Cognitive Enhancement as a Target for Cocaine Pharmacotherapy

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.

Study Overview

• Status: Completed
• Conditions: Addiction
• Intervention / Treatment: Drug: Placebo; Drug: Galantamine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 93
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • West Haven, Connecticut, United States, 06516
      • Department of Veterans Affairs

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male and females, between the ages of 18 and 60
2. 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
3. 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
4. Are fluent in English and have a 6th grade or higher reading level; AND
5. Can commit to at least 13 weeks of treatment and are willing to be randomized to treatment

Exclusion Criteria:

1. 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
2. Current DSM-IV diagnosis of drug or alcohol dependence (other than cocaine, or tobacco)
3. 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

4. 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
5. Have a screening liver function test (AST or ALT) greater than 3 times normal; OR
6. Known allergy or adverse reaction to galantamine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute on Drug Abuse (NIDA)
• Investigators: Principal Investigator: Mehmet Sofuoglu, M.D., Ph.D., Yale University

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: December 7, 2011
• First Submitted That Met QC Criteria: February 7, 2012
• First Posted (Estimate): February 10, 2012

Study Record Updates

• Last Update Posted (Actual): October 26, 2018
• Last Update Submitted That Met QC Criteria: October 25, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Keywords: Cocaine use decreases, increases or stays the same
• Additional Relevant MeSH Terms: Compulsive Behavior; Impulsive Behavior; Behavior, Addictive; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Nootropic Agents; Cholinesterase Inhibitors; Parasympathomimetics; Galantamine
• Other Study ID Numbers: 1007007119; R01DA029577 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED