Major Depressive Disorder
Conditions
Keywords
Major Depressive Disorder (MDD)
Brief summary
The purpose of this study is to assess the safety and tolerability of ascending multiple oral doses of brexpiprazole as adjunctive therapy in the treatment of elderly subjects with MDD.
Detailed description
This is a phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose trial in 3 sequential cohorts of elderly subjects (age 70 to 85 years old) with MDD. Brexpiprazole will be administered as an adjunct treatment to the current antidepressant therapy that the subject is receiving. Total individual subject duration is expected to be no more than 119 days (a 30-day screening period, a 14-day washout period, up to 45-day in-clinic treatment period, and a 30-day follow-up after the last dose of trial medication).
Interventions
DRUGBrexpiprazole
up to 3mg oral dose once daily
DRUGPlacebo
Sponsors
H. Lundbeck A/S
Otsuka Pharmaceutical Development & Commercialization, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
70 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Subjects who are able to provide written informed consent * Ability to understand the nature of the trial and follow protocol requirements * Male and female patients 70 to 85 years of age * Subjects with normal or clinically stable findings on physical examination, medical history, clinical laboratory determinations, ECGs in relation to age * BMI of 18 to 35 kg/m2. * Stable subjects with a principal psychiatric diagnosis of MDD * Subjects willing to discontinue all prohibited psychotropic and other prohibited medication
Exclusion criteria
* Sexually active males who are not practicing 2 different methods of birth control during the trial and for 30 days after the last dose of trial medication or who will not remain abstinent during the trial and for 30 days after the last dose * Subjects who have had a vagus nerve stimulation device implanted or who have received ECT within 6 months of Screening * Subjects with a current Axis I (DSM-IV-TR) diagnosis of: * Delirium, dementia, amnestic, or other cognitive disorder * Eating disorder (including anorexia nervosa or bulimia) * Obsessive-compulsive disorder * Panic disorder * Posttraumatic stress disorder or current or prior Axis I (DSM-IV-TR) diagnosis of Schizophrenia, schizoaffective disorder, or other psychotic disorder, Bipolar I or II disorder or bipolar disorder not otherwise specified * Subjects with a clinically significant current Axis II (DSM-IV-TR) diagnosis of borderline, antisocial, paranoid, schizoid, schizotypal, or histrionic personality disorder * Subjects experiencing hallucinations, delusions, or any psychotic symptomatology * Subjects who have Active Suicidal Ideation with Some Intent to Act and whose most recent episode occurred within the last 6 months * Subjects who have met DSM-IV-TR criteria for substance abuse or dependence within the past 180 days * Subjects with hypothyroidism or hyperthyroidism and/or an abnormal result for free T4 at Screening * Subjects who currently have clinically significant neurological, hepatic, renal, metabolic, hematological, immunological, cardiovascular, pulmonary, or gastrointestinal disorders * Subjects with IDDM * Subjects with uncontrolled hypertension (DBP \> 95 mmHg) or symptomatic hypotension * Subjects with epilepsy, a history of epilepsy, or a history of seizure * Subjects with a positive drug screen for cocaine or other drugs of abuse * The following laboratory test and ECG results are exclusionary: 1. Platelets ≤ 75,000/mm3 2. Hemoglobin ≤ 9 g/dL 3. Neutrophils, absolute ≤ 1000/mm3 4. AST \> 3 × upper limit of normal 5. ALT \> 3 × upper limit of normal 6. Creatinine ≥ 2 mg/dL 7. HbA1c ≥ 7% 8. QTcF ≥ 450 msec * Treatment with a MAOI within the 2 weeks prior to the first dose of trial medication * Use of benzodiazepines and/or hypnotics within 1 week prior the first dose of trial medication * Use of oral neuroleptics within 30 days prior to or long-acting approved neuroleptics ≤ 1 full cycle plus 14 days prior to the first dose of trial medication on Day 1 * Prohibited concomitant medications used prior to randomization or anticipated need for such medications during the trial * Subjects who would be likely to require prohibited concomitant therapy during the trial * Subjects who received brexpiprazole in any prior clinical trial * Subjects with a history of neuroleptic malignant syndrome * Subjects with a history of true allergic response to more than 1 class of medications * Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness * Subjects who participated in a clinical trial within the last 180 days or who participated in more than 2 clinical trials within the past year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Tolerated Brexpiprazole | 45 Days | Safety and tolerability of brexpiprazole was noted to be primary outcome measure. Brexpiprazole was judged to be tolerated if at least 6 out of 8 (75%) of the participants in a test cohort tolerated the dose after 14 days of QD dosing at the end of the fixed dose phase based on the blinded data. Dose toleration was defined as follows: during the course of the trial, the participants did not experience any moderate or severe adverse events (AEs) or potentially clinically relevant changes from Baseline in laboratory values, vital signs, electrocardiogram (ECG) tracings, Columbia-Suicide Severity Rating Scale (C-SSRS), or extrapyramidal symptom (EPS) ratings, which were assessed as possibly related to the study drug, and would have warranted a dose decrease or discontinuation of the study drug. The safety and tolerability of brexpiprazole was defined by parameters: AEs, laboratory values, vital signs, ECG, C-SSRS, or EPS ratings, the results of each of the parameters reported separately. |
| Number of AEs Reported. | Throughout the study, up to 119 days | The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial. AEs were measured throughout the 14-day titration and 28-day fixed dose phase until follow-up (30 \[±2\] days after last dose of study medication). |
| Incidence of Laboratory Values of Potential Clinical Significance | Titration Day 7, Fixed dose Day 14 and 28 and Last Visit | The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria. |
| Incidence of Vital Signs of Potential Clinical Significance | Baseline, Titration Day 1, 2, 7, 8, Fixed Days 1, 2, 14, 15, 28, 29, Early Termination and Last Visit. | The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria. |
| Incidence of ECG Evaluations of Potential Clinical Significance | Titratrion Day 1 and 7, Fixed dose Day 1, 14, 28, Early Termination | The measurement of ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in heart rate and ECG intervals of PR, QRS, QT, QTcB, and QTcF that were identified based on pre-defined criteria. |
| Incidence of Physical Examination Evaluation of Potential Clinical Significance | Physical examination was performed at Screening, check-in, and discharge | The physical examination evaluation was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae. |
| Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | End of Titration, Day 15, Day 29, Early Termination and Last visit | EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The SAS is a rating scale used to measure EPS. The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40. |
| Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | End of Titration, Day 15, Day 29, Early Termination and Last visit | EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The Barnes Akathisia Rating Scale was an EPS rating scale. The Barnes Akathisia Rating Scale was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia). |
| Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | End of Titration, Day 15, Day 29, Early Termination and Last visit | EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The AIMS Scale was an EPS rating scale. The AIMS is a 12 item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28. |
| Change From Baseline to Study Completion in C-SSRS Score. | Baseline, End of Titration, Fixed dose Day 14 and 28, Day 15 and 29, Early Termination, Last Visit | The C-SSRS was one of the primary parameters to measure the safety and tolerability of individual participants. Suicidality was monitored during the trial using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post-baseline evaluation that focuses on suicidality since the last trial visit. |
Countries
United States
Participant flow
Recruitment details
This was a phase 1, multicenter, randomized, double-blind, placebo-controlled, multiple ascending dose trial planned in 3 sequential cohorts of elderly participants (70 to 85 years old) with major depressive disorder (MDD). Brexpiprazole was administered as an adjunct treatment to the current antidepressant therapy that the participant received.
Pre-assignment details
The study included a 30-day screening period, a 14-day washout period, up to 45-day inpatient treatment period (titration: received brexpiprazole or placebo once daily \[QD\] for 14 or 21 days and fixed dose phase: received assigned fixed dose for 14 or 28 days), and a 30-day follow-up after the last dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Brexpiprazole-Cohort 1 In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 2 mg brexpiprazole QD for 14 days, followed by 3 mg brexpiprazole QD for 14 days. | 6 |
| Brexpiprazole-Cohort 2 In the titration phase, participants received 0.5 mg brexpiprazole QD for 7 days, followed by 1 mg brexpiprazole QD for 7 days. In the fixed dose phase, participants received 3 mg brexpiprazole QD for 14 days. | 7 |
| Placebo In the titration phase, participants received 0.5 mg placebo QD for 7 days, followed by 1 mg placebo QD for 7 days. In the fixed dose phase, Cohort 1: participants received 2 mg placebo QD for 14 days, followed by 3 mg placebo QD for 14 days. Cohort 2: participants received 3 mg placebo QD for 14 days. | 5 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 | 0 |
| Overall Study | Participant met withdrawal criteria | 0 | 0 | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Brexpiprazole-Cohort 1 | Brexpiprazole-Cohort 2 | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 73.2 Years STANDARD_DEVIATION 4 | 76.0 Years STANDARD_DEVIATION 5.3 | 72.6 Years STANDARD_DEVIATION 1.5 | 74.1 Years STANDARD_DEVIATION 4.2 |
| Sex: Female, Male Female | 4 Participants | 5 Participants | 4 Participants | 13 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 1 / 5 |
| serious Total, serious adverse events | 0 / 6 | 0 / 6 | 0 / 5 |
Outcome results
Primary
Change From Baseline to Study Completion in C-SSRS Score.
The C-SSRS was one of the primary parameters to measure the safety and tolerability of individual participants. Suicidality was monitored during the trial using the C-SSRS. This scale consists of a baseline evaluation that assesses the lifetime experience of the participant with suicide events and suicidal ideation and a post-baseline evaluation that focuses on suicidality since the last trial visit.
Time frame: Baseline, End of Titration, Fixed dose Day 14 and 28, Day 15 and 29, Early Termination, Last Visit
Population: Safety Sample includes all randomized participants who receive at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole-Cohort 1 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal behaviour | 0 Participants |
| Brexpiprazole-Cohort 1 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidality | 0 Participants |
| Brexpiprazole-Cohort 1 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal ideation | 0 Participants |
| Brexpiprazole-Cohort 2 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidality | 0 Participants |
| Brexpiprazole-Cohort 2 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal behaviour | 0 Participants |
| Brexpiprazole-Cohort 2 | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal ideation | 0 Participants |
| Placebo | Change From Baseline to Study Completion in C-SSRS Score. | Suicidality | 0 Participants |
| Placebo | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal ideation | 0 Participants |
| Placebo | Change From Baseline to Study Completion in C-SSRS Score. | Suicidal behaviour | 0 Participants |
Primary
Incidence of ECG Evaluations of Potential Clinical Significance
The measurement of ECG was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in heart rate and ECG intervals of PR, QRS, QT, QTcB, and QTcF that were identified based on pre-defined criteria.
Time frame: Titratrion Day 1 and 7, Fixed dose Day 1, 14, 28, Early Termination
Population: The safety dataset included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Ventricular premature beat | 3 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Symmetrical T-wave inversions | 1 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Myocardial ischemia | 1 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Supraventricular premature beat | 0 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcF | 1 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcB | 1 Participants |
| Brexpiprazole-Cohort 1 | Incidence of ECG Evaluations of Potential Clinical Significance | Left bundle-branch block | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Myocardial ischemia | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Supraventricular premature beat | 2 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Ventricular premature beat | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Left bundle-branch block | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Symmetrical T-wave inversions | 1 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcB | 3 Participants |
| Brexpiprazole-Cohort 2 | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcF | 2 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Symmetrical T-wave inversions | 0 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Ventricular premature beat | 1 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcF | 2 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Increase in QTcB | 2 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Myocardial ischemia | 0 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Left bundle-branch block | 1 Participants |
| Placebo | Incidence of ECG Evaluations of Potential Clinical Significance | Supraventricular premature beat | 1 Participants |
Primary
Incidence of Laboratory Values of Potential Clinical Significance
The laboratory values were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal values in serum chemistry, hematology, urinalyses and prolactin tests that were identified based on pre-defined criteria.
Time frame: Titration Day 7, Fixed dose Day 14 and 28 and Last Visit
Population: The safety dataset included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Prolactin | 2 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Uric acid | 0 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Triglycerides, fasting | 2 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | LDL direct, fasting | 0 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Glucose | 0 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Cholesterol, fasting | 0 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Laboratory Values of Potential Clinical Significance | Hematocrit | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Triglycerides, fasting | 1 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Cholesterol, fasting | 1 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Glucose | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | LDL direct, fasting | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Uric acid | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Hematocrit | 2 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Laboratory Values of Potential Clinical Significance | Prolactin | 0 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Uric acid | 1 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Glucose | 1 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Prolactin | 0 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Hematocrit | 1 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Triglycerides, fasting | 3 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | LDL direct, fasting | 1 Participants |
| Placebo | Incidence of Laboratory Values of Potential Clinical Significance | Cholesterol, fasting | 1 Participants |
Primary
Incidence of Physical Examination Evaluation of Potential Clinical Significance
The physical examination evaluation was one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance include abnormal changes in the following body systems: head, ears, eyes, nose, and throat; thorax; abdomen; urogenital; extremities; neurological; and skin and mucosae.
Time frame: Physical examination was performed at Screening, check-in, and discharge
Population: Safety Sample was analyzed. Any clinically significant condition present at the post-treatment physical examination that was not present at the baseline examination was documented as an adverse event and followed to a satisfactory conclusion. There were no clinically significant physical examination findings reported in this study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brexpiprazole-Cohort 1 | Incidence of Physical Examination Evaluation of Potential Clinical Significance | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Physical Examination Evaluation of Potential Clinical Significance | 0 Participants |
| Placebo | Incidence of Physical Examination Evaluation of Potential Clinical Significance | 0 Participants |
Primary
Incidence of Vital Signs of Potential Clinical Significance
The vital signs were one of the primary parameters to measure the safety and tolerability of individual participants. Incidence of TEAEs of potential clinical relevance included abnormal values in heart rate, systolic and diastolic blood pressure, respiratory rate and weight that were identified based on pre-defined criteria.
Time frame: Baseline, Titration Day 1, 2, 7, 8, Fixed Days 1, 2, 14, 15, 28, 29, Early Termination and Last Visit.
Population: The safety dataset included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole-Cohort 1 | Incidence of Vital Signs of Potential Clinical Significance | Weight increase | 2 Participants |
| Brexpiprazole-Cohort 1 | Incidence of Vital Signs of Potential Clinical Significance | Supine hypotension, decrease | 1 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Vital Signs of Potential Clinical Significance | Weight increase | 0 Participants |
| Brexpiprazole-Cohort 2 | Incidence of Vital Signs of Potential Clinical Significance | Supine hypotension, decrease | 0 Participants |
| Placebo | Incidence of Vital Signs of Potential Clinical Significance | Weight increase | 0 Participants |
| Placebo | Incidence of Vital Signs of Potential Clinical Significance | Supine hypotension, decrease | 0 Participants |
Primary
Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score.
EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The AIMS Scale was an EPS rating scale. The AIMS is a 12 item scale. The first 10 items are rated from 0 to 4 (0=best, 4=worst). Items 11 and 12, related to dental status, have dichotomous responses, 0=no and 1=yes. The AIMS Total Score is the sum of the ratings for the first seven items. The possible total scores are from 0 to 28.
Time frame: End of Titration, Day 15, Day 29, Early Termination and Last visit
Population: Safety Sample includes all randomized participants who receive at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Early Termination (N= 0, 1, 1) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 29 (N= 6, 0, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | End of Titration (N= 6, 6, 4) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 15 (N= 0, 5, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Last Visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 29 (N= 6, 0, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | End of Titration (N= 6, 6, 4) | 0.2 Units on a scale | Standard Deviation 0.4 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 15 (N= 0, 5, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Early Termination (N= 0, 1, 1) | 0.0 Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Last Visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Last Visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Early Termination (N= 0, 1, 1) | 0.0 Units on a scale | — |
| Placebo | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | End of Titration (N= 6, 6, 4) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 29 (N= 6, 0, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Abnormal Involuntary Movement Scale (AIMS) Rating Score. | Day 15 (N= 0, 5, 2) | 0.0 Units on a scale | Standard Deviation 0 |
Primary
Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score
EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The Barnes Akathisia Rating Scale was an EPS rating scale. The Barnes Akathisia Rating Scale was used to assess the presence and severity of akathisia. This scale consists of 4 items. Only the 4th item, the Global Clinical Assessment of Akathisia, was evaluated in this trial. This item is rated on a 6 point scale, with 0 being best (absent) and 5 being worst (severe akathisia).
Time frame: End of Titration, Day 15, Day 29, Early Termination and Last visit
Population: Safety Sample includes all randomized participants who receive at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Early Termination (N= 0, 1, 1) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 29 (N= 6, 0, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | End of Titration (N= 6, 6, 4) | -0.2 Units on a scale | Standard Deviation 0.4 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 15 (N= 0, 5, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Last visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 29 (N= 6, 0, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | End of Titration (N= 6, 6, 4) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 15 (N= 0, 5, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Early Termination (N= 0, 1, 1) | 0.0 Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Last visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Last visit (N= 6, 6, 5) | -0.4 Units on a scale | Standard Deviation 0.5 |
| Placebo | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Early Termination (N= 0, 1, 1) | 0.0 Units on a scale | — |
| Placebo | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | End of Titration (N= 6, 6, 4) | -0.5 Units on a scale | Standard Deviation 0.6 |
| Placebo | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 29 (N= 6, 0, 2) | -0.5 Units on a scale | Standard Deviation 0.7 |
| Placebo | Mean Change From Baseline to Study Completion in Barnes Akathisia Global Score | Day 15 (N= 0, 5, 2) | -0.5 Units on a scale | Standard Deviation 0.7 |
Primary
Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score
EPS was one of the primary parameters to measure the safety and tolerability of individual participants. The SAS is a rating scale used to measure EPS. The SAS scale consists of a list of 10 symptoms of parkinsonism (gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, head rotation, glabella tap, tremor, salivation, and akathisia), with each item rated from 0 to 4, with 0 being normal and 4 being the worst. The SAS Total score is sum of ratings for all 10 items, with possible Total scores from 0 to 40.
Time frame: End of Titration, Day 15, Day 29, Early Termination and Last visit
Population: Safety Sample includes all randomized participants who receive at least one dose of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Early Termination (N= 0, 1, 1) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 29 (N=6, 0, 2) | -0.3 Units on a scale | Standard Deviation 0.4 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | End of Titration (N= 6, 6, 4) | -0.3 Units on a scale | Standard Deviation 0.5 |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 15 (N= 0, 5, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 1 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Last visit (N= 6, 6, 5) | -0.2 Units on a scale | Standard Deviation 0.4 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 29 (N=6, 0, 2) | NA Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | End of Titration (N= 6, 6, 4) | -0.5 Units on a scale | Standard Deviation 0.8 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 15 (N= 0, 5, 2) | 0.2 Units on a scale | Standard Deviation 0.4 |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Early Termination (N= 0, 1, 1) | -1.0 Units on a scale | — |
| Brexpiprazole-Cohort 2 | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Last visit (N= 6, 6, 5) | 0.0 Units on a scale | Standard Deviation 0.6 |
| Placebo | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Last visit (N= 6, 6, 5) | -0.6 Units on a scale | Standard Deviation 0.9 |
| Placebo | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Early Termination (N= 0, 1, 1) | 0.0 Units on a scale | — |
| Placebo | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | End of Titration (N= 6, 6, 4) | -1.0 Units on a scale | Standard Deviation 0.8 |
| Placebo | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 29 (N=6, 0, 2) | 0.0 Units on a scale | Standard Deviation 0 |
| Placebo | Mean Change From Baseline to Study Completion in Simpson-Angus Scale (SAS) Total Score | Day 15 (N= 0, 5, 2) | -1.5 Units on a scale | Standard Deviation 0.7 |
Primary
Number of AEs Reported.
The AEs were one of the primary parameters to measure the safety and tolerability of individual participants. The AEs were captured for all participants from the time the ICF was signed until the end of the trial. AEs were measured throughout the 14-day titration and 28-day fixed dose phase until follow-up (30 \[±2\] days after last dose of study medication).
Time frame: Throughout the study, up to 119 days
Population: The safety dataset included all randomized participants who received at least one dose of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Brexpiprazole-Cohort 1 | Number of AEs Reported. | Treatment emergent adverse events (TEAEs) | 6 Events |
| Brexpiprazole-Cohort 1 | Number of AEs Reported. | Adverse events | 12 Events |
| Brexpiprazole-Cohort 1 | Number of AEs Reported. | Serious adverse events | 0 Events |
| Brexpiprazole-Cohort 2 | Number of AEs Reported. | Treatment emergent adverse events (TEAEs) | 6 Events |
| Brexpiprazole-Cohort 2 | Number of AEs Reported. | Adverse events | 33 Events |
| Brexpiprazole-Cohort 2 | Number of AEs Reported. | Serious adverse events | 0 Events |
| Placebo | Number of AEs Reported. | Adverse events | 5 Events |
| Placebo | Number of AEs Reported. | Serious adverse events | 0 Events |
| Placebo | Number of AEs Reported. | Treatment emergent adverse events (TEAEs) | 3 Events |
Primary
Number of Participants Who Tolerated Brexpiprazole
Safety and tolerability of brexpiprazole was noted to be primary outcome measure. Brexpiprazole was judged to be tolerated if at least 6 out of 8 (75%) of the participants in a test cohort tolerated the dose after 14 days of QD dosing at the end of the fixed dose phase based on the blinded data. Dose toleration was defined as follows: during the course of the trial, the participants did not experience any moderate or severe adverse events (AEs) or potentially clinically relevant changes from Baseline in laboratory values, vital signs, electrocardiogram (ECG) tracings, Columbia-Suicide Severity Rating Scale (C-SSRS), or extrapyramidal symptom (EPS) ratings, which were assessed as possibly related to the study drug, and would have warranted a dose decrease or discontinuation of the study drug. The safety and tolerability of brexpiprazole was defined by parameters: AEs, laboratory values, vital signs, ECG, C-SSRS, or EPS ratings, the results of each of the parameters reported separately.
Time frame: 45 Days
Population: Tolerability assessed in phase 1 trial in healthy participants (18-45 years) with MDD as adjunct therapy to ADTs; the efficacy assessed in phase 3 trials in participants (18-65 years) with MDD as adjunct therapy to ADTs. Thus, safety/tolerability of brexpiprazole in participants (\>65 years) with MDD as adjunct therapy to ADTs was not characterized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Brexpiprazole-Cohort 1 | Number of Participants Who Tolerated Brexpiprazole | 6 participants |
| Brexpiprazole-Cohort 2 | Number of Participants Who Tolerated Brexpiprazole | 7 participants |
| Placebo | Number of Participants Who Tolerated Brexpiprazole | 5 participants |