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Clinical Trial Results:
A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression

Summary
EudraCT number	2013-004005-11
Trial protocol	BE
Global end of trial date	25 Sep 2015

Results information
Results version number	v1(current)
This version publication date	13 Aug 2016
First version publication date	13 Aug 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

ESKETINTRD2003

ISRCTN number

US NCT number

NCT01998958

WHO universal trial number (UTN)

Sponsor organisation name

Janssen-Cilag International NV

Sponsor organisation address

Turnhoutseweg 30, Beerse, Belgium, 2340

Public contact

Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com

Scientific contact

Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

25 Sep 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Sep 2015

Was the trial ended prematurely?

Main objective of the trial

The main objective of this study was to assess the efficacy and dose response of intranasal esketamine (Panel A: 28 mg, 56 mg, 84 mg; Panel B: 14 mg and 56 mg) compared with placebo in improving depressive symptoms in participants with treatment-resistant depression (TRD), as assessed by a change from baseline in the Montgomery-Asberg Depression Rating Scale (MADRS) total score for the combined periods in the double-blind treatment phase.

Protection of trial subjects

Safety evaluations included monitoring of adverse events (AEs), clinical laboratory tests (hematology, serum chemistry, and urinalysis), vital sign measurements, physical examination, height and body weight and electrocardiograms (ECG).

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Belgium: 11

Country: Number of subjects enrolled

Japan: 41

Country: Number of subjects enrolled

United States: 56

Worldwide total number of subjects

108

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

108

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Recruitment period: 28 January 2014 - 25 September 2015

Screening details

A total of 126 participants were screened for entry in Panel A, of these 67 participants were randomized and received treatment. A total of 54 participants were screened for entry in Panel B, of these 41 participants were randomized and treated with treatment.

Period 1 title

Double-Blind Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants in Panel A and B were self-administered intranasal placebo on Days 1 and 4 during the double-blind phase. Depending on response on Day 8, participants received intranasal placebo on Days 8 and 11 or were re-randomized to receive intranasal placebo or esketamine at a dose of 28 mg, 56 mg, or 84 mg (Panel A) or 14 mg or 56 mg (Panel B) on Day 8 and Day 11.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants self-administered with placebo as an intranasal formulation 1 spray into each nostril at t=0, 5, and 10 minutes on each dosing day.

Esketamine 56 milligrams (mg)/Esketamine 56 mg

Arm description

Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Arm type

Experimental

Investigational medicinal product name

Esketamine 56 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants self-administered 1 to 6 sprays of esketamine 56 mg as an intranasal formulation into each nostril on Days 1, 4, 8, and 11.

Esketamine 84 mg/Esketamine 84 mg

Arm description

Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Arm type

Experimental

Investigational medicinal product name

Esketamine 84 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of esketamine 84 mg as an intranasal formulation for up to 2 weeks (Days 1, 4, 8, 11).

Placebo/Placebo

Arm description

Participants in Panel A and B (who received placebo on Day 1 and 4 and responders [Quick Inventory of Depressive Symptomatology – 16-item Self Report {QIDS-SR16} total score less than 11]) were self-administered with Placebo on Day 8 and 11; non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to [>=] 11) on Day 8 were re-randomized to intranasal placebo or esketamine on Days 8 and 11 during the double-blind phase.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of placebo as an intranasal formulation for up to 2 weeks (Days 1, 4, 8, and 11).

Placebo/Esketamine 14 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Esketamine 14 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants self-administered with esketamine 14 mg as an intranasal formulation into each nostril on Days 8 and 11.

Placebo/Esketamine 28 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Esketamine 28 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of esketamine 28 mg as an intranasal formulation on Day 8, 11.

Placebo/Esketamine 56 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Esketamine 56 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of esketamine 56 mg as an intranasal formulation on Days 8, and 11.

Placebo/Esketamine 84 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

Esketamine 84 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of intranasal esketamine 84 mg on Days 8 and 11.

Esketamine 14 mg/Esketamine 14 mg

Arm description

Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Arm type

Experimental

Investigational medicinal product name

Esketamine 14 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11.

Esketamine 28 mg

Arm description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

Arm type

Experimental

Investigational medicinal product name

Esketamine 28 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered 1 to 6 sprays of esketamine 28 mg as an intranasal formulation into each nostril.

Esketamine 28 mg/ Esketamine 28 mg

Arm description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Arm type

Experimental

Investigational medicinal product name

Esketamine 28 mg

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Participants were self-administered with esketamine 28 mg as an intranasal formulation on Days 1, 4, 8, and 11.

Number of subjects in period 1	Placebo	Esketamine 56 milligrams (mg)/Esketamine 56 mg	Esketamine 84 mg/Esketamine 84 mg	Placebo/Placebo	Placebo/Esketamine 14 mg	Placebo/Esketamine 28 mg	Placebo/Esketamine 56 mg	Placebo/Esketamine 84 mg	Esketamine 14 mg/Esketamine 14 mg	Esketamine 28 mg	Esketamine 28 mg/ Esketamine 28 mg
Started	1	20	12	23	5	8	12	5	11	3	8
Completed	0	20	10	23	5	8	10	5	11	0	8
Not completed	1	0	2	0	0	0	2	0	0	3	0
Consent withdrawn by subject	-	-	1	-	-	-	1	-	-	1	-
Adverse event, non-fatal	-	-	1	-	-	-	1	-	-	1	-
Other	1	-	-	-	-	-	-	-	-	-	-
Lack of efficacy	-	-	-	-	-	-	-	-	-	1	-

Period 2 title

Open-label Phase

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Esketamine

Arm description

Participants were received intranasal esketamine with a starting dose of 56-mg on Day 15 and subsequent doses on Days 18, 22, 25, 32, 39, and 46 and on Days 18, 22, and 25 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability) in Panel A and Panel B respectively.

Arm type

Experimental

Investigational medicinal product name

Esketamine

Investigational medicinal product code

Other name

Pharmaceutical forms

Nasal spray

Routes of administration

Nasal use

Dosage and administration details

Number of subjects in period 2 ^[1]	Esketamine
Started	96
Completed	80
Not completed	16
Consent withdrawn by subject	5
Adverse event, non-fatal	1
Other	6
Lost to follow-up	1
Lack of efficacy	3

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 100 subjects were completed the double blind phase, However only 96 subjects were entered into open label treatment phase.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Esketamine 56 milligrams (mg)/Esketamine 56 mg

Reporting group description

Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Esketamine 84 mg/Esketamine 84 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Placebo/Placebo

Reporting group description

Reporting group title

Placebo/Esketamine 14 mg

Reporting group description

Reporting group title

Placebo/Esketamine 28 mg

Reporting group description

Reporting group title

Placebo/Esketamine 56 mg

Reporting group description

Reporting group title

Placebo/Esketamine 84 mg

Reporting group description

Reporting group title

Esketamine 14 mg/Esketamine 14 mg

Reporting group description

Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

Reporting group title

Esketamine 28 mg/ Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group values	Placebo	Esketamine 56 milligrams (mg)/Esketamine 56 mg	Esketamine 84 mg/Esketamine 84 mg	Placebo/Placebo	Placebo/Esketamine 14 mg	Placebo/Esketamine 28 mg	Placebo/Esketamine 56 mg	Placebo/Esketamine 84 mg	Esketamine 14 mg/Esketamine 14 mg	Esketamine 28 mg	Esketamine 28 mg/ Esketamine 28 mg	Total
Number of subjects	1	20	12	23	5	8	12	5	11	3	8	108
Title for AgeCategorical
Units: subjects
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	1	20	12	23	5	8	12	5	11	3	8	108
From 65 to 84 years	0	0	0	0	0	0	0	0	0	0	0	0
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0
Title for AgeContinuous
Units: years
arithmetic mean (standard deviation)	52 ± 0	44 ± 9.55	49.8 ± 9.29	45.1 ± 6.84	50.6 ± 9.37	42.1 ± 12.17	42.4 ± 9.25	45.4 ± 10.31	42.2 ± 9.43	48.7 ± 5.77	39.6 ± 10.81	-
Title for Gender
Units: subjects
Female	0	13	6	10	2	5	8	2	4	1	4	55
Male	1	7	6	13	3	3	4	3	7	2	4	53

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Esketamine 56 milligrams (mg)/Esketamine 56 mg

Reporting group description

Participants in Panel A and B were self-administered with intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Esketamine 84 mg/Esketamine 84 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Placebo/Placebo

Reporting group description

Reporting group title

Placebo/Esketamine 14 mg

Reporting group description

Reporting group title

Placebo/Esketamine 28 mg

Reporting group description

Reporting group title

Placebo/Esketamine 56 mg

Reporting group description

Reporting group title

Placebo/Esketamine 84 mg

Reporting group description

Reporting group title

Esketamine 14 mg/Esketamine 14 mg

Reporting group description

Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

Reporting group title

Esketamine 28 mg/ Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase.

Reporting group title

Esketamine

Reporting group description

Subject analysis set title

Panel A: Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects who received Placebo in Panel A.

Subject analysis set title

Panel A: Esketamine 28 mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

subjects who received at least one dose of Intranasal Esketamine 28 mg in Panel A.

Subject analysis set title

Panel A: Esketamine 56mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subject who received at least one dose of Intranasal Esketamine 56 mg in Panel A.

Subject analysis set title

Panel A: Esketamine 84mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects who received at least one dose of Intranasal Esketamine 84mg in Panel A.

Subject analysis set title

Panel B: Placebo

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects who received Placebo in Panel B were included.

Subject analysis set title

Panel B: Esketamine 14mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

subjects who received Intranasal Esketamine 14mg in Panel B were included.

Subject analysis set title

Panel B: Esketamine 56 mg

Subject analysis set type

Intention-to-treat

Subject analysis set description

Subjects who received Intranasal Esketamine 56 mg in Panel B were included.

Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

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End point title

Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

End point description

The MADRS is a clinician-rated scale designed to measure depression severity and to detect changes due to antidepressant treatment. The scale consists of 10 items, each of which is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score less than 11) to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.

End point type

Primary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: Units on a scale
least squares mean (standard error)
Double-blind(DB): Period 1 (n=33,11,11,12,21,11,9)	-4.9 ± 1.74	-9.8 ± 2.72	-12.4 ± 2.66	-15.3 ± 2.56	-6.6 ± 1.53	-4.8 ± 2.13	-10.3 ± 2.36
DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)	-4.5 ± 2.92	-7.6 ± 2.49	-8.9 ± 2.51	-11.4 ± 2.68	-0.7 ± 3.32	-6.6 ± 4.02	-1.2 ± 6.04

Statistical analyses: Panel A: 1

Comparison groups

Panel A: Esketamine 28 mg v Panel A: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.021

Method

ANCOVA

Parameter type

Mean Difference

Point estimate

-4.2

Confidence interval

level

90%

sides

2-sided

lower limit

-7.67

upper limit

-0.79

Variability estimate

Standard error of the mean

Dispersion value

2.09

Statistical analyses: Panel A: 2

Comparison groups

Panel A: Placebo v Panel A: Esketamine 56mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001

Method

ANCOVA

Parameter type

Mean Difference

Point estimate

-6.3

Confidence interval

level

90%

sides

2-sided

lower limit

-9.71

upper limit

-2.88

Variability estimate

Standard error of the mean

Dispersion value

2.07

Statistical analyses: Panel A: 3

Comparison groups

Panel A: Placebo v Panel A: Esketamine 84mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Parameter type

Mean Difference

Point estimate

-9

Confidence interval

level

90%

sides

2-sided

lower limit

-12.53

upper limit

-5.52

Variability estimate

Standard error of the mean

Dispersion value

2.13

Statistical analyses: Panel B: 1

Comparison groups

Panel B: Placebo v Panel B: Esketamine 14mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Consistency

Point estimate

-10.5

Confidence interval

level

90%

sides

2-sided

lower limit

-29.27

upper limit

8.23

Variability estimate

Standard error of the mean

Dispersion value

11.72

Statistical analyses: Panel B: 2

Comparison groups

Panel B: Esketamine 56 mg v Panel B: Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Consistency

Point estimate

1.8

Confidence interval

level

90%

sides

2-sided

lower limit

-21.42

upper limit

24.94

Variability estimate

Standard error of the mean

Dispersion value

14.49

Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

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End point title

Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

End point description

Sustained response was defined as at least 50% improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.

End point type

Secondary

End point timeframe

Day 2 to Day 15

End point values	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	8	11	12	11	9
Units: participants	1	1	3	2	2

No statistical analyses for this end point

Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

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End point title

Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

End point description

A subject was defined as a responder at a given timepoint if the percentage improvement from baseline (ie, reduction from baseline) in the subject’s MADRS total score was greater than or equal to (> =) 50 %. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: Participants
number (not applicable)
Period 1 Day 1 DB: 2 h (n=33,11,11,12,21,11,9)	6	6	4	7	7	4	4
Period 1 Day 2 DB (n=33,11,11,12,21,11,9)	1	4	3	5	6	4	4
Period 1 Day 8 DB (n=33,11,11,12,21,11,9)	2	1	2	5	5	2	2
Period 2 Day 1 DB: 2 h (n=6,8,9,5,5,5,3)	1	1	2	2	0	3	0
Period 2 Day 2 DB (n=6,8,9,5,5,5,3)	0	0	1	2	0	4	0
Period 2 Day 8 DB (n=6,8,9,5,5,5,3)	0	1	0	1	0	0	1

No statistical analyses for this end point

Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

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End point title

Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

End point description

A subject was defined as a remitter at a given timepoint if the subject’s MADRS total score was less than or equal to 10. Here 'n' signifies the number of participants evaluated at this time point. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: participants
number (not applicable)
Period 1 Day 1 DB: 2 h (n=33,11,11,12,21,11,9)	1	3	2	2	4	4	3
Period 1 Day 2 DB (n=33,11,11,12,21,11,9)	0	4	2	3	4	3	3
Period 1 Day 8 DB (n=33,11,11,12,21,11,9)	1	1	1	3	3	2	2
Period 2 Day 1 DB: 2 h (n=6,8,9,5,5,5,3)	1	1	0	2	0	3	0
Period 2 Day 2 DB (n=6,8,9,5,5,5,3)	0	0	0	1	0	4	0
Period 2 Day 8 DB (n=6,8,9,5,5,5,3)	0	1	0	1	0	0	0

No statistical analyses for this end point

Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

Top of page

End point title

Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

End point description

The QIDS-SR16 is a patient reported measure designed to assess the severity of depressive symptoms. The QIDS-SR16 assesses all the criterion symptom domains designated by the DSM-IV to diagnose a major depressive episode. This assessment can be used to screen for depression, although it has been used predominantly as a measure of symptom severity. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: participants
least squares mean (standard error)
DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)	-1.8 ± 0.93	-4 ± 1.43	-4.4 ± 1.43	-4.2 ± 1.39	-1.1 ± 0.78	-0.6 ± 1.1	-3 ± 1.2
DB: Period 2 (n=6, 8, 9, 5, 5, 5, 3)	-2 ± 1.5	-3.1 ± 1.35	-2 ± 1.41	-3.3 ± 1.48	-2.1 ± 1.78	-5.7 ± 1.78	-1.5 ± 2.31

Statistical analyses_Panel A_1

Comparison groups

Panel A: Placebo v Panel A: Esketamine 28 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.069 ^[1]

Method

ANCOVA

Confidence interval

Notes
[1] - One sided P-value

Statistical analyses_Panel A_3

Comparison groups

Panel A: Placebo v Panel A: Esketamine 84mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.046 ^[2]

Method

ANCOVA

Confidence interval

Notes
[2] - One sided P-value

Statistical analyses_Panel A_2

Comparison groups

Panel A: Placebo v Panel A: Esketamine 56mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.096 ^[3]

Method

ANCOVA

Confidence interval

Notes
[3] - One sided P-value

Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

Top of page

End point title

Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

End point description

The CGI-S rating scale is a 7-point global assessment that measures the clinician's impression of the severity of illness exhibited by a participant. A rating of 1 is equivalent to "Normal, not at all ill" and a rating of 7 is equivalent to "Among the most extremely ill participants". Higher scores indicate worsening. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: participants
median (full range (min-max))
DB: Period 1 (n=33,11,11,12,21,11,9)	5 (1 to 6)	4 (3 to 5)	4 (1 to 5)	4 (1 to 6)	4 (1 to 6)	4 (2 to 6)	3 (3 to 6)
DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)	5 (4 to 5)	4 (3 to 5)	5 (4 to 6)	4 (3 to 5)	4 (3 to 6)	3 (3 to 4)	4 (4 to 5)

Statistical analyses_Panel A_1

Comparison groups

Panel A: Placebo v Panel A: Esketamine 28 mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Confidence interval

Statistical analyses_Panel A_2

Comparison groups

Panel A: Placebo v Panel A: Esketamine 56mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.001

Method

ANCOVA

Confidence interval

Statistical analyses_Panel A_3

Comparison groups

Panel A: Placebo v Panel A: Esketamine 84mg

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.004

Method

ANCOVA

Confidence interval

Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

Top of page

End point title

Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

End point description

The PGI-S is a 4-point scale that requires the participant to rate the severity of their illness at the time of assessment, relative to the participant's past experience. Considering their total experience, the patient assesses the severity of their depression illness at the time of rating as none, mild, moderate, or severe. Paper and pen format will be used for this study. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: participants
median (full range (min-max))
DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)	3 (2 to 4)	3 (1 to 4)	3 (1 to 3)	3 (1 to 4)	3 (2 to 4)	3 (1 to 3)	3 (2 to 3)
DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)	3 (2 to 4)	3 (2 to 4)	4 (2 to 4)	3 (2 to 4)	3 (2 to 3)	3 (2 to 3)	3 (2 to 4)

No statistical analyses for this end point

Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

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End point title

Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

End point description

The GAD-7 is a 7-item self-report assessment of severity of anxiety. Each item is scored on a 4-point scale (0-3), with a total score range of 0-30. The standard recall period used is 2 weeks, but in the current study we plan to use a 7-day recall. Intent-to-treat population included all participants randomly assigned to treatment in Period 1 and who were considered non-responders to placebo treatment in Period 1 and were then randomly reassigned to a treatment group in Period 2. Here 'n' signifies the number of participants evaluated at this time point.

End point type

Secondary

End point timeframe

Day 1 to Day 15

End point values	Panel A: Placebo	Panel A: Esketamine 28 mg	Panel A: Esketamine 56mg	Panel A: Esketamine 84mg	Panel B: Placebo	Panel B: Esketamine 14mg	Panel B: Esketamine 56 mg
Number of subjects analysed	33	11	11	12	21	11	9
Units: participants
least squares mean (standard error)
DB: Period 1 (n= 33, 11, 11, 12, 21, 11, 9)	-1.7 ± 0.88	-1.5 ± 1.34	-3.1 ± 1.34	-5.1 ± 1.3	-1.7 ± 0.68	-1.9 ± 0.94	-3.2 ± 1.03
DB: Period 2 (n= 6, 8, 9, 5, 5, 5, 3)	0.4 ± 1.02	-1.6 ± 0.87	1 ± 0.98	-0.9 ± 1.02	-2.7 ± 1.68	-6.6 ± 1.68	-0.7 ± 2.27

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

up to follow-up phase (8 weeks after last dose of drug administration)

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

18.0

Reporting group title

Placebo/Placebo

Reporting group description

Reporting group title

Placebo

Reporting group description

Reporting group title

Placebo/Esketamine 14 mg

Reporting group description

Participants in Panel B (who received placebo on Day 1 and 4 and non-responders (Quick Inventory of Depressive Symptomatology – 16-item Self Report [QIDS-SR16] total score greater than or equal to (>=) 11) on Day 8) were self-administered intranasal esketamine 14 mg on Days 8, and 11 during the double-blind phase and continued in the open label treatment phase for up to 2 weeks (Days 15, 18, 22, and 25). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

Reporting group title

Placebo/Esketamine 28 mg

Reporting group description

Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 28 mg on Days 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks (Days 15, 18, 22, 25, 32, 39, 46, 60, and 74). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

Reporting group title

Placebo/Esketamine 56 mg

Reporting group description

Participants in Panel A and B (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 56 mg on Day 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks in Panel A and up to 2 weeks in Panel B. The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

Reporting group title

Placebo/Esketamine 84 mg

Reporting group description

Participants in Panel A (who received placebo on Day 1 and 4 and non-responders [QIDS-SR16 total score >=11] on Day 8) were self-administered intranasal esketamine 84 mg on Days 8 and 11 during the double-blind phase and continued in the open label treatment phase for up to 9 weeks (Days 15, 18, 22, 25, 32, 39, 46, 60, and 74). The dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability.

Reporting group title

Esketamine 28 mg/Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60, and 74. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

Reporting group title

Esketamine 28 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 28 mg on Days 1, and 4 during the double-blind phase.

Reporting group title

Esketamine 14 mg/Esketamine 14 mg

Reporting group description

Participants in Panel B were self-administered intranasal esketamine 14 mg on Days 1, 4, 8, and 11 during the double-blind phase and intranasal esketamine on Days 15, 18, 22, and 25 during the optional open-label phase. During the optional open-label phase, participants were started with treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

Reporting group title

Esketamine 84 mg/Esketamine 84 mg

Reporting group description

Participants in Panel A were self-administered intranasal esketamine 84 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine for up to 9 weeks. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

Reporting group title

Esketamine 56 mg/Esketamine 56 mg

Reporting group description

Participants in Panel A and B were self-administered intranasal esketamine 56 mg on Days 1, 4, 8, and 11 during the double-blind phase and in optional open-label phase intranasal esketamine for up to 9 weeks in Panel A and for up to 2 weeks in Panel B. During the optional open-label phase, all participants were started treatment with a 56-mg dose of intranasal esketamine on Day 15 (the dose of esketamine was adjusted based on the Investigator's clinical judgement of efficacy and tolerability).

Serious adverse events	Placebo/Placebo	Placebo	Placebo/Esketamine 14 mg	Placebo/Esketamine 28 mg	Placebo/Esketamine 56 mg	Placebo/Esketamine 84 mg	Esketamine 28 mg/Esketamine 28 mg	Esketamine 28 mg	Esketamine 14 mg/Esketamine 14 mg	Esketamine 84 mg/Esketamine 84 mg	Esketamine 56 mg/Esketamine 56 mg
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events
Gastrointestinal disorders
Oesophagitis
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo/Placebo	Placebo	Placebo/Esketamine 14 mg	Placebo/Esketamine 28 mg	Placebo/Esketamine 56 mg	Placebo/Esketamine 84 mg	Esketamine 28 mg/Esketamine 28 mg	Esketamine 28 mg	Esketamine 14 mg/Esketamine 14 mg	Esketamine 84 mg/Esketamine 84 mg	Esketamine 56 mg/Esketamine 56 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	15 / 23 (65.22%)	1 / 1 (100.00%)	5 / 5 (100.00%)	4 / 8 (50.00%)	11 / 12 (91.67%)	5 / 5 (100.00%)	6 / 8 (75.00%)	2 / 3 (66.67%)	8 / 11 (72.73%)	10 / 12 (83.33%)	18 / 20 (90.00%)
Vascular disorders
Hot Flush
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Hypertension
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	3 / 12 (25.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	7	0	0	0	1	4	4
Peripheral Coldness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	2 / 20 (10.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 23 (8.70%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	3	0	0	0	0	0	0	0	1	0	0
Chills
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Discomfort
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3
Energy Increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Feeling Abnormal
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	2 / 11 (18.18%)	1 / 12 (8.33%)	4 / 20 (20.00%)
occurrences all number	2	0	6	0	0	0	2	0	8	10	12
Feeling Drunk
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2
Feeling Hot
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Feeling Jittery
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Gait Disturbance
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Hangover
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0
Injection Site Haemorrhage
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Malaise
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Pain
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Product Taste Abnormal
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Pyrexia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Sluggishness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Thirst
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dry Throat
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Hyperventilation
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Nasal Congestion
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	2	0
Nasal Discomfort
subjects affected / exposed	2 / 23 (8.70%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	3	0	0	0	0	1	1
Nasal Dryness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	3	0
Nasal Mucosal Disorder
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0
Nasal Obstruction
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Nasal Oedema
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Nasal Pruritus
subjects affected / exposed	0 / 23 (0.00%)	1 / 1 (100.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	1	1	0
Oropharyngeal Pain
subjects affected / exposed	2 / 23 (8.70%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)	1 / 20 (5.00%)
occurrences all number	2	0	0	0	0	2	0	0	2	1	2
Pharyngeal Disorder
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Pharyngeal Hypoaesthesia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1
Sneezing
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0
Throat Irritation
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	1	1	0	0	10	0
Upper-Airway Cough Syndrome
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	2	0	0	0	1	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Confusional State
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Daydreaming
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Dissociation
subjects affected / exposed	0 / 23 (0.00%)	1 / 1 (100.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	4 / 12 (33.33%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	3 / 12 (25.00%)	6 / 20 (30.00%)
occurrences all number	0	1	1	0	5	2	0	0	0	7	18
Dissociative Disorder
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	3 / 12 (25.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	2	0	2	0	1	0	8	3
Dysphoria
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Fear
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Hallucination, Visual
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	2	1	0	0	0	0	0	2
Illusion
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1
Insomnia
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	2	0	0	0	0	0	0
Merycism
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Somatic Hallucination
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Suspiciousness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Thinking Abnormal
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4
Investigations
Blood Pressure Diastolic Increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1
Blood Pressure Increased
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	2 / 20 (10.00%)
occurrences all number	1	0	4	0	0	1	0	0	0	0	5
Blood Pressure Systolic Increased
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Oxygen Saturation Decreased
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	1	0	0
Scratch
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1
Skin Abrasion
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Cardiac disorders
Bradycardia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Palpitations
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	1	0	0
Sinus Bradycardia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Nervous system disorders
Akathisia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Altered State of Consciousness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Coordination Abnormal
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Disturbance in Attention
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0
Dizziness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	2 / 5 (40.00%)	0 / 8 (0.00%)	4 / 12 (33.33%)	3 / 5 (60.00%)	4 / 8 (50.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	5 / 12 (41.67%)	7 / 20 (35.00%)
occurrences all number	0	0	3	0	6	6	16	0	2	11	25
Dizziness Postural
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1
Dysaesthesia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Dysgeusia
subjects affected / exposed	6 / 23 (26.09%)	0 / 1 (0.00%)	1 / 5 (20.00%)	1 / 8 (12.50%)	2 / 12 (16.67%)	3 / 5 (60.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	3 / 12 (25.00%)	4 / 20 (20.00%)
occurrences all number	13	0	2	2	4	6	4	0	4	8	13
Dysgraphia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4
Dyskinesia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Headache
subjects affected / exposed	5 / 23 (21.74%)	0 / 1 (0.00%)	0 / 5 (0.00%)	2 / 8 (25.00%)	3 / 12 (25.00%)	1 / 5 (20.00%)	3 / 8 (37.50%)	1 / 3 (33.33%)	2 / 11 (18.18%)	2 / 12 (16.67%)	4 / 20 (20.00%)
occurrences all number	8	0	0	2	4	1	4	1	5	2	5
Hypersomnia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 11 (18.18%)	1 / 12 (8.33%)	4 / 20 (20.00%)
occurrences all number	2	0	1	0	1	0	1	0	4	1	15
Loss of Consciousness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Mental Impairment
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0
Paraesthesia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Psychomotor Hyperactivity
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Sedation
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	3 / 20 (15.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	6
Slow Speech
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Somnolence
subjects affected / exposed	7 / 23 (30.43%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	2 / 11 (18.18%)	0 / 12 (0.00%)	3 / 20 (15.00%)
occurrences all number	12	0	2	0	3	0	2	0	3	0	9
Syncope
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 3 (33.33%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Tremor
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Tunnel Vision
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	2 / 12 (16.67%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	7	0
Visual Field Defect
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4
Ear and labyrinth disorders
Ear Congestion
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Vertigo
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	1 / 8 (12.50%)	1 / 3 (33.33%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	4	0	1	1	0	4	0
Eye disorders
Accommodation Disorder
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Conjunctival Hyperaemia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Vision Blurred
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	1	2	0
Visual Impairment
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	2
Gastrointestinal disorders
Abdominal Pain
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Abdominal Pain Upper
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Diarrhoea
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0
Hypoaesthesia Oral
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	1 / 5 (20.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	3 / 20 (15.00%)
occurrences all number	0	0	0	0	3	1	1	0	0	3	8
Nausea
subjects affected / exposed	3 / 23 (13.04%)	0 / 1 (0.00%)	1 / 5 (20.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	2 / 5 (40.00%)	2 / 8 (25.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	3 / 12 (25.00%)	6 / 20 (30.00%)
occurrences all number	8	0	1	0	2	2	3	0	2	3	9
Oral Discomfort
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Paraesthesia Oral
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	4
Salivary Hypersecretion
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Stomatitis
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	1
Skin and subcutaneous tissue disorders
Dermatitis Contact
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Hyperhidrosis
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	2 / 12 (16.67%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Scab
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	1 / 8 (12.50%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Renal and urinary disorders
Bladder Pain
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Micturition Urgency
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Polyuria
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1
Musculoskeletal and connective tissue disorders
Back Pain
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	1 / 12 (8.33%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0
Limb Discomfort
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	2	0
Muscle Tightness
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Myalgia
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Pain in Extremity
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	0 / 20 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0
Infections and infestations
Cystitis
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Nasopharyngitis
subjects affected / exposed	1 / 23 (4.35%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	0 / 11 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Decreased Appetite
subjects affected / exposed	0 / 23 (0.00%)	0 / 1 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 12 (0.00%)	0 / 5 (0.00%)	0 / 8 (0.00%)	0 / 3 (0.00%)	1 / 11 (9.09%)	0 / 12 (0.00%)	1 / 20 (5.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

06 Dec 2013

The purpose of this Amendment was: A new panel (Panel B) was added to evaluate the efficacy of intranasal esketamine in Japanese subjects with treatment-resistant depression (TRD); Text was added to indicate that review of the number of re-randomized and drop-out subjects at the end of Period 1 was a blinded Interactive Web Response System (IWRS) review; Clinical Global Assessment of Alertness was added to the safety evaluations to further assess the subject’s level of alertness after dosing; Nasal tolerability questionnaire and Clinical Global Assessment of Alertness were added into the recommended order of assessments; Text revised to indicate that clinical assessment of major depressive disorder (MDD) used diagnostic criteria from Diagnostic and Statistical Manual of Mental Disorders (4th edition), text revised (DSM-IV-TR) instead of Diagnostic and Statistical Manual of Mental Disorders (5th edition) (DSM-5); Risk language used to describe enrollment criteria and prohibitions and restrictions was revised; Lower end of the age range was revised from 18 to 20 years of age to align Panels A and B; Rhinoplasty was added to the list of excluded anatomical or medical conditions in the exclusion criteria; Additional clarification and guidance for study procedures provided (eg, information regarding staff and equipment requirements for dosing, frequency of pulse oximetry monitoring, duration and recording of prestudy and concomitant therapies, study diary procedures, reasons for withdrawal, requirements for early termination visit, dose adjustment in open-label treatment phase, statistical analysis methods for safety data, prohibited therapies, tympanic temperature, completion of the MGH-ATRQ).

04 Mar 2014

The purpose of this Amendment was: Duration of the optional open-label treatment phase for Panel A was extended to allow exploration of the efficacy and safety of intranasal esketamine when the frequency of administration was tapered from twice per week to once per week to once every other week; Safety evaluation (ie, BPIC-SS assessment) was added to monitor subjects for symptoms of cystitis; Timing of the clinical laboratory tests was modified to ensure tests were performed over the extended duration of the open-label treatment phase; Text revised to specify that pharmacogenomic evaluations were only to be used for research releated to esketamine; Potential interim PK/PD analysis was added for Panel A; The PHQ-9 was added to the efficacy measures to provide data on this assessment in the event it is used as the self-report depression rating scale in further studies of intranasal esketamine in subjects with TRD; Text added to specify how the sleep and appetite items of the modified MADRS were to be handled; Respiratory rate was added to the list of vital sign assessments on all dosing days; Exclusion criteria were revised: to exclude subjects with a current or prior diagnosis of post-traumatic stress disorder (PTSD) or obsessive-compulsive disorder (OCD), to permit enrollment of subjects with signs and symptoms of rhinitis, to add a criterion that defined clinically significant ECG abnormalities that were exclusionary, to exclude subjects with a history or current symptoms of fibromyalgia, and to clarify timing of procedures related to exclusion criteria; Time and Events Schedule was revised: to add evaluation of potential withdrawal symptoms following last dose of study medication in the open-label treatment phase, to add a PK sample on Days 1 and 11, to include a definition of postdose, and to specify collection of past psychiatric and family psychiatric history.

28 Apr 2014

The purpose of this Amendment was to included the following changes; Objective cognitive assessments (Cogstate® computerized test battery and HVLT-R) were added to formally assess cognition in Panel A subjects receiving esketamine during the open-label treatment phase; Additional BPIC-SS assessment and urinalysis were added on Day 46 for Panel A; Prohibitions and restrictions of prestudy and concomitant therapies were revised to avoid potential impact of certain therapies on cognitive and/or efficacy assessments.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results:
A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Clinical trials

Clinical Trial Results: A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

Primary: Change From Baseline to the 1-week Endpoint in Montgomery Asberg Depression Rating Scale (MADRS) Total Score

Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

Secondary: Percentage of Participants With Sustained Response (>=50% Reduction From Baseline in MADRS Total Score) With Onset by Day 2 Through the end of the Double-blind Phase (Day 15)

Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

Secondary: Percentage of Responders (>=) 50 Percent (%) Reduction From Baseline in MADRS Total Score) at Each Visit

Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

Secondary: Percentage of Remitters (Proportion of Subjects in Remission MADRS Total Score ≤10) at Each Visit

Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

Secondary: Quick Inventory of Depressive Symptomatology – 16-Item Self Report (QIDS-SR16 )

Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Clinical Global Impression Severity (CGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

Secondary: Change From Baseline in Severity of Illness Using the Patient Global Impression - Severity (PGI-S) Scale

Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

Secondary: Change From Baseline in Anxiety Symptoms, as Measured by the Generalized Anxiety Disorder 7-Item (GAD-7) Scale

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Double-Blind, Doubly-Randomized, Placebo-Controlled Study of Intranasal Esketamine in an Adaptive Treatment Protocol to Assess Safety and Efficacy in Treatment-Resistant Depression