Conditions: Bipolar Disorder
Keywords: Bipolar Disorder Cognition
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

Brief summary:
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, 12-week trial design.

Detailed description:
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).

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. 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 increased every week to a target of 4.5 mg/day. 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 with this dose range, as 4.5 mg/day was allowed in our study in BD depression (Goldberg et al. 2004). 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).

Arms:
arm 1: Pramipexole, by mouth. Dosing will be initiated at 0.25 mg on night one, followed by 0.25 mg twice-a-day day two onward, and increased every week to a target of 4.5 mg/day for the 12-week duration of the study. arm 2: Placebo, by mouth. Dosing will be initiated at 0.25 mg on night one, followed by 0.25 mg twice-a-day day two onward, and increased every week to a target of 4.5 mg/day for the 12-week duration of the study.

Interventions: intervention 1: Pramipexole intervention 2: Placebo
Intervention descriptions: intervention 1: Up to 4.5mg, PO, (by mouth) per day of the 12-week study. intervention 2: placebo match study drug

Protocol document:
Prot_SAP_001.pdf: 
 
1 
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 


 
2 
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 


 
3 
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. 


 
4 
 
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) 
 
 


 
5 
 
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 


 
6 
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). 
 


 
7 
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 


 
8 
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 


 
9 
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. 
 
X. REFERENCES 
 
Baumann B, Bogerts B. Neuroanatomical studies on bipolar disorder. Br J 
Psychiatry Suppl 2001;41: s142-s147 
 
Bilder RM, Volavka J, Czobor P, et al. Neurocognitive correlates of the COMT 
Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002;52: 
701-707 
 
Blumberg HP, Stern E, Martinez D, et al. Increased anterior cingulate and caudate 
activity in bipolar mania. Biol Psychiatry 2000;48: 1045-1052 
 
Bowie CR, Depp C, McGrath JA, Wolyniec P, Mausbach BT, Thornquist MH, 
Luke J, Patterson TL, Harvey PD, Pulver AE. Prediction of real-world functional 
disability in chronic mental disorders: a comparison of schizophrenia and bipolar 
disorder. Am J Psychiatry. 2010 Sep;167(9):1116-24. 
 
Burdick KE, Funke B, Goldberg JF, et al. COMT genotype increases risk for 
bipolar I disorder and influences neurocognitive performance. Bipolar Disord 
2007;9: 370-376 
 


 
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Burdick KE, Braga RJ, Goldberg JF, Malhotra AK. Cognitive dysfunction in 
bipolar disorder: Future place for pharmacotherapy. CNS Drugs. 
2007;21(12):971-981. 
 
Burdick KE, DeRosse P, Kane JM, Lencz T, Malhotra AK. Genetic Variation in 
the MET Proto-oncogene is Associated with Schizophrenia and General 
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Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK (b). 
Placebo-controlled adjunctive trial of pramipexole in patients with bipolar 
disorder: targeting cognitive dysfunction. J Clin Psychiatry. 2012 Jan;73(1):103-
12. doi: 10.4088/JCP.11m07299. Epub 2011 Nov 29 
 
Depp CA, Mausbach BT, Harmell AL,et. al. (2012) Meta-analysis of the 
association between cognitive abilities and everyday functioning in bipolar 
disorder. Bipolar Disord. 2012 May;14(3):217-26. doi: 10.1111/j.1399-
5618.2012.01011.x. 
 
Dickinson D, Elvevag B. Genes, cognition and brain through a COMT lens. 
Neuroscience 2009;164: 72-87 
 
Drevets WC, Ongur D, Price JL. Neuroimaging abnormalities in the subgenual 
prefrontal cortex: implications for the pathophysiology of familial mood 
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Egan MF, Goldberg TE, Kolachana BS, et al. Effect of COMT Val108/158 Met 
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Goldberg JF, Burdick KE. Summary and assessment: Recommendations for 
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Goldberg JF, Chengappa KN. Identifying and treating cognitive impairment in 
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Gruber SA, Rogowska J, Yurgelun-Todd DA. Decreased activation of the anterior 
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pergolide. Neuropsychologia 2003;41: 1020-1027 
 
Kirov G, Murphy KC, Arranz MJ, et al. Low activity allele of catechol-O-
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Prot_SAP_003.pdf: 
 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
1 
Revised  9/2/14 
MSSM Protocol Template HRP-503a 
Instructions: 
1. Prepare a document with the following sections. Note that, depending on the nature of your research, 
certain sections below may not be applicable. Indicate N/A as appropriate, explaining where possible. 
2. For any items described in the sponsor’s protocol, grant application or other source documents 
submitted with the application, you may reference the title and page numbers of these documents rather 
than cutting and pasting into this document. Do NOT refer to any derived documents, such as the 
Sample Consent document, or other internal documents required with the submission. 
3.  If you reference page numbers, attach those pages to this protocol. 
4. When you write a protocol, keep an electronic copy. You will need to modify this copy when making 
changes. 
 
Brief Summary of Research (250-400 words): 
 
1) Objectives: 
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, 12-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. 
 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
2 
Revised  9/2/14 
 
2) Background 
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 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
3 
Revised  9/2/14 
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 
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. 
 
3) Setting of the Human Research 
 
The Icahn School of Medicine at Mount Sinai (ISMMS) site has ideal facilities for the 
proposed study. The research activities will be conducted in the Clinical Neuroscience 
Center located at 53-55 E. 96th Street, 1st floor suite. This space, completely renovated in 
2014, consists of a seven-room suite with ample space for research staff, interview 
rooms, and an exam room.  
 
4) Resources Available to Conduct the Human Research 
Recruitment for this study will be done across Mount Sinai and will include: 
 
Psychiatry Outpatient Clinic  
The Mount Sinai Psychiatry outpatient department (OPD) serves a large catchment area 
that includes both an affluent neighborhood on the Upper East Side of Manhattan and an 
economically challenged neighborhood in East Harlem.  Mount Sinai is the primary 
provider of medical care (and mental health care) for many area residents.  On a monthly 
basis, approximately 60 new patients are seen in the adult OPD, of whom 40% have a 
diagnosis of mood disorder.  Approximately 90 subjects with bipolar disorder are 
currently treated in the OPD; 82 new intakes per year have a diagnosis of bipolar 
disorder.  Any patient referred to the Mount Sinai Psychiatry Outpatient Clinic is 
presented at intake meetings and research eligible patients are referred to a research 
psychiatrist in MAP.  
  
Mood and Anxiety Disorders Program (MAP)   
The Mood and Anxiety Disorders Program (Director: Dan V. Iosifescu, M.D.; Co-I on 
this study) is one of the major research and clinical programs of the Department of 
Psychiatry. 
 
Referrals are anticipated for the proposed study from the following sources: (1) patients 
with bipolar disorder currently receiving treatment in the MAP program; (2) the Mount 
Sinai Hospital Adult Outpatient Psychiatry Department; (3) self-referrals from patients 
who have completed other research protocols in the MAP program; (4) clinicians within 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
4 
Revised  9/2/14 
and outside of the Mount Sinai Hospital system, including affiliates with large numbers 
of underserved patients such as Elmhurst Hospital in Queens; (5) self-referrals from 
individuals attending presentations on bipolar disorder in the New York State and tri-state 
area and from media advertisements.  In addition, we anticipate the receipt of referrals 
from consumer advocacy groups specializing in severe, treatment resistant mood 
disorders, including NAMI and the Mood Disorders Support Group (MDSG) of New 
York.   
 
5) Study Design 
a) Recruitment Methods 
Subjects will be recruited from MAP and the OPD as described above. Community 
advertisements will be placed if needed (none currently attached for review). Potentially 
eligible patients are identified by the patient’s clinical care taker (nurse practitioner 
and/or physician), who would then ask the patient’s permission for our research team to 
approach and explain the protocol. A research member will approach that individual and 
explain the study objectives, procedures, risks and benefits, and begin the informed 
consent process if the patient wishes.  
b) Inclusion and Exclusion Criteria 
Inclusion criteria: 1. Age 18-65. 2. DSM-IV 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 12-week study period. 
Exclusion criteria: 1. History of CNS trauma, neurological disorder, ADHD, or learning 
disability. 2. Positive urine toxicology or DSM-IV 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 
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 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
5 
Revised  9/2/14 
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.  
c) Number of Subjects 
Up to 50 affectively stable patients with Bipolar Disorder will be randomized via 
recruitment through MAP, the Mount Sinai OPD, and community advertisements if 
necessary. Additional subjects will be screened, with an assumption of some not meeting 
eligibility; therefore, we estimate 70 patients to be consented for 50 to be randomized. 
d) Study Timelines 
There will be a 2-month start-up, 28 months of recruitment and 6 months of follow-up. 
The last patient randomized will be mid-way through Year 2 to ensure study completion 
by end of Year 3. Analyses and manuscript preparation will be completed immediately 
thereafter. We will screen ~3 patients per month (~1 patient randomized/month), totaling 
70 patients screened and 50 patients randomized.  
e) Study Endpoints 
The primary endpoints related to the safety and efficacy on neurocognitive functioning of 
pramipexole will be measured. Neurocognitive performance on the MATRICS 
Consensus Cognitive Battery will be measured at baseline, week 6, and 12 (or end of 
study). Safety measures will be assessed at each visit throughout the study. Co-primary 
measures of everyday functioning (described below) will be assessed at baseline and 
week 12 (or end of study).  


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
6 
Revised  9/2/14 
 
f) Procedures Involved in the Human Research 
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).  
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. 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 increased every week 
to a target of 4.5 mg/day. 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 with this 
dose range, as 4.5 mg/day was allowed in our study in BD depression (Goldberg et al. 
2004). 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). 
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 Gambing 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; 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-IV (SCID–IV) – (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) 
 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
7 
Revised  9/2/14 
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) 
 
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 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
8 
Revised  9/2/14 
g) Specimen Banking 
 N/A 
h) Data Management and Confidentiality 
If a participant agrees to be in this study, we will collect health information that identifies 
them [“Protected Health Information” (PHI)]. We may collect the results of tests, 
questionnaires and interviews. We may collect information from a patient’s medical 
record.  We will only collect information that is needed for the research. This information 
is described in the consent form. By signing the consent form a participant gives us 
permission (authorization) to collect, use and share their health information. 
Data collected will include questionnaires and assessments as described above in section 
(5f). Labs and tests will be performed at the MSMC laboratory and information sent to 
the PI. These data will be stored in a binder which will be secured in a double locked 
fashion. Blood samples will be labeled with de-identified codes, which cannot be 
associated with individual subjects. PHI, such as patient name and DOB, will only be 
included in a separate file including the consent documents. The file linking de-identified 
data with participant PHI will be stored on an encrypted drive. PHI data will be stored 
indefinitely, as well as for potential future research. All other data collected for the study 
will be de-identified and stored apart from PHI, identified by a study number linked to 
PHI in a secure file. This data will be stored indefinitely. 
The PI will be responsible for receipt and transmission of study data and specimens. 
Quality control of the data collected will include double data entry and data quality 
checks by investigators after each 5 subjects completed. 
Study staff will have access to data and records and these may be reviewed by the Mount 
Sinai School of Medicine Institutional Review or government agencies (i.e. NIH) in order 
to meet federal or state research regulations.  Participants will be made aware in the 
consent process that once private information is disclosed, it is subject to re-disclosure by 
the recipient and can no longer be considered protected.  If research records are used for 
decisions related to clinical care, then a participant has the right to review this 
information and to request changes. This is limited to information about their treatment, 
and does not include information related to procedures or tests that are for research 
purposes only. Participants may access this information only after the study analysis is 
complete.   
Data from this study may be used in medical publications or presentations.  The 
information will be de-identified so that individual subjects cannot be recognized and the 
information will no longer be considered PHI.  The information that is collected for 
research will be analyzed for many years and it is not possible to know how long this 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
9 
Revised  9/2/14 
analysis and follow-up will take. Therefore, participants are allowing access to this 
information indefinitely. 
Participants will only be identified with a numerical code in compliance with HIPAA 
regulations. Raw subject data will be secured in double locked physical control. Digitized 
raw data will be similarly de-identified using coding and will be secured on an MS SQL 
server with Windows-integrated security.  
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). 
 
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 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
10 
Revised  9/2/14 
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.  


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
11 
Revised  9/2/14 
Sample size/Power: A total of one hundred patients will be randomized 1:1(50 from 
ISMMS, 50 from ZHH). 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 
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. 
 
i) Provisions to Monitor the Data to Ensure the Safety of subjects 
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 Hillside 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; ISMMS 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 every 6 months following study start up (regardless 
of site). In addition to the DSMB, the PI at each site will review safety data in real time to 
address any concerning adverse events.  
Part I: Elements of a Data and Safety Monitoring Plan  
1. MSSM Principal Monitor: 
Indicate whether this person is the PI, a Team Member, or is Independent: PI 
 
Last Name: Burdick 
First Name: Katherine 
Academic Title: Professor 
Department: Psychiatry 
Mailing Address: One Gustave L. Levy Place, Box 1230, New York, NY 10029 
Phone: 212-659-8841 
Fax: 212-996-8931 
E-mail: katherine.burdick@mssm.edu 
 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
12 
Revised  9/2/14 
MSSM Additional Monitor: 
Indicate whether this person is the PI, a Team Member, or is Independent: Team Member 
(co-investigator) 
 
Last Name: Iosifescu 
First Name: Dan 
Academic Title: Associate Professor 
Department: Psychiatry 
Mailing Address: One Gustave L. Levy Place, Box 1230, New York, NY 10029 
Phone: 212-241-4480 
Fax: 212-241-3354 
E-mail: dan.iosifescu@mssm.edu 
 
 2. Dr. Burdick has been responsible for running two previous studies using this agent in 
bipolar disorder (Goldberg et al 2004; Burdick et al 2012).  
 
3. Adverse events, subject compliance with the protocol, and drop outs will be monitored 
for safety. 
  
4. ACCUMULATED safety and data information (items listed in number 3 above and 
interim analysis of efficacy outcomes) will be reviewed by the monitors or the Data 
Monitoring Committee (DMC) twice a year.  
 
5. Alteration of the study design is not expected; however, SAEs will be considered for 
unblinding and relatedness to drug will be assessed. 
 
6. In order to minimize toxicity we are only allowing up to a max of the FDA 
recommended dose – dosing is flexible based on AEs and tolerability. 
  
7. There will be no specialized grading system used to evaluate adverse events. 
 
8. Procedures that will be used to assure data accuracy and completeness include double 
data entry and frequent queries of database. 
  
9. Should a temporary or permanent suspension of your study occur, in addition to the 
PPHS, we will report the occurrence to NIH as well as ZHH, the other site conducting 
study. 
 
 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
13 
Revised  9/2/14 
j) Withdrawal of Subjects 
Participants with an exacerbation of mania/depression (YMRS > 15 or HRSD > 18) will 
be discontinued and treated by the study physician. Suicidal ideation will be assessed at 
each visit with the Columbia Suicide Severity Rating Scale (C-SSRS). Significant 
suicidal ideation will be addressed immediately using the standard clinical response at 
ISMMS (evaluation at the walk-in clinic for potential need for hospitalization).  
Participants at risk for suicidal behavior will be discontinued. Side effects will be rated 
by a study physician at each visit. Any side effect deemed to be a serious adverse event or 
an unanticipated follow up will be reported to the PI, and the ISSMS Institutional Review 
Board (IRB) and appropriate follow up will be conducted. In addition, participants who 
exhibit an inability to follow the protocol will be discontinued and withdrawn from the 
study.  
To ensure orderly termination from the study, the study physician would meet with the 
participant to discuss termination and discontinuation of medication. Safety measures 
would be collected and a follow-up visit by phone would be scheduled to further ensure 
safe discontinuation. Pramipexole should be tapered off at a rate of 0.75mg per day until 
the daily dose has been reduced to 0.75mg. Thereafter, the dose should be reduced by 
0.375mg per day. We will schedule an in-person follow-up visit by phone to address any 
remaining concerns the participant may have. 
Participants may withdraw from the study for any reason at any time by contacting the 
principle investigator or any of the research staff. It is also possible to withdraw 
permission for the use and disclosure of any protected information for research but it 
must be done in writing to the principle investigator. In the event permission is 
withdrawn, information that was already collected may still be used if that information is 
necessary to complete the research study.  
 
6) Risks to Subjects 
During the informed consent process, participants will be informed of the potential risks 
associated with the study. At each weekly visit the study physician will meet with 
participants and conduct a thorough review of symptoms including mood, and suicidal 
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 
participant receives emergency care or hospitalization. Participation in the study will be 
discontinued in any case of clear symptom worsening. Between weekly visits, the 
participants will have emergency contact information.  
Along with closely monitoring for symptom exacerbation, each visit with the study 
physician will entail a detailed side effect evaluation, which will include vital signs and a 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
14 
Revised  9/2/14 
side effect checklist. The most common side effects of pramipexole are nausea, headache, 
dizziness, insomnia, constipation, muscle weakness, abnormal dreams, confusion, 
memory problems, urinary frequency. Participants will be educated about the potential 
for these side effects. Rare side effects have also been reported including sedating effects, 
impulse control symptoms (e.g. gambling), hallucinations, and orthostatic hypotension. 
The informed consent process will alert participants to these potential risks and close 
monitoring will ensure prompt response to any adverse effects with appropriate treatment 
and/or study discontinuation, as indicated.  
 
7) Provisions for Research Related Injury 
In accordance with Federal Regulations, if anyone is injured from being in the study, they 
will receive medical care and treatment as needed from Mount Sinai Medical Center. 
However, participants are responsible for the costs of such medical treatment, directly or 
through their medical insurance and/or other forms of medical coverage. No money shall 
be given to them.  
 
8) Potential Benefits to Subjects 
There may be no immediate potential benefit to the participant 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 BD. 
 
9) Provisions to Protect the Privacy Interests of Subjects 
Participants are free to refuse to answer any of the questions that are being asked 
of them in the study. If the withheld information is critical to study eligibility the 
participant may not be enrolled. While enrolled in the study, all tests and 
procedures will be done in a research office at ISMMS ensuring privacy. All 
research staff will be open to answering any questions and will address any 
concerns of the participants throughout the duration of the study. 
 
10) 
Economic Impact on Subjects 
There is no cost to participants for participating in the study. 
 


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
15 
Revised  9/2/14 
11) 
Payment to Subjects 
Participants will be informed during the consent process of the study compensation. 
Participants will be paid $100 for the screening visit; $50 for baseline and week 6; $20 
for week 1, 2, 3, 4, 8; $100 for week 12.  Total possible payment of $400 for study 
completion.. Screen failures will receive the screening rate ($100) provided they undergo 
study procedures at that visit. 
 
12) 
Consent Process 
A potential participant will be approached by a member of the study team after she/he has 
been given permission to do so by the patient’s clinician. We will be following SOP 
HRP-090. Only English speaking subjects will be consented into the study. The research 
team member will explain the study objectives, procedures, risks and benefits, and 
answer all the questions the potential participant may have. Participants are advised that 
they can withdraw from the study at any time. Participants will receive a copy of the 
consent form for the study. Informed consent will be documented when the subject signs 
the consent form that has been approved by ISMMS PPHS.  
 
13) 
Process to Document Consent in Writing 
All participants must provide written informed consent. The consent form will be 
documented in writing. The consent form has been derived from the standard PPHS 
template. 
 
14) 
Vulnerable Populations 
The following population types will be excluded from the study: adults unable to consent, 
individuals who are not yet adults, wards of the state, pregnant women, and prisoners.  
 
15) 
Multi-Site Human Research (Coordinating Center) 
The overall organization of this project is provided by the PIs, Drs. Burdick and 
Malhotra. Each site [Icahn School of Medicine at Mount Sinai (ISMMS) and the Zucker 
Hillside Hospital (ZHH)] will be responsible for managing the activities of their site. 
Overall organization and management of sites will be provided by ISMMS. All PIs and 
Co-Is will participate in monthly conference calls over the first 2.5 years of the study. 
During the data analytic phase, the frequency of conference calls will be increased to 
weekly.  


 
Protocol Title: 
1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
Principal Investigator 
Name/Contact Info:  
Katherine Burdick, PhD 
Primary Contact 
Name/Contact Info 
Megan Shanahan  
megan.shanahan@mssm.edu 
Date Revised: 
March 23, 2016 – date of IRB approval May 6, 2017 
Study Number: 
GCO 13-0237, HS 14-00328 
 
16 
Revised  9/2/14 
Mount Sinai will serve as the coordinating site for this trial; therefore, Dr. Burdick will 
be the contact PI and responsible for all interactions between sites and with NIH. All 
procedures specific to the clinical trial will be identical at the two sites. Rater training 
will be initiated with an in-person, on-site meeting to ensure adequate reliability for 
clinical and neurocognitive assessments. We are uniquely situated to ensure reliability, as 
Dr. Burdick was formerly the Director of the Neurocognitive Assessment Unit at the 
second site (ZHH) and she conducted training with staff at both sites. All statistical 
analyses will be led by the statistician (Co-I) Michael Parides from ISMMS. This will 
include intermittent safety data analyses for the Data Safety and Monitoring Committee 
(DSMB) review and all analyses at the conclusion of the trial. 
 
16) 
Community-Based Participatory Research 
 
 
N/A 
 
17) 
Sharing of Results with Subjects 
If any preliminary results arise from this study or any related studies are published that 
change the risks associated with this protocol, we will notify all participants who have 
participated. Otherwise, results from the analyses will be published in peer reviewed 
journal articles but will not be transmitted directly to the participants involved in the 
research.  
 
18) 
IRB Review History 
 
N/A 
 
19) 
Control of Drugs, Biologics, or Devices 
Note: The IDS has its own forms that must be completed and a review process 
that must be followed before the IDS representative will sign off on Appendix B 
for submission to the PPHS. 
 
The study drug will be stored and distributed by the research pharmacy. 
 
 

ICF_002.pdf: 
Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
Page 1 of 14 
 
Subject Identification 
Protocol Title: 1/2-Pramipexole in Bipolar Disorder: Targeting Cognition 
(PRAM-BD) 
 
Principal Investigator: Katherine Burdick, PhD 
 
Site Principal Investigator:       
 
Description of Subject Population: Bipolar Disorder 
About this consent form 
 
Please read this form carefully.  It tells you important information about a research study.  A 
member of our research team will also talk to you about taking part in this research study.  
People who agree to take part in research studies are called “subjects.”  This term will be used 
throughout this consent form. 
 
Partners HealthCare System is made up of Partners hospitals, health care providers, and 
researchers.  In the rest of this consent form, we refer to the Partners system simply as 
“Partners.” 
 
If you have any questions about the research or about this form, please ask us.  Taking part in 
this research study is up to you.  If you decide to take part in this research study, you must sign 
this form to show that you want to take part.  We will give you a signed copy of this form to 
keep. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you.  At most, the Web 
site will include a summary of the results.  You can search this Web site at any time. 
 
Why is this research study being done? 
 
We are doing this research study to find out if Pramipexole can help people with bipolar disorder 
who have problems with their cognitive abilities (i.e. attention, memory). We will evaluate the 
extent of the problems that you are experiencing to determine if they are severe enough for you 
to be eligible for this study. 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 2 of 14 
 
Subject Identification 
Pramipexole is approved by the U.S. Food and Drug Administration (FDA) to treat Parkinson’s 
Disease and restless leg syndrome, but Pramipexole is not approved by the FDA to treat bipolar 
disorder. 
 
This research study will compare Pramipexole to placebo.  The placebo looks exactly like 
Pramipexole, but contains no Pramipexole.  During this study you may get a placebo instead of 
Pramipexole.  Placebos are used in research studies to see if the results are due to the study drug 
or due to other reasons. 
 
We are asking you to take part in this research study because you have bipolar disorder.  Bipolar 
disorder is a brain disorder that causes unusual shifts in mood, energy, activity levels, and the 
ability to carry out day-to-day tasks. 
 
About 100 subjects will take part in this research study.  About 15 subjects will take part at 
Brigham and Women’s Hospital (BWH). 
 
Funds for conducting this research are provided by Brigham and Women’s Hospital. 
 
How long will I take part in this research study? 
 
It will take you about 14 weeks to complete this research study.  During this time, we will ask 
you to make 9 study visits to BWH. 
 
What will happen in this research study? 
 
If you choose to take part in this study, we will ask you to sign this consent form before we do 
any study procedures. 
 
Screening Visit (Visit 1) 
 
The Screening Visit will take about 2 hours.  At this visit, we will do some tests and procedures 
to see if you qualify to take part in this research study.  The study doctor will review the results 
of these tests and procedures.  If you don’t qualify, the study doctor will tell you why.   
 
At this visit, we will: 
 Ask you about your medical history 
 Do a physical exam, including height and weight and blood pressure 
 Draw a blood sample (approx. 2 TSP) 
 Ask you for a urine sample 
 Test your urine for certain drugs  
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 3 of 14 
 
Subject Identification 
 Test your urine for pregnancy, if you are a female able to become pregnant.  
Pregnant women cannot take part in this research study. 
 Ask you to complete paper and pencil as well as computer tasks that measure 
cognitive functioning (for example, attention, memory, and reasoning) 
 Do an ECG (electrocardiogram) 
 
This test checks the electrical activity of your heart. We will place several small, 
 
sticky pads on your chest, arms, and legs. Each pad has a wire attached. The wires 
 
connect to a machine that makes a recording of your heart rhythm. This   
      painless test takes about 15 minutes.  
 Ask you to fill out some questionnaires about your general health and well-being, 
quality of life, mental health, emotional health, mood, and memory 
 
Urine Drug Screen 
During this study, we will test your urine for certain drugs, including illegal drugs, e.g., cocaine, 
marijuana.  If your urine shows you have taken any of these drugs, you can’t be in this study.  
The results of the urine drug test will not become part of your medical record.  These test results 
will, however, remain part of your study record.   
 
Baseline Visit (Visit 2) – Assignment to a Study Group 
 
Visit 2 will take about 3 hours.  At this visit, we will: 
 
 Ask you about your current mood and behaviors 
 Measure your blood pressure and height and weight 
 Ask you to complete a battery of pencil and paper and computer tests to look at 
cognition (for example, thinking, memory, and concentration) 
 
If you still qualify for the study, we will assign you by chance (like a coin toss) to the 
Pramipexole group or the placebo group.  There are 4 study drug assignment groups in total, 
each of those depends on what medication you are taking and whether or not you meet a cut-off 
for depressive symptoms. Across these 4 groups, there is an equal chance of being assigned to 
the Pramipexole group. You and the study doctor cannot choose your study group.  
 
You and the study doctor won’t know which study group you are in, but s/he can find out if 
necessary. 
 
Taking the Study Drug 
We will give you a supply of study drug to take home with you. 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 4 of 14 
 
Subject Identification 
You will take the study drug by mouth, either once or twice a day for the entire study. The first 
day you take the study drug, we will ask you to take it at night. For the rest of the study you will 
take it once in the morning and once in the evening. It is important for you to follow our 
instructions about how to take the study drug.  Although Pramipexole has not been shown to 
impair your functioning, please exercise caution when driving or participating in activities that 
require you to be alert, until you know how the medication affects you. In addition, you should 
avoid drinking alcoholic beverages for the duration of the study. Bring any unused study drug 
with you to your next study visit.  
 
Your Study Drug Diary 
We will give you a study diary to fill out at home each day.  You will write down the times each 
day you take the study drug.  Bring this diary with you to each study visit, so we can track your 
progress. 
 
Study Drug Phase (Visits 3-9) 
You will take the study drug for 12 weeks. While you are taking the study drug, you will come 
in for a study visit about every week for the first 4 weeks and then every two weeks for the 
remaining 8 weeks of the study. These study visits will take between 1 and 4 hours, depending 
on the visit. At the end of each visit, we will remind you of what will happen at your next visit.  
 
Each Visit 
At each visit during this part of the study, we will:  
 Ask you about your current mood and behaviors 
 Ask you to fill out some questionnaires about your general health and well-being, quality 
of life, mental health, emotional health, mood, and memory 
 Measure your blood pressure and height and weight 
 Ask you about any side effects you may be experiencing 
 Ask you for the previous week’s drug diary and any leftover study drug 
 
Some Visits 
At some visits, we will also:  
 Ask you to complete paper and pencil as well as computer tasks that measure 
cognitive functioning (for example, attention, memory, and reasoning) 
 Do an ECG (electrocardiogram) 
 
 
After You Complete the Study 
After you complete the study, we will refer you back to your own doctor for your ongoing 
medical care.  
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 5 of 14 
 
Subject Identification 
Stopping the Study Early 
 
If you decide to stop taking part in the study for any reason, we will ask you to make a final 
study visit.  You will need to return all unused study drug and your study diary at this visit.  The 
final study visit will take about 4 hours.  At this visit, we will: 
 Do a physical exam, including height and weight and blood pressure 
 Draw a blood sample (approx. 2 TSP) 
 Ask you for a urine sample 
 Test your urine for certain drugs  
 Test your urine for pregnancy, if you are a female able to become pregnant.  
Pregnant women cannot take part in this research study. 
 Ask you to complete paper and pencil as well as computer tasks that measure 
cognitive functioning (for example, attention, memory, and reasoning) 
 Do an ECG (electrocardiogram) 
 Ask you to fill out some questionnaires about your general health and well-being, 
quality of life, mental health, emotional health, mood, and memory 
 Ask you for the previous week’s drug diary and any leftover study drug 
 
When you end your participation in the study, the study drug will need to be tapered for a period 
of 7-10 days, depending on the amount of drug you were taking at the end of the study. The 
study doctor will provide you with amount of study drug to take each day during this period. You 
will not have to return to BWH for a study visit, unless medically necessary, but someone from 
the study team will reach out to you by phone and/or email to check on how you’re doing during 
this taper period.  
 
Also, the study doctor may take you out of the study without your permission.  This may happen 
because: 
 The study doctor thinks it is best for you to stop taking the study drug 
 You can’t make the required study visits 
 We stop doing the study for other reasons 
 
If this happens, the study doctor will explain why you need to stop taking part in the study.  We 
will ask you to come in for a final study visit as described above. 
 
Study Information Included in Your Electronic Medical Record 
 
A notation that you are taking part in this research study may be made in your electronic medical 
record.  Information from the research that relates to your general medical care may be included 
in the record (for example: list of allergies, results of standard blood tests done at the hospital 
labs). 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 6 of 14 
 
Subject Identification 
 
Please ask your study doctor if you have any questions about what information will be included 
in your electronic medical record. 
 
What are the risks and possible discomforts from being in this research 
study? 
 
Risks of Taking Pramipexole 
 
Taking Pramipexole may cause you to have one or more of the side effects listed below. 
 
Common side effects: 
 Headache  
 Nausea  
 Insomnia, or any difficulty sleeping  
 
Less common side effects: 
 Dizziness 
 Constipation 
 Physical weakness or lack of energy 
 Hallucinations 
 
Uncommon side effects: 
 Narcolepsy, excessive uncontrollable daytime sleepiness 
 Restlessness 
 Problems with impulse control 
 
Additionally, in 2012 the FDA announced a potential risk of Pramipexole related to heart failure. 
The FDA drug safety communication recommends continuing the use of Pramipexole, as there 
have been no statistically significant findings to date. These findings do not indicate the reported 
heart failure in patients taking Pramipexole is associated with the drug, however data is still 
being reviewed. To minimize this potential risk, if you have a history of heart failure you will not 
be allowed to participate in the study. We will also assess cardiac risk factors at the time of 
screening and will monitor symptoms of heart failure in all participants throughout the study, 
including vital signs during all visits and ECGs on weeks 6 and 12. 
 
If you agree to participate in the study, it is possible that your Bipolar I or II Disorder may put 
you at increased risk of having a manic episode or psychosis or other mood disturbance or 
impulse control problems due to this drug and its possible side effects. Please notify study staff is 
you notice any worsening in psychiatric symptoms. 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 7 of 14 
 
Subject Identification 
 
There may be other risks of Pramipexole that are currently unknown. 
 
As with any drug, an allergic reaction can occur.  Allergic reactions can be mild or more serious, 
and can even result in death.  Common symptoms of an allergic reaction are rash, itching, skin 
problems, swelling of the face and throat, or trouble breathing.  If you think you are having an 
allergic reaction, call the study doctor right away.  If you are having trouble breathing, call 911 
immediately.  
 
Risks to an Embryo or Fetus, or to a Breastfeeding Infant 
 
The effect of Pramipexole on an embryo or fetus (developing baby still in the womb), or on a 
breastfeeding infant, is unknown and may be harmful.  Because of these unknown risks, women 
cannot take part in this study if they are: 
 Pregnant 
 Trying to become pregnant  
 Breastfeeding 
 
If you are a menopausal woman and have not had a menstrual period for the past 12 months or 
more, you will not need to have a pregnancy test.  Also, if you have had any well-documented 
method of surgical sterilization, you will not need to have a pregnancy test.  Methods of surgical 
sterilization include having had a hysterectomy (removal of the uterus), bilateral oophorectomy 
(removal of both ovaries), a tubal ligation (having your tubes tied), and transvaginal occlusion 
(plugging the opening of the tubes with a coil).  All other female subjects must have a negative 
pregnancy test before starting the study drug. 
 
If you are sexually active and able to become pregnant, you must agree to use one of the birth 
control methods listed below.  You must use birth control for the entire study and for at least 
30 days after your last dose of study drug.  
 
Acceptable birth control methods for use in this study are: 
 hormonal methods, such as birth control pills, patches, injections, vaginal 
rings, or implants 
 barrier methods (such as a condom or diaphragm) used with a spermicide (a 
foam, cream, or gel that kills sperm) 
 intrauterine device (IUD) 
 abstinence (no sex) 
 
Hormonal contraceptives, implants, and injections are only considered effective if used properly 
and started at least one month before you begin the study, continuing throughout the study and 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 8 of 14 
 
Subject Identification 
for one month after the end of the study. You should ask your study doctor if you should 
continue birth control for longer than 30 days after the end of the study. If you are unsure 
whether the method of birth control you use is acceptable to use while participating in this study, 
you should ask your study doctor before you begin the study. 
 
If you miss a period, or think you might be pregnant during the study, you must tell the study 
doctor immediately.  If you become pregnant, you must stop taking the study drug and stop 
taking part in the study.  The study doctor may ask for your permission to collect information 
about the outcome of your pregnancy and the condition of your newborn.  
 
Risks of Taking Pramipexole with Other Medications 
 
Do not take the following family of over the counter medications commonly used to treat 
gastrointestinal symptoms (heart burn, sour stomach, indigestion, etc.) while you are in the 
study: over the counter (OTC) H2 blockers such as cimetidine/Tagamet or famotidine/Pepcid or 
ranitidine/Zantac. Taking these drugs and Pramipexole together may cause serious side effects. 
 
For your safety during this study, call your study doctor BEFORE you take any: 
 new medications prescribed by your own doctor 
 other medications sold over-the-counter without a prescription 
 dietary or herbal supplements 
 
Risks of Blood Draws 
 
You may have a bruise (a black and blue mark) or pain where we take the blood samples.  There 
is also a small risk of infection, lightheadedness, and/or fainting.  
 
Other Risks 
 
Some of the questions that you will be asked during your study participation may be unsettling, 
but most will not be. You may ask to see the questions before deciding whether or not to 
participate. You may also become fatigued during the testing. You are encouraged to notify the 
examiner if you wish to take a break. You may refuse to answer any questions that you so choose 
and you may discontinue testing if you feel that you cannot continue. 
 
There always exists the potential for loss of private information; however, there are procedures 
in place to minimize the risk.   
 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 9 of 14 
 
Subject Identification 
What are the possible benefits from being in this research study? 
 
You may not benefit from taking part in this research study.  If you receive Pramipexole, it is 
possible that some of your cognitive problems associated with bipolar disorder will improve 
while you are taking it.  
 
Others with bipolar disorder may benefit in the future from what we learn in this study.  
 
 
What other treatments or procedures are available for my condition? 
 
You do not have to take part in this research study to be treated for bipolar disorder. Instead of 
being in this research study, your choices may include: Pramipexole is available by prescription 
from your treating doctor to be used off-label without the need to participate in this study. 
   
Talk with the study doctor if you have questions about any of these treatments or procedures. 
 
 
Can I still get medical care within Partners if I don’t take part in this 
research study, or if I stop taking part?  
 
Yes.  Your decision won’t change the medical care you get within Partners now or in the future.  
There will be no penalty, and you won’t lose any benefits you receive now or have a right to 
receive. 
 
Taking part in this research study is up to you.  You can decide not to take part.  If you decide to 
take part now, you can change your mind and drop out later.  We will tell you if we learn new 
information that could make you change your mind about taking part in this research study. 
 
 
What should I do if I want to stop taking part in the study? 
 
If you take part in this research study, and want to drop out, you should tell us.  We will make 
sure that you stop the study safely.  We will also talk to you about follow-up care, if needed. 
 
Also, it is possible that we will have to ask you to drop out of the study before you finish it.  If 
this happens, we will tell you why.  We will also help arrange other care for you, if needed. 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template – Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
Page 10 of 14 
 
Subject Identification 
 
Will I be paid to take part in this research study? 
 
We will pay you $400 if you complete the study.  If you do not complete the study, you will  
receive different amounts depending on the length of the visit. You will be paid $100 for the 
screening visit; $50 for baseline and week 6; $20 for week 1, 2, 3, 4, 8; $100 for week 12. All 
payments will be made by check processed through the Partners AP “eCheck” system. In 
addition, you will receive the study drug at no cost for the entire study period.  
 
 
What will I have to pay for if I take part in this research study? 
 
Study funds will pay for study drug, study-related procedures, study visits that are done only for 
research. 
 
 
What happens if I am injured as a result of taking part in this research 
study?
 
We will offer you the care needed to treat any injury that directly results from taking part in this 
research study.  We reserve the right to bill your insurance company or other third parties, if 
appropriate, for the care you get for the injury.  We will try to have these costs paid for, but you 
may be responsible for some of them.  For example, if the care is billed to your insurer, you will 
be responsible for payment of any deductibles and co-payments required by your insurer. 
 
Injuries sometimes happen in research even when no one is at fault.  There are no plans to pay 
you or give you other compensation for an injury, should one occur.  However, you are not 
giving up any of your legal rights by signing this form. 
 
If you think you have been injured or have experienced a medical problem as a result of taking 
part in this research study, tell the person in charge of this study as soon as possible.  The 
researcher's name and phone number are listed in the next section of this consent form. 
 
 
If I have questions or concerns about this research study, whom can I 
call? 
 
You can call us with your questions or concerns.  Our telephone numbers are listed below.  Ask 
questions as often as you want.
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
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IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 11 of 14 
 
Subject Identification 
Katherine Burdick, PhD is the person in charge of this research study.  You can call her at 617-
732-5789 Monday-Friday from 9am to 5pm. You can also call Meg Shanahan at phone number 
617-732-5790 Monday-Friday from 9am to 5pm with questions about this research study. 
 
To reach a physician member of the study team 24 hours a day, 7 days a week, you can call the 
BWH hospital operator, 617-732-5500, indicate that it is a research matter, and ask the operator 
to page the study doctor assigned to you (you will know who your study doctor is once the 
screening visit takes place). 
 
If you have questions about the scheduling of appointments or study visits, call Meg Shanahan at 
phone number 617-732-5790.
 
If you want to speak with someone not directly involved in this research study, please contact 
the Partners Human Research Committee office.  You can call them at 857-282-1900. 
 
You can talk to them about: 
 Your rights as a research subject 
 Your concerns about the research 
 A complaint about the research 
 
Also, if you feel pressured to take part in this research study, or to continue with it, they want to 
know and can help. 
 
 
If I take part in this research study, how will you protect my privacy? 
 
During this research, identifiable information about your health will be collected.  In the rest of 
this section, we refer to this information simply as “health information.”  In general, under 
federal law, health information is private.  However, there are exceptions to this rule, and you 
should know who may be able to see, use, and share your health information for research and 
why they may need to do so. 
 
In this study, we may collect health information about you from: 
 Past, present, and future medical records 
 Research procedures, including research office visits, tests, interviews, and 
questionnaires 
 
Who may see, use, and share your identifiable health information and why they may 
need to do so: 
 Partners research staff involved in this study 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 12 of 14 
 
Subject Identification 
 The sponsor(s) of this study, and the people or groups it hires to help perform this 
research 
 Other researchers and medical centers that are part of this study and their ethics boards 
 A group that oversees the data (study information) and safety of this research 
 Non-research staff within Partners who need this information to do their jobs (such as for  
treatment, payment (billing), or health care operations) 
 The Partners ethics board that oversees the research and the Partners research quality 
improvement programs. 
 People from organizations that provide independent accreditation and oversight of 
hospitals and research 
 People or groups that we hire to do work for us, such as data storage companies, insurers, 
and lawyers 
 Federal and state agencies (such as the Food and Drug Administration, the Department of 
Health and Human Services, the National Institutes of Health, and other US or foreign 
government bodies that oversee or review research)  
 Public health and safety authorities (for example, if we learn information that could mean 
harm to you or others, we may need to report this, as required by law) 
 Other:        
 
Some people or groups who get your health information might not have to follow the same 
privacy rules that we follow and might use or share your health information without your 
permission in ways that are not described in this form.  For example, we understand that the 
sponsor of this study may use your health information to perform additional research on various 
products or conditions, to obtain regulatory approval of its products, to propose new products, 
and to oversee and improve its products’ performance.  We share your health information only 
when we must, and we ask anyone who receives it from us to take measures to protect your 
privacy.  The sponsor has agreed that it will not contact you without your permission and will not 
use or share your information for any mailing or marketing list.  However, once your information 
is shared outside Partners, we cannot control all the ways that others use or share it and cannot 
promise that it will remain private. 
 
Because research is an ongoing process, we cannot give you an exact date when we will either 
destroy or stop using or sharing your health information. 
 
The results of this research study may be published in a medical book or journal, or used to teach 
others.  However, your name or other identifying information will not be used for these purposes 
without your specific permission. 
 
Your Privacy Rights 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 13 of 14 
 
Subject Identification 
 
You have the right not to sign this form that allows us to use and share your health information 
for research; however, if you don’t sign it, you can’t take part in this research study.    
 
You have the right to withdraw your permission for us to use or share your health information 
for this research study.  If you want to withdraw your permission, you must notify the person in 
charge of this research study in writing.  Once permission is withdrawn, you cannot continue to 
take part in the study. 
 
If you withdraw your permission, we will not be able to take back information that has already 
been used or shared with others. 
 
You have the right to see and get a copy of your health information that is used or shared for 
treatment or for payment.  To ask for this information, please contact the person in charge of this 
research study.  You may only get such information after the research is finished. 
 
 
Informed Consent and Authorization 
 
Statement of Person Giving Informed Consent and Authorization 
 
 I have read this consent form. 
 This research study has been explained to me, including risks and possible benefits (if 
any), other possible treatments or procedures, and other important things about the study. 
 I have had the opportunity to ask questions. 
 I understand the information given to me. 
 
 
 
Signature of Subject: 
 
I give my consent to take part in this research study and agree to allow my health information to 
be used and shared as described above. 
 
 
 
 
 
 
 
Subject 
Date 
Time (optional) 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
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IRB AME No: AME4


Partners HealthCare System 
Research Consent Form 
 
 
 
General Template - Drug Clinical Trial 
Version Date:  August 2016 
 
 
 
 
Page 14 of 14 
 
Subject Identification 
Signature of Study Doctor or Person Obtaining Consent: 
 
Statement of Study Doctor or Person Obtaining Consent 
 
 I have explained the research to the study subject. 
 I have answered all questions about this research study to the best of my ability. 
 
 
 
 
 
 
 
 
Study Doctor or Person Obtaining Consent 
Date 
Time (optional) 
 
 
 
Consent Form Version:  8/29/18 
 
Consent Form Title: pram consent 8 29 18 clean
IRB Protocol No: 2017P001185
Consent Form Valid Date: 9/6/2018
IRB Expiration Date: 9/12/2019
Sponsor Protocol No: N/A
Sponsor AME No: N/A
IRB AME No: AME4

Prot_SAP_000.pdf: 
 
 
Version Date 10/23/17 
1
  
 
 
TITLE: Pramipexole in Bipolar Disorder: Targeting Cognition (PRAM-BD) 
 
 
PRINCIPAL INVESTIGATOR: 
Anil Malhotra, M.D. 
 
 
CO-INVESTIGATORS: 
Raphael Braga, M.D. 
  
 
 
 
Lauren Hanna, M.D. 
  
 
 
 
Jose Rubio-Lorente, M.D. 
  
 
 
 
 
 
 
CONTACT INFORMATION:  
Zucker Hillside Hospital, Div. of Psychiatry Research 
 
75-59 263rd Street 
 
Glen Oaks, NY 11004 
 
 
Phone:  
718-470-8012 
 
Fax:  
718-343-1659 
 
Email:  
amalhotra@northwell.edu 
 
 
 
SUBMITTED TO: 
The Institutional Review Board  
The Feinstein Institute for Medical Research  
Northwell Health  
3333 New Hyde Park Road, Suite 317 
 
New Hyde Park, New York 11042 
 
 
 
SIGNATURE: 
 
 
 
____________________________________ 
Anil Malhotra, Prinicipal Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Version Date 10/23/17 
2
  
 
INTRODUCTION, BACKGROUND MATERIAL, SIGNIFIGANCE AND 
PRELIMINARY DATA 
 
PROJECT SUMMARY 
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, 12-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. 
 
BACKGROUND 
 
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. Our collaborator, Katherine Burdick and 
team, recently completed one of the first controlled trials of cognition as a treatment target in BD 
(Burdick et al. 2012). They 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, 


 
 
Version Date 10/23/17 
3
  
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 collaborating 
group (Burdick et al. 2007). In a sample of 52 Caucasian BD probands and 102 Caucasian 
healthy controls, they 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). They 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 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. 
 
SIGNFICANCE 
Neurocognition in Bipolar Disorder (BD). Historically, it was believed that BD patients achieve 
complete inter-episode recovery, particularly with regard to cognition (Kraeplin, 1913), 
contributing to the notion that the cognitive deficits in BD are transient and merely a 
consequence of acute symptoms. While some of the impairment seen during acute episodes 
may be ameliorated by effective treatment, remitted BD patients demonstrate deficits in 
attention, verbal learning, and executive function (Arts et al. 2008; Bora et al. 2009; Robinson et 
al. 2006; Torres et al., 2007) at around -1 standard deviation vs.  healthy controls. As has been 
repeatedly shown in SZ (Green, 1996, Green et al. 2000; McClure et al. 2007; McGurk & 
Mueser, 2006; Novick et al. 2009; Perlick et al. 2008; Shamsi et al. 2011; Ventura et al. 2009), 
these deficits contribute significantly to functional disability in BD (Martinez-Aran et al. 2007; Jaeger 
et al. 2007; Brissos et al. 2008; Bowie et al. 2010; Burdick et al. 2010; Harvey et al. 2010) 
making them a critical treatment target (Burdick et al. 2007). 
 
Functional Disability in BD. Although BD has been characterized as an illness with an episodic 
course and resultant functional recovery (Murray & Lopez, 1997); data clearly document that 
neither complete symptomatic nor functional recovery are the norm. Even early in the illness, 
patients have strikingly high levels of subthreshold symptomatology despite standard treatment 
(Tohen et al. 2003). Real-world functioning is significantly impaired. Only 19-23%of patients are 
married vs. 60% of the general population (Abood et al. 2002). Unemployment rates in BD are 
57-65% (Dion et al. 1988) and only ½ of those who were employed had returned to their 
premorbid work-level, suggesting that ~80% of BD patients are at least partially vocationally 
disabled. Finally, 19-58% of patients do not live independently, requiring family support (Kupfer 
et al. 2002).  
Early data suggest that, as in SZ, 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. 


 
 
Version Date 10/23/17 
4
  
2007). There are several ongoing large-scale clinical trials targeting cognition in SZ, with a 
parallel need existing in BD.  
Rationale for Targeting Dopamine (DA). 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). 
DA also plays an important role in other BD-relevant symptom domains that will be the focus of our 
exploratory aim in this revised submission. Namely, mood regulation, affective processing, and 
reward-based decision-making are all influenced by DA and will be carefully assessed in this 
project. 
Pramipexole. In addition to these lines of evidence supporting the use of a DA agent to enhance 
cognition, recent evidence suggests that pramipexole, a 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. Our collaborator previously reported on the 
safety and efficacy of pramipexole in a 6-week controlled trial in BD patients with treatment 
resistant depression (Goldberg et al. 2004). They administered a brief battery of psychomotor and 
attention tests pre- and post-treatment. Results from that study indicated that pramipexole 
significantly improved attention (Burdick et al. 2007); however, due to the improvement in 
depressive symptom severity, they were unable to disentangle the effects on cognition from the 
antidepressant effect. We designed a follow-up study to test for its potential pro-cognitive effects in 
affectively-stable patients with BD, which was funded by the Stanley Medical Research Institute 
(PIs Burdick & Malhotra). This was the first controlled trial of a DA agonist with cognition as the 
primary outcome measure in patients with BD. We hypothesized that pramipexole would 
significantly improve attention and working memory due to their link with PFC function. 
Data from this 8-week, randomized, controlled cognitive enhancement trial (Burdick et al. 2012) are 
detailed below. Our findings suggest that pramipexole is effective in improving cognition in a 
subgroup of patients with BD. These results warrant follow-up, with an eye toward optimizing 
study design. Specifically, our results highlight several methodological challenges in designing 
cognitive trials in patients with BD.  


 
 
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1) The episodic nature of the illness requires careful consideration of baseline symptom severity, 
particularly in light of data suggesting a significant influence of affective symptoms on cognitive 
performance (Martinez-Aran et al. 2000; Basso et al. 2002). In the case that symptomatic patients 
are included and cognitive improvement is reported, it may be difficult to rule out pseudospecificity. 
As noted above, preliminary data from our first trial (Goldberg et al. 2004) provided evidence of a 
potential role for pramipexole as a cognitive enhancement agent; however, the patients in that trial 
also improved with regard to depression, making it impossible to determine the extent to which the 
cognitive improvement was related to the amelioration of depressive symptoms. This trial is 
specifically designed to address this issue, by stratifying randomization based upon 
presence/absence of depressive symptoms at baseline. This will increase recruitment feasibility 
given the prevalence of persistent low-grade depression in BD and will provide direct data on the 
influence of baseline mood on cognitive outcome.  
2) A second methodological issue concerns the considerable cognitive heterogeneity that is 
seen in BD, with about 40% displaying ‘normal’ cognition (Martino et al. 2008; Reichenberg et 
al. 2009; Bora et al. 2010). We did not impose a minimal impairment for inclusion; however, the 
potential utility of doing so is reflected in that lower baseline performance correlates with greater 
improvement due to pramipexole (Burdick et al. 2012). Moreover, ceiling effects in BD are of 
real concern. The current proposal is designed to address this issue by pre-screening subjects 
for objective evidence of global cognitive dysfunction and including only these patients. 
3) Another limitation, as in most studies of BD patients, is the use of concomitant psychotropic 
medications. Although it is impractical/unethical to require a washout of medications in a stable 
patient, our data indicate that certain restrictions may optimize benefits. Given the limited sample 
size, we were only able to superficially determine the effects of concomitant medications by 
dividing groups based on the presence/absence of specific drug classes (e.g. antipsychotics, 
lithium). In using a DA agonist to target cognition, the use of antipsychotics was of particular 
concern due to their action at the D2 receptor; however, given their widespread use in BD, it was 
not feasible to exclude all subjects taking these agents. Our data suggest that antipsychotics may 
indeed limit the degree of improvement attributed to pramipexole (see preliminary data); thus, this 
proposal will address this issue more conclusively by recruiting a large enough sample to allow for 
stratification by concomitant antipsychotic status at the time of randomization.  
4) In our previous study, we utilized a fixed-dose design with a highly conservative maximum daily 
dose (1.5 mg/day) in an effort to reduce the chances of mania or psychosis induction, which may 
have limited the potential for cognitive benefit. There were no concerning side-effects or clinical 
worsening; 100% of subjects reached the maximum dosage by week 4. In pramipexole trials in BD 
depression, efficacious and tolerable doses ranged from 1.0 to 5.0 mg/day suggesting that a higher 
dose would be well-tolerated and may have greater beneficial effects. There is some indication of a 
dose-response relationship in BD depression (Aiken, 2007). The current study will test this 
potential by using the recommended slow titration (Boehringer Ingelheim International, 2007) but 
allowing for flexible dosing up to a maximum of 4.5 mg/day (the maximum FDA-approved dosage 
in PD).  
5) Finally, as the previous trial included an 8-week treatment phase, our ability to measure the 
long-term safety and efficacy of pramipexole was limited. Moreover, improving quality of life and 
day-to-day functioning is an important goal in any study targeting cognition. The measurement of 
social and occupational capacities in the context of an 8-week trial is inadequate, as it is very 
unlikely that a person’s occupational status would change that rapidly even if the study drug was 
highly effective. Therefore, in an effort to extend our safety and efficacy data and to allow for the 
assessment of changes in community functioning, we will lengthen the treatment and follow-up 
phase of the current trial to 12-weeks and include detailed co-primary measures of functional 
capacity. 


 
 
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Pramipexole: Safety Data. In our published reports (Goldberg et al. 2004; Burdick et al. 2012), 
pramipexole was a safe adjunctive in the treatment of depression and cognitive dysfunction in BD. 
In studies of pramipexole in affective patients, the most common side effects included nausea, 
headache, and somnolence (Aiken, 2007). In Burdick et al. (2012), only a single adverse event 
(restlessness) was reported more frequently in the active vs the placebo group. Importantly, there 
is no evidence to suggest a high risk for medication-induced manic switching, with combined data 
indicating a switch rate of ~5% for hypomania and ~1% for mania over an average of 14 weeks. 
These rates are lower than those reported with other antidepressants (~11% hypomania; ~8% 
mania; Aiken, 2007). Although in Parkinson’s trials, psychosis has been reported, most commonly 
in the form of visual hallucinations, the rates of psychosis in mood disordered patients is less than 
1% (Aiken, 2007) and in our own work, we have not experienced any psychosis-related adverse 
events (Goldberg et al. 2004; Burdick et al. 2012).  
 DA is not only implicated in normal cognition but is also known to play a critical role in reward-
based learning (Schultz, 2006; Balleine et al., 2007). While several studies have demonstrated 
beneficial cognitive effects of pro-dopaminergic agents on attention and working memory (Costa et 
al., 2009; Granon et al., 2000; Mehta et al., 2000; Mattay et al., 2000), pramipexole and other DA 
agonists have also been implicated in the emergence of risk-seeking behaviors such as 
pathological gambling in Parkinson disease (PD) patients (Dodd et al., 2005; Voon et al., 2006; 
Potenza, Voon, & Weintraub, 2007; Lader, 2008; Bodi et al., 2009; Weintraub et al., 2010; 
Weintraub et al., 2006; Voon et al., 2006a; Voon et al., 2006b; Pontone et al., 2006). A purported 
mechanism for this effect is related to pramipexole’s high selective affinity for D3 receptors, which 
are primarily expressed in the mesocorticolimbic DA pathway – a circuitry active during impulsive 
decision-making (Madden et al., 2010). Although there is a paucity of data on the potential for 
pramipexole to cause DA disinhibition syndrome in BD, given the data in other clinical samples and 
the predisposition toward impulsive behaviors in BD (Adida et al. 2008; Adida et al., 2011, Jollant 
et al., 2007, Malloy-Diniz et al., 2009, Malloy-Diniz et al., 2009; Martino et al., 2011; Yechiam et al., 
2008), it would be reasonable to predict heightened susceptibility to the development of behaviors 
associated with poor decision-making when taking a DA agonist. We measured emotional 
decision-making, using the Iowa Gambling Task (IGT), before and after drug administration and 
found an increase in high-risk/high-reward choices after active treatment. There were no reports of 
disinhibited behaviors (e.g. gambling, hypersexuality), nor any increase in mania (Burdick et al. 
2013). Currently the clinical significance of this change is unknown; however, follow-up is 
warranted over a longer duration. The current proposal will include several sophisticated cognitive-
neuroscience-based measures of reward processing to carefully assess potential changes 
associated with pramipexole in BD patients who might be especially vulnerable to these 
deleterious effects. 
INNOVATION 
The current proposal will represent the first long-term, controlled treatment trial of pramipexole as a 
pro-cognitive agent in stable BD patients. In this 2-site study, we will randomize 100 stable BD 
patients with objective evidence of global cognitive impairment to 12-weeks of pramipexole vs. 
placebo. Randomization will be 1:1 and stratified for concomitant antipsychotic status and 
presence/absence of subthreshold baseline depressive symptoms. 
Target: The first innovative aspect of this study is its primary focus on targeting the RDoC relevant 
phenotype of neurocognition in BD, as opposed to the affective symptoms of the illness. While 
there are many ongoing trials in SZ, there are very few cognitive enhancement studies in BD. 
There have been a handful of case reports/series described in the literature that have included an 
assessment of cognition as part of a treatment trial in BD patients; however most have utilized 
subjective (patient-rated) reports of cognitive improvement (Jacobsen et al. 1999; Schrauwen et al. 
2006; Teng et al. 2006) and no objective cognitive tests were administered. Given the lack of 
correlation between subjective ratings of cognition and neuropsychological test results in BD 


 
 
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patients (Burdick et al. 2005; Martinez-Aran et al. 2005) the extent to which previously reported 
cognitive improvement represented cognitive enhancement as opposed to an effect on mood or 
general well-being is unknown. Limited data derived from studies of the cholinesterase inhibitor, 
galantamine, in BD are promising (Ghaemi et al. 2009; Iosifescu et al. 2009) and are ongoing in 
work being conducted by a Co-I on this proposal (R01 MH079157; PI: Iosifescu). Intervention: In 
considering intervention strategies that might be efficacious, we chose to focus on enhancing DA 
neurotransmission using an already marketed agent. Although by definition, this agent is not novel, 
the ‘re-purposing’ of already approved medications is highlighted as an important component of 
continuing drug discovery by Tom Insel (NIH Director; Insel, 2012). Pramipexole is a partial/full 
D2/D3 agonist with an 8-fold greater affinity for D3 over the D2 receptor (Mierau et al. 1995; 
Gerlach et al. 2003). Its relative specificity allows for a unique opportunity to enhance DA in 
phylogenetically older brain regions associated with emotion regulation, reward, and cognitive 
function (Camacho-Ochoa et al. 1995). Consistent with this mechanism of action, pramipexole has 
a direct antidepressant effect in PD patients (Leentjens et al. 2009) above its efficacy for motor 
symptoms (Barone et al. 2010). This antidepressant effect has also been noted in affective 
disordered patients (Aiken, 2007; Goldberg et al. 2004; Zarate et al. 2004) and preclinical data 
suggest a neurotrophic effect of pramipexole in neurodegenerative models (Lauterbach et al. 2010) 
mediated by the anti-apoptotic protein bcl-2 (Takata et al. 2000), supporting its use in cognitive 
remediation strategies (Lauterbach & Mendez, 2011).   
 
PRELIMINARY DATA 
Data from our previous work provided below support: 1) the feasibility of completing the proposed 
study by including the original investigators and staff involved in the prior successful trial; 2) the 
efficacy of adjunctive pramipexole in targeting cognition in BD patients; 3) the safety of adjunctive 
pramipexole in BD; and 4) the importance of addressing several confounds to optimize cognitive 
enhancement strategies in BD. 
1) Feasibility: To address potential concerns related to the feasibility of completing a 12-week 
clinical trial in stable BD patients, we note our successful completion of a trial very similar in 
scope to the proposed project (led by both of the site PIs Burdick and Malhotra). We 
randomized 50 stable BD patients to pramipexole vs. placebo in an 8-week trial with 90% 
completion rate. Recruitment and retention efforts will parallel those used. Safety and efficacy 
measures will be collected by experienced staff members trained by the PIs most of whom 
participated in the prior trial. Although the sample was more heterogeneous in our earlier work, 
we have optimized our recruitment strategies based upon prior experience. We will now allow 
subthreshold depression, which will also increase feasibility. At both sites, our study physicians 
carry large case-loads of BD patients and are responsible for their ongoing clinical care. This 
will be critical in capturing those patients who are not taking antipsychotic medications or who 
can be safely discontinued (e.g. those subjects who are taking very low doses for sleep or other 
indications). We have evaluated our own databases to determine the feasibility of recruiting 
sufficient numbers of patients with global impairment (based on MCCB composite scores of at 
least -1 SD) and find that while approximately 35% of healthy controls meet this threshold (as 
might be expected based on normal curves), approximately 72% of our euthymic BD patients 
meet this criterion. While this may present as an increased challenge, it is critically important to 
ensure that the subjects being enrolled are the subjects that are best suited for intervention. We 
believe that this is a wholly feasible recruitment goal. 
 2) Cognitive efficacy of pramipexole in BD:  Study 1(Goldberg et al. 2004) -We conducted a 6-
week, controlled study demonstrating the safety and efficacy of pramipexole, in treatment resistant 
BD depression (Goldberg et al. 2004). We included a brief assessment of psychomotor functioning 


 
 
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and attention. In a small sample (n=7), pramipexole had significant effects on concentration and 
visual search efficiency. Cognitive enhancement was evidenced by a significant change in 
performance on an index of concentration (t=-2.9, df=6, p=0.03; Burdick et al. 2007).  These data 
provided the motivation for the subsequent study directly targeting cognition in BD. 
Study 2 (Burdick et al. 2012) – In an effort to disentangle the antidepressant effects and the pro-
cognitive effects of pramipexole in BD subjects, we designed 
our second study to include only patients who were not 
experiencing significant depression or mania (HamD <12; 
CARS-M <8) and we utilized cognition as the primary 
outcome. Results indicated a slight but statistically non-
significant improvement in the pramipexole arm vs. placebo 
in the full sample of completers (n=45). Post hoc analyses 
revealed a significant effect of pramipexole in the euthymic 
subset of the sample (n=34; Fig. 1; F=2.62; df=1,33; 
p=0.030). We found significantly greater improvement in the 
patients taking pramipexole vs. placebo for WAIS Digits Backward (F=4.98; df=1,33; p=0.033) and 
Stroop Color (F=10.37; df=1,33; p=0.003), with a generalized pattern of greater improvement in the 
pramipexole group. 
3) Safety of pramipexole in BD: In Study 1 (Goldberg et al. 2004), BD depressed subjects reported 
higher rates of nausea in the active arm (58%) vs. the placebo (20%) and 1 subject developed 
mania at week 6 while on pramipexole. In Study 2 (Burdick et al. 2012), affectively-stable BD 
subjects reported higher rates of restlessness in the active arm (25%) vs the placebo arm 
(0%);(χ2=5.4; p=0.02) and there were no exacerbations of mania, depression, or psychosis. No 
subject discontinued due to side effects in either study. Overall, pramipexole appears safe when 
used as an adjunctive in depressed and affectively-stable BD patients.  
As described above, DA agonists, as a class, increase the risk of developing impulse-control 
disorders, such as pathological gambling, in PD patients, albeit at a very low rate (Aiken, 2007). 
For additional safety data collection in Burdick et al. (2012), we evaluated performance on the IGT 
in a subset of the sample (measure added part way 
through trial) at baseline and again after 8-weeks of 
treatment. Healthy individuals learn over 5 blocks to 
choose cards from the more conservative decks and to 
avoid the high-risk/high-reward decks, as they result in a 
net loss –  represented in Figure 2 (dotted blue line). RM 
ANCOVA revealed a significant main effect of Time 
(F=6.03; df=1; p=0.02) and a significant three-way 
interaction for Time x Block x Group (F=2.54; df=4; 
p=0.04) indicating that after 8-weeks of treatment, the 
BD subjects in the placebo group show evidence of 
learning (practice effects/improvement) – approaching a 
normal learning curve, while the patients pramipexole develop an abnormal pattern of learning 
(reverse learning curve; red arrow). This pattern is indicative of a preference for high risk/high 
reward card choices that was not present at baseline and these results are now published (Burdick 
et al. 2013).  
This abnormal pattern of performance did not correlate with risky or impulsive behaviors, or with 
manic symptoms so this change is of unknown clinical relevance but will be a focus of the 
proposed application. We will administer this task as we did previously and extend the time of 
follow-up to ensure that these data do not indicate impending affective instability that may not have 
been adequately captured in the 8-week trial. We will use changes in IGT performance at week 8 
Baseline 
 
Post Tx (8-weeks) 
Fig. 2 
Fig. 1 


 
 
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as a potential predictor of changes in mood state at all subsequent visits to address whether it 
signals the very early stages of manic switch. Our prior data did not allow for this analysis, as the 
IGT testing was done at the end of the trial and clinical follow up did not continue beyond that time.  
4) Confounds to prior design:  As described in Burdick et al. (2012), several design issues limited 
the efficacy signal of the initial trial. The proposed 2-site collaborative effort will allow for enhanced 
recruitment and increased selectivity of subjects to address the following issues: a) BD subjects 
with subsyndromal levels of depression did not fare as well as euthymic patients. A considerably 
larger effect size improvement was noted in the subgroup of euthymic subjects who received 
pramipexole in comparison with the full (unselected) sample in the active arm. These data 
alongside evidence from our group and others that indicate pramipexole as an effective anti-
depressant in BD are somewhat counterintuitive, making the decision to include or exclude 
subjects with subthreshold depression less obvious one. In the first application we suggested that it 
was prudent to limit enrollment to euthymic BD patients; however, we modify this strategy in the 
revision to enhance feasibility and generalizability and to provide more data on the potential 
interactions between baseline mood state and cognitive outcome. We will now allow subthreshold 
depressive symptoms at baseline and stratify randomization based upon this factor; b) Subjects 
with greater baseline impairment improved more. We carried out correlations with the hypothesis 
that baseline performance on a given measure would have a significant relationship with the 
change score calculated for the same measure (week 8 performance – baseline performance). In 
the placebo group, baseline performance on WAIS Digits Backward was not correlated with the 
Digits Backward change score (r=0.23; p=0.28) nor the Stroop change score (r=-0.28; p=0.18); 
however, correlations between these variables in the pramipexole group were strong and 
statistically significance (Digits r=-0.61; p=0.003); (Stroop r=-0.42; p=0.05). These results suggest 
that higher levels of baseline cognitive impairment (lower scores) is associated with greater 
cognitive improvement post-pramipexole treatment. This does not reflect a general tendency or 
regression toward the mean, as it is not noted in the placebo sample. Taken together with 
evidence suggesting that there is significant cognitive heterogeneity in BD (Reichenberg et al. 
2009), we will address this by prescreening and excluding those subjects who are least likely to 
benefit from  cognitive enhancement due to a lack of sufficient baseline impairment; and c) 
Concomitant antipsychotic medications appeared to diminish the beneficial effect of pramipexole. 
Specifically the improvements noted on WAIS Digits Backward were considerably stronger in the 
subjects who were not taking antipsychotic medications (Eta2=0.32) than in those taking 
antipsychotics (Eta2=0.12). Likewise, improvement on Stroop Color was greater in subjects not 
taking antipsychotics (Eta2=0.33) vs. subjects on antipsychotics (Eta2=0.16). While this suggests a 
potential interaction, the data are not definitive. In the current proposal, we will stratify 
randomization by concomitant antipsychotics and allow only half of the total sample to be on 
antipsychotics and we will directly test for effects of this factor.   
 
 
OBJECTIVE(S)/SPECIFIC AIMS AND HYPOTHESES 
 
COLLABORATIVE PLAN 
The overall organization of this project is provided by the PIs, Drs. Burdick and Malhotra. Each 
site [Icahn School of Medicine at Mount Sinai (ISMMS) and the Zucker Hillside Hospital (ZHH)] 
will be responsible for managing the activities of their site. Overall organization and 
management of sites will be provided by ISMMS. All PIs and Co-Is will participate in monthly 
conference calls over the first 3.5 years of the study. During the data analytic phase, the 
frequency of conference calls will be increased to weekly.  


 
 
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Mount Sinai will serve as the coordinating site for this trial; therefore, Dr. Burdick will be the 
contact PI and responsible for all interactions between sites and with NIH. All procedures 
specific to the clinical trial will be identical at the two sites. Rater training will be initiated with an 
in-person, on-site meeting to ensure adequate reliability for clinical and neurocognitive 
assessments. We are uniquely situated to ensure reliability, as Dr. Burdick was formerly the 
Director of the Neurocognitive Assessment Unit at the second site (ZHH) and she conducted 
training with staff at both sites. All statistical analyses will be led by the statistician (Co-I) 
Michael Parides from ISMMS. This will include intermittent safety data analyses for the Data 
Safety and Monitoring Committee (DSMB) review and all analyses at the conclusion of the trial. 
The PIs will work together to discuss any changes in the research project and reprogramming of 
funds, if necessary. This study team has a long track record of collaborating successfully do not 
anticipate problems. All co-investigators will first identify primary publications and then negotiate 
the order of authorship using a principle of fairness. PIs will coordinate publication efforts so 
that: manuscripts can be submitted and published in a timely fashion; authorship can be 
apportioned consistently and fairly among the investigators; disputes about authorship can be 
resolved through respectful negotiations; and junior investigators at each site can write 
manuscripts. All manuscripts/abstracts shall have author representation from each site. No 
author will be listed who has not made a material contribution to the scientific content. If a 
conflict develops, the PIs shall meet to resolve the dispute. If they fail, the disagreement will be 
referred to a multiple PI arbitration committee composed of faculty of ISMMS and ZHH. The PIs 
agree that any decisions made will be final and binding. 
OBJECTIVE 
The current proposal will represent the first long-term, controlled treatment trial of pramipexole 
as a pro-cognitive agent in stable BD patients. In this 2-site study, we will randomize 100 stable 
BD patients with objective evidence of global cognitive impairment to 12-weeks of pramipexole 
vs. placebo. Randomization will be 1:1 and stratified for concomitant antipsychotic status and 
presence/absence of subthreshold baseline depressive symptoms. 
SPECIFIC AIMS 
Specific aims are:  
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. 
 
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. 
 
3. 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. 
 
EXPERIMENTAL DESIGN 
 


 
 
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METHODS 
Subjects:  Subjects will be recruited primarily from The Zucker Hillside Hospital, a very large 
acute care psychiatric facility serving a very diverse patient population from the greater New 
York City area, and its affiliated programs and outpatient clinics.  Recruitment will include word 
of mouth and posting of IRB approved advertisements throughout The Zucker Hillside Hospital, 
on internet webpages (e.g.craigslist) and in local newsletters (e.g. NAMI). Krasnoff Quality 
Management Institute (KQMI) will be used to provide lists of potentially eligible patients within 
the health system that meet study criteria.  A letter will be mailed to these potential participants 
that include an explanation of why they are being contacted, a basic description of the study and 
how to contact the study team if interested. If necessary, we will recruit through community 
advertisements. Up to 50 affectively stable patients with Bipolar Disorder will be randomized. 
Additional subjects will be screened, with an assumption of some not meeting eligibility; 
therefore, we estimate 90  patients to be consented for 50 to be randomized. 
 
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 4 or more concomitant psychotropic medications. 1st 
generation antipsychotics 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.  
 
PROCEDURES 
 
Subjects will be recruited from the Zucker Hillside Hospital and its affiliates as described above. 
Community advertisements will be placed if needed (none currently attached for review). 
Potentially eligible patients are identified by the patient’s clinical care taker (nurse practitioner 
and/or physician), who would then grant permission for our research team to approach and 
explain the protocol. A research member will approach that individual and explain the study 
objectives, procedures, risks and benefits, and begin the informed consent process if the patient 
wishes.  
 
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).  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. 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/day and increased every week to a target of 4.5 mg/day. 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 


 
 
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maximum approved dosage in Parkinson’s disease) to ensure adequate target engagement. We 
are familiar with this dose range, as 4.5 mg/day was allowed in our study in BD depression 
(Goldberg et al. 2004). Dosing will be flexible based on side effects; however, if 1.5 mg/day 
cannot be tolerated, the subject will be discontinued. Ideally, 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). 
Measures are described in detail below. 
 
Clinical Assessments and their frequency: Research study visits will occur at baseline, weeks 1 
2, 3, 4, 6, 8, and 12. Patients who will be terminating early will be asked to also complete week 
12 assessments at their end-of-study visit. 
 
Safety Outcome Measures 
PRISE Side Effects Checklist (physician administered) – (all visits) 
Vital signs including blood pressure (standing/supine) – (all visits) 
Electrocardiogram (ECG) – (screening, week 6 and week 12) 
Liver function tests; chemistry panel; CBC; urinalysis – (screening, week 12) 
Medication log of current medications and all medications administered during previous week – 
(all visits) 
Pregnancy test for women of childbearing age – (screening, week 12) 
Urine toxicology – (screening, week 12) 
 
Clinical/Symptom Measures 
Structured Clinical Interview for the DSM-IV (SCID–IV) – (screening) 
Symptom rating scales: Young Mania Rating Scale (YMRS); Hamilton Rating Scale for 
Depression (HRSD); Brief Psychiatric Rating Scale (BPRS) – (all visits) 
Columbia Suicide Severity Rating Scale – (all visits, except screening) 
Smoking Questionnaire – (baseline, week 6, week 12) 
 
Neurocognitive/Functional Measures 
Screening cognitive battery (see inclusion criteria 4 and 6.) – (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) 
Iowa Gambing Task – (baseline, week 6, week 12)  
UCSD Performance Skills Assessment (UPSA) – (baseline, week 12) 
World Health Organization Disability Assessment Schedule – self-administered version 
(WHODAS 2.0) – (baseline, week 12) 
 
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 


 
 
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STUDY TIMELINE 
There will be a 2-month start-up, 40 months of recruitment and 6 months of follow-up. The last 
patient randomized will be mid-way through Year 3 to ensure study completion by end of Year 
4. Analyses and manuscript preparation will be completed immediately thereafter. We will 
screen ~3 patients per month (~1 patient randomized/month), totaling 70 patients screened and 
50 patients randomized.  
 
STUDY ENDPOINTS 
The primary endpoints related to the safety and efficacy on neurocognitive functioning of 
pramipexole will be measured. Neurocognitive performance on the MATRICS Consensus 
Cognitive Battery will be measured at baseline, week 6, and 12 (or end of study). Safety 
measures will be assessed at each visit throughout the study. Co-primary measures of everyday 
functioning will be assessed at baseline, week 6 and 12.  
 
SPECIMEN BANKING 
Blood samples collected through this project for the purposes of genetic analyses will be stored 
in the laboratory of the Division of Psychiatric Genomics within the Department of Psychiatry at 
ISMMS. Any and all identifying information connected to these blood samples will be removed 
before the samples are sent to this lab. 32 ml (2 tbsp) of blood will be collected for these 
purposes if the participant chooses to partake in this optional component. 
 
INCLUSION AND EXCLUSION CRITERIA Subject Selection 
 
Human Subject Involvement, Characteristics and Design 
 
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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Involvement:  The study will involve human subjects as their participation is required to obtain 
information about pramipexole in patients with bipolar disorder. 
 
Subject Characteristics:  Fifty subjects will be randomized for this clinical trial comparing the 
effects of pramipexole treatment on cognition in patients with bipolar disorder versus placebo 
capsules.   
 
Inclusion Criteria will be: (1) Age 18-65. (2) DSM-IV 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 (CVLT). Clinically-significant impairment will be 
defined as scoring > 1 SD below normative means on any one of these measures. This will be 
done by standardizing each score and computing a mean z-score. (5) Clinically-acceptable, 
stably-dosed, mood stabilizing medication regimen for > 1 month prior to enrollment, with no 
medication changes planned over the 12-week study period. (6) Wide Range Achievement Test 
(WRAT-3) score of >70. 
Exclusion Criteria will be: (1) History of CNS trauma, neurological disorder, ADHD, MR, and/or 
learning disability. (2) Positive urine toxicology inconsistent with participant report or DSM-IV 
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) 4 or more 
concomitant psychotropic meds.  (6). Any disallowed medications per Concomitant Medications 
section of protocol, such as 1st generation antipsyhotics or drugs known to interact with 
pramipexole.  (7) Abnormal lab or ECG result at screen. (8) Any significant cardiovascular risk 
factors as determined by the study physician. (9) Significant suicidal risk (HRSD item 3 > 2 or by 
clinical judgment). (10) Pregnancy, breastfeeding, not using contraception. (11) Participation in 
any other investigational cognitive enhancement study within 30 days. (12) ECT in the past 12 
months. 
 
Participants are free to refuse to answer any of the questions that are being asked of them in the 
study. If the withheld information is critical to study eligibility the participant may not be 
enrolled. 
 
Rationale for inclusion criteria:  The diagnostic, age and medical exclusions are derived from 
requirements specific to the proposed study (e.g. safety requirements specific to pramipexole 
treatment).  Evidence of current symptoms is required to allow assessment of treatment effects.   
 
 
Inclusion of Women and Minorities: There are no restrictions related to gender, race or ethnicity 
to study participation.   
 
RECRUITMENT PROCEDURES 
 
Recruitment will follow procedures that are IRB approved.  Referrals for the study will come 
from clinicians or self-referral by patients.  Patients may find out about the study through IRB-


 
 
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approved recruitment flyers and other approved advertisements. If a clinician referral, the 
clinician will first seek permission from the patient for referral.  The consent process begins with 
an assessment of the patient’s ability to give informed consent.  Patients who on initial 
evaluation by the study investigator are deemed not to be capable of giving informed consent 
will not be evaluated further.  Patients who are deemed capable of giving informed consent will 
then be provided with a full and complete description of the study.   
 
We will review a list of participants from a prior study (05-069) which corresponded to Aim #1 of 
this protocol.  Those subjects that are likely to be eligible will be contacted via phone or email 
and given the option to participate in this study. The consent form for study 05-069 did not 
provide an option to decline future contact.  
 
INFORMED CONSENT 
 
Consent will follow IRB approved procedures. A potential participant will be approached by a 
member of the study team after she/he has been given permission to do so by the patient’s 
clinician. The research team member will explain the study objectives, procedures, risks and 
benefits, and answer all the questions the potential participant may have. Participants are 
advised that they can withdraw from the study at any time. Participants will receive a copy of the 
consent form for the study. Informed consent will be documented when the subject signs the 
consent form that has been approved by the Institutional Review Board.   
 
 
DISCOMFORTS AND RISKS 
Potential Risks 
 
During the informed consent process, participants will be informed of the potential risks 
associated with the study. At each weekly visit the study physician will meet with participants 
and conduct a thorough review of symptoms including mood, and suicidal 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 participant receives emergency care or 
hospitalization. Participation in the study will be discontinued in any case of clear symptom 
worsening. Between weekly visits, the participants will have emergency contact information.  
Along with closely monitoring for symptom exacerbation, each visit with the study physician will 
entail a detailed side effect evaluation, which will include vital signs and a side effect checklist.  
 
The main risks to subjects are: 1) risks directly associated with study treatment, 2) risks of blood 
collection, 4) risks of other study procedures, 5) risks of loss of confidentiality.  These are 
presented below followed by a discussion in the next section on procedures to minimize risks. 
 
Risks directly associated with study treatment:   
 
Risks associated with pramipexole treatment:  The most common side effects of pramipexole 
are nausea, headache, dizziness, insomnia, constipation, muscle weakness, abnormal dreams, 
confusion, memory problems, urinary frequency. Participants will be educated about the 
potential for these side effects. Rare side effects have also been reported including sedating 
effects, impulse control symptoms, restlessness, hallucinations, and orthostatic hypotension.  
 
Risks associated with abrupt cessation of pramipexole treatment: 


 
 
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If pramipexole is stopped too quickly, withdrawal symptoms including fever, confusion, and 
severe muscle stiffness may occur. Participants will also be advised that there is a risk of side 
effects associated with the abrupt discontinuation of medication. They will be educated on how 
to taper-off the medication at the completion of the study and be provided with a subject specific 
titration schedule (see also Discontinuation of Study; Drug Information).  The informed consent 
process will alert participants to these potential risks and close monitoring will ensure prompt 
response to any adverse effects with appropriate treatment and/or study discontinuation, as 
indicated.  
     
Risks associated with blood collection include bruising at the blood collection site and the 
possibility of infection. 
 
Risks of other study procedures include the possibility that subjects will become annoyed or 
upset with the assessment questions. 
 
Risks of loss of confidentiality include the possibility that subject information may become 
known to unauthorized individuals. 
 
Protections to Minimize Specific Risks 
 
Medication treatments:  Careful monitoring of subjects is a key aspect of the study.  Subjects 
progress will be monitored by research psychiatrists and side effects assessed by standardized 
instruments. 
 
Phlebotomy risks:  Experienced and certified personnel will be used for all blood collections. 
Distress from assessments:  As part of the consent process, subjects will have been informed 
that they can stop study procedures at any time that they wish.  Interviewers will be experienced 
conducting assessments and will be trained to be sensitive to subject concerns.  If a subject 
becomes distressed, study procedures will be stopped.   
 
Loss of Confidentiality:  All information collected will be maintained in accordance with the 
standards mandated by the IRB.  We will apply for a Certificate of Confidentiality at study onset. 
Any information gained from this research will be kept confidential. Reports from patients' 
clinical records concerning research observations will not be made available to outside medical 
facilities without written consent of the patient. Each subject will be assigned a unique 
identification number and data will be coded using this number.  The coded link to subjects’ 
identities will be kept separate from the database in a locked file cabinet accessible only to the 
study staff.  All research staff are required to demonstrate their understanding of human 
subjects protection issues, including confidentiality issues, by means of passing examinations 
mandated by the IRB.  PHI will need to be collected for subjects to insure that subjects receive 
the proper treatment for them (e.g. preventing medication errors) and from all subjects to 
schedule assessments.  The study data files will not have nor need PHI included as the unique 
identification number will suffice.  Information that carries personally identifying material and 
links to subject identities will be kept in locked files and will be accessible only by the PI and his 
designees (e.g., research coordinator). All computer entries will be identified by code only and 
kept confidential. Patients' identities will not be revealed in any description or publication of this 
research. The Northwell Health, its members and healthcare providers conform to the Health 
Insurance Portability and Accountability Act (HIPAA). This act includes rules that protect the 
privacy of health information about subjects that will either be created or used in connection with 


 
 
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this research study. We will ask all subjects to grant authorization to use their health information 
in the informed consent. 
 
 
POTENTIAL BENEFITS 
 
 
Potential Benefits of the Proposed Research to Human Subjects and Others 
 
There may be no immediate potential benefit to the participant 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 BD. 
 
All subjects will receive compensation for their time performing research procedures at rates 
approved by the IRB. Participants will be informed during the consent process of the study 
compensation. Participants will be paid $100 for the screening visit; $50 for baseline and week 
6; $20 for weeks 1, 2, 3, 4, and 8; $100 for week 12. In the consent there is an optional DNA 
blood draw. If the participant chooses to consent to this they will receive an extra $10 at the time 
of the blood draw. Total possible payment is $410 for study completion and DNA blood draw. 
Screen failures will receive the screening rate ($100) provided they undergo study procedures 
at that visit. 
 
DISCONTINUATION OF STUDY/ SUBJECT WITHDRAWAL 
 
 
The study may be discontinued at any time.  Prior to the study being discontinued, all subjects 
will have been informed of their treatment allocation during the study.  Study data in the case of 
early study termination will be retained to allow for future study analyses. 
 
Subjects may be prematurely terminated from the study if the investigators assess that the 
subject’s clinical condition requires treatment(s) not available within the study context.   
 
Participants with an exacerbation of mania/depression (YMRS > 15 or HRSD > 18) will be 
discontinued and treated by the study physician. Suicidal ideation will be assessed at each visit 
with the Columbia Suicide Severity Rating Scale (C-SSRS). Significant suicidal ideation will be 
addressed immediately using the standard clinical response at ISMMS (evaluation at the walk-in 
clinic for potential need for hospitalization).  Participants at risk for suicidal behavior will be 
discontinued. Side effects will be rated by a study physician at each visit. Any side effect 
deemed to be a serious adverse event or an unanticipated follow up will be reported to the PI, 
and the ISSMS Institutional Review Board (IRB) and appropriate follow up will be conducted. In 
addition, participants who exhibit an inability to follow the protocol will be discontinued and 
withdrawn from the study.  
 
Participants may withdraw from the study for any reason at any time by contacting the principle 
investigator or any of the research staff. It is also possible to withdraw permission for the use 
and disclosure of any protected information for research but it must be done in writing to the 
principle investigator. In the event permission is withdrawn, information that was already 
collected may still be used if that information is necessary to complete the research study.  


 
 
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To ensure orderly termination from the study, the study physician would meet with the 
participant to discuss termination and discontinuation of medication at their last study visit 
(whether this occurs at study completion at week 12 or at an earlier study visit, if the participant 
chooses to withdraw or is withdrawn by staff). Safety measures will be collected and a follow-up 
visit by phone will be scheduled to further ensure safe discontinuation. Pramipexole will then be 
tapered-off at a rate of .75 mg/day over the course of ten (10) days. A subject-specific day-to-
day titration schedule (based on the maximum dose of study medication at the end of study 
completion) will be provided to the subject. A member of the study team will follow-up with the 
subject via phone at the end of the 10 day titration to assure compliance and check on any 
reported symptoms. If there are any remaining concerns by the participant, we will schedule an 
in-person follow-up visit. 
THE DATA AND SAFETY MONITORING PLAN 
 
Monitoring of the study will follow the guidelines of the respective study IRBs.  In addition, 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 Hillside 
Hospital (ZHH). The DSMB monitors all clinical trials conducted under the aegis of the Center.  
Meetings are held via teleconference.  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; ISMMS Co-I), the DSMB will be asked 
to review data on this trial (both sites) at any time that there is a serious adverse event, 
reportable to the Institutional Review Board (IRB) and every 6 months.As the DSMB has a set 
meeting schedule and cannot meet on demand, the study will be reviewed at the first meeting 
following the enrollment of the first subject (0-6 months from time of enrollment). The study will 
be on the schedule for review every 6 months thereafter. The DSMB will have access to all 
relevant clinical data on all subjects necessary to assess the adequacy of human subjects 
protection provided throughout the study.  The complete protocol and consent form are provided 
to the DSMB.  In addition to the DSMB, the PI at each site will review safety data in real time to 
address any concerning adverse events.  
 
The trial will be registered in Clinical Trials.gov. 
 
 
CRITERIA FOR EVALUATING RESPONSE/STATISTICAL ANALYSIS 
Statistical Analyses 
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 


 
 
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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 4, 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). 
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. 


 
 
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Power and sample size considerations:  A total of one hundred patients will be randomized 
1:1(50 from ISMMS, 50 from ZHH). 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 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. 
 
 
 
 
 
 
SCHEDULE OF EVENTS: 
Measure 
Screen 
Baseline 
Wk1 
Wk2 
Wk3 
Wk4 
Wk6 
Wk8 
Wk12 
SCID 
xx 
 
 
 
 
 
 
 
 
Ncog-Sc 
xx 
 
 
 
 
 
 
 
 
YMRS 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
HRSD 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
CSSRS 
 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
MCCB 
 
xx 
 
 
 
 
xx 
 
xx 
PSST 
 
xx 
 
 
 
 
xx 
 
xx 
UPSA 
 
xx 
 
 
 
 
 
 
xx 
WHODAS  
 
xx 
 
 
 
 
 
 
xx 
AEs 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
IGT 
 
xx 
 
 
 
 
xx 
 
xx 
BPRS 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Smoking 
 
xx 
 
 
 
 
xx 
 
xx 
ECG 
xx 
 
 
 
 
 
xx 
 
xx 
Labs 
xx 
 
 
 
 
 
 
 
xx 
Vitals 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
TABLE KEY: Safety Outcome Measures: Adverse Events (AEs) measured by the PRISE side effects checklist 
(physician administered); Vital signs/blood pressure (standing/supine); Electrocardiogram (ECG); liver function tests; 
chemistry panel; CBC; urinalysis; Beck Scale for Suicidal Ideation (BSI) and Columbia Suicide Severity Rating Scale 
(CSSR); Iowa Gambling Task (IGT). Clinical/Symptom Measures: Structured Clinical Interview for the DSM-IV 
(SCID); Symptom rating scales including Young Mania Rating Scale (YMRS), Hamilton Rating Scale for Depression 
(HRSD) and Brief Psychiatric Rating Scale (BPRS). Neurocognitive/Functional Measures: MATRICS Consensus 
Cognitive Battery (MCCB); Probabilistic Stimulus Selection Task (PSST); UCSD Performance Skills Assessment 
(UPSA); World Health Organization Disability Assessment Schedule (WHODAS) (self-administered version)and 
Smoking Questionnaire. 
 
 
CONFLICT OF INTEREST 
 
Dr. Malhotra has no conflicts of interest to disclose. 
 


 
 
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DRUG INFORMATION 
Randomization will be conducted via a computer generated program and all study staff, except 
pharmacy 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. The study 
medication blinding will be done per prescriptions by local site pharmacy. 
Active drug dosing: 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 QD 
and increased every week to a target of 4.5 mg/day. 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 PD) to ensure adequate target engagement. We are familiar with this dose range, as 
4.5 mg/day was allowed in our study in BD depression (Goldberg et al. 2004). 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 5 and then efforts will be made to maintain the 
same dose until the completion of the trial (week 12). As previously mentioned, at the 
completion of the trial (week 12) the subject will be titrated off the study medication at a rate of 
.75 mg/day over the course of 10 days. Also, see Appendix 
 
ADVERSE EVENTS 
 
The study includes structured assessments of side effects at each study visit. All subjects will be 
seen by research psychiatrists who will provide appropriate clinical management of adverse 
events. 
 
Adverse events will be reported to the IRB following the current IRB guidelines in effect at the 
time of the adverse event occurrence.  Adverse events will also be presented to the Data Safety 
and Monitoring Board (DSMB) following the guidelines established by the DSMB for the study. 
 
DRUG ACCOUNTABILITY 
Pramipexole tablets that are used in this study are purchased by the pharmacy from several 
different manufacturers and a small research stock is maintained by the pharmacist. 
The research coordinator will be responsible for getting the prescription to the pharmacist as well 
as communicating possible doses that would be needed.   
 
Encapsulation Process 
1. 
If patient is on active Pramipexole the pharmacist places Pramipexole tablet into an 
orange, blue or white capsule (according to dosing protocol) size 1 or 0, using gloves, 
and fills each capsule with lactose powder.   The compounded capsules are cleaned 
with tissue and placed into a prescription vial with child proof cap. 
2. 
If patient is on placebo the pharmacist places lactose powder into an orange, blue or 
white capsule (according to dosing protocol) size 1 or 0, using gloves.  The 
compounded capsules are cleaned with tissue and placed into a prescription vial with 
child proof cap. 
3. 
Pharmacist will log all lot numbers, manufacturer information and expiration dates of 
medication, capsules and lactose powder in patient specific compounding log. 


 
 
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4. 
The Pharmacist will create a patient specific compound lot number and new 
expiration date for compounded capsules.  Expiration date is calculated as 1 year 
from current date or 50% of manufacturer’s expiration date, whichever is less. 
 
Drug Storage: The medication will be stored in a temperature controlled environment that is in 
the range of 15°C to 30°C (59° to 86° F) monitored 24 hours a day and checked by regular 
temperature checks. The pharmacy uses a daily room temperature log and when temperatures 
are out of range the following procedure will be followed. Temperatures rechecked after 1 hour 
and if temperatures remain out of range then pharmacy supervisor & engineering department 
will be notified. The medications will be removed and placed in another temperature monitored 
location. When the temperature is in an acceptable range the medications will be returned to 
their original location.  
 
 
INSTITUTIONAL REVIEW BOARD (IRB) 
 
The Northwell Health IRB will be the IRB for the study.  Also study procedures will follow the 
guidelines of the IRB.  Specifically, prior approval of the protocol and the informed consent form 
will be required prior to any study subject procedures being performed.   
 
CONFIDENTIALITY 
 
All information collected will be maintained in accordance with the standards mandated by the 
IRB.  We will apply for a Certificate of Confidentiality at study onset. Any information gained 
from this research will be kept confidential. Reports from patients' clinical records concerning 
research observations will not be made available to outside medical facilities without written 
consent of the patient. Each subject will be assigned a unique identification number and data 
will be coded using this number.  The coded link to subjects’ identities will be kept separate from 
the database in a locked file cabinet accessible only to the study staff.  All research staff are 
required to demonstrate their understanding of human subjects protection issues, including 
confidentiality issues, by means of passing examinations mandated by the IRB.  PHI will need to 
be collected for subjects to insure that subjects receive the proper treatment for them (e.g. 
preventing medication errors) and from all subjects to schedule assessments.  The study data 
files will not have nor need PHI included as the unique identification number will suffice.  
Information that carries personally identifying material and links to subject identities will be kept 
in locked files and will be accessible only by the PI and his designees (e.g., research 
coordinator). All computer entries will be identified by code only and kept confidential. Patients' 
identities will not be revealed in any description or publication of this research. The Northwell 
Health, its members and healthcare providers conform to the Health Insurance Portability and 
Accountability Act (HIPAA). This act includes rules that protect the privacy of health information 
about subjects that will either be created or used in connection with this research study. We will 
ask all subjects to grant authorization to use their health information in the informed consent. 
 
 
 
 
 
 
 
Contacting Via Texting/ Email  
 
We have found that it is often easier to reach participants for the purposes of scheduling 
and confirming activities via text message or email.  Text messages or emails will only 
be sent to remind participants of upcoming appointments and/or to request that the 


 
 
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participant contact the coordinator for additional information.  No PHI will be transmitted 
via text message or email.  Any cell phone number or email address that specifically 
identifies the participant will not be used to report information about the project and will 
be stored separately from other data in order to protect the identity of the participant to 
the maximum extent. 
 
 
DATA DISCLOSURE/PUBLICATION/CONFIDENTIALITY 
 
All study publications will report only de-identified data.  Only de-identified data sets are eligible 
for data sharing.  Any data sharing must confirm with the IRB guidelines in effect at the time for 
the proposed data sharing. 
 
APPENDICES 
 
Data on the pramipexole formulation to be used is included in the Appendix. Literature Cited 
 
Baumann B, Bogerts B. Neuroanatomical studies on bipolar disorder. Br J Psychiatry 
Suppl 2001;41: s142-s147 
 
Bilder RM, Volavka J, Czobor P, et al. Neurocognitive correlates of the COMT 
Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002;52: 701-707 
 
Blumberg HP, Stern E, Martinez D, et al. Increased anterior cingulate and caudate 
activity in bipolar mania. Biol Psychiatry 2000;48: 1045-1052 
 
Bowie CR, Depp C, McGrath JA, Wolyniec P, Mausbach BT, Thornquist MH, Luke J, 
Patterson TL, Harvey PD, Pulver AE. Prediction of real-world functional disability in 
chronic mental disorders: a comparison of schizophrenia and bipolar disorder. Am J 
Psychiatry. 2010 Sep;167(9):1116-24. 
 
Burdick KE, Funke B, Goldberg JF, et al. COMT genotype increases risk for bipolar I 
disorder and influences neurocognitive performance. Bipolar Disord 2007;9: 370-376 
 
Burdick KE, Braga RJ, Goldberg JF, Malhotra AK. Cognitive dysfunction in bipolar 
disorder: Future place for pharmacotherapy. CNS Drugs. 2007;21(12):971-981. 
 
Burdick KE, DeRosse P, Kane JM, Lencz T, Malhotra AK. Genetic Variation in the MET 
Proto-oncogene is Associated with Schizophrenia and General Cognitive Ability. 
American Journal of Psychiatry, 2010; 167(4): 436-43. 
 
Burdick KE, Braga RJ, Nnadi CU, Shaya Y, Stearns WH, Malhotra AK (b). Placebo-
controlled adjunctive trial of pramipexole in patients with bipolar disorder: targeting 
cognitive dysfunction. J Clin Psychiatry. 2012 Jan;73(1):103-12. doi: 
10.4088/JCP.11m07299. Epub 2011 Nov 29 
 


 
 
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Depp CA, Mausbach BT, Harmell AL,et. al. (2012) Meta-analysis of the association 
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