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

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ClinicalTrials.gov Identifier: NCT01998958
Recruitment Status : Completed
First Posted : December 3, 2013
Results First Posted : June 12, 2019
Last Update Posted : June 12, 2019
Sponsor:
Information provided by (Responsible Party):
Janssen Research & Development, LLC

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Treatment Resistant Depressive Disorder
Interventions Drug: Esketamine 14 mg
Drug: Esketamine 28 mg
Drug: Esketamine 56 mg
Drug: Esketamine 84 mg
Drug: Placebo
Enrollment 108
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo (Panel A: Period 1) Esketamine 28 mg (Panel A: Period 1) Esketamine 56 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 1) Placebo (Panel B: Period 1) Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel B: Period 1) Placebo (Panel A: Period 2) QIDS >= 11 Participants Placebo (Panel A: Period 2) QIDS<11 Participants Placebo to Esketamine 28mg (Panel A: Period 2) Placebo to Esketamine 56 mg (Panel A: Period 2) Placebo to Esketamine 84 mg (Panel A: Period 2) Esketamine 28 mg (Panel A: Period 2) Esketamine 56 mg (Panel A: Period 2) Esketamine 84 mg (Panel A: Period 2) Placebo (Panel B: Period 2) QIDS >=11 Participants Placebo (Panel B: Period 2) QIDS<11 Participants Placebo to Esketamine 14mg (Panel B: Period 2) Placebo to Esketamine 56mg (Panel B: Period 2) Esketamine 14 mg (Panel B: Period 2) Esketamine 56 mg (Panel B: Period 2) Placebo/Placebo/Open Label Esketamine (Panel A) Placebo/Esketamine/Open Label Esketamine (Panel A) Esketamine/Esketamine/Open Label Esketamine (Panel A) Placebo/Placebo/Open Label Esketamine (Panel B) Placebo/Esketamine/Open Label Esketamine (Panel B) Esketamine/Esketamine/Open Label Esketamine (Panel B) Placebo: Follow up Phase Esketamine 14 mg: Follow up Phase Esketamine 28 mg: Follow up Phase Esketamine 56 mg: Follow up Phase Esketamine 84 mg: Follow up Phase
Hide Arm/Group Description Participants self-administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 28 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score greater than or equal to [>=] 11) were re-randomized to receive Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel A continued to receive placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were re-randomized to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who received esketamine 28 mg in Period 1 of Panel A continued to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who received esketamine 56 mg in Period 1 of Panel A continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2. Participants who received esketamine 84 mg in Period 1 of Panel A continued to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2. Participants who were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were re-randomized to receive placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes using 4 separate devices) on Days 8 and 11 of Period 2 in Panel B. Participants who were responders with QIDS-SR16 score <11 at the end of Period 1 continued to receive placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes using 4 separate devices) on Days 8 and 11 in Period 2. Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were re-randomized to receive esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo in other nostril at 0 minute and 1 spray of placebo in each nostril at 5 minutes using 4 separate devices) on Days 8 and 11 in Period 2. Participants who received placebo in Period 1 and were non-responders (with QIDS-SR16 score >=11) at the end of Period 1 in Panel B were re-randomized to receive esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2. Participants who received esketamine 14 mg in Period 1 of Panel B continued to receive esketamine 14 mg (1 spray of esketamine 14 mg to one nostril and 1 spray of placebo into other nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 in Period 2. Participants who received esketamine 56 mg in Period 1 of Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2. Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74. Participants who received Placebo in Period 1 and esketamine in Period 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74. Participants who received esketamine in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15, 18, 22, 25, 32, 39, 46, 60 and 74. The doses for the optional open-label treatment phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25, 32, 39, and 46 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. The same dose administered on Day 46 was administered on Day 60 and Day 74. Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. Participants who received Placebo in Period 1 and esketamine in Period 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. Participants who received esketamine in Period 1 and 2 of Panel A and elected to continue with open label phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22 and 25. The doses for the optional open-label treatment phase included 14, 28 and 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22 and 25 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. All participants whose last dose was Placebo in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 14 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 28 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 56 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 84 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks.
Period Title: Period 1 (Panel A and B)
Started 33 11 11 12 21 11 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Rerandomized to Esketamine 56 mg 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Rerandomized to Esketamine 28mg 8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Rerandomized to Esketamine 84mg 5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Completed 32 8 11 12 21 11 9 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Not Completed 1 3 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Reason Not Completed
Withdrawal by Subject             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Lack of Efficacy             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Adverse Event             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Other             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Period Title: Period 2 (Panel A and B)
Started 0 0 0 0 0 0 0 6 4 8 9 5 8 11 12 5 8 5 3 11 9 0 0 0 0 0 0 0 0 0 0 0
Completed 0 0 0 0 0 0 0 6 4 8 8 5 8 11 10 5 8 5 2 11 9 0 0 0 0 0 0 0 0 0 0 0
Not Completed 0 0 0 0 0 0 0 0 0 0 1 0 0 0 2 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0
Reason Not Completed
Adverse Event             0             0             0             0             0             0             0             0             0             0             1             0             0             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             1             0             0             0             0             0             0             0             0             0             0             0             0             0
Period Title: Open Label Phase (Optional)
Started 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 10 20 27 13 7 19 0 0 0 0 0
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 7 11 23 13 7 19 0 0 0 0 0
Not Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 3 9 4 0 0 0 0 0 0 0 0
Reason Not Completed
Adverse Event             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             0             0             0
Other             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             5             1             0             0             0             0             0             0             0             0
Lost to Follow-up             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             0             0             0             0             0             0             0             0             0
Lack of Efficacy             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             1             2             0             0             0             0             0             0             0             0             0
Withdrawal by Subject             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             0             2             1             2             0             0             0             0             0             0             0             0
Period Title: Follow-up Phase
Started 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 4 12 39 42
Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 4 12 39 42
Not Completed 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
Arm/Group Title Placebo (Panel A: Period 1) Esketamine 28 mg (Panel A: Period 1) Esketamine 56 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 1) Placebo (Panel B: Period 1) Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel B: Period 1) Total
Hide Arm/Group Description Participants self-administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 28 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Total of all reporting groups
Overall Number of Baseline Participants 33 11 11 12 21 11 9 108
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 33 participants 11 participants 11 participants 12 participants 21 participants 11 participants 9 participants 108 participants
44.4  (9.60) 42.1  (10.31) 42.7  (11.23) 49.8  (9.29) 45.3  (7.66) 42.2  (9.43) 45.6  (7.35) 44.6  (9.29)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 11 participants 11 participants 12 participants 21 participants 11 participants 9 participants 108 participants
Female
18
  54.5%
5
  45.5%
9
  81.8%
6
  50.0%
9
  42.9%
4
  36.4%
4
  44.4%
55
  50.9%
Male
15
  45.5%
6
  54.5%
2
  18.2%
6
  50.0%
12
  57.1%
7
  63.6%
5
  55.6%
53
  49.1%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 33 participants 11 participants 11 participants 12 participants 21 participants 11 participants 9 participants 108 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
1
   9.1%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1
   0.9%
Asian
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
21
 100.0%
11
 100.0%
9
 100.0%
41
  38.0%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
9
  27.3%
4
  36.4%
4
  36.4%
1
   8.3%
0
   0.0%
0
   0.0%
0
   0.0%
18
  16.7%
White
24
  72.7%
7
  63.6%
6
  54.5%
11
  91.7%
0
   0.0%
0
   0.0%
0
   0.0%
48
  44.4%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
1.Primary Outcome
Title Panel A and B: Change From Baseline (Day 1) in Montgomery Asberg Depression Rating Scale (MADRS) Total Score at Day 8- Analysis of Covariance (ANCOVA) Analysis
Hide Description MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.
Time Frame Baseline (Day 1) and Endpoint (Day 8) of Period 1
Hide Outcome Measure Data
Hide Analysis Population Description
Period 1 Intent-to-treat (ITT) analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
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Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
-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)
2.Primary Outcome
Title Panel A and B: Change From Baseline (Day 8) in Montgomery Asberg Depression Rating Scale Total Score at Day 15- ANCOVA Analysis
Hide Description MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.
Time Frame Baseline (Day 8) and Endpoint (Day 15) of Period 2
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Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A:Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B:Period 2 Esketamine 56 mg
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Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
-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)
3.Secondary Outcome
Title Panel A and B: Percentage of Participants With Sustained Response Based on MADRS Total Score in Participants Who Have Completed the Double-Blind Phase and Received the Same Treatment for Both Periods
Hide 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. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame Day 2 Up to Day 15
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Hide Analysis Population Description
Population analyzed included participants from double-blind (DB) ITT (who were randomly assigned to treatment during the double-blind phase) who completed the double-blind phase and received the same treatment for both periods.
Arm/Group Title Panel A: Placebo (Period 1 and 2) Panel A: Esketamine 28 mg (Period 1 and 2) Panel A: Esketamine 56 mg (Period 1 and 2) Panel A: Esketamine 84 mg (Period 1 and 2) Panel B: Placebo (Period 1 and 2) Panel B: Esketamine 14 mg (Period 1 and 2) Panel B: Esketamine 56 mg (Period 1 and 2)
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Participants who received same placebo (1 spray to each nostril at 0, 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 28mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same placebo (1 spray to each nostril at 0 and 5 minutes) treatment in Period 1 and 2 of Panel B.
Participants who received same esketamine 14 mg (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) treatment in Period 1 and 2 of Panel B.
Participants who received same esketamine 56 mg (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) treatment in Period 1 and 2 of Panel B.
Overall Number of Participants Analyzed 10 8 11 10 13 11 9
Measure Type: Number
Unit of Measure: Percentage of participants
0 12.5 9.1 30.0 15.4 18.2 22.2
4.Secondary Outcome
Title Panel A and B: Percentage of Participants With Sustained Response Based on MADRS Total Score in Participants Who Received the Same Treatment for Both Periods, Including Participants Who Did Not Complete the Double-blind Phase
Hide Description Sustained response was defined as at least 50 percent (%) improvement from baseline in the MADRS total score with onset by Day 2 that is maintained to study Day 15. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame Day 2 Up to Day 15
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Hide Analysis Population Description
Population analyzed included participants from DB ITT (who were randomly assigned to treatment during the double-blind phase) who received the same treatment for both periods, including participants who did not complete the double-blind Phase.
Arm/Group Title Panel A: Placebo (Period 1 and 2) Panel A: Esketamine 28 mg (Period 1 and 2) Panel A: Esketamine 56 mg (Period 1 and 2) Panel A: Esketamine 84 mg (Period 1 and 2) Panel B: Placebo (Period 1 and 2) Panel B: Esketamine 14 mg (Period 1 and 2) Panel B: Esketamine 56 mg (Period 1 and 2)
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Participants who received same placebo (1 spray to each nostril at 0, 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 28mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) treatment in Period 1 and 2 of Panel A.
Participants who received same placebo (1 spray to each nostril at 0 and 5 minutes) treatment in Period 1 and 2 of Panel B.
Participants who received same esketamine 14 mg (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) treatment in Period 1 and 2 of Panel B.
Participants who received same esketamine 56 mg (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) treatment in Period 1 and 2 of Panel B.
Overall Number of Participants Analyzed 10 8 11 12 13 11 9
Measure Type: Number
Unit of Measure: Percentage of participants
0 12.5 9.1 25.0 15.4 18.2 22.2
5.Secondary Outcome
Title Panel A and B: Percentage of Participants With Response Based on MADRS Total Score
Hide Description A participant is defined a responder at a given time point if the percent improvement in MADRS is greater than or equal to (>=) 50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame Period 1: Days 1 (2 hour), 2 and 8 of Double-blind Phase
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Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Measure Type: Number
Unit of Measure: Percentage of participants
Day 1 (2 hour) 18.2 54.5 36.4 58.3 33.3 36.4 44.4
Day 2 3.0 36.4 27.3 41.7 28.6 36.4 44.4
Day 8 6.1 9.1 18.2 41.7 23.8 18.2 22.2
6.Secondary Outcome
Title Panel A and B: Percentage of Participants With Response Based on MADRS Total Score
Hide Description A participant is defined a responder at a given time point if the percent improvement in MADRS is >=50%. Participant who do not meet such criterion, worsen or discontinue during the DB phase for any reason was considered as non-responders, that is, was assigned a value of 0. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame Period 2: Days 1 (2 hour), 2 and 8 of Double-blind Phase
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Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Measure Type: Number
Unit of Measure: Percentage of participants
Day 1 (2 hour) 16.7 12.5 22.2 40.0 0 60.0 0
Day 2 0 0 11.1 40.0 0 80.0 0
Day 8 0 12.5 0 20.0 0 0 33.3
7.Secondary Outcome
Title Panel A and B: Percentage of Participants in Remission Based on MADRS Total Score at Days 1, 2 and 8 of Double-blind Phase
Hide Description Participants who had a MADRS total score of <=10 were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition.
Time Frame Days 1, 2 and 8 of Double-blind Phase of Period 1
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Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1: Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1: Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Measure Type: Number
Unit of Measure: Percentage of participants
Day 1 3.0 27.3 18.2 25.0 19.0 36.4 33.3
Day 2 0 36.4 18.2 25.0 19.0 27.3 33.3
Day 8 3.0 9.1 9.1 25.0 14.3 18.2 22.2
8.Secondary Outcome
Title Panel A and B: Percentage of Participants in Remission Based on MADRS Total Score at Days 1, 2 and 8 of Double-blind Phase
Hide Description Participants who had a MADRS total score of less than or equal to (<=10) were considered remitters. MADRS is clinician-rated scale designed to measure depression severity, and to detect changes due to antidepressant treatment. Scale consists of 10 items (apparent sadness, reported sadness, inner tension, sleep, appetite, concentration, lassitude, interest level, pessimistic thoughts, and suicidal thoughts), each of which is scored from 0 (item is not present or is normal) to 6 (severe or continuous presence of symptoms), summed for a total possible score of 0 to 60. Higher scores represent more severe condition. A negative change in score indicates improvement.
Time Frame Days 1, 2 and 8 of Double-blind Phase of Period 2
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Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Measure Type: Number
Unit of Measure: Percentage of participants
Day 1 16.7 12.5 0 40.0 0 60.0 0
Day 2 0 0 0 20.0 0 80.0 0
Day 8 0 12.5 0 20.0 0 0 0
9.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 1) in Quick Inventory of Depressive Symptomatology-16-item Self Report (QIDS-SR16) Total Score at Day 8 in the Double-Blind Treatment Phase- ANCOVA Analysis
Hide Description QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.
Time Frame Baseline (Day 1) and Endpoint (Day 8) of Period 1
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Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
-1.8  (0.93) -4.0  (1.43) -4.4  (1.43) -4.2  (1.39) -1.1  (0.78) -0.6  (1.10) -3.0  (1.20)
10.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 8) in Quick Inventory of Depressive Symptomatology-16-item Self Report Total Score at Day 15 in the Double-Blind Treatment Phase- ANCOVA Analysis
Hide Description QIDS-SR16 is self-rated scale assesses severity of depressive symptoms. Total scores range from 0-27. Higher score indicates greater severity of depression. Negative change in score indicates improvement. Total score obtained by adding scores for each of 9 symptom domains of Diagnostic and Statistical Manual of Mental Disorders-4th edition major depressive disorder (DSM-IV MDD) criteria: depressed mood, loss of interest/pleasure, concentration/decision making, self-outlook, suicidal ideation, energy/fatigability, sleep, weight/appetite change, psychomotor changes. 16 items used to rate 9 criterion domains: 4 items used to rate sleep disturbance (early/middle/late insomnia/hypersomnia); 2 items used to rate psychomotor disturbance (agitation, retardation); 4 items used to rate appetite/weight disturbance. 1 item used to rate 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, suicidal ideation). Each item was rated 0-3.
Time Frame Baseline (Day 8) and Endpoint (Day 15) of Period 2
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Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
-2.0  (1.50) -3.1  (1.35) -2.0  (1.41) -3.3  (1.48) -2.1  (1.78) -5.7  (1.78) -1.5  (2.31)
11.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 1) in Clinical Global Impression – Severity (CGI-S) Total Score at Day 8 in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks
Hide Description CGI-S provides measure of severity of participant’s illness including participant’s history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant’s condition at given time. A negative change in score indicates improvement.
Time Frame Baseline (Day 1) and Endpoint (Day 8) of Period 1
Hide Outcome Measure Data
Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Median (Full Range)
Unit of Measure: Units on a scale
5.0
(1 to 6)
4.0
(3 to 5)
4.0
(1 to 5)
4.0
(1 to 6)
4.0
(1 to 6)
4.0
(2 to 6)
3.0
(3 to 6)
12.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 8) in Clinical Global Impression – Severity Total Score at Day 15 in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks
Hide Description CGI-S provides measure of severity of participant’s illness including participant’s history, psychosocial circumstances, symptoms, behavior and impact of symptoms on ability to function. CGI-S evaluates severity of psychopathology on scale of 0 to 7. Considering total clinical experience, participant is assessed on severity of mental illness according to: 0=not assessed; 1=normal (not at all ill); 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among most extremely ill patients. CGI-S permits global evaluation of participant’s condition at given time. A negative change in score indicates improvement.
Time Frame Baseline (Day 8) and Endpoint (Day 15) of Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Median (Full Range)
Unit of Measure: Units on a scale
5.0
(4 to 5)
4.0
(3 to 5)
5.0
(4 to 6)
4.0
(3 to 5)
4.0
(3 to 6)
3.0
(3 to 4)
4.0
(4 to 5)
13.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 1) in Generalized Anxiety Disorder (GAD-7) Total Score at Day 8 (Double-Blind Treatment Phase) ANCOVA Analysis
Hide Description GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21).
Time Frame Baseline (Day 1) and Endpoint (Day 8) of Period 1
Hide Outcome Measure Data
Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
-1.7  (0.88) -1.5  (1.34) -3.1  (1.34) -5.1  (1.30) -1.7  (0.68) -1.9  (0.94) -3.2  (1.03)
14.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 8) in Generalized Anxiety Disorder-7 Total Score at Day 15 (Double-Blind Treatment Phase)- ANCOVA Analysis
Hide Description GAD-7 is a brief and validated 7-item self-report assessment of overall anxiety. Participants respond to each item using a 4-point scale with response categories of 0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day. Item responses are summed to yield a total score with a range of 0 to 21, where higher scores indicate more anxiety. The recall period is 2 weeks. The severity of the GAD-7 is categorized as follows: None (0-4), Mild (5-9), Moderate (10-14) and Severe (15 -21).
Time Frame Baseline (Day 8) and Endpoint (Day 15) of Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Least Squares Mean (Standard Error)
Unit of Measure: Unit on a scale
0.4  (1.02) -1.6  (0.87) 1.0  (0.98) -0.9  (1.02) -2.7  (1.68) -6.6  (1.68) -0.7  (2.27)
15.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 1) in Patient Global Impression of Severity (PGI-S) Score Total Score at Day 8 in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks
Hide Description PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question ‘Considering all aspects of your depression right now would you say your depression is?’ with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition.
Time Frame Baseline (Day 1) and Endpoint (Day 8) of Period 1
Hide Outcome Measure Data
Hide Analysis Population Description
Period 1 ITT analysis set included all participants randomly assigned to treatment in period 1.
Arm/Group Title Panel A: Period 1 Placebo Panel A: Period 1 Esketamine 28 mg Panel A: Period 1 Esketamine 56 mg Panel A: Period 1 Esketamine 84 mg Panel B: Period 1 Placebo Panel B: Period 1 Esketamine 14 mg Panel B: Period 1 Esketamine 56 mg
Hide Arm/Group Description:
Participants self administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 28 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1.
Participants self administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1.
Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1.
Overall Number of Participants Analyzed 33 11 11 12 21 11 9
Median (Full Range)
Unit of Measure: Unit on a scale
3.0
(2 to 4)
3.0
(1 to 4)
3.0
(1 to 3)
3.0
(1 to 4)
3.0
(2 to 4)
3.0
(1 to 3)
3.0
(2 to 3)
16.Secondary Outcome
Title Panel A and B: Change From Baseline (Day 8) in Patient Global Impression of Severity Score Total Score at Day 15 in the Double-Blind Treatment Phase- ANCOVA Analysis on Ranks
Hide Description PGI-S is a patient-rated scale that assesses the severity of their illness at the time of assessment, relative to participants past experience. It is a 4-point (1 to 4) scale in response to the question ‘Considering all aspects of your depression right now would you say your depression is?’ with scores as follows: 1: none; 2: mild; 3: moderate; 4: severe. A higher score implies a more severe condition. A negative change in score indicates improvement.
Time Frame Baseline (Day 8) and Endpoint (Day 15) of Period 2
Hide Outcome Measure Data
Hide Analysis Population Description
Period 2 ITT analysis set included non-responders (QIDS-SR16 total score >=11) to placebo treatment in Period 1 and were then randomly re-assigned to a treatment group in Period 2. Only placebo participants with a QIDS-SR16 score >= 11 at End Point Period 1 who were re-randomized in Period 2 are included in the Period 2 summary.
Arm/Group Title Panel A: Period 2 Placebo Panel A: Period 2 Esketamine 28 mg Panel A: Period 2 Esketamine 56 mg Panel A: Period 2 Esketamine 84 mg Panel B: Period 2 Placebo Panel B: Period 2 Esketamine 14 mg Panel B: Period 2 Esketamine 56 mg
Hide Arm/Group Description:
Participants who were non-responders at the end of Period 1 in Panel A (with Quick Inventory of Depressive Symptomatology – 16-item Self Report (QIDS-SR16) score >=11) were randomly re-assigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR 16 score >=11) were randomly re-assigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2.
Participants who were non-responders with QIDS-SR 16 score >=11 received placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes) on Days 8 and 11 of Period 2.
Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 received esketamine 14 mg intranasally (1 spray of esketamine into one nostril and 1 spray of placebo in other nostril at 0 minutes and 1 spray of placebo in each nostril at 5 minutes) in Period 2.
Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2.
Overall Number of Participants Analyzed 6 8 9 5 5 5 3
Median (Full Range)
Unit of Measure: Unit on a scale
3.0
(2 to 4)
3.0
(2 to 4)
4.0
(2 to 4)
3.0
(2 to 4)
3.0
(2 to 3)
3.0
(2 to 3)
3.0
(2 to 4)
Time Frame Up to 21 weeks
Adverse Event Reporting Description Safety analysis set for double-blind and open-label phase included all randomized participants who receive at least 1 dose of study drug in the respective phases. For follow-up phase safety population included all participants who entered in follow up phase.
 
Arm/Group Title Placebo (Panel A and B: Period 1) Esketamine 28 mg (Panel A: Period 1) Placebo (Panel A and B: Period 2) QIDS >=11 Participants Placebo to Esketamine 14mg (Panel B: Period 2) Placebo to Esketamine 28mg (Panel A: Period 2) Placebo to Esketamine 56mg (Panel A and B: Period 2) Placebo to Esketamine 84 mg (Panel A: Period 2) Placebo (Panel A and Panel B: Period 2) Esketamine 14 mg (Panel B: Period 2) Esketamine 28 mg (Panel A: Period 2) Esketamine 56 mg (Panel A and B: Period 2) Placebo/Placebo/Open Label Esketamine (Panel A and B) Placebo/Esketamine/Open Label Esketamine (Panel A and B) Esketamine/Esketamine/Open Label Esketamine (Panel A and B) Placebo: Follow up Phase Esketamine 14 mg: Follow up Phase Esketamine 28 mg: Follow up Phase Esketamine 56 mg: Follow up Phase Esketamine 84 mg: Follow up Phase Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel A and B: Period 1) Esketamine 84 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 2)
Hide Arm/Group Description Panel A: Participants self-administered placebo intranasally (1 spray to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Panel B: Participants self-administered placebo intranasally (1 spray to each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Participants self administered esketamine 28 milligram (mg) intranasally (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Panel A: Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly reassigned to receive same Placebo (1 spray to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2 in Panel A. Panel B: Participants who were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were randomly assigned to receive placebo intranasally (1 spray of placebo into each nostril at 0 and 5 minutes using 4 separate devices) on Days 8 and 11 of Period 2 in Panel B. Participants who received placebo in Period 1 and were non-responders with QIDS-SR16 score >=11 at the end of Period 1 were randomly reassigned to receive esketamine 14 mg intranasally (1 spray of esketamine 14 mg into once nostril and 1 spray of placebo in other nostril at 0 minute and 1 spray of placebo in each nostril at 5 minutes using 4 separate devices) on Days 8 and 11 in Period 2 of Panel B. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly reassigned to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2 in Panel A. Panel A: Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly reassigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2 in Panel A. Panel B: Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2 of Panel B. Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly reassigned to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2 in Panel A. All participants who received placebo in Period 2 of Panel A and B (including participants with QIDS-SR16 score >=11 and QIDS-SR16 score <11) in double-blind phase. Participants who received esketamine 14 mg in Period 1 of Panel B continued to receive esketamine 14 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2 of Panel B. Participants who received esketamine 28 mg in Period 1 of Panel A continued to receive esketamine 28 mg (1 spray of esketamine 14 mg to each nostril at 0 minute and 1 spray of placebo to each nostril at 5 and 10 minutes) on Days 8 and 11 of Period 2 in Panel A. Panel A: Participants who were non-responders at the end of Period 1 in Panel A (with QIDS-SR16 score >=11) were randomly re-assigned to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 of Period 2. Panel B: Participants who were responders (with QIDS-SR16 score <11) at the end of Period 1 in Panel B continued to receive esketamine 56 mg (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 8 and 11 in Period 2. Panel A: Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with open label (OL) phase received up to 9 single doses of intranasal esketamine on Days 15,18,22,25,32, 39, 46,60,74. Doses for optional OL phase included 28, 56, and 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18,22,25,32,39,46 could be adjusted to next lower or higher dose, based on investigator’s clinical judgment. Same dose administered on Day 46 was administered on Day 60, 74. Panel B: Participants who received Placebo in Period 1 and 2 of Panel A and elected to continue with OL phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22, 25. Doses for OL phase included 14, 28, 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25 could be adjusted to next lower or higher dose, based on investigator’s clinical judgment. Panel A: Participants who received Placebo in Period 1, esketamine in Period 2 and elected to continue with OL phase received up to 9 single doses of intranasal esketamine on Days 15,18,22,25,32,39,46,60, 74. Doses for OL phase included 28,56,84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18,22,25,32,39, 46 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. Same dose administered on Day 46 was administered on Day 60,74. Panel B: Participants who received Placebo in Period 1 and esketamine in Period 2 of Panel A and elected to continue with OL phase received up to 4 single doses of intranasal esketamine on Days 15,18,22,25. Doses for OL phase included 14,28,56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18,22,25 could be adjusted to next lower or higher dose, based on the investigator’s clinical judgment. Panel A: Participants who received esketamine in Period 1 and 2 and elected to continue with open label phase received up to 9 single doses of intranasal esketamine on Days 15,18,22,25,32,39,46,60,74. Doses for OL treatment phase included 28, 56, 84 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22,25,32,39, 46 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. Same dose administered on Day 46 was administered on Day 60,74.Panel B: Participants who received esketamine in Period 1 and 2 of Panel A and elected to continue with OL phase received up to 4 single doses of intranasal esketamine on Days 15, 18, 22, 25. Doses for OL phase included 14, 28, 56 mg of esketamine. All participants started with intranasal esketamine 56 mg on Day 15. Subsequent doses on Days 18, 22, 25 could be adjusted to the next lower or higher dose, based on the investigator’s clinical judgment. All participants whose last dose was Placebo in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 14 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 28 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 56 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. All participants whose last dose was esketamine 84 mg in the double-blind phase or open label phase and were not consent withdrawn were followed for safety for 8 weeks. Participants self administered esketamine 14 mg intranasally (1 spray of esketamine 14 mg into one nostril and 1 spray of placebo into other nostril at 0 minute and then 1 spray of placebo to each nostril at 5 minutes) on Days 1 and 4 of Period 1 in Panel B. Panel A: Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0 and 5 minute and 1 spray of placebo to each nostril at 10 minutes) on Days 1 and 4 of Period 1. Panel B: Participants self administered esketamine 56 mg intranasally (1 spray of esketamine 14 mg into each nostril at 0 and 5 minutes) on Days 1 and 4 of Period 1. Participants self administered esketamine 84 mg intranasally (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 1 and 4 of Period 1 in Panel A. Participants who received esketamine 84 mg in Period 1 of Panel A continued to receive esketamine 84 mg (1 spray of esketamine 14 mg to each nostril at 0, 5 and 10 minutes) on Days 8 and 11 of Period 2 in Panel A.
All-Cause Mortality
Placebo (Panel A and B: Period 1) Esketamine 28 mg (Panel A: Period 1) Placebo (Panel A and B: Period 2) QIDS >=11 Participants Placebo to Esketamine 14mg (Panel B: Period 2) Placebo to Esketamine 28mg (Panel A: Period 2) Placebo to Esketamine 56mg (Panel A and B: Period 2) Placebo to Esketamine 84 mg (Panel A: Period 2) Placebo (Panel A and Panel B: Period 2) Esketamine 14 mg (Panel B: Period 2) Esketamine 28 mg (Panel A: Period 2) Esketamine 56 mg (Panel A and B: Period 2) Placebo/Placebo/Open Label Esketamine (Panel A and B) Placebo/Esketamine/Open Label Esketamine (Panel A and B) Esketamine/Esketamine/Open Label Esketamine (Panel A and B) Placebo: Follow up Phase Esketamine 14 mg: Follow up Phase Esketamine 28 mg: Follow up Phase Esketamine 56 mg: Follow up Phase Esketamine 84 mg: Follow up Phase Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel A and B: Period 1) Esketamine 84 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo (Panel A and B: Period 1) Esketamine 28 mg (Panel A: Period 1) Placebo (Panel A and B: Period 2) QIDS >=11 Participants Placebo to Esketamine 14mg (Panel B: Period 2) Placebo to Esketamine 28mg (Panel A: Period 2) Placebo to Esketamine 56mg (Panel A and B: Period 2) Placebo to Esketamine 84 mg (Panel A: Period 2) Placebo (Panel A and Panel B: Period 2) Esketamine 14 mg (Panel B: Period 2) Esketamine 28 mg (Panel A: Period 2) Esketamine 56 mg (Panel A and B: Period 2) Placebo/Placebo/Open Label Esketamine (Panel A and B) Placebo/Esketamine/Open Label Esketamine (Panel A and B) Esketamine/Esketamine/Open Label Esketamine (Panel A and B) Placebo: Follow up Phase Esketamine 14 mg: Follow up Phase Esketamine 28 mg: Follow up Phase Esketamine 56 mg: Follow up Phase Esketamine 84 mg: Follow up Phase Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel A and B: Period 1) Esketamine 84 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/54 (0.00%)   0/11 (0.00%)   1/23 (4.35%)   0/5 (0.00%)   0/8 (0.00%)   0/12 (0.00%)   0/5 (0.00%)   1/23 (4.35%)   0/16 (0.00%)   0/16 (0.00%)   0/32 (0.00%)   0/23 (0.00%)   0/27 (0.00%)   1/46 (2.17%)   0/1 (0.00%)   0/4 (0.00%)   1/12 (8.33%)   1/39 (2.56%)   1/42 (2.38%)   0/11 (0.00%)   0/20 (0.00%)   0/12 (0.00%)   0/17 (0.00%) 
Gastrointestinal disorders                                               
Oesophagitis * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  1/23 (4.35%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
General disorders                                               
General Physical Health Deterioration * 1  0/1 (0.00%)  0/3 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/16 (0.00%)  0/12 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  1/42 (2.38%)  /11  /20  /12  /17 
Pregnancy, puerperium and perinatal conditions                                               
Ectopic Pregnancy * 1  0/1 (0.00%)  0/3 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/16 (0.00%)  0/12 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  /11  /20  /12  /17 
Psychiatric disorders                                               
Completed Suicide * 1  0/1 (0.00%)  0/3 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/16 (0.00%)  0/12 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  1/39 (2.56%)  0/42 (0.00%)  /11  /20  /12  /17 
Confusional State * 1  0/1 (0.00%)  0/3 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/16 (0.00%)  0/12 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  /11  /20  /12  /17 
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA Version 18.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Placebo (Panel A and B: Period 1) Esketamine 28 mg (Panel A: Period 1) Placebo (Panel A and B: Period 2) QIDS >=11 Participants Placebo to Esketamine 14mg (Panel B: Period 2) Placebo to Esketamine 28mg (Panel A: Period 2) Placebo to Esketamine 56mg (Panel A and B: Period 2) Placebo to Esketamine 84 mg (Panel A: Period 2) Placebo (Panel A and Panel B: Period 2) Esketamine 14 mg (Panel B: Period 2) Esketamine 28 mg (Panel A: Period 2) Esketamine 56 mg (Panel A and B: Period 2) Placebo/Placebo/Open Label Esketamine (Panel A and B) Placebo/Esketamine/Open Label Esketamine (Panel A and B) Esketamine/Esketamine/Open Label Esketamine (Panel A and B) Placebo: Follow up Phase Esketamine 14 mg: Follow up Phase Esketamine 28 mg: Follow up Phase Esketamine 56 mg: Follow up Phase Esketamine 84 mg: Follow up Phase Esketamine 14 mg (Panel B: Period 1) Esketamine 56 mg (Panel A and B: Period 1) Esketamine 84 mg (Panel A: Period 1) Esketamine 84 mg (Panel A: Period 2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   27/54 (50.00%)   8/11 (72.73%)   15/23 (65.22%)   5/5 (100.00%)   4/8 (50.00%)   11/12 (91.67%)   5/5 (100.00%)   12/23 (52.17%)   11/16 (68.75%)   8/16 (50.00%)   26/32 (81.25%)   23/23 (100.00%)   22/27 (81.48%)   39/46 (84.78%)   0/1 (0.00%)   1/4 (25.00%)   4/12 (33.33%)   10/39 (25.64%)   7/42 (16.67%)   6/11 (54.55%)   18/20 (90.00%)   10/12 (83.33%)   12/17 (70.59%) 
Cardiac disorders                                               
Bradycardia * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Palpitations * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  1/23 (4.35%)  1/16 (6.25%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Sinus Bradycardia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Sinus Tachycardia * 1  0/1 (0.00%)  0/3 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/11 (0.00%)  0/8 (0.00%)  0/16 (0.00%)  0/12 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Ear and labyrinth disorders                                               
Ear Congestion * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Vertigo * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  2/12 (16.67%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  2/32 (6.25%)  2/23 (8.70%)  3/27 (11.11%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  1/17 (5.88%) 
Eye disorders                                               
Accommodation Disorder * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Conjunctival Hyperaemia * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Vision Blurred * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  1/5 (20.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  1/23 (4.35%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  2/17 (11.76%) 
Visual Impairment * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  1/23 (4.35%)  1/27 (3.70%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Conjunctivitis Allergic * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Gastrointestinal disorders                                               
Abdominal Pain * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  1/23 (4.35%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Abdominal Pain Upper * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Hypoaesthesia Oral * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  2/12 (16.67%)  1/5 (20.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  3/32 (9.38%)  2/23 (8.70%)  1/27 (3.70%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  3/20 (15.00%)  1/12 (8.33%)  2/17 (11.76%) 
Nausea * 1  5/54 (9.26%)  2/11 (18.18%)  3/23 (13.04%)  1/5 (20.00%)  0/8 (0.00%)  2/12 (16.67%)  2/5 (40.00%)  2/23 (8.70%)  1/16 (6.25%)  1/16 (6.25%)  3/32 (9.38%)  4/23 (17.39%)  6/27 (22.22%)  6/46 (13.04%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  5/20 (25.00%)  2/12 (16.67%)  2/17 (11.76%) 
Oral Discomfort * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Paraesthesia Oral * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  2/23 (8.70%)  0/27 (0.00%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Salivary Hypersecretion * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Stomatitis * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Vomiting * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  3/27 (11.11%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  1/39 (2.56%)  0/42 (0.00%)  1/11 (9.09%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Dry Mouth * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/12 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Diarrhoea * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Erosive Oesophagitis * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Gastritis * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/32 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Oesophageal Stenosis * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
General disorders                                               
Asthenia * 1  0/54 (0.00%)  0/11 (0.00%)  2/23 (8.70%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  2/23 (8.70%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  2/23 (8.70%)  0/27 (0.00%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  1/39 (2.56%)  0/42 (0.00%)  1/11 (9.09%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Chills * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Discomfort * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Energy Increased * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  1/17 (5.88%) 
Feeling Abnormal * 1  1/54 (1.85%)  2/11 (18.18%)  1/23 (4.35%)  2/5 (40.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  1/23 (4.35%)  4/16 (25.00%)  0/16 (0.00%)  3/32 (9.38%)  4/23 (17.39%)  4/27 (14.81%)  7/46 (15.22%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  2/11 (18.18%)  4/20 (20.00%)  1/12 (8.33%)  1/17 (5.88%) 
Feeling Drunk * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  1/32 (3.13%)  1/23 (4.35%)  0/27 (0.00%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Feeling Hot * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Feeling Jittery * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  1/8 (12.50%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Gait Disturbance * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  1/27 (3.70%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Hangover * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Injection Site Haemorrhage * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Malaise * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  2/23 (8.70%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  1/39 (2.56%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Pain * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Product Taste Abnormal * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  1/17 (5.88%) 
Pyrexia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Sluggishness * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Thirst * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Infections and infestations                                               
Cystitis * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  1/27 (3.70%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Nasopharyngitis * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  1/27 (3.70%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  5/39 (12.82%)  1/42 (2.38%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Gastroenteritis * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Pharyngitis * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Injury, poisoning and procedural complications                                               
Contusion * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Scratch * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Skin Abrasion * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Arthropod Bite * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Investigations                                               
Blood Pressure Diastolic Increased * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  1/8 (12.50%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  0/32 (0.00%)  0/23 (0.00%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Blood Pressure Increased * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  1/5 (20.00%)  0/8 (0.00%)  0/12 (0.00%)  1/5 (20.00%)  1/23 (4.35%)  1/16 (6.25%)  0/16 (0.00%)  1/32 (3.13%)  4/23 (17.39%)  3/27 (11.11%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  2/20 (10.00%)  0/12 (0.00%)  1/17 (5.88%) 
Blood Pressure Systolic Increased * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Oxygen Saturation Decreased * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  1/5 (20.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
C-Reactive Protein Increased * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Metabolism and nutrition disorders                                               
Decreased Appetite * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  1/12 (8.33%)  1/39 (2.56%)  1/42 (2.38%)  1/11 (9.09%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Musculoskeletal and connective tissue disorders                                               
Back Pain * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  1/27 (3.70%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Limb Discomfort * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Muscle Tightness * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Myalgia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  1/17 (5.88%) 
Pain in Extremity * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Muscle Spasms * 1  0/54 (0.00%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Nervous system disorders                                               
Akathisia * 1  1/54 (1.85%)  0/11 (0.00%)  0/23 (0.00%)  1/5 (20.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Altered State of Consciousness * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Coordination Abnormal * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  1/27 (3.70%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Disturbance in Attention * 1  1/54 (1.85%)  0/11 (0.00%)  1/23 (4.35%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Dizziness * 1  1/54 (1.85%)  4/11 (36.36%)  0/23 (0.00%)  2/5 (40.00%)  0/8 (0.00%)  4/12 (33.33%)  3/5 (60.00%)  0/23 (0.00%)  2/16 (12.50%)  2/16 (12.50%)  11/32 (34.38%)  7/23 (30.43%)  9/27 (33.33%)  14/46 (30.43%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  7/20 (35.00%)  5/12 (41.67%)  5/17 (29.41%) 
Dizziness Postural * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  2/32 (6.25%)  2/23 (8.70%)  0/27 (0.00%)  4/46 (8.70%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  1/39 (2.56%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Dysaesthesia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  1/23 (4.35%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Dysgeusia * 1  9/54 (16.67%)  2/11 (18.18%)  6/23 (26.09%)  1/5 (20.00%)  1/8 (12.50%)  2/12 (16.67%)  3/5 (60.00%)  4/23 (17.39%)  2/16 (12.50%)  1/16 (6.25%)  4/32 (12.50%)  4/23 (17.39%)  6/27 (22.22%)  9/46 (19.57%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  4/20 (20.00%)  3/12 (25.00%)  4/17 (23.53%) 
Dysgraphia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  1/27 (3.70%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Dyskinesia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  1/20 (5.00%)  0/12 (0.00%)  0/17 (0.00%) 
Headache * 1  4/54 (7.41%)  4/11 (36.36%)  5/23 (21.74%)  0/5 (0.00%)  2/8 (25.00%)  3/12 (25.00%)  1/5 (20.00%)  4/23 (17.39%)  1/16 (6.25%)  2/16 (12.50%)  3/32 (9.38%)  4/23 (17.39%)  5/27 (18.52%)  5/46 (10.87%)  0/1 (0.00%)  1/4 (25.00%)  0/12 (0.00%)  0/39 (0.00%)  4/42 (9.52%)  2/11 (18.18%)  4/20 (20.00%)  2/12 (16.67%)  1/17 (5.88%) 
Hypersomnia * 1  0/54 (0.00%)  1/11 (9.09%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Hypoaesthesia * 1  0/54 (0.00%)  1/11 (9.09%)  1/23 (4.35%)  1/5 (20.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  1/23 (4.35%)  3/16 (18.75%)  0/16 (0.00%)  4/32 (12.50%)  3/23 (13.04%)  4/27 (14.81%)  8/46 (17.39%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  1/11 (9.09%)  3/20 (15.00%)  1/12 (8.33%)  0/17 (0.00%) 
Loss of Consciousness * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  1/16 (6.25%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Mental Impairment * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  1/12 (8.33%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  1/32 (3.13%)  0/23 (0.00%)  1/27 (3.70%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Paraesthesia * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  1/23 (4.35%)  0/27 (0.00%)  1/46 (2.17%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  1/42 (2.38%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%) 
Psychomotor Hyperactivity * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  1/8 (12.50%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  0/46 (0.00%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  0/12 (0.00%)  0/17 (0.00%) 
Sedation * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  1/8 (12.50%)  0/12 (0.00%)  1/5 (20.00%)  0/23 (0.00%)  0/16 (0.00%)  1/16 (6.25%)  1/32 (3.13%)  3/23 (13.04%)  2/27 (7.41%)  3/46 (6.52%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  3/20 (15.00%)  0/12 (0.00%)  1/17 (5.88%) 
Slow Speech * 1  0/54 (0.00%)  0/11 (0.00%)  0/23 (0.00%)  0/5 (0.00%)  0/8 (0.00%)  0/12 (0.00%)  0/5 (0.00%)  0/23 (0.00%)  0/16 (0.00%)  0/16 (0.00%)  0/32 (0.00%)  0/23 (0.00%)  0/27 (0.00%)  2/46 (4.35%)  0/1 (0.00%)  0/4 (0.00%)  0/12 (0.00%)  0/39 (0.00%)  0/42 (0.00%)  0/11 (0.00%)  0/20 (0.00%)  1/12 (8.33%)  0/17 (0.00%)