spray in Treatment-resistant Depression
Summary
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EudraCT number |
2015-003578-34 |
Trial protocol |
DE GB BE ES PL HU CZ SK LT AT FI BG IT |
Global end of trial date |
30 Dec 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
14 Jan 2024
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First version publication date |
14 Jan 2024
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Other versions |
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 |
54135419TRD3008
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02782104 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Janssen Research & Development, LLC
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Sponsor organisation address |
920 Route 202 South, Raritan, New Jersey, United States, 08869
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Public contact |
Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
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Scientific contact |
Clinical Registry Group, Janssen Research & Development, LLC, 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 |
30 Dec 2022
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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 |
30 Dec 2022
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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 main objective of this trial was to assess the long term safety and tolerability of esketamine nasal spray in subjects with treatment-resistant depression (TRD).
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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 Practice and applicable regulatory requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
21 Jun 2016
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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 |
Türkiye: 24
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Country: Number of subjects enrolled |
Taiwan: 22
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Country: Number of subjects enrolled |
United States: 328
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Country: Number of subjects enrolled |
South Africa: 48
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Country: Number of subjects enrolled |
Argentina: 71
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Country: Number of subjects enrolled |
Australia: 16
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Country: Number of subjects enrolled |
Austria: 4
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Country: Number of subjects enrolled |
Belgium: 18
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Country: Number of subjects enrolled |
Bulgaria: 50
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Country: Number of subjects enrolled |
Brazil: 100
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Country: Number of subjects enrolled |
Canada: 15
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Country: Number of subjects enrolled |
Czechia: 90
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Country: Number of subjects enrolled |
Germany: 13
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Country: Number of subjects enrolled |
Spain: 41
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Country: Number of subjects enrolled |
Estonia: 9
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Country: Number of subjects enrolled |
Finland: 1
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Country: Number of subjects enrolled |
France: 23
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Country: Number of subjects enrolled |
United Kingdom: 8
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Country: Number of subjects enrolled |
Hungary: 20
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Country: Number of subjects enrolled |
Italy: 8
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Country: Number of subjects enrolled |
Korea, Republic of: 7
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Country: Number of subjects enrolled |
Lithuania: 2
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Country: Number of subjects enrolled |
Mexico: 46
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Country: Number of subjects enrolled |
Malaysia: 9
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Country: Number of subjects enrolled |
Poland: 101
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Country: Number of subjects enrolled |
Slovakia: 9
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Country: Number of subjects enrolled |
Sweden: 65
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Worldwide total number of subjects |
1148
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EEA total number of subjects |
454
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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) |
1026
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From 65 to 84 years |
122
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||||
Pre-assignment
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Screening details |
A total of 1148 subjects were enrolled in the study out of which 458 subjects entered in the induction (IND) phase and 1110 subjects entered in the optimization/maintenance (OP/MA) phase. Of the 458 subjects who participated in the IND phase, 420 subjects continued to the OP/MA phase. | ||||||||||||||||||||||||||||||||
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 | ||||||||||||||||||||||||||||||||
Arms
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Arm title
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Esketamine Nasal Spray | ||||||||||||||||||||||||||||||||
Arm description |
Subjects who entered the induction phase (IND) from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams [mg] or 84 mg for subjects less than [<]65 years; 28 mg, 56mg or 84mg for subjects greater than or equal to [>=]65 years). Subjects who entered the optimization and maintenance (OP/MA) phase from the IND phase of study 54135419TRD3008, continued on the same dose of esketamine from the IND phase, weekly. Subjects who entered from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or 54135419TRD3006 were administered esketamine nasal spray, 56mg or 84mg, once weekly. Subjects who entered study ESKETINTRD3005 received esketamine nasal spray (28mg in Week 1; 28 or 56mg in Week 2; and 28, 56 or 84mg in Weeks 3 and 4) once weekly. | ||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Esketamine
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Investigational medicinal product code |
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Other name |
JNJ-54135419
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Pharmaceutical forms |
Nasal spray
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Routes of administration |
Nasal use
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Dosage and administration details |
Induction Phase: Esketamine was self-administered twice per week for 4 weeks as a flexible dose regimen (56 mg or 84 mg for subjects < 65 years; 28 mg, 56 mg or 84 mg for subjects >= 65 years). OP/MA Phase: Esketamine was self-administered weekly, every 2 weeks or every 4 weeks (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4).
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Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: Only reported subjects were included in IND phase. |
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Baseline characteristics reporting groups
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Reporting group title |
Esketamine Nasal Spray
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Reporting group description |
Subjects who entered the induction phase (IND) from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams [mg] or 84 mg for subjects less than [<]65 years; 28 mg, 56mg or 84mg for subjects greater than or equal to [>=]65 years). Subjects who entered the optimization and maintenance (OP/MA) phase from the IND phase of study 54135419TRD3008, continued on the same dose of esketamine from the IND phase, weekly. Subjects who entered from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or 54135419TRD3006 were administered esketamine nasal spray, 56mg or 84mg, once weekly. Subjects who entered study ESKETINTRD3005 received esketamine nasal spray (28mg in Week 1; 28 or 56mg in Week 2; and 28, 56 or 84mg in Weeks 3 and 4) once weekly. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Esketamine Nasal Spray
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Reporting group description |
Subjects who entered the induction phase (IND) from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams [mg] or 84 mg for subjects less than [<]65 years; 28 mg, 56mg or 84mg for subjects greater than or equal to [>=]65 years). Subjects who entered the optimization and maintenance (OP/MA) phase from the IND phase of study 54135419TRD3008, continued on the same dose of esketamine from the IND phase, weekly. Subjects who entered from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or 54135419TRD3006 were administered esketamine nasal spray, 56mg or 84mg, once weekly. Subjects who entered study ESKETINTRD3005 received esketamine nasal spray (28mg in Week 1; 28 or 56mg in Week 2; and 28, 56 or 84mg in Weeks 3 and 4) once weekly. | ||
Subject analysis set title |
Esketamine Nasal Spray (IND Phase)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who entered induction phase (IND) from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams [mg] or 84 mg for subjects less than [<] 65 years; 28 mg, 56 mg or 84 mg for subjects greater than or equal to [>=] 65 years).
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Subject analysis set title |
Esketamine Nasal Spray (OP/MA Phase)
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who entered the OP/MA phase from the IND phase of study 54135419TRD3008, continued on the same dose of esketamine from the IND phase, weekly. Subjects who entered from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Subjects who entered study ESKETINTRD3005 were received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimisation and maintenance phase (OP/MP). After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all subjects was adjusted based upon efficacy and tolerability.
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End point title |
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Detection Test (DET) Score [1] | ||||||||||||
End point description |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. The DET is a measure of psychomotor function and uses a well-validated simple reaction time. In this outcome measure, speed of performance of subjects (calculated as mean of the logarithmic base 10 transformed reaction times) for correct responses was reported. Total score ranged from 2 to 3.3 log 10 milliseconds (msec). Lower score indicated better performance. Higher change from baseline indicated better performance. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Identification Test (IDN) Score [2] | ||||||||||||
End point description |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. IDN test is a measure of visual attention (choice reaction time) and scored for speed of response (mean of the log10 transformed reaction times for correct responses). Total score ranged from 2 to 3.3 log 10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Card Learning Test (OCL) Score [3] | ||||||||||||
End point description |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. OCL test is a measure of visual episodic memory and visual recall test scored using arcsine transformation of the percentage of correct responses (CR). The range for OCL is 0 to 100 percent (%) accuracy; presented as an arcsin transformation, the range is 0 to 1.57. Higher score indicated better performance. Higher change from baseline indicated better performance. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Study Baseline in Computerized Cognitive Battery Domain Score: One Back Test (ONB) Score [4] | ||||||||||||
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). Total score ranges from 2 to 3.54 log10 msec. Lower score indicated better performance. Higher change from baseline indicated better performance. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Study Baseline in Computerized Cognitive Battery Domain Score: Groton Maze Learning Test (GMLT) Score [5] | ||||||||||||
End point description |
This battery is a series of computerized cognition tests (detection, identification, one card learning, one back and groton maze learning) designed to measure reaction time, visual learning and memory, and executive function/sequencing. GMLT measures executive function; maze/sequencing test, scored for total number of errors. Total score ranges from 0 to 999 number of errors. Lower score indicated better performance. Higher change from baseline indicated better performance. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Study Baseline in Hopkins Verbal Learning Test-Revised (HVLT-R) Score [6] | ||||||||||||||||||||||||
End point description |
The HVLT-R measures performance in verbal memory, learning, and long-term recall in which a list of words is read up to three times. Approximately 20-25 minutes later, a delayed recall trial and a recognition trial are completed. Delayed recall: free recall of any words remembered. The recognition trial: 24 words, including the 12 target words and 12 false-positives. When scoring the HVLT, the 3 learning trials are combined to calculate a total recall score (0-36); the delayed recall trial creates the delayed recall score (0-12); the total number of true-positive errors (0-12); and the range of recognition discrimination index is comprised by subtracting the total number of false positives from the total number of true positives. A higher score indicated higher cognition. All enrolled analysis set: who were eligible to enter this study and received at least 1 dose of intranasal study medication. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Percentage of Subjects Based on Columbia-Suicide Severity Rating Scale (C-SSRS) Score [7] | ||||||||||||||||||||||||||||||
End point description |
C-SSRS: interview-based instrument to systematically assess suicidal ideation (SI) and behavior, to assess whether subject experienced any of following: completed suicide, suicide attempt (response of "yes" on "actual attempt"), preparatory acts toward imminent suicidal behavior ("yes" on "preparatory acts or behavior", "aborted attempt" or "interrupted attempt"), suicidal ideation ("yes" on "wish to be dead", "non-specific active suicidal thoughts", "active SI with methods without intent to act or some intent to act, without or with specific plan and intent), any self-injurious behavior with no suicidal intent ("yes" on "has subject engaged in non-suicidal self-injurious behavior"). Here, percentage of subjects with >=1 positive behavior, subjects with >=1 positive ideations; no event were reported. Full analysis set: all subjects who received at least 1 dose of study medication in this study. Here, 'N' (number analysed): number of subjects analysed for this endpoint.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Number of Subjects with Treatment Emergent Adverse Events (TEAEs) [8] | |||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the intervention. Any AE occurring at or after the initial administration of study intervention up to end of study was considered as treatment-emergent. All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication.
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End point type |
Primary
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End point timeframe |
IND Phase: up to 4 weeks; OP/MA Phase: up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Heart Rate [9] | ||||||||||||
End point description |
Change from baseline (predose) in heart rate were reported. Full analysis set included subjects who received at least 1 dose of intranasal study medication in this study.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Systolic and Diastolic Blood Pressure [10] | ||||||||||||||||||
End point description |
Change from baseline in systolic and diastolic blood pressure were reported. Full analysis set included subjects who received at least 1 dose of intranasal study medication in this study.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Respiratory Rate [11] | ||||||||||||
End point description |
Change from baseline in respiratory rate were reported. Full analysis set included subjects who received at least 1 dose of intranasal study medication in this study.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Blood Oxygen Saturation [12] | ||||||||||||
End point description |
Change from baseline in blood oxygen saturation (predose) were reported. Full analysis set included subjects who received at least 1 dose of intranasal study medication in this study.
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End point type |
Primary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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Notes [12] - 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: Descriptive statistics was done, no inferential statistical analysis was performed. |
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Montgomery Asberg Depression Rating Scale (MADRS) Total Score | ||||||||||||
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), summed for a total possible score of 0 to 60. Higher scores indicate more severe condition. Negative change in score indicates improvement. Missing data was imputed using last observation carried forward (LOCF) method. Full analysis set included all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Subject-Reported Depressive Symptoms Using the Patient Health Questionnaire - 9 (PHQ-9) Total Score | ||||||||||||
End point description |
Change from baseline in PHQ-9 total score were reported. The PHQ-9 was a 9-item, patient-reported outcome measure to assess depressive symptoms. The scale scores each of the 9 symptom domains of the Diagnostic and Statistical Manual of Mental Disorders. 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). The subject's item responses were summed to provide a total score (range of 0 to 27) with higher scores indicating greater severity of depressive symptoms. Full analysis set included all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Clinical Global Impression-severity (CGI-S) Score | ||||||||||||
End point description |
The CGI-S provides an overall clinician-determined summary measure of the severity of the subject's illness that takes into account all available information, including 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 1 to 7. Considering total clinical experience, a subject is assessed on severity of mental illness at the time of rating according to: 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 subject. Negative change in score indicates improvement. Full analysis set: all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed): number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Sheehan Disability Scale (SDS) Total Score | ||||||||||||
End point description |
Change from baseline in SDS total score were reported. The SDS, a patient-reported outcome measure, was a 5 item questionnaire which had been widely used and accepted for assessment of functional and associated disability impairment. The first three items assessed 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 were summed to create a total score of 0-30 where a higher score indicated greater impairment. Full analysis set included all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Subject-Reported Health-related Quality of Life as Assessed by EuroQol-5 Dimension-5 Level (EQ-5D-5L) Valuation Index Score (VAS) | ||||||||||||
End point description |
Change from baseline in subject-reported health-related quality of life as assessed by EQ-5D-5L VAS was reported. The EQ-5D-5L is a standardized 2-part instrument for use as a measure of health outcome, primarily designed for self-completion by respondents. It essentially consists of the EQ-5D-5L descriptive system and the EQ-VAS. EQ-VAS self-rating records the respondent's own assessment of his/her overall health status at time of completion, on a scale of 0 (worst health you can imagine) to 100 (best health you can imagine). Positive change in score indicates improvement. Full analysis set: who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline as Assessed by EQ 5D-5L: Sum Score | ||||||||||||
End point description |
EQ-5D-5L consists of EQ-5D-5L descriptive system and EQ-VAS. EQ-5D-5L descriptive system comprises of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each has 5 levels of perceived problems (1-no problem, 2-slight problems, 3-moderate problems, 4-severe problems, 5-extreme problems). Sum score ([sum of the scores from the 5 dimensions – 5]*5) ranges from 0 to 100. Higher score indicates worst health state. Full analysis set: all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed): number of subjects analysed for this endpoint.
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End point type |
Secondary
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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End point title |
Change From Baseline in Subject- Reported Health Related Quality of Life Using the Quality of Life in Depression Scale (QLDS) | ||||||||||||
End point description |
Change from baseline in subject- reported health related quality of life using the QLDS. The QLDS is a disease-specific validated patient-reported outcome (PRO) measure which assesses the impact that depression has on a subject's quality of life. It is a 34-item self-rated questionnaire which consists of dichotomous response questions, with the response being either True/Not True. Each statement on the QLDS is given a score of "1" or "0". A score of "1" is indicative of adverse quality of life. All item scores are summed to give a total score that ranges from 0 (good quality of life) to 34 (very poor quality of life). A higher score indicates a more severe condition. Full analysis set included all subjects who received at least 1 dose of intranasal study medication in this study. Here, 'N' (number analysed) signifies number of subjects analysed for this endpoint .
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End point type |
Secondary
|
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End point timeframe |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
IND Phase: Baseline up to 4 weeks; OP/MA Phase: Baseline up to 78 months
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Adverse event reporting additional description |
All enrolled analysis set included all subjects who were eligible to enter this study and received at least 1 dose of intranasal study medication.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.1
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Reporting groups
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Reporting group title |
Esketamine Nasal Spray (IND Phase)
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Reporting group description |
Subjects who entered IND from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 received esketamine nasal spray twice per week on Day 1 for 4 weeks as a flexible dose regimen (56 milligrams [mg] or 84 mg for subjects less than [<] 65 years; 28 mg, 56 mg or 84 mg for subjects greater than or equal to [>=] 65 years). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Esketamine Nasal Spray (OP/MA Phase)
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Reporting group description |
Subjects who entered the OP/MA phase from the IND phase of study ESKETINTRD3008 continued on the same dose of esketamine from the IND phase weekly. Subjects who entered from studies ESKETINTRD3001, ESKETINTRD3002, ESKETINTRD3003, ESKETINTRD3004, or ESKETINTRD3006 were administered esketamine nasal spray, 56 mg or 84 mg, once weekly. Subjects who entered study ESKETINTRD3005 were received esketamine nasal spray (28 mg in Week 1; 28 or 56 mg in Week 2; and 28, 56 or 84 mg in Weeks 3 and 4) once weekly in optimization and maintenance (OP/MP) phase. After Week 4 (starting at Week 5), based on the Investigator's clinical judgment, the dose of esketamine for all subjects was adjusted based upon efficacy and tolerability. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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14 Dec 2016 |
The purpose of the amendment was to update the entry pathways from other Phase 3 esketamine protocols into this protocol and made other administrative changes to the protocol. |
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21 Aug 2017 |
The purpose of the amendment was to allow the investigator to adjust the frequency of intranasal dosing sessions to every 2 weeks instead of every 4 weeks, depending on the subject's depressive symptomatology, in order to allow greater flexibility with the aim of preventing depression relapse and to review machine read ECG tracing where initiation of treatment or safety follow-up was time-critical or if action needed to be taken for safety reasons; to clarify the rationale for removal of the Mini Mental State Examination to more clearly
outline the clinical rationale; to clarify that pulse oximetry was to be performed at all intranasal dosing sessions; corrected erroneous text relating to the MADRS assessment that was no longer relevant; and permitted benzodiazepine medication during the study. |
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24 Apr 2019 |
The purpose of the amendment was to extend the study to collect data characterizing the safety risks of long-term effects of esketamine on cognitive function and urinary symptoms (cystitis); and to update categories of treatment-emergent adverse events (TEAEs) of special interest.
Updated Attachment 1 of the protocol (Prohibited Concomitant Medications With
Esketamine Nasal Spray Study Medication) with new guidelines. |
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05 Oct 2020 |
The purpose of the amendment was following the conclusion post-marketing requirement of the Food and Drug Administration (FDA) for 3 years of US data at the end of 2020, the sponsor extended the study duration to allow for ongoing subjects to continue to receive esketamine treatment if clinically warranted and until it was available in the subject's respective country, or December 2022, whichever was earlier. The number/frequency of assessments was therefore reduced to mimic clinical practice and reduce burden on sites and subjects while ensuring adequate clinical oversight and monitoring of subject safety. |
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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. | |||
None reported |