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Double-Blind, Placebo-Controlled Trial of Ketamine Therapy in Treatment-Resistant Depression (TRD)

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ClinicalTrials.gov Identifier: NCT01920555
Recruitment Status : Completed
First Posted : August 12, 2013
Results First Posted : April 17, 2018
Last Update Posted : June 19, 2018
Sponsor:
Collaborators:
National Institute of Mental Health (NIMH)
Baylor College of Medicine
Icahn School of Medicine at Mount Sinai
Stanford University
University of Texas
Yale University
Information provided by (Responsible Party):
Maurizio Fava, MD, Massachusetts General Hospital

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Treatment Resistant Depression
Interventions Drug: Ketamine
Drug: Placebo Midazolam
Enrollment 99
Recruitment Details  
Pre-assignment Details The screening period served as a wash-out period for any prohibited medications that could be discontinued safely. Discontinuation of medications were discussed in consultation with the prescribing clinician.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo)
Hide Arm/Group Description

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

Period Title: Overall Study
Started 18 20 22 20 19
Completed 14 16 21 17 18
Not Completed 4 4 1 3 1
Reason Not Completed
Physician Decision             1             2             1             2             0
Lack of Efficacy             2             0             0             0             0
Travel Difficulties             1             1             0             0             1
Lost to Follow-up             0             1             0             1             0
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo) Total
Hide Arm/Group Description

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

Total of all reporting groups
Overall Number of Baseline Participants 18 20 22 20 19 99
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants 99 participants
43.1  (11.9) 45.5  (14.6) 48.6  (12.9) 47.4  (10.1) 45.6  (13.8) 46.04  (12.64)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants 99 participants
Female
10
  55.6%
9
  45.0%
11
  50.0%
8
  40.0%
11
  57.9%
49
  49.5%
Male
8
  44.4%
11
  55.0%
11
  50.0%
12
  60.0%
8
  42.1%
50
  50.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants 99 participants
Hispanic or Latino
1
   5.6%
0
   0.0%
2
   9.1%
0
   0.0%
0
   0.0%
3
   3.0%
Not Hispanic or Latino
17
  94.4%
20
 100.0%
20
  90.9%
20
 100.0%
19
 100.0%
96
  97.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
BMI  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants 99 participants
25.2  (3.1) 24.9  (3.7) 25.3  (5.7) 26.1  (3.8) 26.3  (4.1) 24.96  (4.08)
Abnormal and Clinically Significant Labs   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants 99 participants
CBC
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Chemistry
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Hormonal Measures (testosterone, SHBG, Free T)
0
   0.0%
2
  10.0%
0
   0.0%
0
   0.0%
0
   0.0%
2
   2.0%
Hormonal Measures (DHEA)
0
   0.0%
0
   0.0%
0
   0.0%
1
   5.0%
0
   0.0%
1
   1.0%
Hormonal Measures (remaining tests)
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Pregnancy Test
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Urine Toxicology Screen
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
[1]
Measure Description: Collected at Screening and Day 0 (Day 0 is pre-treatment) CBC, Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid),Hormonal Measures in female subjects: Estradiol, Progesterone, FSH, LH, SHBG, Testosterone; Free testosterone, Hormonal Measures in male subjects: Testosterone, free testosterone, SHBG, DHEA, Progesterone, TSH, Pregnancy Test, Urine Tox Screen
1.Primary Outcome
Title Hamilton Rating Scale for Depression - 6 Items
Hide Description The HAMD6 is a 6-item clinician-rated scale, where clinicians rate the presence of depression symptoms (i.e., depressed mood, guilt, work and interests, psychomotor retardation, psychic anxiety, somatic symptoms) on a 5-point scale, where 0 = not present, and 1-4 represent increasingly severe symptoms. One item (i.e., somatic symptoms) is rated on only a 3-point scale, ranging from 0-2. The possible scale range is 0-22, where higher values represent more severe depression. This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms. This structured interview has been validated for use with time frames shorter than one week. In this study, the HAMD6 was used to assess symptoms occurring in the past 24 hours.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1, & 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
12.5555556  (1.8221585) 12.7500000  (2.4894514) 12.5909091  (1.4690162) 12.6315789  (2.0872770) 13.0526316  (2.2967050)
Day 1 Number Analyzed 16 participants 20 participants 22 participants 20 participants 19 participants
7.5000000  (4.3204938) 9.2631579  (3.6944719) 5.8636364  (4.4859087) 6.9000000  (4.5061362) 10.6666667  (3.3606722)
Day 3 Number Analyzed 15 participants 19 participants 22 participants 20 participants 19 participants
6.8000000  (4.6167397) 8.4736842  (4.9818384) 5.9047619  (4.3000554) 7.2000000  (3.8196170) 9.0555556  (4.5435439)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.14
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.18
Confidence Interval (2-Sided) 95%
-5.93 to -0.43
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.79
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.13
Confidence Interval (2-Sided) 95%
-3.75 to 1.49
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.01
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.79
Confidence Interval (2-Sided) 95%
-7.35 to -2.24
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.76
Confidence Interval (2-Sided) 95%
-6.37 to -1.15
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.04
Confidence Interval (2-Sided) 95%
-5.04 to 0.95
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.80
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.36
Confidence Interval (2-Sided) 95%
-3.18 to 2.46
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.14
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.12
Confidence Interval (2-Sided) 95%
-5.97 to -0.44
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.72
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.84
Confidence Interval (2-Sided) 95%
-4.65 to 0.96
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Montgomery-Asberg Depression Rating Scale (MADRS)
Hide Description The MADRS is a 10-item clinician-rated scale measuring depression severity. Symptoms are rated on a 7-point scale, where 0 = "not present", and 1-6 represent increasing severity. Values 2, 4, and 6 have specific anchoring text (e.g., 2="Difficulties in starting activities." 4="Difficulties in starting simple routine activities which are carried out with effort, 6="Complete lassitude. Unable to do anything without help.") Values 1, 3, and 5 do not have specific text. The possible scale range is 0-60, where higher values represent higher severity. In this study, the MADRS was used to rate symptoms occurring in the past 3 days.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0 and 3.
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
33.8333333  (5.9334545) 34.4500000  (8.4571676) 31.5909091  (3.9359042) 32.6500000  (5.8873191) 33.6315789  (7.0884141)
Day 3 Number Analyzed 15 participants 19 participants 21 participants 20 participants 18 participants
19.6666667  (10.8144524) 22.6315789  (11.7294052) 14.7619048  (8.9883523) 17.1000000  (11.5708345) 24.8333333  (10.5286723)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.33
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -5.15
Confidence Interval (2-Sided) 95%
-12.44 to 2.14
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.53
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.16
Confidence Interval (2-Sided) 95%
-9.03 to 4.72
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -9.85
Confidence Interval (2-Sided) 95%
-16.56 to -3.15
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were four pairwise comparisons of interest (see Analysis 1-4), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.08
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.72
Confidence Interval (2-Sided) 95%
-14.52 to -0.93
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Clinical Global Impressions–Severity (CGI-S)
Hide Description The CGI-S is a clinician rated single-item scale: "How depressed is the patient at this time?", rated on a 7-point response scale: 1 = Normal, not at all depressed, 2 = Borderline depressed, 3 = Mildly depressed, 4 = Moderately depressed. 5 = Markedly depressed, 6 = severely depressed, 7 = Among the most severely depressed patients. When rating patients, clinicians were asked to consider the past 24 hours.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
5.0000000  (0.7669650) 5.2000000  (0.6958524) 4.8636364  (0.6396021) 5.2000000  (0.7677719) 5.000000  (0.7453560)
Day 1 Number Analyzed 16 participants 19 participants 22 participants 20 participants 18 participants
3.5625000  (1.4591664) 4.2631579  (1.2401660) 3.2727273  (1.2792043) 3.5000000  (1.1002392) 4.555556  (0.7838234)
Day 3 Number Analyzed 15 participants 19 participants 21 participants 20 participants 18 participants
3.4000000  (1.6388149) 3.7368421  (1.4848159) 3.1428571  (1.3887301) 3.3000000  (1.4545754) 4.1666667  (1.3394468)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.08
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.03
Confidence Interval (2-Sided) 95%
-1.83 to -0.22
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.26
Confidence Interval (2-Sided) 95%
-1.02 to 0.51
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.00720
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.28
Confidence Interval (2-Sided) 95%
-2.02 to -0.54
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.04884
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.05
Confidence Interval (2-Sided) 95%
-1.81 to -0.29
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.48
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.71
Confidence Interval (2-Sided) 95%
-1.70 to 0.28
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.39
Confidence Interval (2-Sided) 95%
-1.32 to 0.55
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.16
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.00
Confidence Interval (2-Sided) 95%
-1.91 to -0.09
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.27
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.86
Confidence Interval (2-Sided) 95%
-1.78 to 0.07
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Clinical Global Impressions–Improvement (CGI-I) Scale
Hide Description The CGI-I is a clinician rated single-item scale: "Compared to the patient’s condition at admission, how much has the patient changed?", rated on a 7-point response scale: 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. In this case, "admission" referred to the CGI-S screening assessments performed between Day -28 an -7, one conducted during the screening visit, and a second rating conducted by a remote, independent rater.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
3.8888889  (0.3233808) 4.0500000  (0.2236068) 4.1363636  (0.7101613) 4.0000000  (0.4588315) 4.1578947  (0.6021404)
Day 1 Number Analyzed 16 participants 19 participants 22 participants 20 participants 18 participants
3.0625000  (1.4361407) 3.3684211  (1.0651305) 2.6363636  (0.9021379) 3.0500000  (1.2343760) 3.6111111  (0.6076850)
Day 3 Number Analyzed 15 participants 19 participants 22 participants 20 participants 18 participants
2.9333333  (1.2798809) 2.8421053  (1.2588865) 2.5714286  (0.9258201) 2.5500000  (1.0990426) 3.1666667  (1.0431852)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.54
Confidence Interval (2-Sided) 95%
-1.25 to 0.17
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.10
Confidence Interval (2-Sided) 95%
-0.78 to 0.58
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.98
Confidence Interval (2-Sided) 95%
-1.64 to -0.31
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.56
Confidence Interval (2-Sided) 95%
-1.24 to 0.11
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.19
Confidence Interval (2-Sided) 95%
-0.96 to 0.57
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.21
Confidence Interval (2-Sided) 95%
-0.93 to 0.51
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.52
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.64
Confidence Interval (2-Sided) 95%
-1.35 to 0.06
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.54
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.62
Confidence Interval (2-Sided) 95%
-1.33 to 0.10
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Symptoms of Depression Questionnaire (SDQ)
Hide Description The SDQ is a 44-item self-report scale, which aims to measure depression more comprehensively by including the assessment of symptoms in the anxiety–depression spectrum, including symptoms of irritability, anger attacks, and anxiety. Items are rated on an 6-point Likert scale, where participants are asked to rate if a specific symptom (e.g. "How has your mood been over the past 24 hours?") is normal for him or her (score = 2), what is better than normal (score = 1), and what is worse than normal (scores = 3–6). The total scale score is calculated by averaging across the items, resulting in a possible range from 1 to 6. Higher scores indicate greater depression severity. When rating, patients were asked to consider their symptoms during the past 24 hours.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
3.5164141  (0.5081856) 3.4636364  (0.5416735) 3.5392562  (0.5838397) 3.4113636  (0.4336652) 3.4264507  (0.4719770)
Day 1 Number Analyzed 16 participants 19 participants 22 participants 20 participants 18 participants
2.5752843  (0.7091841) 2.9096195  (0.7123910) 2.3109504  (0.6315677) 2.6113636  (0.500567) 2.9200573  (0.6464210)
Day 3 Number Analyzed 15 participants 18 participants 21 participants 20 participants 18 participants
2.5106061  (0.7158120) 2.7828283  (0.7398734) 2.5573593  (0.9017779) 2.5909091  (0.5736341) 2.8751353  (0.6668931)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.74
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.35
Confidence Interval (2-Sided) 95%
-0.79 to 0.08
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.04
Confidence Interval (2-Sided) 95%
-0.37 to 0.45
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.02
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.61
Confidence Interval (2-Sided) 95%
-1.01 to -0.21
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.80
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.31
Confidence Interval (2-Sided) 95%
-0.72 to 0.10
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.88
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.33
Confidence Interval (2-Sided) 95%
-0.83 to 0.18
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.05
Confidence Interval (2-Sided) 95%
-0.53 to 0.44
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.88
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.32
Confidence Interval (2-Sided) 95%
-0.79 to 0.15
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.88
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.29
Confidence Interval (2-Sided) 95%
-0.76 to 0.19
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Clinical Positive Affect Scale (CPAS)
Hide Description The CPAS is a 16-item self-report scale to assess the level to which participants experience persistent distress due to feeling that they have not returned to their normal or premorbid state. Items (e.g., "I look forward to things") are rated on a 5-point scale (0=not at all, 1=very much less than normal, 2=much less than normal, 3=slightly less than normal, 4=same as best or normal self). The possible scale range is 0 to 64, with higher scores indicating greater recovery from depression. Patients were asked to rate their experience of the past 24 hours.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
19.3333333  (12.1896774) 20.5000000  (15.4357753) 20.6363636  (11.7008158) 21.2500000  (14.6785737) 21.2631579  (12.1052886)
Day 1 Number Analyzed 16 participants 19 participants 22 participants 20 participants 18 participants
35.2500000  (20.9936498) 27.0526316  (18.8516833) 40.8696964  (19.5284785) 33.0000000  (16.2642650) 24.4444444  (15.2053482)
Day 3 Number Analyzed 15 participants 18 participants 21 participants 20 participants 16 participants
38.8666667  (22.8666667) 28.3888889  (20.2459550) 39.7619048  (22.5319878) 37.4500000  (18.7096232) 33.3750000  (15.8445574)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.49
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 11.18
Confidence Interval (2-Sided) 95%
-0.94 to 23.29
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.37
Confidence Interval (2-Sided) 95%
-10.19 to 12.93
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.03
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 16.54
Confidence Interval (2-Sided) 95%
5.31 to 27.77
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.82
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 8.68
Confidence Interval (2-Sided) 95%
-2.81 to 20.16
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 5.11
Confidence Interval (2-Sided) 95%
-8.83 to 19.05
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -6.64
Confidence Interval (2-Sided) 95%
-19.87 to 6.59
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 7.64
Confidence Interval (2-Sided) 95%
-5.26 to 20.53
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.80
Confidence Interval (2-Sided) 95%
-8.31 to 17.91
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Snaith-Hamilton Pleasure-Scale (SHAPS)
Hide Description The SHAPS is a 14-item self-report scale to measure hedonic tone. Items (e.g., "I would enjoy reading a book, magazine, or newspaper.") are rated on a 4-point scale (1=strongly disagree, 2=disagree, 3=agree, 4=strongly agree). Either of the ‘disagree’ responses scores 1 point, and either of the ‘agree’ responses scores 0 points, for a total scale range of 0-14. Higher scores indicate greater inability to experience pleasure. Patients were asked to rate their experience of the past 24 hours.
Time Frame A baseline assessment was made on Day 0, preceding infusion (i.e., treatment). Outcome assessments were made on days 1, 3, 5, 7, 14, and 30. The primary endpoint for this study was Day 3. Thus, the outcome measure table provides data on Days 0, 1 and 3
Hide Outcome Measure Data
Hide Analysis Population Description
Several subjects dropped out of the study in between Day 0, Day 1 and Day 3.
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Day 0 Number Analyzed 18 participants 20 participants 22 participants 20 participants 19 participants
7.2222222  (3.9040786) 7.5500000  (3.9132030) 6.5909091  (3.2316749) 7.3500000  (4.1961762) 6.4736842  (3.7471237)
Day 1 Number Analyzed 16 participants 19 participants 22 participants 20 participants 18 participants
3.9375000  (4.2812576) 5.7368421  (4.2536534) 2.22727273  (3.5748036) 4.3000000  (4.5664682) 5.0000000  (4.6272848)
Day 3 Number Analyzed 15 participants 18 participants 21 participants 20 participants 16 participants
3.5333333  (3.3777987) 6.3888889  (4.5262488) 3.0000000  (3.7815341) 3.6500000  (4.8370826) 4.2500000  (3.8384024)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.21
Confidence Interval (2-Sided) 95%
-3.99 to 1.56
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.17
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.76
Confidence Interval (2-Sided) 95%
-1.90 to 3.43
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.30
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.74
Confidence Interval (2-Sided) 95%
-5.32 to -0.16
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 1:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.71
Confidence Interval (2-Sided) 95%
-3.35 to 1.93
Estimation Comments [Not Specified]
Show Statistical Analysis 5 Hide Statistical Analysis 5
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.1 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.29
Confidence Interval (2-Sided) 95%
-3.25 to 2.66
Estimation Comments [Not Specified]
Show Statistical Analysis 6 Hide Statistical Analysis 6
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.2 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.39
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.76
Confidence Interval (2-Sided) 95%
-0.06 to 5.59
Estimation Comments [Not Specified]
Show Statistical Analysis 7 Hide Statistical Analysis 7
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 0.5 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.17
Confidence Interval (2-Sided) 95%
-3.91 to 1.58
Estimation Comments [Not Specified]
Show Statistical Analysis 8 Hide Statistical Analysis 8
Statistical Analysis Overview Comparison Group Selection Ketamine 0.1mg, Ketamine 0.2mg, Ketamine 0.5mg, Ketamine 1.0mg, Midazolam 0.045mg
Comments

Ketamine 1.0 mg/kg vs. midazolam at Day 3:

As estimated by the repeated measures fixed effects model with DAY (0, 1, 3), GROUP (5 groups as specified above), and the DAY*GROUP interaction effect. Because there were eight pairwise comparisons of interest (see Analysis 1-8), we used Holm’s method to protect family-wise error rate in the presence of multiple testing.

Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.00
Comments Holm’s method was applied to the model-produced differences of least squares for the eight a priori identified contrasts of interest, that is, the difference between each ketamine group vs. placebo at Days 1 and 3.
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.43
Confidence Interval (2-Sided) 95%
-3.22 to 2.35
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Clinician-Administered Dissociative States Scale (CADSS) Scores During Infusion
Hide Description The CADSS is a 23-item self-report scale for the assessment of dissociative states. It is a reliable, valid self-report instrument. The severity of each dissociative symptom ranges from 0 (not present) to 4 (extreme). The total score is calculated by summing across items, with a total possible range of 0-92. The CADSS was administered right before infusion, and 40, 80 minute and 120 minutes after the start of infusion. The timeframe is “at this moment”.
Time Frame Day 0/baseline at 0, 40, 80, and 120 minutes
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Mean (Standard Deviation)
Unit of Measure: units on a scale
Minute 0 0.1111111  (0.4714045) 0.1000000  (0.4472136) 0  (0) 0.1000000  (0.3077935) 0.4210526  (1.01739326)
Minute 40 3.0000000  (5.0758946) 4.0500000  (4.2608993) 14.2727273  (9.6076644) 24.6842105  (17.7108022) 2.6842105  (3.5127171)
Minute 80 0.4444444  (0.7838234) 0.1000000  (0.4472136) 0.7727273  (2.1141658) 1.8000000  (2.9664794) 1.1578947  (1.8337320)
Minute 120 0.0555556  (0.2357023) 0  (0) 0.1363636  (0.6396021) 0.6500000  (1.5985191) 0.5789474  (0.9015905)
9.Secondary Outcome
Title Number of Participants Reporting Suicidal Ideation/Behavior on the Columbia Suicide Severity Rating Scale (C-SSRS)
Hide Description The Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is a low-burden measure of the spectrum of suicidal ideation and behavior that was developed in the National Institute of Mental Health Treatment of Adolescent Suicide Attempters Study to assess severity and track suicidal events through any treatment. It is a clinical interview providing a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. The C-SSRS can also be used during treatment to monitor for clinical worsening or improvement. It contains 5 rating scale questions (yes/no) for suicidal ideation increasing severity and 5 rating scale questions (yes/no) for suicidal behavior of increasing severity. The time frame is for both lifetime and the past six months for the Baseline/Screening scale and since the last visit for the Since Last Visit scale.
Time Frame Screening Visit and Days 0, 1, 3, 5, 7, 14 and 30 combined
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Measure Type: Count of Participants
Unit of Measure: Participants
Screening: # with suicidal ideation/behavior
17
  94.4%
15
  75.0%
17
  77.3%
14
  70.0%
17
  89.5%
Follow-Up: # with suicidal ideation/behavior
15
  83.3%
9
  45.0%
10
  45.5%
6
  30.0%
13
  68.4%
10.Secondary Outcome
Title Number of Participants With Abnormal and Clinically Significant CBC and Chemistry Labs by Treatment
Hide Description
  1. CBC
  2. Chemistry (Total bilirubin, AST, ALT, GGT, ALK Phosphatase, Creatinine, BUN/Urea, Glucose, Uric Acid)

Testing was performed by study site laboratories and used institutional normal lab value ranges.

Time Frame Day 3 and Early Termination Visit (approximately 3 weeks following intervention)
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam 0.045mg
Hide Arm/Group Description:

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of Midazolam (active placebo) - one single infusion
Overall Number of Participants Analyzed 18 20 22 20 19
Measure Type: Count of Participants
Unit of Measure: Participants
Chemistry ALT(SGPT)
0
   0.0%
1
   5.0%
0
   0.0%
0
   0.0%
0
   0.0%
Chemistry AST(SGOT)
0
   0.0%
1
   5.0%
0
   0.0%
0
   0.0%
0
   0.0%
Chemistry Total Bilirubin
0
   0.0%
1
   5.0%
0
   0.0%
0
   0.0%
0
   0.0%
Chemistry Remaining Tests
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
CBC
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Time Frame Number of patients with adverse events post infusion (treatment) up to 30 days.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo)
Hide Arm/Group Description

Patients in this arm will receive 0.1 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.1 mg/kg - one single infusion

Patients in this arm will receive 0.2 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.2 mg/kg - one single infusion

Patients in this arm will receive 0.5 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 0.5 mg/kg - one single infusion

Patients in this arm will receive 1.0 mg/kg of Ketamine - one single infusion

Ketamine: Dose of Ketamine will be 1.0 mg/kg - one single infusion

Patients in this arm will receive 0.045 mg/kg of midazolam - one single infusion

Placebo Midazolam: Dose of Midazolam (active placebo) will be 0.045 mg/kg - one single infusion

All-Cause Mortality
Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/18 (0.00%)      0/20 (0.00%)      0/22 (0.00%)      0/20 (0.00%)      0/19 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/18 (0.00%)      1/20 (5.00%)      0/22 (0.00%)      0/20 (0.00%)      0/19 (0.00%)    
Psychiatric disorders           
Suicide Attempt   0/18 (0.00%)  0 1/20 (5.00%)  1 0/22 (0.00%)  0 0/20 (0.00%)  0 0/19 (0.00%)  0
Indicates events were collected by systematic assessment
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Ketamine 0.1mg Ketamine 0.2mg Ketamine 0.5mg Ketamine 1.0mg Midazolam (Active Placebo)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   17/18 (94.44%)      18/20 (90.00%)      14/22 (63.64%)      17/20 (85.00%)      10/19 (52.63%)    
Blood and lymphatic system disorders           
White Blood Cell Count Decreased   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Cardiac disorders           
Blood Pressure Increase   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  2/20 (10.00%)  0/19 (0.00%) 
Tachycardia   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Hypertension   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Gastrointestinal disorders           
Nausea   2/18 (11.11%)  0/20 (0.00%)  3/22 (13.64%)  3/20 (15.00%)  0/19 (0.00%) 
Vomiting   1/18 (5.56%)  1/20 (5.00%)  1/22 (4.55%)  1/20 (5.00%)  0/19 (0.00%) 
Dyspepsia   0/18 (0.00%)  2/20 (10.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Diarrhea   1/18 (5.56%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Increased Appetite   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
General disorders           
Dizziness   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Presyncope   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Hepatobiliary disorders           
Hepatic Enzyme Increased   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Infections and infestations           
Tooth Abscess   0/18 (0.00%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Gastroenteritis Viral   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Respiratory Tract Infection   0/18 (0.00%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Sinusitis   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Upper Respiratory Tract Infection   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Viral Upper Respiratory Tract Infection   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Injury, poisoning and procedural complications           
Exposure to Toxic Agent   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Fall   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Musculoskeletal and connective tissue disorders           
Back Pain   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Pain In Extremity   1/18 (5.56%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Arthralgia   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Nervous system disorders           
Headache   3/18 (16.67%)  2/20 (10.00%)  1/22 (4.55%)  3/20 (15.00%)  0/19 (0.00%) 
Asthenia   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Loss of Consciousness   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Psychiatric disorders           
Depression   1/18 (5.56%)  1/20 (5.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Abnormal Dreams   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  1/19 (5.26%) 
Insomnia   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Poor Quality Sleep   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Suicidal Ideation   1/18 (5.56%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Dissociation   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  1/20 (5.00%)  0/19 (0.00%) 
Initial Insomnia   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Intentional Self-Injury   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Malaise   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Overdose   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Self Injurious Behavior   0/18 (0.00%)  0 0/20 (0.00%)  0 0/22 (0.00%)  0 0/20 (0.00%)  0 1/19 (5.26%)  1
Reproductive system and breast disorders           
Blood Testosterone   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Respiratory, thoracic and mediastinal disorders           
Nasal Congestion   0/18 (0.00%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  1/19 (5.26%) 
Cough   0/18 (0.00%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Skin and subcutaneous tissue disorders           
Dermatitis   0/18 (0.00%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  1/19 (5.26%) 
Dermatitis Contact   0/18 (0.00%)  1/20 (5.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Vascular disorders           
Flushing   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Hot Flush   1/18 (5.56%)  0/20 (0.00%)  0/22 (0.00%)  0/20 (0.00%)  0/19 (0.00%) 
Vertigo   0/18 (0.00%)  0/20 (0.00%)  1/22 (4.55%)  0/20 (0.00%)  0/19 (0.00%) 
Indicates events were collected by systematic assessment
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Maurizio Fava, MD
Organization: Massachusetts General Hospital
Phone: 617-724-2513
Publications:
Responsible Party: Maurizio Fava, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01920555     History of Changes
Other Study ID Numbers: RAP-003
271201100006I-0-27100007-1 ( U.S. NIH Grant/Contract )
First Submitted: August 8, 2013
First Posted: August 12, 2013
Results First Submitted: December 28, 2017
Results First Posted: April 17, 2018
Last Update Posted: June 19, 2018