Phase 1 Study to Assess the Safety/Tolerability of Brexpiprazole as Adjunctive Therapy in Elderly Subjects With Major Depressive Disorder

Study Overview
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Brief Summary
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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
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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).

Official Title
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A Phase 1, Multicenter, Randomized, Double-blind, Sequential Cohort, Placebo-controlled Trial to Assess the Safety and Tolerability of Ascending Multiple Oral Doses of Brexpiprazole as Adjunctive Therapy in the Treatment of Elderly Subjects With Major Depressive Disorder

Conditions
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Major Depressive Disorder

Intervention / Treatment
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* Drug: Brexpiprazole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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: Platelets ≤ 75,000/mm3 Hemoglobin ≤ 9 g/dL Neutrophils, absolute ≤ 1000/mm3 AST > 3 × upper limit of normal ALT > 3 × upper limit of normal Creatinine ≥ 2 mg/dL HbA1c ≥ 7% 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.

Ages Eligible for Study
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Minimum Age: 70 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>14 day titration phase and two fixed dose phases. The first fixed dose phase is 14 days with a daily dose of 2mg brexpiprazole/placebo. The second fixed dose phase is 14 days with a daily dose of 3 mg brexpiprazole/placebo. | Drug: Brexpiprazole<br>* up to 3mg oral dose once daily<br>|
| Experimental: Cohort 2<br>14 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo. | Drug: Brexpiprazole<br>* up to 3mg oral dose once daily<br>|
| Experimental: Cohort 3<br>21 day titration phase and a 14 day fixed dose phase a daily dose of 3mg brexpiprazole/placebo. | Drug: Brexpiprazole<br>* up to 3mg oral dose once daily<br>|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 45 Days | 
| 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). | Throughout the study, up to 119 days | 
| 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. | Titration Day 7, Fixed dose Day 14 and 28 and Last Visit | 
| 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. | Baseline, Titration Day 1, 2, 7, 8, Fixed Days 1, 2, 14, 15, 28, 29, Early Termination and Last Visit. | 
| 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. | Titratrion Day 1 and 7, Fixed dose Day 1, 14, 28, Early Termination | 
| 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. | Physical examination was performed at Screening, check-in, and discharge | 
| 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. | End of Titration, Day 15, Day 29, Early Termination and Last visit | 
| 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). | End of Titration, Day 15, Day 29, Early Termination and Last visit | 
| 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. | End of Titration, Day 15, Day 29, Early Termination and Last visit | 
| 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. | Baseline, End of Titration, Fixed dose Day 14 and 28, Day 15 and 29, Early Termination, Last Visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Major Depressive Disorder (MDD)