Trial Outcomes & Findings for A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD) (NCT NCT03149991)

Last Updated: 2020-07-24

Results Overview

Superiority will be demonstrated by a statistically significant greater decrease (p\<0.05, 2 sided) on the SDQ total score for participants receiving brexpiprazole versus placebo therapy. Symptoms of Depression Questionnaire (SDQ): This validated self-rating instrument has 44 items on a scale of 1-6, measuring multiple depressive symptom domains, with higher scores indicating worse depression symptoms. Participants reported on their experiences over the past three days.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

51 participants

Primary outcome timeframe

SDQ was assessed on Days 0, 1, 2, 5, 8, 11, 14, 17, 21, 23, 28

Results posted on

2020-07-24

Participant Flow

Participant milestones

Participant milestones
Measure	Ketamine/Brexpiprazole Arm Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Overall Study STARTED	25	26
Overall Study Completed Primary Endpoint (Day 14)	25	24
Overall Study Exited	4	2
Overall Study COMPLETED	21	24
Overall Study NOT COMPLETED	4	2

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

A Study of Brexpiprazole Plus Ketamine in Treatment-Resistant Depression (TRD)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Total n=51 Participants Total of all reporting groups
Age, Continuous	40.8 years STANDARD_DEVIATION 12.4 • n=5 Participants	44.6 years STANDARD_DEVIATION 13.9 • n=7 Participants	42.7 years STANDARD_DEVIATION 13.2 • n=5 Participants
Sex: Female, Male Female	14 Participants n=5 Participants	12 Participants n=7 Participants	26 Participants n=5 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	14 Participants n=7 Participants	25 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	22 Participants n=5 Participants	25 Participants n=7 Participants	47 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	2 Participants n=7 Participants	5 Participants n=5 Participants
Race (NIH/OMB) White	21 Participants n=5 Participants	23 Participants n=7 Participants	44 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Clinical Severity at Baseline -SDQ	3.7 units on a scale STANDARD_DEVIATION 0.6 • n=5 Participants	3.7 units on a scale STANDARD_DEVIATION 0.5 • n=7 Participants	3.7 units on a scale STANDARD_DEVIATION 0.6 • n=5 Participants
Clinical Severity at Baseline- MADRS	33.8 units on a scale STANDARD_DEVIATION 4.0 • n=5 Participants	34.2 units on a scale STANDARD_DEVIATION 5.5 • n=7 Participants	34.0 units on a scale STANDARD_DEVIATION 4.8 • n=5 Participants
Clinical Severity at Baseline- HAM-D6	12.0 units on a scale STANDARD_DEVIATION 2.0 • n=5 Participants	11.9 units on a scale STANDARD_DEVIATION 2.2 • n=7 Participants	12.0 units on a scale STANDARD_DEVIATION 2.1 • n=5 Participants
Clinical Severity at Baseline- CGI-S	5.0 units on a scale STANDARD_DEVIATION 0.6 • n=5 Participants	4.8 units on a scale STANDARD_DEVIATION 0.7 • n=7 Participants	4.9 units on a scale STANDARD_DEVIATION 0.7 • n=5 Participants
Clinical Severity at Baseline- CGI-I	4.2 units on a scale STANDARD_DEVIATION 0.4 • n=5 Participants	4.2 units on a scale STANDARD_DEVIATION 0.5 • n=7 Participants	4.2 units on a scale STANDARD_DEVIATION 0.4 • n=5 Participants
Duration of Current Major Depressive Episode	4.6 years STANDARD_DEVIATION 6.1 • n=5 Participants	4.3 years STANDARD_DEVIATION 7.0 • n=7 Participants	4.4 years STANDARD_DEVIATION 6.5 • n=5 Participants
Number of current comorbid psychiatric conditions	0.1 Conditions STANDARD_DEVIATION 0.3 • n=5 Participants	0.2 Conditions STANDARD_DEVIATION 0.5 • n=7 Participants	0.1 Conditions STANDARD_DEVIATION 0.4 • n=5 Participants
Number of comorbid medical conditions	2.6 Conditions STANDARD_DEVIATION 2.0 • n=5 Participants	2.5 Conditions STANDARD_DEVIATION 1.9 • n=7 Participants	2.5 Conditions STANDARD_DEVIATION 1.9 • n=5 Participants

PRIMARY outcome

Timeframe: SDQ was assessed on Days 0, 1, 2, 5, 8, 11, 14, 17, 21, 23, 28

Population: A total of 54 people were randomized, but only 51 received the study drug or placebo and were included in outcome analyses. Of these, 49 (96%) completed study assessments for the primary endpoint, and n=45 (88%) completed the study. See participant flow data for more information.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 28	2.9 score on a scale Standard Deviation 0.6	3.0 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 0	3.7 score on a scale Standard Deviation 0.6	3.7 score on a scale Standard Deviation 0.5
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 1	3.5 score on a scale Standard Deviation 0.6	3.5 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 2	3.5 score on a scale Standard Deviation 0.6	3.3 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 5	3.4 score on a scale Standard Deviation 0.6	3.3 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 8	3.3 score on a scale Standard Deviation 0.5	3.2 score on a scale Standard Deviation 0.5
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 11	3.1 score on a scale Standard Deviation 0.5	3.1 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 14	3.0 score on a scale Standard Deviation 0.5	3.2 score on a scale Standard Deviation 0.7
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 17	3.1 score on a scale Standard Deviation 0.6	3.2 score on a scale Standard Deviation 0.7
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 21	3.0 score on a scale Standard Deviation 0.7	3.2 score on a scale Standard Deviation 0.6
Change From Baseline on Symptoms of Depression Questionnaire (SDQ) SDQ, Day 23	2.8 score on a scale Standard Deviation 0.6	3.0 score on a scale Standard Deviation 0.6

SECONDARY outcome

Timeframe: MADRS was assessed on Days 0, 2, 3, 8, 11, 14, 17, 21, 23, 28; 50% reduction compared Day 28 to Baseline.

The table below compares percentages of participants in each arm who achieved a 50% or greater reduction on the Montgomery-Asberg Depression Rating Scale (MADRS) on Day 28 compared with baseline. This 10- item clinician-rated instrument measures depression severity with higher scores indicating more severity. Each item can be scored from 0 to 6 for a total sore range of 0 to 60. It was administered with a structured interview guide. Experiences over the past 3 days were rated.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Long-term Sustained Response, as Measured by Achieving a 50% Reduction on the Montgomery-Asberg Depression Rating Scale (MADRS) on Day 28 (Number and Percentage of Participants Achieving Sustained Response Reported)	10 Participants	8 Participants

SECONDARY outcome

Timeframe: These secondary outcome variables were assessed on Days 0, 1 (except for MADRS this day), 2, 5, 8, 11, 14, 17, 21, 23, 28

Montgomery-Asberg Depression Rating Scale (MADRS):This 10-item clinician-rated instrument measures depression severity. Total score range of 0-60 with higher scores indicating more severity. 6-item Hamilton Rating Scale for Depression (HAM-D6): This instrument is completed with a structured interview guide by the clinician based on his/her assessment of the patient's symptoms, with higher scores indicating worse depression. Scores range from 0-22. Experiences were rated based on the past 3 days. Clinical Global Impressions-Severity (CGI-S) and Clinical Global Impressions-Improvement (CGI-I) scales: These clinician-rated scales rate the severity of the disorder and the global improvement since beginning of the study. Further information is in the baseline measures section.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Efficacy on Secondary Outcome Variables CGI-S, Day 1	4.56 score on a scale Standard Deviation 0.77	4.15 score on a scale Standard Deviation 0.73
Efficacy on Secondary Outcome Variables CGI-S, Day 2	4.61 score on a scale Standard Deviation 0.66	4.12 score on a scale Standard Deviation 0.59
Efficacy on Secondary Outcome Variables CGI-S, Day 5	4.33 score on a scale Standard Deviation 0.92	4 score on a scale Standard Deviation 1.02
Efficacy on Secondary Outcome Variables CGI-S, Day 8	4.29 score on a scale Standard Deviation 0.95	3.68 score on a scale Standard Deviation 1.22
Efficacy on Secondary Outcome Variables CGI-S, Day 11	3.78 score on a scale Standard Deviation 1.04	3.38 score on a scale Standard Deviation 1.13
Efficacy on Secondary Outcome Variables CGI-S, Day 14	3.48 score on a scale Standard Deviation 1.08	3.33 score on a scale Standard Deviation 1.24
Efficacy on Secondary Outcome Variables MADRS, Day 0	33.84 score on a scale Standard Deviation 4.03	34.19 score on a scale Standard Deviation 5.54
Efficacy on Secondary Outcome Variables MADRS, Day 2	31.87 score on a scale Standard Deviation 5.96	28.19 score on a scale Standard Deviation 6.79
Efficacy on Secondary Outcome Variables MADRS, Day 5	29.46 score on a scale Standard Deviation 7.56	27.42 score on a scale Standard Deviation 8.75
Efficacy on Secondary Outcome Variables MADRS, Day 8	27.64 score on a scale Standard Deviation 7.60	24.48 score on a scale Standard Deviation 9.16
Efficacy on Secondary Outcome Variables MADRS, Day 11	23.63 score on a scale Standard Deviation 8.94	21.83 score on a scale Standard Deviation 9.95
Efficacy on Secondary Outcome Variables MADRS, Day 14	21.28 score on a scale Standard Deviation 9.53	22.08 score on a scale Standard Deviation 12.10
Efficacy on Secondary Outcome Variables MADRS, Day 17	20.92 score on a scale Standard Deviation 10.92	23.52 score on a scale Standard Deviation 12.07
Efficacy on Secondary Outcome Variables MADRS, Day 21	20.5 score on a scale Standard Deviation 12.34	23.75 score on a scale Standard Deviation 10.63
Efficacy on Secondary Outcome Variables MADRS, Day 23	18.36 score on a scale Standard Deviation 11.29	23.57 score on a scale Standard Deviation 10.53
Efficacy on Secondary Outcome Variables MADRS, Day 28	18.39 score on a scale Standard Deviation 11.86	22.13 score on a scale Standard Deviation 9.98
Efficacy on Secondary Outcome Variables HAMD6, Day 0	11 score on a scale Standard Deviation 3.37	11.6 score on a scale Standard Deviation 2.07
Efficacy on Secondary Outcome Variables HAMD6, Day 1	10.24 score on a scale Standard Deviation 2.35	9.19 score on a scale Standard Deviation 3.09
Efficacy on Secondary Outcome Variables HAMD6, Day 2	10.48 score on a scale Standard Deviation 2.45	8.62 score on a scale Standard Deviation 3.51
Efficacy on Secondary Outcome Variables HAMD6, Day 5	10.08 score on a scale Standard Deviation 2.53	9.21 score on a scale Standard Deviation 3.09
Efficacy on Secondary Outcome Variables HAMD6, Day 8	9.4 score on a scale Standard Deviation 2.58	7.64 score on a scale Standard Deviation 4.13
Efficacy on Secondary Outcome Variables HAMD6, Day 11	7.96 score on a scale Standard Deviation 3.03	7.71 score on a scale Standard Deviation 4.14
Efficacy on Secondary Outcome Variables HAMD6, Day 14	7.36 score on a scale Standard Deviation 3.0	7.54 score on a scale Standard Deviation 4.68
Efficacy on Secondary Outcome Variables HAMD6, Day 17	6.96 score on a scale Standard Deviation 3.79	8.09 score on a scale Standard Deviation 4.33
Efficacy on Secondary Outcome Variables HAMD6, Day 21	6.83 score on a scale Standard Deviation 3.82	7.83 score on a scale Standard Deviation 4.25
Efficacy on Secondary Outcome Variables HAMD6, Day 23	6.68 score on a scale Standard Deviation 3.41	7.48 score on a scale Standard Deviation 4.18
Efficacy on Secondary Outcome Variables HAMD6, Day 28	6.43 score on a scale Standard Deviation 4.04	7.58 score on a scale Standard Deviation 3.69
Efficacy on Secondary Outcome Variables CGI-S, Day 0	4.96 score on a scale Standard Deviation 0.61	4.77 score on a scale Standard Deviation 0.71
Efficacy on Secondary Outcome Variables CGI-S, Day 17	3.42 score on a scale Standard Deviation 1.32	3.48 score on a scale Standard Deviation 1.34
Efficacy on Secondary Outcome Variables CGI-S, Day 21	3.46 score on a scale Standard Deviation 1.44	3.58 score on a scale Standard Deviation 1.21
Efficacy on Secondary Outcome Variables CGI-S, Day 23	3.14 score on a scale Standard Deviation 1.39	3.48 score on a scale Standard Deviation 1.27
Efficacy on Secondary Outcome Variables CGI-S, Day 28	3.17 score on a scale Standard Deviation 1.56	3.46 score on a scale Standard Deviation 1.14
Efficacy on Secondary Outcome Variables CGI-I, Day 0	4.16 score on a scale Standard Deviation 0.37	4.15 score on a scale Standard Deviation 0.46
Efficacy on Secondary Outcome Variables CGI-I, Day 1	3.8 score on a scale Standard Deviation 0.5	3.35 score on a scale Standard Deviation 0.85
Efficacy on Secondary Outcome Variables CGI-I, Day 2	3.65 score on a scale Standard Deviation 0.78	3.42 score on a scale Standard Deviation 0.76
Efficacy on Secondary Outcome Variables CGI-I, Day 5	3.5 score on a scale Standard Deviation 0.78	3.29 score on a scale Standard Deviation 1.0
Efficacy on Secondary Outcome Variables CGI-I, Day 8	3.2 score on a scale Standard Deviation 0.87	2.92 score on a scale Standard Deviation 1.0
Efficacy on Secondary Outcome Variables CGI-I, Day 11	2.87 score on a scale Standard Deviation 0.92	2.7 score on a scale Standard Deviation 0.92
Efficacy on Secondary Outcome Variables CGI-I, Day 14	2.8 score on a scale Standard Deviation 0.96	2.54 score on a scale Standard Deviation 0.98
Efficacy on Secondary Outcome Variables CGI-I, Day 17	2.67 score on a scale Standard Deviation 1.09	2.83 score on a scale Standard Deviation 1.19
Efficacy on Secondary Outcome Variables CGI-I, Day 21	2.75 score on a scale Standard Deviation 1.29	2.83 score on a scale Standard Deviation 1.13
Efficacy on Secondary Outcome Variables CGI-I, Day 23	2.41 score on a scale Standard Deviation 1.18	2.74 score on a scale Standard Deviation 1.14
Efficacy on Secondary Outcome Variables CGI-I, Day 28	2.48 score on a scale Standard Deviation 1.27	2.54 score on a scale Standard Deviation 1.18

SECONDARY outcome

Timeframe: Blood pressure was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21. This vital sign was measured 6 times following the intranasal administration of ketamine: 15 minutes post dose, 30 minutes post dose, 45 minutes

Blood pressure was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21. This vital sign was measured 6 times following the intranasal administration of ketamine: 15 minutes post dose, 30 minutes post dose, 45 minutes post dose, 1 hour post dose, 90 minutes post dose, and 2 hours post dose. Average blood pressure per group was assessed. Medical staff monitoring the ketamine administration were prepared to treat increases in blood pressure greater than 180/110 mm Hg or follow their institutional guidelines if more conservative, if these elevations did not resolve spontaneously within a short time period. Data presented are number of participants with elevated blood pressure at any of the listed time points.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Number of Participants With Abnormal Vital Signs (Elevated Blood Pressure)	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Heart rate was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21.

Heart rate was measured during each administration of ketamine, occurring on days 0, 5, 8, 11, 14, and 21. This vital sign was measured 6 times following the intranasal administration of ketamine: 15 minutes post dose, 30 minutes post dose, 45 minutes post dose, 1 hour post dose, 90 minutes post dose, and 2 hours post dose. Average heart rate per group was assessed. Medical staff monitoring the ketamine administration were prepared to treat heart rate greater than 110 bpm, or follow their institutional guidelines if more conservative, if these elevations did not resolve spontaneously within a short time period. Data presented are number of participants with elevated heart rate at any of the listed time points.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Number of Participants With Abnormal Vital Signs (Elevated Heart Rate)	1 Participants	1 Participants

SECONDARY outcome

Timeframe: ECGs were conducted at baseline and 5, 8, 11, 14, and 21 days after baseline

Electrocardiograms (ECGs) were conducted at baseline, and follow-up visits conducted 5, 8, 11, 14, and 21 days after baseline. Any found to be abnormal were evaluated by a clinician as to the clinical significance of the ECG abnormality.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Total Number of Abnormal ECGs	60 Number of abnormal ECGs	56 Number of abnormal ECGs

SECONDARY outcome

Timeframe: ECGs were conducted at baseline and 5, 8, 11, 14, and 21 days after baseline

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Baseline	12 participants	9 participants
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Day 5	9 participants	9 participants
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Day 8	11 participants	12 participants
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Day 11	10 participants	10 participants
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Day 14	10 participants	7 participants
Safety and Tolerability Outcomes: 12-lead Electrocardiogram (ECG) - Number of Participants With Abnormal ECGs # of participants with abnormal ECGs, Day 21	8 participants	9 participants

SECONDARY outcome

Timeframe: Chemistry and CBC laboratory tests were obtained during screening and on Day 14 and 28 follow-ups

Chemistry and CBC laboratory tests were obtained during the screening visit and on Day 14 and 28 follow-ups. If a test result was abnormal (i.e., outside of the site-specific pre-specified range of expected values), it was evaluated by a clinician as to its clinical significance.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Number of Participants With Abnormal Laboratory Test Results Abnormal lab results at Screening	1 Participants	2 Participants
Safety and Tolerability Outcomes: Number of Participants With Abnormal Laboratory Test Results Abnormal lab results at Day 14	1 Participants	0 Participants
Safety and Tolerability Outcomes: Number of Participants With Abnormal Laboratory Test Results Abnormal lab results at Day 28	1 Participants	0 Participants

SECONDARY outcome

Timeframe: Adverse events were recorded on a rolling basis from screening through Day 28

Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28). For patients who reported any AEs, the average number of AEs per person per group were recorded. Site investigators rated whether AEs were possibly or probably related to treatment.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Treatment-emergent Adverse Events (Number of Participants Reporting)	17 Participants	18 Participants

SECONDARY outcome

Timeframe: The outcome was recorded on a rolling basis from screening through Day 28

Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28). For patients who reported any adverse events, the mean number of adverse events per person per group were calculated and are reported below.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Treatment-emergent Adverse Events (Average Number Per Person Per Group)	3.8 Adverse events Standard Error 3.1	3.6 Adverse events Standard Error 3.5

SECONDARY outcome

Timeframe: The CHRT was used at each study visit through Day 28

The clinician rated behavioral module of the Concise Health Risk Tracking (CHRT) scale was used at each study visit to identify suicidal ideation and behavior. The first item assesses suicidal ideation. All subsequent items assess suicidal behavior. The below table is for Item 1.

Outcome measures

Outcome measures
Measure	Ketamine/Brexpiprazole Arm n=25 Participants Brexpiprazole up to 3 mg/day for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks	Ketamine/Placebo Arm n=26 Participants Placebo for four weeks in combination with bi-weekly administration of intranasal ketamine (40 mg) for two weeks, followed by weekly administration of intranasal ketamine (40 mg) for two weeks
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Screening	9 Participants	4 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Baseline	4 Participants	4 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 1	5 Participants	5 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 2	5 Participants	2 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 5	5 Participants	7 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 8	5 Participants	8 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 11	3 Participants	3 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 14	5 Participants	3 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 17	4 Participants	2 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 21	4 Participants	3 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 23	2 Participants	4 Participants
Safety and Tolerability Outcomes: Suicidal Ideation and Behavior Suicidal Ideation-Day 28	2 Participants	4 Participants

Adverse Events

Brexpiprazole

Serious events: 0 serious events

Other events: 17 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Rebecca Hock

Massachusetts General Hospital

Phone: 617-872-3711

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Brexpiprazole n=25 participants at risk Brexpiprazole combined with intranasal ketamine	Placebo n=26 participants at risk Placebo combined with intranasal ketamine
Ear and labyrinth disorders Dizziness	16.0% 4/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	26.9% 7/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Headache	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	23.1% 6/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Alteration in Taste	16.0% 4/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	7.7% 2/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Dissociation/Detachment	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	11.5% 3/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Insomnia/Sleep disturbance	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	11.5% 3/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Restlessness/Akathisia	12.0% 3/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Sedation	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Gastrointestinal disorders Constipation	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Euphoria	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Gastrointestinal disorders Gastric Distress	8.0% 2/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Reproductive system and breast disorders Irregular/Early Menses	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Gastrointestinal disorders Nausea	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Musculoskeletal and connective tissue disorders Bi-lateral hand pain	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Eye disorders Blurred vision	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Bruxism	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Diplopia	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Dry mouth	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Hepatobiliary disorders Elevated alt	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Reproductive system and breast disorders Hot flashes	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Increased salivation post dose	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Gastrointestinal disorders Increased appetite	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Irritability	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Lethargy	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Light headedness	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Lower extremity edema, bilateral	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Musculoskeletal and connective tissue disorders Muscle aches	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Panic episode	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Restless legs	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Shakiness	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
General disorders Tachycardia	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Tinnitus	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Twitching of left side lower lip	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Nervous system disorders Unsteadiness of gait	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Renal and urinary disorders Urinary hesitancy	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Vivid dreams	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Metabolism and nutrition disorders Weight gain	4.0% 1/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	0.00% 0/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).
Psychiatric disorders Suicidal Ideation	0.00% 0/25 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).	3.8% 1/26 • Adverse events were recorded on a rolling basis from screening until the last day of the study (i.e., Day 28).