Targeting Cognition in Bipolar Disorder With Pramipexole

Study Overview
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Brief Summary
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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
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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).

Official Title
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Pramipexole in Bipolar Disorder: Targeting Cognition (PRAM-BD)

Conditions
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Bipolar Disorder

Intervention / Treatment
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* Drug: Pramipexole
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Age 18-65 DSM-IV BD I or II diagnosis 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. Evidence of clinically-significant neurocognitive impairment at screening 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: History of CNS trauma, neurological disorder, ADHD, or learning disability Positive urine toxicology or DSM-IV diagnosis of substance abuse/dependence within 3 months Active, unstable medical problem that may interfere with cognition Recent history of rapid-cycling Abnormal lab or ECG result at screen History of heart failure Significant suicidal risk (HRSD item 3 > 2 or by clinical judgment) Estimated IQ in MR range as per Wide Range Achievement Test (WRAT) standard score of less than 70 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) Women who are breastfeeding Participation in any other investigational cognitive enhancement study within 30 days

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pramipexole<br>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. | Drug: Pramipexole<br>* Up to 4.5mg, PO, (by mouth) per day of the 12-week study.<br>* Other names: Mirapex;|
| Placebo Comparator: Placebo<br>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. | Drug: Placebo<br>* placebo match study drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MATRICS Consensus Cognitive Battery | MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance. | Baseline | 
| MATRICS Consensus Cognitive Battery | MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance. | Week 6 | 
| MATRICS Consensus Cognitive Battery | MATRICS Consensus Cognitive Battery (MCCB) as measure of Neurocognitive/Functional Measures is a standardized battery designed to measure cognitive functioning in people with schizophrenia. The MCCB is represented as a composite T score. This T-score scale has a mean of 50 and a standard deviation of 10, where higher scores reflect better performance. | Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Young Mania Rating Scale (YMRS) | Mean change of symptoms of mania throughout the study. YMRS contains 7 items rated from 0 (symptom absent) to 4 (severe symptom) and 4 items scored 0 (symptom absent) to 8 (severe symptom), with total range from 0 to 60, where higher score indicates manic symptoms. | Baseline and week 12 | 
| Hamilton Rating Scale for Depression (HRSD) | Mean change of symptoms of depression throughout the study. HRSD consists of 14 items, each defined by a series of symptoms. Each item is rated on a 5-point scale, ranging from 0 (not present) to 4 (severe), with a total score range of 0-56, where higher score indicates more depressive symptoms. | Baseline and week 12 | 
| Brief Psychiatric Rating Scale (BPRS) | Mean change for positive symptoms throughout the study. BPRS consists of 18 items, each defined by a series of symptoms. Each item is rated on a 7-point scale, ranging from 1 (not observed) to 7 (very severe), with a total score range from 18-126, where higher scores indicate psychiatric symptoms. | Baseline and week 12 | 
| Number of Participants With Suicidal Acknowledgements | Number of individual participants who acknowledged at least one item on the Columbia Suicide Severity Rating Scale (C-SSRS) over the 12-week study period. Examples of items on the scale are suicidal ideation (having thoughts, planning) and suicidal behavior (preparing, attempting). | up to Week 12 | 
| The Probabilistic Stimulus Selection Task | The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups. | Baseline | 
| The Probabilistic Stimulus Selection Task | The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups. | Week 6 | 
| The Probabilistic Stimulus Selection Task | The probabilistic selection task assesses the tendency to learn from positive versus negative outcomes. In the probabilistic stimulus selection task, participants are trained to choose one of two paired stimuli; three sets of paired stimuli are shown in total (AB, CD, and EF) and are presented randomly during the training period. To minimize verbal encoding, stimuli are Japanese Hiragana characters. Probabilistic feedback regarding the correct choice is provided. We report the mean percentage of accuracy on choosing the correct paired stimuli among the two treatment groups. | Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bipolar Disorder, Cognition