Brexpiprazole in Borderline Personality Disorder

Study Overview
=================
Brief Summary
-----------------
The primary objective of the proposed study is to evaluate the safety and efficacy of Brexpiprazole in adults with borderline personality disorder (BPD). The hypothesis to be tested is that brexpiprazole will be more effective and well tolerated in adults with BPD compared to placebo. The proposed study will provide needed data on the treatment of a disabling disorder.

Detailed Description
-----------------
Borderline personality disorder is characterized by mood instability, cognitive symptoms, impulsive behavior, and disturbed relationships (1-3). A variety of psychotherapies have been developed (4-6) and, while research on the use of medication is ongoing, no drug has been approved in the United States or elsewhere for its treatment (7). Second generation antipsychotics have been the most intensively studied (8-11). Current treatments for BPD are often inadequate. Dialectical behavioral therapy has been shown to reduce BPD but finding trained psychologists is difficult. Dysfunctions in the serotoninergic and dopaminergic systems have been demonstrated in-and considered as possible causes for-symptoms associated with the disorder (25-28). Several studies on the use of traditional (29) and atypical antipsychotic agents in patients with borderline personality disorder (30-31) have shown a positive effect on individual symptoms (29, 32-36). However, we are not aware of any study evaluating Brexpiprazole in the treatment of patients with borderline personality disorder. In the proposed double-blind, placebo-controlled study, the influence of Brexpiprazole on the multifaceted psychopathological symptoms and aggression of patients with borderline personality disorder will be investigated. Brexpiprazole therefore has distinctive properties that make it a promising option for patients with BPD. Brexpiprazole is a novel D2 partial agonist, has affinity for 5-HT1A, acts as an antagonist of the noradrenergic α1/2 receptor, partial agonist for D3, and antagonist for 5-HT2A (37-39). In addition, because of low rates of side effects, Brexpiprazole should be a well-tolerated and in fact desired medication approach to BPD.

Official Title
-----------------
A Double-Blind, Placebo-Controlled Study of Brexpiprazole in the Treatment of Borderline Personality Disorder.

Conditions
-----------------
Borderline Personality Disorder

Intervention / Treatment
-----------------
* Drug: Rexulti
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men and women age 18-65; Primary diagnosis of BPD Zanarini scale score of at least 9 at baseline Ability to understand and sign the consent form. Exclusion Criteria: Unstable medical illness based on history or clinically significant abnormalities on baseline physical examination Subjects with schizophrenia or bipolar I disorder Subjects with an active substance use disorder Current pregnancy or lactation, or inadequate contraception in women of childbearing potential Subjects considered an immediate suicide risk based on the Columbia Suicide Severity rating Scale (C-SSRS) (www.cssrs.columbia.edu/docs) Illegal substance use based on urine toxicology screening Initiation of psychological interventions within 3 months of screening Use of any other psychotropic medication Previous treatment with Brexpiprazole Cognitive impairment that interferes with the capacity to understand and self-administer medication or provide written informed consent

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>1 milligram per day for the first week and 1 milligram per day for the final taper week 2 milligrams per day for 10 weeks between taper periods. | Drug: Placebo<br>* Pill that contains no medicine<br>* Other names: no other names;|
| Experimental: Rexulti<br>1 milligram per day day for the first week and 1 milligram per day for the final taper week 2 milligrams per day for 10 weeks between taper periods. | Drug: Rexulti<br>* Atypical antipsychotic<br>* Other names: Brexpiprazole;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Zanarini Rating Scale for Borderline Personality Disorder | A clinician-administered scale assessing Borderline Personality Scale severity at all study visits. Scores range from 0-36. Higher scores represent worse Borderline Personality Disorder severity, and lower scores represent milder Borderline Personality Disorder severity. | Baseline (Visit 1), Week 1 (Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 8 (Visit 6), Week 10 (Visit 7), Week 12 (Visit 8) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Modified Overt Aggression Scale (MOAS) | A clinician-administered behavior rating scale measuring four types of aggressive behavior that will be assessed at all 9 visits. The subsets range on a scale from 0-4 with 0 indicating no aggression present. This scale tracks changes in level of aggression over time. The total weighted sum of the sections of the scale is recorded. Higher total scores indicate higher aggression levels. | Baseline (Visit 1), Week 1 (Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 8 (Visit 6), Week 10 (Visit 7), Week 12 (Visit 8) | 
| Young Mania Rating Scale | A clinician-administered, 11 item scale that assesses manic symptoms at baseline and over time. Higher total scores indicate higher severity of manic symptoms. This scale is used to rate the severity of manic abnormality in the patient. Subsets of the scale range from 0-4 with 0 indicating no severity. This scale will be assessed at all visits. | Baseline (Visit 1), Week 1 (Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 8 (Visit 6), Week 10 (Visit 7), Week 12 (Visit 8) | 
| Self Report Version of Zanarini Scale | A self-report scale assessing Borderline Personality severity that will be assessed at all visits.This scale is assessing severity and change in BPD symptoms. This is a 9-item scale measuring severity of different aspects of Borderline Personality Disorder, with each item rated on a 0-4 scale, 0=no symptoms, 4=severe symptoms. Total scores range from 0-36. | Baseline (Visit 1), Week 1 (Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 8 (Visit 6), Week 10 (Visit 7), Week 12 (Visit 8) | 
| Borderline Evaluation of Severity Over Time (BEST) | A self rated scale used to measure severity and change. The first 12 items of the scale are on a scale from 1-5, with 5 meaning that the item caused extreme distress, severe difficulties in relationships, and/or kept them from getting things done. The lowest rating (1) means it caused little or no problems. Items 13-15 (positive behaviors) are rated according to frequency. Completed at every visit. | Assessed at Visits 1 to 8, change in scores from Visit 1 to Visit 8 (baseline to week 12) is reported | 
| Barratt Impulsiveness Scale (BIS) | A self-report assessment of impulsivity that will be assessed at baseline and visit 8. The BIS is composed of 30 items describing common impulsive or non-impulsive (for reverse scored items) behaviors and preferences. Items are scored on a 4-point scale: (Rarely/Never = 1, Occasionally = 2, Often = 3, Almost Always/Always = 4). These scores are summed to produce an overall impulsivity score ranging from 30 (not impulsive) to 120 (extremely impulsive). | Baseline (Visit 1), Week 12 (Visit 8) | 
| Symptom Checklist-90 Revised | An instrument that helps evaluate a broad range of psychological problems and symptoms of Borderline Personality Disorder psychopathology. This will be assessed at baseline and visit 8.The 115 items are rated by using a 5-step Likert scale (0=not at all, 4=very strong) and provide a global picture of borderline psychopathology. Global scores of borderline psychopathology are calculated by summing 12 items and range from 0-48. Higher scores indicate more severe symptoms of Borderline Personality Disorder. | Baseline, Visit 8 (Week 12) | 
| Hamilton Anxiety Rating Scale (HAM-A) | A clinician-administered assessment of anxiety that will be assessed at all study visits (Visit 1-Visit 8). Changes in scores from baseline to final visit will be assessed. Higher scores (up to 56) indicate higher levels of anxiety, with 0 being no symptoms of anxiety. | assessed at Visits 1 to 8, change in scores from Visit 1 to Visit 8 (baseline to Week 12) is reported | 
| Hamilton Depression Rating Scale (HAM-D) | A clinician-administered assessment of depression that will be assessed at all study visits (Visits 1-8). Higher total scores indicate higher levels of depression (up to 52), while a score of 0 would indicate no depressive symptoms. | Assessed at Visits 1 to 8, change in scores from Visit 1 to Visit 8 (baseline to week 12) is reported | 
| MINI International Neuropsychiatric Interview | A short-structured interview that assesses comorbid psychiatric disorders according to the DSM 5 criteria. This assessment will be done during the baseline visit. | Baseline (Week 1) | 
| Sheehan Disability Scale (SDS) | Subjects will complete the SDS at all visits. The change in scores from baseline to study completion will be assessed. The scale itself assesses the level of disability from borderline personality disorder (or target disorder) with higher scores indicating a more debilitating disorder. Scores range from 0-30. | Baseline (Visit 1), Week 1 (Visit 2), Week 2 (Visit 3), Week 4 (Visit 4), Week 6 (Visit 5), Week 8 (Visit 6), Week 10 (Visit 7), Week 12 (Visit 8) | 
| Quality of Life Inventory (QOLI) | A self-report assessment of patient perceived quality of life that will be assessed at baseline and visit 8. Higher scores indicate a higher quality of life, whereas lower scores indicate a lower quality of life. Participants are asked to rate the importance of each domain on a 3-point scale ranging from 1=not important to 3=very important, and to rate how satisfied they are with that domain on a 6-point scale, ranging from -3=very dissatisfied to +3=very satisfied. In scoring, importance ratings are multiplied by satisfaction ratings to produce weighted satisfaction scores for each of the 16 domains. Weighted satisfaction scores are summed and divided by the number of domains that were rated as important or very important to produce a raw score, which is then converted to a t-score, which provides a proxy measurement for perceived quality of life. T-scores range from very low perceived quality of life (0-36) to high perceived quality of life (58-77). | Baseline (Week 1), Week 12 (Visit 8) | 
| Columbia Suicide Severity Rating Scale (CSSRS) | A self-report scale measuring suicidality. Subjects will complete the scale at all visits. Subjects are asked about suicidal thoughts. If answers are no, rater can proceed to suicidal behavior section where subject is asked about any non-suicidal self injurious behavior. If yes, subject is asked about intensity of ideations. In the event of serious threat to themselves, the subject will be escorted to the emergency room. Total score indicates severity of suicidal ideation and behavior, with lower scores representing lower levels of suicidality and higher scores representing higher levels of suicidality. A score of 0 would reflect no suicidality present, whereas a maximum score of 5 would reflect active suicidal ideation with intent to act. | Baseline (Visit 1), Week 12 (Visit 8) |