Cognitive Enhancement as a Target for Cocaine Pharmacotherapy

Study Overview
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Brief Summary
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Specific Aim #1: To determine if galantamine (8 or 16 mg/day) is more effective than placebo in reducing cocaine use as measured by cocaine urine results and self-report days of use. Specific Aim # 2: To determine if galantamine (8 or 16 mg/day) is more effective than placebo in improving attention, assessed with the Rapid Visual Information Processing (RVIP) and the Simple Reaction Time (SRT) tests Specific Aim # 3: To determine if improvement in attention during the first four weeks of treatment will mediate galantamine's efficacy in reducing cocaine use.

Detailed Description
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This will be a double-blind, placebo-controlled, randomized clinical trial. One hundred and twenty cocaine-dependent men and women will be randomized to one of three treatment groups: placebo (n=40), 8 mg/day (n=40), and 16 mg/day (n=40) of extended release (ER) galantamine. An urn randomization will be used to balance the groups for gender, severity of cocaine use (measured by days of cocaine use), baseline cognitive functioning [determined via the Shipley Institute of Living Scale (SILS)], and smoking status. Gender and severity of cocaine use have been shown to predict treatment responses in cocaine users (76). Similarly, balancing the treatment groups for baseline cognitive functioning, assessed with the SILS scores, will minimize the influence of baseline differences on cognitive outcomes (77, 78). Smoking status is also an important baseline variable, given galantamine's actions on nicotinic receptors and its potential efficacy for smoking cessation (65). The initial dose of galantamine will be 8 mg/day as a single dose, as recommended for clinical use. For those assigned to 16 mg/day, the dose of galantamine will be increased to 16 mg at the end of week 4. Treatment groups will remain on their full dosage through week 13. All participants will receive contingency management (CM) targeting treatment compliance. In three previous cocaine pharmacotherapy trials using bupropion, desipramine or levodopa, medication efficacy on cocaine use was evident only when medications were combined with CM, but not with standard care (79-81). These findings provide a strong rationale for using CM in our clinical trial. Recruitment is continuing. This protocol was amended as of May 2014 to come to one dispensing visit and up too, two clinic visits. The payment has changed from gift cards to cash. This change should help increase the number of completers. Currently there are 40 completers with 9 active and 6 in follow up phase. The follow up phase ended June 2016. Currently in analysis.

Official Title
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Cognitive Enhancement as a Target for Cocaine Pharmacotherapy

Conditions
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Addiction

Intervention / Treatment
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* Drug: Galantamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and females, between the ages of 18 and 60 Are using cocaine more than once per week in the previous 30 days, provide a cocaine-positive urine specimen at screening, and fulfill criteria for current cocaine dependence according to DSM-IV For women of child-bearing age, have a negative pregnancy test at screening, agree to adequate contraception to prevent pregnancy, and agree to have monthly pregnancy tests Are fluent in English and have a 6th grade or higher reading level; AND Can commit to at least 13 weeks of treatment and are willing to be randomized to treatment Exclusion Criteria: Meet DSM-IV psychiatric classifications for lifetime schizophrenia or bipolar disorder, or have a depressive or anxiety disorder with current use of a prescribed psychotropic medication that cannot be discontinued Current DSM-IV diagnosis of drug or alcohol dependence (other than cocaine, or tobacco) Demonstrate significant medical conditions, including asthma or chronic obstructive lung disease, history or current gastrointestinal ulcer, hepatic or renal deficit and cardiac rhythm disturbances or any other medical conditions that the study physician deems contraindicated for galantamine treatment Use of other medications including: drugs that slow heart rate (e.g., beta-blockers), which may increase the risk of bradycardia and atrioventricular (AV) block and non-steroidal anti-inflammatory drugs (NSAIDs); increased potential for developing ulcers/active or occult gastrointestinal bleeding Have a screening liver function test (AST or ALT) greater than 3 times normal; OR Known allergy or adverse reaction to galantamine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sugar Pill<br>Sugar Pill will be compared with the active medication Galantamine | Drug: Placebo<br>* Placebo dose.<br>* Other names: Sugar Pill;|
| Active Comparator: Galantamine<br>Comparing the active medication with the placebo medication to see if the self administration cocaine decreases. | Drug: Galantamine<br>* 8mg or 16mg<br>* Other names: Razadyne ER;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Urine Toxicology | Presented are the average number of urine samples positive for cocaine over 12 weeks. This outcome was corrected from the protocol registration when the study data were entered. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Heart Rate | Pulse | once a day for up to two days over 12 Weeks | 
| Blood Pressure- Systolic | Blood Pressure is taken for safety reasons | 2 times a week for 12 weeks | 
| Blood Pressure- Diastolic | Blood Pressure is taken for safety reasons | 2 times a week for 12 weeks | 
| CANTAB RVIP Measure: RVP A | RVIP is a computerized measure of attention. This is given at baseline and every 4 weeks over the course of the 12-week study. RVP A' (aka RVIP A PRIME): is a signal detection measure of target sensitivity (i.e., successful response to targets and withholding of responses to non-targets). Range of 0 to 1. Higher scores are better. | Baseline and 12 Weeks | 
| CANTAB RVIP Measure: RVP B | RVIP is a computerized measure of attention. This is given at baseline and every 4 weeks over the course of the 12-week study. RVP B: A measure of response bias (i.e., bias towards under-responding (to targets) versus over-responding (i.e., to non-targets)) range from -1 to +1, respectively. | Baseline and 12 Weeks | 
| CANTAB RVIP Measure: RVP FALSE ALARM | RVIP is a computerized measure of attention. This is given at baseline and every 4 weeks over the course of the 12-week study. RVP FALSE ALARM is probability of false alarm. False alarms are responses to non-targets. Higher numbers are worse (i.e., could be seen as a measure of poor response inhibition). Scores range from 0-1 where 1 is the least desirable probablity. | Baseline and 12 Weeks | 
| CANTAB SST- SSRT | This is the CANTAB SST measure which evaluates response inhibition. Stop Signal Reaction Time (SSRT): The estimate of the length of time between the go stimulus and the stop stimulus at which the subject is able to successfully inhibit their response on 50% of the trials. Range of scores from 0 to 1500 (unit=milliseconds) and lower scores are 'better'. | Baseline and 12 Weeks | 
| CANTAB SST- Median Correct | This is the CANTAB SST measure which evaluates response inhibition. Stop Signal Reaction Time (SSRT): The estimate of the length of time between the go stimulus and the stop stimulus at which the subject is able to successfully inhibit their response on 50% of the trials. Range of scores from 0 to 1500 (unit=milliseconds) and lower scores are 'better'. Median correct is the median of response times across 'go' trials where the subject has responded on the correct button (right or left). | Baseline and 12 Weeks | 
| CANTAB SST- SD Correct | This is the CANTAB SST measure which evaluates response inhibition. Stop Signal Reaction Time (SSRT): The estimate of the length of time between the go stimulus and the stop stimulus at which the subject is able to successfully inhibit their response on 50% of the trials. Range of scores from 0 to 1500 (unit=milliseconds) and lower scores are 'better'. SD Correct is the standard deviation of response times across 'go' trials where the subject has responded on the correct button (right or left). | Baseline and 12 Weeks | 
| Stroop- RT Correct Neutral | Drug Stroop Task is a computerized task which presents words either cocaine-related ('drug') words or non-drug-related ('neutral') words written in colored font. The subject is asked to press a button to indicate the color of the font as quickly and accurately as possible. The task is thought to measure attentional bias to drug-related stimuli. RT Correct Neutral is the mean response time to neutral trials where the subject pressed the correct color response. | weeks 0, 4, 8, 12, 16, 24, 36 | 
| Stroop- RT Correct Drug | Drug Stroop Task is a computerized task which presents words either cocaine-related ('drug') words or non-drug-related ('neutral') words written in colored font. The subject is asked to press a button to indicate the color of the font as quickly and accurately as possible. The task is thought to measure attentional bias to drug-related stimuli. RT Correct Drug is the mean response time to drug trials where the subject pressed the correct color response. | weeks 0, 4, 8, 12, 16, 24, 36 | 
| Stroop- Effect Drug Neutral Mean Correct | Drug Stroop Task is a computerized task which presents words either cocaine-related ('drug') words or non-drug-related ('neutral') words written in colored font. The subject is asked to press a button to indicate the color of the font as quickly and accurately as possible. The task is thought to measure attentional bias to drug-related stimuli. Stroop Effect is difference in response time to drug versus neutral trials (i.e., RT Correct Drug - RT Correct Neutral). A larger stroop effect is 'worse' (thought to indicate more attentional bias to drug related stimuli). | weeks 0, 4, 8, 12, 16, 24, 36 | 
| Digit Span- LDSF | Digit Span Task description: Orally administered (not computerized) task where subjects are read-aloud lists of digits and asked to repeat them in the same order they heard them (Forward condition). Subjects are given a pair of lists for each digit length - and given a point for each list they get entirely correct. If they get at least one out of the two correct for that length, then the researcher gives them another one of a longer length (one digit longer). If they get both wrong at a given length- that task is ended. The task is then repeated with different digit lists to recall, but they are asked to repeat them or in the reverse order that they heard them (Backward condition). Longest Digit Span Forward (LDSF) is the longest digit span a participant gets correct, in the forward condition. Higher scores are better (Scale of 0 to 9). | Baseline and 12 Weeks | 
| Digit Span- DSF | Digit Span Task description: Orally administered (not computerized) task where subjects are read-aloud lists of digits and asked to repeat them in the same order they heard them (Forward condition). Subjects are given a pair of lists for each digit length - and given a point for each list they get entirely correct. If they get at least one out of the two correct for that length, then the researcher gives them another one of a longer length (one digit longer). If they get both wrong at a given length- that task is ended. The task is then repeated with different digit lists to recall, but they are asked to repeat them or in the reverse order that they heard them (Backward condition). Digit Span Forward (DSF) is the number of digit span trials participants got correct in the forward condition. Higher scores are better (Scale of 0 to 14). | Baseline and 12 Weeks | 
| Digit Span- LDSB | Digit Span Task description: Orally administered (not computerized) task where subjects are read-aloud lists of digits and asked to repeat them in the same order they heard them (Forward condition). Subjects are given a pair of lists for each digit length - and given a point for each list they get entirely correct. If they get at least one out of the two correct for that length, then the researcher gives them another one of a longer length (one digit longer). If they get both wrong at a given length- that task is ended. The task is then repeated with different digit lists to recall, but they are asked to repeat them or in the reverse order that they heard them (Backward condition). Longest Digit Span Backward (LDSB) is the longest digit span participants got correct, in the backward condition. Higher scores are better (Scale of 0 to 8). | Baseline and 12 Weeks | 
| Digit Span- DSB | Digit Span Task description: Orally administered (not computerized) task where subjects are read-aloud lists of digits and asked to repeat them in the same order they heard them (Forward condition). Subjects are given a pair of lists for each digit length - and given a point for each list they get entirely correct. If they get at least one out of the two correct for that length, then the researcher gives them another one of a longer length (one digit longer). If they get both wrong at a given length- that task is ended. The task is then repeated with different digit lists to recall, but they are asked to repeat them or in the reverse order that they heard them (Backward condition). Digit Span Forward (DSB) is the number of digit span trials participants got correct in the backward condition. Higher scores are better (Scale of 0 to 14). | Baseline and 12 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cocaine use decreases, increases or stays the same