Pramipexole in Bipolar Disorder: Targeting Cognition (PRAM-BD)
Phase: PHASE4
Conditions: Bipolar Disorder
Sponsor: Brigham and Women's Hospital

 
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Detailed Protocol Title: 1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
PI: Katherine Burdick, PhD 
Version Date: 8/29/18 
 
I.  
BACKGROUND AND SIGNIFICANCE 
 
Data suggest that, as in schizophrenia (SZ), bipolar disorder (BD) patients’ everyday 
functioning is directly influenced by persistent symptomatology and cognitive 
dysfunction (Bowie et al. 2010; Burdick et al. 2010). A recent meta-analysis indicated 
significant correlations (mean r=.27) between cognition and functional measures in BD 
(Depp et al. 2012), with little evidence for differences across cognitive domains. These 
data strongly support the role of cognition in quality of life in BD and highlight the need 
for treatment and prevention efforts targeting this domain (Burdick et al. 2007). There are 
several ongoing large-scale clinical trials targeting cognition in SZ, with a parallel need 
existing in BD. We recently completed one of the first controlled trials of cognition as a 
treatment target in BD (Burdick et al. 2012). We approached the initial question of which 
agent to test based upon prior evidence that enhancing dopamine may result in 
improvements in neurocognition in other clinical samples. 
Although the neurobiological basis of persistent cognitive impairment in BD is not well-
understood, convergent evidence suggests that the enhancement of DA activity may be a 
useful remediation strategy. Neuroimaging studies highlight structural brain 
abnormalities in BD in regions rich in DA receptors, including anterior cingulate, 
dorsolateral, orbital, and subgenual cortex (Drevets et al. 1998; Lopez-Larson et al. 2002) 
and the basal ganglia (Baumann et al. 2001). Abnormal activation in these regions has 
been reported in BD during cognitive tasks using fMRI (Blumberg et al. 2000; Gruber et 
al. 2004). Moreover, in previous studies of healthy subjects increasing levels of DA via 
agents such as pergolide, a D1 agonist (Kimberg et al. 2003) or bromocriptine, a D2 
agonist, (Kimberg et al. 1997; Luciana et al. 1998) improves cognition, particularly in 
cognitive domains linked to prefrontal cortex (PFC) functions. Finally, molecular genetic 
studies support the importance of DA in normal cognitive functions. Several cognitive 
studies have focused on the gene coding for catechol-o-methyl transferase (COMT), an 
enzyme responsible for the degradation of catecholamines, including DA, in the PFC 
(Dickinson et al. 2009). Convergent results demonstrate an association between genetic 
variation within COMT and cognitive function in SZ (Bilder et al. 2002; Egan et al. 2001) 
and healthy controls (Malhotra et al. 2002; Tsai et al. 2003). COMT has also been 
implicated in the susceptibility for BD (Kirov et al. 1998; Papolos et al. 1998), including 
work by our group (Burdick et al. 2007). In a sample of 52 Caucasian BD probands and 
102 Caucasian healthy controls, we detected a modest but significant association between 
SNP rs165599 and BD, with the g allele being over-represented in cases vs. controls 
(OR=2.41; genotypic p=0.04; allelic p=0.02). We found a relationship between the risk 
allele at this SNP and poorer performance on verbal memory tasks (California Verbal 
Learning Test; CVLT Trials 1-5; p=0.005; eta2=0.07) particularly with regard to PFC 
aspects of learning (CVLT semantic cluster; p=0.037; eta2=0.04) in BD patients and in 
healthy controls (Burdick et al. 2007). In addition to these lines of evidence supporting 
the use of a DA agent to enhance cognition, recent evidence suggests that pramipexole, a 

 
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novel D2/D3 agonist, may be an effective adjunctive anti-depressant in BD. Pramipexole 
(Mirapex®) is an FDA-approved medication for Parkinson’s disease (PD) and restless 
leg syndrome. 
 
II. SPECIFIC AIMS 
 
Converging evidence suggests that patients with bipolar disorder suffer from deficits in 
neurocognitive functioning that persist, despite remission of acute affective symptoms. 
These impairments contribute directly to functional disability, highlighting the need for 
interventions above and beyond standard treatments in order to achieve a full inter-
episode recovery. The current study aims to investigate the safety and efficacy of a 
dopamine agonist (pramipexole), on these persistent cognitive abnormalities in euthymic 
bipolar patients using a placebo-controlled, adjunctive, 14-week trial design.  
 
Aim 1: Baseline to Week 6 
a) To determine the short-term efficacy of pramipexole on neurocognitive functioning in 
stable BD patients. b) To determine the short-term safety of pramipexole on 
neurocognitive functioning in stable BD patients.  
Aim 2: Week 6 to Week 12  
 a) To determine the long-term efficacy of pramipexole on neurocognitive functioning in 
stable BD patients. b) To determine the long-term safety of pramipexole on 
neurocognitive functioning in stable BD patients.  
Exploratory Aim: To integrate results from multiple dopamine-based domains 
(cognition; affect; reward processing) to evaluate the main and interactive effects of 
pramipexole on these factors in stable BD patients. 
 
III. SUBJECT SELECTION 
a.   Inclusion criteria: 1. Age 18-65. 2. DSM-V BD I or II diagnosis. 3. Affective 
stability, defined by a Young Mania Rating Scale (YMRS) rating of < 8 and a Hamilton 
Depression Rating Scale (HRSD) rating of < 16 at screening and baseline. We will 
further require that any subsyndromal depression has not significantly worsened in the 4 
weeks prior to randomization so as to avoid enrolling subjects who are on the verge of a 
full depressive episode. 4. Evidence of clinically-significant neurocognitive impairment 
at screening. This will be formally assessed using a short battery of tests including Trails 
B, Wechsler Adult Intelligence Scale (WAIS-IV) Digit Symbol, WAIS-IV Digit Span 
Forward and Backward, Wisconsin Card Sorting Test (WCST), and California Verbal 
Learning Test – Second Edition (CVLT-II). Clinically-significant impairment will be 
defined as scoring > 1 SD below normative means on at least one of these measures. 5. 
Clinically-acceptable, stably-dosed, mood stabilizing medication regimen for > 1 month 
prior to enrollment, with no medication changes planned over the 14-week study period. 
Exclusion criteria: 1. History of CNS trauma, neurological disorder, ADHD, or learning 
disability. 2. Positive urine toxicology or DSM-V diagnosis of substance 
abuse/dependence within 3 months. 3. Active, unstable medical problem that may 
interfere with cognition. 4. Recent history of rapid-cycling. 5. Abnormal lab or ECG 

 
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result at screen. 6. History of heart failure. 7. Significant suicidal risk (HRSD item 3 > 2 
or by clinical judgment). 8. Estimated IQ in MR range as per Wide Range Achievement 
Test (WRAT) standard score of less than 70. 9. Pregnant women or women of child 
bearing potential who are not using a medically accepted means of contraception 
(including oral contraceptive or implant, condom, diaphragm, spermicide, intrauterine 
device, tubal ligation, or partner with vasectomy) 10. Women who are breastfeeding. 11. 
Participation in any other investigational cognitive enhancement study within 30 days. 
Concomitant Medications: Practical and ethical considerations prevent a focus on 
medication-free patients. Medications with known adverse cognitive effects will be 
disallowed (i.e., topiramate, anticholinergics), as will agents that may enhance cognition 
(e.g., amphetamine, other DA agonists). Benzodiazepines will not be allowed within 6 
hours of testing. ECT in the past 12 months will be disallowed, as will any drug known to 
interact with pramipexole. With regard to antipsychotic medications specifically, only 
half of the sample will be allowed to be taking any antipsychotics. Recruitment efforts 
will be adjusted to ensure 50% of the sample is antipsychotic-free at baseline. Further, we 
will exclude any subject who is taking more than 4 concomitant psychotropic 
medications. Older generation neuroleptics will be specifically disallowed due to their 
high binding potential at the D2 receptor (Kapur et al. 1999). Although some of the 
standard treatments for BD (e.g. lithium) may influence cognition, it is impractical to 
exclude these medications given their widespread use; therefore, data will be coded for 
medication classes and dosages to determine a load score (as per Hassel et al. 2008) to be 
included as a covariate in statistical analyses.  
b.   Subjects will be recruited from the BWH outpatient psychiatry department per 
guidelines of PHRC. 
 
IV. SUBJECT ENROLLMENT 
 
a.   Enrollment will be done through the outpatient psychiatry department at BWH (see 
section III.b. above for detail on recruitment). Randomization is done from one list, 
created by Co-I at Icahn School of Medicine at Mount Sinai. The list is evenly spread 
across sites. Subjects will be randomized on a 1:1 ratio with stratification for concomitant 
antipsychotic status and depression at baseline (Hamilton Rating Scale for Depression 
score <8 vs > 8). 
 
b.   Potential subjects are given general information about the research through or 
discussion with their treating physicians, and if they are interested in learning more about 
the study, they contact or agree to be contacted by study staff. One of the study staff then 
meets with the potential subject to review and to discuss the details of the research study 
using the informed consent document as a guide. Potential subjects are then given a copy 
of the informed consent document to take home so they can carefully read the document 
and discuss the research with their family, friends and/or physician and develop questions 
to ask at their next meeting with the research staff. Once they have read the consent 
document and their questions are answered by a study physician, if they agree to 
participate in the research, they sign and date the informed consent document, which will 
then also be signed by the study physician. 

 
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c.   Randomization will be conducted via a computer generated program and all study 
staff will be blinded unless un-blinding is required for safety reasons. Subjects will be 
randomized on a 1:1 ratio with stratification for concomitant antipsychotic status and 
depression at baseline (HRSD <8 vs > 8). Study drug will be blinded and matched to 
placebo. 
 
V. STUDY PROCEDURES 
 
a.   All eligible participants will undergo study visits at screening, baseline (week 0), 
week 1, week 2, week 3, week 4, week 6, week 8, and week 12, (end of study). Co-
Investigators Jessica Harder, MD, and Timothy Mariano, MD, PhD, MSc will be 
responsible for consenting subjects, administering drug, and ensuring safety outcome 
measures at each study visit.  
 
Measures are described in detail below: 
Safety Outcome Measures 
 Side Effects Checklist (SEC; physician administered) – (all visits) 
 Columbia Suicide Severity Rating Scale – (all visits) 
 Iowa Gambling Task – (baseline, week 6, week 12)  
 Vital signs including blood pressure (standing/supine) – (all visits) 
 Electrocardiogram (ECG) – (screening, week 6, week 12) 
 Liver function tests; chemistry panel; CBC; (9 mL blood sample); urinalysis – 
(screening, week 12) 
 Pregnancy test for women of childbearing age – (screening, week 12) 
 Urine toxicology – (screening, week 12) 
 Medication log of current medications and all medications administered during   
 
previous week – (all visits) 
Clinical/Symptom Measures 
 Structured Clinical Interview for the DSM-V (SCID–V) – (screening) 
 Symptom rating scales: Young Mania Rating Scale (YMRS); Hamilton Rating 
Scale for Depression (HRSD); Brief Psychiatric Rating Scale (BPRS) – (all visits) 
 Smoking questionnaire – (screening, baseline, week 6, week 12) 
 
Neurocognitive/Functional Measures 
 Screening cognitive battery (see inclusion criteria 4.) – (screening) 
 Cognitive assessment: MATRICS Consensus Cognitive Battery (MCCB- plus; 
see description below) – (baseline, week 6, week 12) 
 The Probabilistic Stimulus Selection Task – (baseline, week 6, week 12) 
 UCSD Performance Skills Assessment (UPSA) – (baseline, week 12) 
 The World Health Organization Disability Assessment Schedule (WHODAS 2.0) 
– (baseline, week 12) 
 
 

 
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b.   Adapting from our previous work in BD and according to package labeling, the 
dosage titration schedule will be slow and flexible. Dosing will be initiated at 0.25 mg 
QHS on night one, followed by 0.25 mg BID day two onward, and ideally increased as 
follows to a target of 4.5 mg/day:  
day 2-week 1 0.25 mg BID;  
week 1-2 0.25 mg QAM/0.50 mg QHS;  
week 2-3 0.75 BID;  
week 3-4 1.0 mg QAM/1.5 mg QHS;  
week 4-5 1.75 mg BID;  
week 5-6 1.5 mg QAM/3.0 mg QHS.  
The dosing stated above is ideal titration, dosing will be flexible at the discretion of the 
study physicians. If subjects can reach a titration of 1.5mg/day by week 4 they will be 
allowed to continue in the study. As compared with our previous maximum 1.5 mg/day 
(Burdick et al. 2012), we opted to allow up to 4.5 mg/day (the maximum approved 
dosage in Parkinson’s disease) to ensure adequate target engagement. We are familiar 
The MATRICS Consensus 
Cognitive Battery 
Domain  
Note/Description 
Category Fluency 
Speed of Processing 
Total animals in 60 seconds 
BACS Symbol Coding 
Speed of Processing 
Matching numbers to 
symbols 
Trail Making Test Part A 
Speed of Processing 
Dot-to-dot: Numbers only 
CPT-Identical Pairs 
Attention/Vigilance 
Computerized numeric 
stimuli 
Letter-Number Span 
Working Memory 
Recoding numbers and 
letters in order 
WMS-III Spatial Span 
Working Memory 
Visual sequence forward and 
backward 
Hopkins Verbal Learning 
(HVLT) 
Verbal Learning 
12 word list x 3 
Brief Visuospatial Memory 
Test (BVMT) 
Visual Learning 
6 designs to be drawn from 
recall 
NAB Mazes 
Reasoning & Problem 
Solving 
Pencil-paper maze solutions 
MSCEIT Managing Emotions 
Social Cognition 
Situational social judgments 
Additional Measures (“Plus”) 
--- 
--- 
Affective Go-no-go 
Affective Neuroscience 
Emotional modulation of 
inhibition 
Emotional Stroop 
Affective Neuroscience 
Affective Bias/Cognitive 
Control 

 
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with this dose range, as 4.5 mg/day was allowed in our study in BD depression (Goldberg 
et al. 2004). As stated above, dosing will be flexible based on side effects; however, if 1.5 
mg/day cannot be tolerated, the subject will be discontinued. Titration will occur up to 
week 6 and then efforts will be made to maintain the same dose until the completion of 
the trial (week 12). Upon week 12/end of study visit, study drug will be tapered over a 7-
10 day period, depending on the dose at week 12/end of study, decreasing by 0.25mg to 
0.75mg daily per the pramipexole package insert instructions.  
c.   Devices to be used: N/A 
d.   Procedures/surgical interventions, etc.: N/A 
 
VI. BIOSTATISTICAL ANALYSIS 
 
Statistical Methods: Preliminary analyses: Groups will be compared on demographics, 
baseline symptom ratings, and concomitant medication load; if necessary, covariates will 
be included in subsequent models. MCCB data are standardized using the MCCB 
program, scores are age- and sex- corrected and reported on a t-score scale (Mean=50, 
SD=10). Any study focusing on improving cognition must consider practice effects 
(Goldberg et al. 2008). The placebo arm will provide estimates of expected practice so 
that we are able to calculate a reliable change index (RCI) to determine the 
meaningfulness of change (Goldberg et al. 2009).  
Primary hypothesis testing: 100 participants will be randomized in a 1:1 allocation to 
treatment with pramipexole or placebo. The primary assessment of safety will be based 
on the incident of adverse event rates and standardized mood ratings at each visit. 
Differences in the incidence of individual adverse events will be compared between 
randomization arms using Poisson regression. Exact 95% confidence intervals (based on 
the Poisson distribution) for the risk ratios for individual adverse events for treatment 
with pramipexole versus placebo will be computed and may incorporate an estimated 
overdispersion parameter if observed variability exceeds that determined by the Poisson 
distribution. Performance on the IGT will also be used to track potential changes in 
impulse-control (baseline, weeks 6 and 12). We will test for correlations between IGT 
performance and mania symptoms at the times of testing (simultaneous measurements). 
Moreover, we will use IGT change scores as predictors in regression models to evaluate 
changes in mania ratings at concurrent time points as well as future time points. This will 
directly address the question of whether or not changes in IGT strategy serve as markers 
of current mania and/or impending affective destabilization. 
The relative specificity of pramipexole in binding to D2/D3 receptors allows for a unique 
opportunity to enhance DA in neural networks associated with specific aspects of 
cognition as well a reward processing, which will be carefully assayed in this study so 
that exploratory analyses will be able to test questions related to the role for these 
receptors across several interacting domains in BD, at least at the level of behavior. 
Exploratory analyses will include specific domains and individual tasks which will be 
modeled to account for main effects and interactions (as described in primary analyses 
below). 
 

 
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The primary outcome for efficacy is change in cognition from baseline to week 6 (MCCB 
Composite). The null hypothesis is that there is no difference in this change between 
patients on pramipexole vs. patients on placebo. This will be tested in an intent-to-treat 
analysis using a 0.05 level two-tailed test based on a mixed effects regression model, with 
patients considered to be a random effect, and randomization group a fixed effect. In 
order to preserve statistical power, change in MCCB Composite will be used as the 
dependent variable; however, secondary analyses will be conducted for MCCB domain 
scores and measure of reward processing. The use of two post baseline evaluations 
(weeks 6 and 12) and the ability of the model to incorporate all available data, also 
improves efficiency (i.e., power). This approach will also be employed in subsequent 
comparisons of specific domains and for measures of reward processing. These additional 
analyses will be conducted at a nominal 0.05 level and will focus on enhancing 
interpretation of the primary analysis by highlighting the specific domains most affected 
by pramipexole. Since randomization is stratified by concomitant antipsychotic use and 
baseline depression status, indicators of stratification will be included in the model as 
fixed effects.   
 
Missing data: Although the mixed effects modeling approach allows patients with 
evaluations at week 4 but missing at week 8 to be included, bias may be introduced if 
missing data are related to patient response. For example, it may be that patients 
responding poorly are less likely to have a week 8 evaluation than those patients with 
better response. The mixed effects analysis would weigh the results of these poorly 
performing patients less (as they provide fewer data) and in the presence of a positive 
effect of pramipexole, decrease power. To assess the extent that any bias has been 
introduced by missing data, we will impute missing week 8 values. Note that if no bias is 
produced by the missing data, analyses with and without imputation should provide 
virtually identical results. If the analyses produce different results, we will work to 
identify the causes by comparing patients with and without missing data. Based on our 
prior trial experience we expect relatively few patients (< 10) to be missing the week-8 
visit due to attrition. Patients with missing data will have their 8 week MCCB score 
imputed via multiple imputation assuming that the data are MAR, i.e., the missing nature 
of the variable is independent of the value of the variable given the observed data. The 
specific imputation model to be used will be determined prior to examination of any 
outcome data, but will include MCCB score at baseline and at 4 weeks. Separate 
imputations will be done for each randomization group. 
 
Due to the 12 week course of the study, mixed models will still be utilized for variables 
collected with sufficient frequency; however, when incorporating missing data, we will 
only be able to do so when at least two time points are included. Subjects with only 
baseline data will be included in descriptive analyses but will be dropped for analyses 
where necessary.  
Sample size/Power: A total of one hundred patients will be randomized 1:1(15 from 
BWH, 35 from Icahn School of Medicine at Mount Sinai, 50 from Zucker Hillside 
Hospital). The adequacy of this sample size is based on the ability to reject the null 
hypotheses of no difference between treatment groups with respect to the MCCB 
composite score with sufficient power (80%). Ideally, sample size would be determined 

 
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to ensure adequate power to detect the minimal clinically important difference. No 
specific guidelines exist to establish such a threshold in this setting but cognitive change 
of at least a moderate effect would likely be necessary to allow for clinical 
meaningfulness. Our sample size provides approximately 80% power to detect a 
standardized difference (e.g., Cohen’s d) of approximately 0.55 with a two-tailed 0.05 
level test. For the pre-specified subgroup analysis based on concomitant use at baseline, 
the detectable standardized difference is about 0.80. 
 
 
 
VII. RISKS AND DISCOMFORTS 
 
Primary risks in this study include the exacerbation of clinical symptoms (psychosis, 
depression, cognitive symptoms); 2) suicidal ideation or homicidal ideation; and 3) 
adverse events or side effects associated with pramipexole. 
Risk Associated with Pramipexole: As pramipexole may have the potential to induce 
manic-like or psychotic symptoms, each participant will be monitored closely for an 
exacerbation and all subjects will be required to be taking a mood stabilizing medication 
in addition to the study drug. We will very closely monitor psychotic and affective 
symptoms on a weekly basis throughout the study period using standardized rating scales 
described above. In addition, at each scheduled visit a physician-level psychiatrist will 
meet with the patients and conduct a thorough review of symptoms including psychosis, 
mood, and suicidal/homicidal ideation.  If there is an acute worsening of symptoms the 
study clinicians will review the case with the PI (or will make an emergency decision as 
needed) to ensure that the subject receives emergency care or hospitalization. 
Participation in the study will be discontinued in any case of clear symptom worsening 
(as outlined in the research plan) and the blind will be broken if warranted. Between 
weekly visits, the patients will have emergency contact information.  
Any signs of suicidal ideation will result in a full risk assessment by trained/licensed 
study staff. Dependent on the determined risk, discontinuation of the trial and/or 
hospitalization will follow as per BWH treatment guidelines.  
Side effects/Adverse events: The most common side effects noted for pramipexole are 
nausea, headache, and insomnia. Rarely more severe side effects can occur including 
hallucinations, narcolepsy, restlessness, and problems with impulse control. Therefore, 
side effects will be monitored and recorded at each visit to ensure patient safety and the 
study drug will be discontinued if side effects are intolerable. For changes in sleep 
specifically, at each visit standardized rating scales will be administered. These scales 
inquire about insomnia, hypersomnia, and lack of need for sleep. Changes on these 
ratings are closely tracked and if changes occur, they are discussed with the patient and if 
significant enough, the patient will be discontinued. A baseline ECG and chemistry 
profile including renal function testing will be carried out prior to exposure to 
pramipexole and again at week 8 and at the end of study (6 months or early termination). 
The following ECG parameters will be recorded: heart rate, PR, QRS, QT, and QTc.  All 
ECG results will be interpreted by a MD Investigator as Normal, Abnormal; not clinically 
significant (NCS), or Abnormal; clinically significant (CS). The MD Investigator will 

 
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refer a subject with an abnormal result to a cardiologist when deemed appropriate to do 
so. In addition, pramipexole can interact with some medications commonly used to treat 
gastrointestinal symptoms (e.g. cimetidine); therefore, subjects taking these medications 
will not be permitted to enroll in this trial. Any significant findings will result in study 
exclusion and/or referral for appropriate medical care. The informed consent process will 
alert subjects to these potential risks and close monitoring will ensure prompt response to 
any adverse effects with appropriate treatment and/or study discontinuation, as indicated.  
In September 2012, the FDA issued the following warning regarding pramipexole, “FDA 
notified healthcare professionals about a possible increased risk of heart failure with 
Mirapex (pramipexole). Results of recent studies suggest a potential risk of heart failure 
that needs further review of available data. Because of the study limitations, FDA is not 
able to determine whether Mirapex increases the risk of heart failure. FDA is continuing 
to work with the manufacturer to clarify further the risk of heart failure with Mirapex and 
will update the public when more information is available. FDA evaluated a pooled 
analysis of randomized clinical trials and found that heart failure was more frequent with 
Mirapex than with placebo; however, these results were not statistically significant. FDA 
also evaluated two epidemiologic studies that suggested an increased risk of new onset of 
heart failure with Mirapex use. However, study limitations make it difficult to determine 
whether excess heart failure was related to Mirapex use or other influencing factors (see 
FDA Drug Safety Communication Data Summary for a detailed discussion of the 
studies).” This potentially serious side effect of the study medication will be addressed in 
our protocol primarily by the exclusion of patients with any prior cardiac disease or at 
high risk for cardiac events (see exclusion criteria). Further, we will monitor for any 
updates to this warning, which in its current form does not suggest any changes to dosing 
or normal clinical usage of this agent. There have been no updates to this warning as of 
early 2017. 
Additional risks are minimal and involve the completion of questionnaires, interviews 
and paper-pencil/computerized tests. Some of the questions may be distressing to the 
individual and subjects will be told that they may refuse to answer any questions that they 
so choose. The testing procedure can sometimes cause fatigue but we will ensure plenty 
of resting periods during the session and will instruct subjects to notify staff if they would 
like an additional break. Pain and bruising may be associated with each 9 mL blood draw; 
however, a trained phlebotomist will perform the procedure to avoid any additional 
discomfort. 
Confidentiality: All subject data will be secured on an MS SQL server with Windows 
integrated security. Only research staff with specific permissions will have access to the 
data. Subjects will only be identified with a numerical code in compliance with HIPPA 
regulations. Moreover, subjects will be apprised of their ensured confidentiality and told 
that clinical data collected from them will be included in a data base for research 
distribution only after all information that can reasonably identify them has been 
removed.   
 
 
 

 
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VIII. POTENTIAL BENEFITS 
 
There may be no immediate potential benefit to the subject from participation in this 
research study; however, the investigational use of the medication for treating 
neurocognitive functioning may result in an improvement in these symptoms in some of 
the subjects. In addition, data from this study may lead to subsequent larger scale studies 
aimed at treating cognitive impairment in patients with bipolar disorder. 
 
IX. MONITORING AND QUALITY ASSURANCE 
 
A formal Data Safety and Monitoring Board (DSMB) will be utilized. The DSMB is 
already established and is operating through the NIH-funded ACISR center grant at 
Zucker Hillsides Hospital (ZHH). The membership includes 2 physician researchers who 
are not involved with the current trial but have experience in clinical trials in psychiatric 
samples, as well as other senior faculty in the Division of Psychiatry Research at ZHH. In 
collaboration with the primary statistician for this trial (Michael Parides; Sinai Co-I), the 
DSMB will be asked to review data on this trial at any time that there is a serious adverse 
event, reportable to the Institutional Review Board (IRB) and after the completion of 
each set of 10 randomized subjects (regardless of site).  
In addition to the DSMB, the PI will review safety data in real time to address any 
concerning adverse events. Dr. Burdick has served as an active member of three IRBs 
over the past 15 years and will ensure that all AEs are appropriately reported and 
followed up. 
 
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