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Targeting Anhedonia in Cocaine Use Disorder

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ClinicalTrials.gov Identifier: NCT02773212
Recruitment Status : Recruiting
First Posted : May 16, 2016
Last Update Posted : October 16, 2018
Sponsor:
Collaborator:
The University of Texas Health Science Center, Houston
Information provided by (Responsible Party):
Margaret.C.Wardle, University of Illinois at Chicago

Brief Summary:
The purpose of this study is to examine anhedonia as a potential moderator of treatment outcomes for Cocaine Use Disorder (CUD). Specifically, this study will investigate how anhedonia affects outcomes in contingency management (CM) treatment for CUD and whether anhedonia mediates the effects of adjunctive treatment with a dopaminergic (DAergic) drug, d-amphetamine, on outcomes in CM for CUD, as well as investigate the contribution of anhedonia to overall CUD severity.

Condition or disease Intervention/treatment Phase
Cocaine-Related Disorders Anhedonia Drug: d-amphetamine Behavioral: Contingency management Drug: Placebo (for d-amphetamine) Phase 2

Detailed Description:

Recent research suggests that anhedonia is a key neurobehavioral dysfunction in Cocaine Use Disorder (CUD) that contributes to treatment outcomes. Anhedonia, defined here as lack of interest or pleasure in non-drug rewards, is frequently found in CUD and is related to neural deficits, such as low striatal dopamine and deficient activation to non-drug rewards in mesocortical circuits. Interestingly, not all individuals in CUD have these deficits. Preliminary data suggests that the presence of self-reported anhedonia predicts worse outcome in contingency management (CM) treatment of CUD. Moreover, low baseline dopamine predicts failure to attain abstinence in CM while medications that enhance DA increase CM success rates and responsiveness to rewards.

This study specifically aims to test the contribution of anhedonia to overall CUD severity, the relationship of anhedonia to outcomes in CM treatment, and the mediating role of anhedonia in medication enhancement of CM in CUD. To accomplish these aims, individuals with CUD will be enrolled and will undergo 4 weeks of intensive CM treatment, either with or without treatment with the dopaminergic drug, d-amphetamine. A medication only group will be included to solely measure the effects of d-amphetamine. Anhedonia will be assessed using multi-modal subjective, psychophysiological and behavioral measures of reward functioning at baseline, and each week of treatment. Functional magnetic resonance imaging (fMRI) measures of reward functioning will also be taken at baseline and week 4 in a subset of participants (n = 24)


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Targeting Anhedonia in Cocaine Use Disorder - Treatment Study
Actual Study Start Date : February 1, 2017
Estimated Primary Completion Date : April 2021
Estimated Study Completion Date : April 2021


Arm Intervention/treatment
Experimental: d-Amphetamine and Contingency Management
Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine with contingency management treatment for cocaine use disorder.
Drug: d-amphetamine
Participants in this group will receive 60 mg of d-amphetamine daily for 4 weeks. There will be a 1 week run up dosing and a 1 week run-down medication period.
Other Names:
  • sustained release d-amphetamine
  • dexedrine

Behavioral: Contingency management
Contingency management is an established cocaine use disorder treatment in which individuals receive monetary rewards for abstinence.

Active Comparator: d-Amphetamine alone
Participants in this group will receive 4 weeks of treatment with 60mg of sustained release d-amphetamine but will not receive contingency management treatment for cocaine use disorder.
Drug: d-amphetamine
Participants in this group will receive 60 mg of d-amphetamine daily for 4 weeks. There will be a 1 week run up dosing and a 1 week run-down medication period.
Other Names:
  • sustained release d-amphetamine
  • dexedrine

Active Comparator: Placebo and Contingency Management
Participants in this group will receive 4 weeks of of placebo treatment, paired with contingency management treatment for cocaine use disorder.
Behavioral: Contingency management
Contingency management is an established cocaine use disorder treatment in which individuals receive monetary rewards for abstinence.

Drug: Placebo (for d-amphetamine)
60 mg of riboflavin and cornstarch as needed.




Primary Outcome Measures :
  1. Number of Participants who were Cocaine Abstinent as Assessed by Urine Screening (Measure of Treatment Efficacy) [ Time Frame: At end of active treatment (Treatment week 4) ]
    Subjects will complete a urine drug screen each visit. Achievement of cocaine abstinence will be defined as two consecutive weeks of cocaine-negative urine samples.

  2. Change in Consummatory Reward Composite (Anhedonia) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Principal components analysis will be used to determine whether consummatory anhedonia measures (SHAPS, TEPS-Consummatory, EPRT, Corrugator and Zygomatic EMG) can be reduced into one composite representing consummatory reward functioning. If this is inappropriate, we will use individual measures (see below under "Secondary Outcome Measures") with pessimistic priors to address multiplicity.

  3. Change in Motivational Reward Composite (Anhedonia) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Principal components analysis will be used to determine whether motivational anhedonia measures (TEPS-Motivational, EPKT, EEfRT) can be reduced into one composite representing motivational reward functioning. If this is inappropriate, we will use individual measures (see below under "Secondary Outcome Measures") with pessimistic priors to address multiplicity.

  4. Change in Reward Learning Composite (Anhedonia) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Principal components analysis will be used to determine whether reward learning measures (PRT and PCT) can be reduced into one composite representing reward learning. If this is inappropriate, we will use individual measures (see below under "Secondary Outcome Measures") with pessimistic priors to address multiplicity.


Secondary Outcome Measures :
  1. Treatment Effectiveness Score [ Time Frame: At end of active treatment (Treatment week 4) ]
    Subjects will complete a urine drug screen each visit. The Treatment Effectiveness Score is defined as the total number of cocaine negative urines across treatment.

  2. Consummatory Reward as Assessed by The Emotional Picture Rating Task (EPRT) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Emotional Picture Rating Task (EPRT) is a behavioral measure of consummatory reward where participants are asked to report positive, negative and aroused feelings while viewing emotional pictures. Valence and arousal ratings of positive pictures are the outcomes.

  3. Motivational Reward as Assessed by the Emotional Picture Keypress Task (EPKT) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Emotional Picture Key-press Task (EPKT) is a measure of motivational reward in which participants expend effort via key-pressing to extend or reduce viewing times for emotional pictures. Key-pressing to extend time viewing positive pictures is the outcome.

  4. Motivational Reward as Assessed by the Effort Expenditure for Rewards Task (EEfRT) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Effort Expenditure for Rewards Task (EEfRT) is a measure of motivational reward where, on each trial, participants choose between a "hard task" requiring many key-presses but worth more money and an "easy task" requiring few key-presses but worth less money. Percent of hard task choices is the outcome.

  5. Consummatory Reward as Assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) Score [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Snaith-Hamilton Pleasure Scale (SHAPS) is a measure of consummatory reward consisting of 14 hedonic capacity statements (e.g. "I would enjoy my favorite television program"). The sum of these scores is the outcome.

  6. Consummatory Reward as Assessed by the Temporal Experience of Pleasure Scale (TEPS) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Temporal Experience of Pleasure Scale (TEPS) contains 18 statements measuring both motivational and consummatory experiences of reward. Half of those statements comprise a subscale for consummatory reward, which is the outcome.

  7. Motivational Reward as Assessed by the Temporal Experience of Pleasure Scale (TEPS) Motivational Score [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Temporal Experience of Pleasure Scale (TEPS) contains 18 statements measuring both motivational and consummatory experiences of reward. Half of those statements comprise a subscale for consummatory reward, which is the outcome.

  8. Reward Learning as Assessed by the Probabilistic Classification Task (PCT) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Probabilistic Classification Task is a measure of reward learning in which participants repeatedly guess whether an image belongs to Category A or B. For half of stimuli from each category, correct answers are rewarded with points (no change for incorrect) and for the other half incorrect guesses are punished with point removal (no change for correct). Learning rates for rewarded stimuli are the outcome.

  9. Reward Learning as Assessed by the Probabilistic Reward Task (PRT) [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    The Probabilistic Reward Task (PRT) is a measure of reward learning consisting of trials in which participants must identify whether a cartoon face has a short or long mouth over a brief presentation. Correct identification of one category (short or long) is rewarded more often. Response bias for the rewarded category is the outcome.

  10. Change in Consummatory Reward Activity as Assessed by fMRI [ Time Frame: Measured 2 times (Baseline and week 4 of treatment) ]
    Consummatory reward will be measured by activity in nucleus accumbens and ventral pallidum and psychophysiological from nucleus accumbens to ventral pallidum, orbitofrontal cortex and rostral anterior cingulate cortex during reward/positive pictures vs. non-reward/neutral pictures during the Emotional Picture fMRI Task and the delay portions of Monetary Incentive Delay Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm)

  11. Change in Motivational Reward Activity as Assessed by fMRI [ Time Frame: Measured 2 times (Baseline and week 4 of treatment) ]
    Motivational reward will be measured by activity in nucleus accumbens, and psychophysiological interactions from accumbens to ventromedial prefrontal cortex, accumbens and amygdala during anticipation of reward vs. non-reward during the anticipation phases of the Monetary Incentive Delay Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm)

  12. Change in Reward Learning as Assessed by fMRI [ Time Frame: Measured 2 times (Baseline and week 4 of treatment) ]
    Reward learning will be measured by Prediction Error signals in neural accumbens, and Psychophysiological Interactions from neural accumbens to dorsolateral prefrontal cortex during prediction errors in the Probabilistic Classification fMRI Task. Note: fMRI data will be collected in only 24 participants (12 in CM/Placebo arm and 12 in CM/Sustained Release-Amphetamine arm)

  13. Magnitude of Zygomatic Activity as a Physiological Measure of Anhedonia [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Activity in the zygomatic (smile) muscle will be recorded using electromyography (EMG) during the EPRT (see above) to measure consummatory reward. Positive pictures enhance zygomatic activity. Magnitude of zygomatic responses during positive pictures is the outcome.

  14. Magnitude of Corrugator Activity as a Physiological Measure of Anhedonia [ Time Frame: Measured 5 times (Baseline and once each treatment week) ]
    Activity in the corrugator (frown) muscle will be recorded using electromyography (EMG) during the EPRT (see above) to measure consummatory reward. Positive pictures suppress corrugator activity. Magnitude of corrugator responses during positive pictures is the outcome.

  15. Heart Rate Variability as a Physiological Measure of Arousal [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Heart rate will be recorded using Electrocardiogram (EKG) during the EPRT (see above) to measure arousal responses to stimuli. High heart rate variability is associated with blunted arousal to positive stimuli and higher rates of depressive symptoms, but its relationship to our other measures of anhedonia, or to cocaine use, is unknown. Thus, this is included as an exploratory variable. Heart rate variability responses during positive, neutral, and negative pictures is the outcome.

  16. Skin Conductance as a Physiological Measure of Arousal [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    Skin conductance measures activity in the eccrine sweat glands during the EPRT (see above). Activity in this gland serves as a measure of arousal responses to stimuli, but its relationship to our other measures of anhedonia, or to cocaine use, is unknown. Thus, this is included as an exploratory variable. The outcome measure is the skin conductance response during positive, neutral, and negative pictures.

  17. Delay Discounting as a Measure of Impulsivity [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included impulsivity, as measured by delay discounting, as another possible predictor of treatment outcome in CM. The outcome will be steepness of discounting (k).

  18. The Avoidance and Inflexibility Scale [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included avoidance and inflexibility as another possible predictor of treatment outcome in CM. The outcome will be the scale total.

  19. The Cocaine Selective Severity Assessment [ Time Frame: Baseline and weeks 1, 2, 3, and 4 of treatment ]
    In the event that our hypothesis is disconfirmed and anhedonia does not predict outcomes, we have included severity of withdrawal as another possible predictor of treatment outcome in CM. The outcome will be the scale total.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • be between 18 and 60 years of age
  • meet Diagnostic and Statistical Manual V (DSM-5) criteria for current cocaine use disorder of at least moderate severity (≥ 4 symptoms)
  • have at least 1 cocaine positive urine sample during the baseline screening period
  • be in acceptable health on the basis of interview, medical history and physical exam, per the judgment of our study physician
  • be able to understand the consent form and provide written informed consent
  • be able to provide the names of at least 2 persons who can generally locate their whereabouts.
  • if female, agree to use an acceptable method of birth control during study (surgical sterilization, approved hormonal contraceptives, barrier methods with spermicide, or intrauterine device).

Exclusion Criteria:

  • current DSM-5 diagnosis for substance use disorder of least moderate severity (≥ 4 symptoms), other than cocaine, nicotine, marijuana, or alcohol
  • Physical dependence on alcohol requiring medically supervised detoxification, in the judgment of the study physician
  • current amphetamine use (by self-report in past 30 days or positive urine drug screen), more than 50 lifetime uses of amphetamine, or history of DSM-5 Amphetamine Use Disorder
  • a current DSM-5 axis I psychiatric disorder or neurological disease or disorder requiring ongoing treatment and/or making study participation unsafe
  • significant current suicidal or homicidal ideation
  • medical conditions contraindicating d-amphetamine (e.g., significant cardiovascular disease, liver or kidney disease, seizure disorder, hypotension or hypertension)
  • taking medications known to have effects on the central nervous system or that could cause significant drug interactions with d-amphetamine (e.g., clonidine, prazosin)
  • having conditions of probation or parole requiring reports of drug use to officers of the court
  • impending incarceration
  • pregnant or nursing for female patients
  • inability to read, write, or speak English

Additional Exclusion Criteria for the functional magnetic resonance (fMRI) Sub-Study (in addition to all listed criteria above for the Main Treatment Study):

  • body mass index (BMI) >30, as this may be incompatible with the magnetic resonance scanner gantry
  • any retained metals in the body, including implants and metallic substances (e.g. aneurysm clips, retained metal particles in metal workers, magnetic dental implants, ferromagnetic ocular implants, iron-based facial tattoos), as this may cause adverse effects to participants and interfere with data collection in the MR magnetic field
  • inability to tolerate small, enclosed spaces (such as the magnetic resonance scanner bore)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02773212


Contacts
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Contact: Laboratory Manager 312-639-1761 addictionlab@uic.edu

Locations
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United States, Illinois
University of Illinois at Chicago Recruiting
Chicago, Illinois, United States, 60607
Contact: Laboratory Manager    312-639-1761    addictionlab@uic.edu   
Sponsors and Collaborators
University of Illinois at Chicago
The University of Texas Health Science Center, Houston
Investigators
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Principal Investigator: Margaret C Wardle, Ph.D. University of Illinois at Chicago

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Responsible Party: Margaret.C.Wardle, Assistant Professor, University of Illinois at Chicago
ClinicalTrials.gov Identifier: NCT02773212     History of Changes
Other Study ID Numbers: 2018-0827
First Posted: May 16, 2016    Key Record Dates
Last Update Posted: October 16, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Amphetamine
Dextroamphetamine
Disease
Cocaine-Related Disorders
Anhedonia
Pathologic Processes
Substance-Related Disorders
Chemically-Induced Disorders
Mental Disorders
Neurobehavioral Manifestations
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Cocaine
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Vasoconstrictor Agents
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents
Central Nervous System Stimulants
Sympathomimetics
Autonomic Agents