Cognitive Enhancement as a Target for Cocaine Pharmacotherapy

• ClinicalTrials.gov Identifier: NCT01531153
• Recruitment Status: Completed
• First Posted: February 10, 2012
• Results First Posted: October 26, 2018
• Last Update Posted: October 26, 2018
• Sponsor: Yale University
• Collaborator: National Institute on Drug Abuse (NIDA)
• Information provided by (Responsible Party): Yale University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Addiction	Drug: Galantamine; Drug: Placebo	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 93 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Cognitive Enhancement as a Target for Cocaine Pharmacotherapy
• Study Start Date: September 2011
• Actual Primary Completion Date: June 2016
• Actual Study Completion Date: June 2016

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Sugar Pill; Sugar Pill will be compared with the active medication Galantamine	Drug: Placebo; Placebo dose.; Other Name: 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

Outcome Measures

Primary Outcome Measures :

1. Urine Toxicology [ Time Frame: 12 weeks ]
   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.

Secondary Outcome Measures :

1. Heart Rate [ Time Frame: once a day for up to two days over 12 Weeks ]
   Pulse
2. Blood Pressure- Systolic [ Time Frame: 2 times a week for 12 weeks ]
   Blood Pressure is taken for safety reasons
3. Blood Pressure- Diastolic [ Time Frame: 2 times a week for 12 weeks ]
   Blood Pressure is taken for safety reasons
4. CANTAB RVIP Measure: RVP A [ Time Frame: Baseline and 12 Weeks ]
   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.
5. CANTAB RVIP Measure: RVP B [ Time Frame: Baseline and 12 Weeks ]
   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.
6. CANTAB RVIP Measure: RVP FALSE ALARM [ Time Frame: Baseline and 12 Weeks ]
   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.
7. CANTAB SST- SSRT [ Time Frame: Baseline and 12 Weeks ]
   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'.
8. CANTAB SST- Median Correct [ Time Frame: Baseline and 12 Weeks ]
   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).
9. CANTAB SST- SD Correct [ Time Frame: Baseline and 12 Weeks ]
   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).
10. Stroop- RT Correct Neutral [ Time Frame: weeks 0, 4, 8, 12, 16, 24, 36 ]
    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.
11. Stroop- RT Correct Drug [ Time Frame: weeks 0, 4, 8, 12, 16, 24, 36 ]
    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.
12. Stroop- Effect Drug Neutral Mean Correct [ Time Frame: weeks 0, 4, 8, 12, 16, 24, 36 ]
    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).
13. Digit Span- LDSF [ Time Frame: Baseline and 12 Weeks ]
    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).
14. Digit Span- DSF [ Time Frame: Baseline and 12 Weeks ]
    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).
15. Digit Span- LDSB [ Time Frame: Baseline and 12 Weeks ]
    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).
16. Digit Span- DSB [ Time Frame: Baseline and 12 Weeks ]
    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).

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Connecticut

Department of Veterans Affairs

West Haven, Connecticut, United States, 06516

Sponsors and Collaborators

Yale University

National Institute on Drug Abuse (NIDA)

Investigators

• Principal Investigator: Mehmet Sofuoglu, M.D., Ph.D.; Yale University

More Information

• Responsible Party: Yale University
• ClinicalTrials.gov Identifier: NCT01531153
• Other Study ID Numbers: 1007007119; R01DA029577 ( U.S. NIH Grant/Contract )
• First Posted: February 10, 2012
• Results First Posted: October 26, 2018
• Last Update Posted: October 26, 2018
• Last Verified: October 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Yale University:

Cocaine use decreases, increases or stays the same

Additional relevant MeSH terms:

Behavior, Addictive; Compulsive Behavior; Impulsive Behavior; Galantamine; Cholinesterase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Parasympathomimetics; Autonomic Agents; Peripheral Nervous System Agents; Nootropic Agents