Conditions: Borderline Personality Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 80
Healthy volunteers: no

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.

Arms:
arm 1: 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. arm 2: 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.

Interventions: intervention 1: Rexulti intervention 2: Placebo
Intervention descriptions: intervention 1: Atypical antipsychotic intervention 2: Pill that contains no medicine

Protocol document:
Prot_SAP_001.pdf: 
Page 1 of 11 
February 12, 2020 
 
Outline of study submission 
 
 
Date Submitted: February 12, 2020 
 
Principal Investigator:   
Jon Grant, JD, MPH, MD (CV attached) 
 
Title: Professor of Psychiatry & Behavioral Neuroscience 
Institution: University of Chicago 
Address: 5841 S. Maryland Avenue, Chicago, IL 60637 
Phone: 773-834-1325 
 
Title  
A Double-Blind, Placebo-Controlled Study of Brexpiprazole in the Treatment of Borderline 
Personality Disorder.  
 
This project will take place at the University of Chicago.  Dr. Jon E. Grant, MD, JD is the 
Principal Investigator and can be phoned at 773-834-1325 or reached by email at 
jongrant@uchicago.edu. 
 
This clinical trial will be conducted in the spirit of Good Clinical Practice and in accordance with 
this IRB-approved protocol.  No deviation from the protocol will be implemented without the 
prior review and approval of the IRB except where it may be necessary to eliminate an 
immediate hazard to a research subject.  In such a case, the deviation will be reported to the IRB 
as soon as possible. 
 
Objective  
The primary objective of the proposed study is to evaluate the safety and efficacy of 
Brexpiprazole in adults with borderline personality disorder (BPD). Eighty subjects with BPD 
will be randomized in a 1:1 fashion to either Brexpiprazole (starting at 1mg/day for one week 
and going to 2mg in a fixed dose fashion after 1 week) or matching placebo for 12 weeks of 
active treatment. The hypothesis to be tested is that Brexpiprazole will result in greater rates of 
reduction in symptoms of BPD compared to placebo (improvement in symptoms will be 
indicated by lower scores on established outcome measures of BPD symptoms that have been 
used in prior studies). 
 
Background of BPD 
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.  
 
Choice of Medication 
One illness that is difficult to treat is borderline personality disorder (12–17), which is 
characterized by a pervasive pattern of severe psychopathological symptoms with instability of 


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February 12, 2020 
affect regulation, impulse control, and aggression (18-24). 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. 
 
The aim of the present study is to examine the efficacy and safety of Brexpiprazole vs. placebo 
in adults with BPD, as indicated by a score of at least 9 on the Zanarini Rating Scale for 
Borderline Personality Disorder (“Zanarini scale”), a scale of illness severity, at the baseline 
visit.  
 
Study Design/Methodology  
Eighty individuals with a prior diagnosis of  BPD will be recruited for a double-blind, placebo-
controlled pilot study in which Brexpiprazole or placebo is administered in a 1:1 fashion. All 80 
subjects will have current BPD per DSM-5 criteria. Following baseline measures, subjects will 
receive Brexpiprazole (1mg/day for one week and then 2mg/day thereafter) or inactive placebo. 
Participants will be seen every week for the first 2 weeks and then every 2 weeks after that. At 
week 12, subjects will start a 1-week taper off the medication. Efficacy and safety measures will 
be performed at each visit.  
 
Study Population/Sample Size 
80 male and female outpatients aged 18-65 with a current primary diagnosis of BPD. 
 
Subjects 
 
Inclusion criteria:  
1) Men and women age 18-65;  
2) Primary diagnosis of BPD  
 
3) Zanarini scale score of at least 9 at baseline 
 
4) Ability to understand and sign the consent form. 
 
Exclusion criteria:  
1) Unstable medical illness based on history or clinically significant abnormalities on 
baseline physical examination  
2) Subjects with schizophrenia or bipolar I disorder 
3) Subjects with an active substance use disorder 
4) Current pregnancy or lactation, or inadequate contraception in women of childbearing 
potential 
5) Subjects considered an immediate suicide risk based on the Columbia Suicide Severity 
rating Scale (C-SSRS) (www.cssrs.columbia.edu/docs)  


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February 12, 2020 
6) Illegal substance use based on urine toxicology screening (excluding marijuana given 
the high rates of marijuana use in BPD and the lack of interaction with brexpiprazole).  
7) Initiation of psychological interventions within 3 months of screening  
8) Use of any new psychotropic medication started within the last 3 months prior to study 
initiation 
9) Previous treatment with Brexpiprazole 
10) Cognitive impairment that interferes with the capacity to understand and self-
administer medication or provide written informed consent  
 
Advertisements will target this study population. Interested individuals will be asked to contact a 
study coordinator or complete an online survey expressing interest. Individuals will then undergo 
a phone screen before being scheduled for a first appointment. After being screened, potential 
subjects will be scheduled for a first appointment in which we will confirm medical and 
psychiatric history, laboratory tests, and inclusion/exclusion criteria.  
 
Drugs, Dosages, and Regimens  
All subjects who are randomized to Brexpiprazole will receive 1mg/day during the first week of 
the study, and then 2mg/day for the remainder of the study. Dosage changes and reductions will 
not be permitted. After study conclusion, the dose will be tapered off during a 1-week follow-up 
period.  
 
Randomization 
 
Participants are randomized (1:1) to receive placebo or brexpiprazole by the investigational 
pharmacy at the University of Chicago. The study blind will be maintained by over-
encapsulation, making placebo and active treatments appear identical in size, weight, shape, and 
color. Dosage changes and reductions will not be permitted during the study and participants will 
be discontinued if they experienced intolerance. 
 
Blinding 
 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency or pregnancy in an individual subject, in which knowledge of the investigational 
product is critical to the subject’s management, the blind for that patient may be broken by the 
treating physician. 
 
Treatment Duration, Visit Frequency, and Procedures   
This is a 13-week study (12 weeks of acute treatment followed by a 1-week tapering phase). 
Subjects will be seen at baseline and then every week for the first 2-4 weeks and then every two 
weeks after that. 
 
Assessments at each visit 
Those subjects who appear appropriate for the study, based on telephone screening, will be 
invited for a baseline assessment. The duration of the baseline assessment will be approximately 
90 minutes and will include the following: Informed consent, Demographic data, Concomitant 
medications (no psychotropic medications will be allowed), Family history data, Medical 
evaluation including physical examination, EKG, weight, and vital signs, Urine pregnancy test 
(for women of childbearing years) and urine drug screen, and a psychiatric evaluation (using the 
following measures: MINI International Neuropsychiatric Interview (40); Depressive symptoms 
will be rated with the 24-item Hamilton Depression Rating Scale (HAM-D) (41); Anxiety 


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February 12, 2020 
symptoms will be assessed using the Hamilton Anxiety Rating Scale (HAM-A) (42); 
Psychosocial functioning will be evaluated using the patient-rated version of the Sheehan 
Disability Scale (SDS) (43); Quality of Life Inventory (QOLI) (44); The Cambridge-Chicago 
Compulsivity Trait Scale (CHI-T); and the Columbia Suicide Severity Rating Scale (C-SSRS)). 
During the consent process, individuals will be given time to review the consent form and given 
the opportunity to ask any questions that may arise before signing the informed consent form. 
Throughout the study, subjects will be asked questions about the study to ensure that they 
continue understanding study procedures. Blood samples will be collected at both baseline and 
last visits to measure blood sugar, glutathione, and cholesterol levels. All follow-up visits will 
include safety measures (adverse events, vital signs, C-SSRS), weight, BPD measures, and other 
psychiatric measures. 
 
Due to the pandemic of COVID19, study participants can perform their baseline and follow-up 
visits online using encrypted Zoom instead of in person visits. All inventories will be assessed. 
Blood samples and urine toxicology, however, will be at the discretion of the study PI. In cases 
where they are considered medically necessary, the participant can have them drawn locally and 
submitted to the study team.  
 
Efficacy evaluation: 
The primary outcome measure will be the change from baseline using the Zanarini Rating Scale 
for Borderline Personality Disorder (“Zanarini scale”) (45). This semistructured interview has 
anchored ratings (0=no symptoms, 4=severe symptoms) on nine items that correspond to the 
DSM-5 BPD criteria. Its subscales will be considered secondary efficacy measures. 
 
Secondary efficacy measures include Modified Overt Aggression Scale (46), the Young Mania 
Rating Scale (47), and the self-report version of the Zanarini scale (48), the Borderline 
Evaluation of Severity Over Time (49), the Barratt Impulsiveness Scale (50) the  
Minnesota Impulsive Disorders Interview (51), the Symptom Checklist–90–Revised (SCL-90-R) 
(52), and the scales listed above (41-44). 
 
Cognitive Measures 
Cognitive assessments consist of two previously validated tests taken from CANTABeclipse 
software. The choice of cognitive challenges was based on the clinical features of BPD. The 
order of the tasks will be fixed and participants will complete the tasks at first visit (baseline), 
midway through 13-week timeline, and endpoint. 
 
Cognitive flexibility, i.e., set-shifting, will be measured using the Intra-dimensional/Extra-
dimensional Shift Task (ID/ED task). Participants are presented with two stimuli on-screen for 
each trial and attempted to learn an underlying ‘rule’ about which stimulus was correct. Key 
outcome measures will be number of errors made at the intra-dimensional shift and at the extra-
dimensional shift stage.  
 
The Tower of London task will be used to examine executive planning. On each trial of the task, 
subjects observe two sets of pockets each containing three colored balls on-screen. On ‘move’ 
trials, subjects have to attempt to work out ‘in mind’ the minimum number of moves required to 
move the balls in one set of pockets to match a goal arrangement also shown in the other set of 
pockets.  
 
The probabilistic beliefs task will allow us to examine the subject’s self-other distinction. 
Participants observe a sequence of neutral images on the screen and are occasionally asked to 


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February 12, 2020 
make responses on a keyboard. Participants will be asked to keep track of the images they see 
and make predictions about what will happen next. They will also be asked to keep track of 
another theoretical person’s beliefs about what will happen next. The task will allow us to submit 
self-other distinctions, a potentially important dimension of BPD, to quantitative assessment and 
computational modelling. 
 
Subject Withdrawal 
If a subject withdraws from the study, all instruments administered at the screening visit will be 
completed at the final visit.  These will be conducted when the subject is able to come in for an 
early termination visit.  Withdrawn subjects will be given the phone number of the principal 
investigator as well as the phone numbers of local resources for depression treatment.   
 
Safety Assessments 
Safety and tolerability will be assessed using spontaneously reported adverse events data, C-
SSRS, vital signs, and by evaluating premature termination.  Safety assessments (sitting blood 
pressure, heart rate, adverse effects, and concomitant medications) will be documented at each 
visit. Subjects who are an immediate suicide risk will be removed from the study and appropriate 
clinical intervention (e.g. hospitalization) will be arranged. Study team members are mandated 
reporters and as such, will arrange for the subject to be taken to the emergency room if any intent 
to harm themselves is expressed. Urine pregnancy tests will be performed at the initial visit. 
Subjects who have a positive urine pregnancy test will be excluded from the study. Assessment 
of side effects will be done at each visit.  
 
Adverse Event Reporting 
Unanticipated (unexpected) problems/events, those that are not already described as potential 
risks in the consent form, or not part of an underlying disease, will be reported to the IRB as 
soon as possible.  The same will be done for serious problems/events and, in the opinion of the 
investigator, are possibly, probably or definitely related to the research procedures.  A follow-up 
report will also be submitted to the IRB with any documentation related to a previously 
submitted adverse event. 
 
Risks 
Participants may experience side effects while taking the drugs used in this study. Side effects 
are usually reversible when the drug is stopped but occasionally continue and may cause serious 
complications, if subjects experience any side effects, they will be asked to contact the study 
doctor immediately.  
 
There may be other risks that could arise which are not reasonably foreseeable. If new 
information becomes available which could influence their willingness to continue, this new 
information will be discussed with the participant. 
 
While taking the study drug, the subject’s condition may remain the same or worsen due to no 
effect of the study drug. 
 
Risks of Brexpiprazole 
The most common side effects associated with Brexpiprazole include: 
 Weight gain 
 Inner sense of restlessness (feeling like one needs to move) 
 
Brexpiprazole may cause more serious side effects including: 


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February 12, 2020 
 Stroke in elderly people 
 Neuroleptic Malignant Syndrome (high fever, stiff muscles, sweating, changes in 
pulse, heart rate and blood pressure) 
 Tardive dyskinesia (uncontrollable body movements) 
 High blood sugar 
 Low white blood cell count 
 Decreased blood pressure 
 Seizures 
 Problems controlling your body temperature so that the individual feel too warm 
 Difficulty swallowing that can cause food or liquid to get into the lungs 
 
Risks of Electrocardiagram 
If subjects are asked to get an ECG, they may have some discomfort when the electrodes (soft 
patches attached using adhesive tape) are removed from their chest and limbs. There is a 
possibility they could develop a minor rash when the electrodes were placed. This rash should go 
away without treatment. 
 
Risks of blood draws 
Needle sticks can cause discomfort, pain, burning sensation or bruising. 
 
Data and Safety Monitoring Plan 
1. Responsibility for Data and Safety Monitoring 
The PI will have overall responsibility for monitoring the integrity of study data and 
participant safety.  
2. Procedures for Monitoring Participant Safety 
The PI will implement the following procedures to ensure data integrity and the safety of 
participants during the study. 
 A number of elements of the research plan are intended to minimize the risks of 
study participation. If subjects become actively suicidal with intent and plan to 
kill themselves, the PI will evaluate them and refer them for immediate non-study 
treatment. Any participant endorsing suicidal thoughts with intent and plan will be 
immediately evaluated by the PI and referred to a higher level of care if clinically 
indicated.  
 The PI will evaluate patient safety and resolve any safety issues if necessary, as 
such issues arise. The PI will also be responsible for preparing written summary 
reports of adverse events and will prepare a written report summarizing any 
decisions that are made pertaining to participant disposition.  
 Data integrity and confidentiality will be safeguarded as discussed above in the 
Data Management and Statistical Analysis section under Research Methods.  
 
Monitoring Committee 
We will establish a monitoring committee and define in detail its role, its composition, and its 
operating procedures for reviewing patient safety and data from this study.  The monitoring 
committee, comprised of two individuals independent of personnel involved in the study, 
including a psychiatrist and a statistician, will come together via conference call yearly. The 
committee will use a standardized approach employing contemporary bio statistical, 
psychiatric/psychological, and ethical principles to review study design and interim data every 
year. The committee will audit the records from the study and will ensure the data are being 
collected, managed and protected. The committee will have the ability to ask for more frequent 


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February 12, 2020 
reviews at any time if they deem it necessary. In addition, the PI will inform the committee of 
any serious adverse event.  
The PI will prepare a specific report for the committee in advance of each meeting. Attention 
will be given to data quality and timeliness, recruitment, risk versus benefit, adverse events and 
other factors that could affect study outcome.  
3. Reporting Adverse Events 
 Any serious adverse event will be reported to the Institutional Review Board 
(IRB) at the University of Chicago in a full written report within 10 working days 
of the event. For fatal/life-threatening serious adverse events, the PI will notify 
the IRB Chair by phone immediately. 
 Any moderate adverse event which appears definitely, probably, or possibly 
related to study participation will be reported to the University of Chicago IRB in 
writing within 20 working days. 
 Any mild adverse event will be summarized in the IRB annual progress reports. 
 
Data Analysis 
Data analysis will involve all visits during the 12-week double-blind treatment phase (up until 
week 12). Data from the tapering phase (weeks 12-13), although collected, will not be included 
for purposes of the primary goal of this study. 
 
All enrolled subjects will be included in the analyses of baseline demographics and safety 
according to an intent-to-treat (ITT) principle. For statistical analysis, the full-analysis set will be 
defined as all participants who took at least 1 dose of the study drug and had at least 1 post-
baseline primary efficacy assessment. The safety-analysis set will be defined as all randomized 
participants who took at least 1 dose of the study drug and completed at least 1 follow-up safety 
assessment.  
 
The statistical model will be a linear mixed-effects regression model (LME) that includes terms 
for treatment group, time, and treatment-by-time interaction.  The analyses will run using the 
nlme package on R for Windows (R Foundation, Vienna, Austria; http://www.r-project.org). 
Literature suggests LME without imputation may provide more accurate and stable results than 
LME models using fixed and multiple imputation methods for handling missing data, so no 
imputation will be undertaken for missing data. All tests of hypotheses will be performed using a 
two-sided significance level of 0.05.  
 
Sample Size 
The sample size was calculated for the primary endpoint of change from baseline. Assuming a 
similar magnitude of effect seen in other studies of medications for BPD, it was determined that 
40 participants would be needed in each treatment group to detect a difference with an overall 
5% type-I error risk. Given the particularly low rates of adverse events reported with 
Brexpiprazole, as well as its more positive side effect profile in terms of sexual side effects, we 
expect few drop-outs from the study and therefore a smaller sample is needed.  
 
Ethical Considerations 
This study will be conducted according to US and international standards of Good Clinical 
Practice (FDA regulations 21 CFR 312 for IND studies and FDA guidance E6) for all studies.  
Applicable government regulations and University of Chicago research policies and procedures 
will also be followed. 
 


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February 12, 2020 
This protocol and any amendments will be submitted to the University of Chicago Institutional 
Review Board (IRB) for formal approval to conduct the study.  The decision of the IRB 
concerning the conduct of the study will be made in writing to the investigator.   
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  This consent form will be submitted with the protocol for review and approval by the 
IRB.  The formal consent of a subject, using the IRB-approved consent form, will be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
Data Handling and Record Keeping 
All subject data will be maintained by the study personnel under the supervision of the principal 
investigator.  Subjects will be seen at the University of Chicago.  Patient binders will be kept in a 
locked room only accessible to research staff.   
 
Estimated Total Costs/Budget 
$400,000. 
 
Publication/Presentation Schedule 
These data will be presented at the American College of Neuropsychopharmacology (ACNP), 
the American Psychiatric Association annual meeting, or the NCDEU annual meeting. The 
resulting article will be submitted to a peer-reviewed publication (e.g., American Journal of 
Psychiatry, Biological Psychiatry) within 3 months of study completion. 
 
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