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5HT2CR Balance in Brain Connectivity in Cocaine Dependence

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ClinicalTrials.gov Identifier: NCT03921151
Recruitment Status : Recruiting
First Posted : April 19, 2019
Last Update Posted : November 7, 2019
Sponsor:
Collaborators:
The University of Texas Medical Branch, Galveston
National Institute on Drug Abuse (NIDA)
Information provided by (Responsible Party):
Virginia Commonwealth University

Tracking Information
First Submitted Date  ICMJE April 10, 2019
First Posted Date  ICMJE April 19, 2019
Last Update Posted Date November 7, 2019
Actual Study Start Date  ICMJE May 13, 2014
Estimated Primary Completion Date December 30, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
Change in Interaction of the serotonin receptor (5-HTR) type-2C Cys23Ser single nucleotide polymorphism (SNP) and a 5-HT2AR antagonist on the functional circuitry underlying impulsive action. [ Time Frame: Baseline to 1 week ]
Change in fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose
Original Primary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
Interaction of the serotonin receptor (5-HTR) type-2C Cys23Ser single nucleotide polymorphism (SNP) and a 5-HT2AR antagonist on the functional circuitry underlying impulsive action. [ Time Frame: 1 day ]
fMRI activation during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose
Change History Complete list of historical versions of study NCT03921151 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2019)
Change in Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR antagonist on the functional circuitry underlying cue reactivity [ Time Frame: Baseline to 1 week ]
Change in fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose
Original Secondary Outcome Measures  ICMJE
 (submitted: April 15, 2019)
Interaction of the 5-HT2CR Cys23Ser SNP and a 5-HT2AR antagonist on the functional circuitry underlying cue reactivity [ Time Frame: 1 day ]
fMRI activation during Attentional bias task with placebo dose vs Mirtazapine dose
Current Other Pre-specified Outcome Measures
 (submitted: November 5, 2019)
  • Change in Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis impulsive action [ Time Frame: Baseline to 1 week ]
    Change in Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose
  • Change in Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis cue reactivity [ Time Frame: Baseline to 1 week ]
    Change in Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose
  • Change in Explore interactions between other 5-HT2CR SNPs and brain activation during attentional bias task after a 5- HT2AR antagonist [ Time Frame: Baseline to 1 week ]
    Change in fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose
  • Change in Explore interactions between other 5-HT2CR SNPs and brain activation during Go/NoGo (impulsivity) task after a 5- HT2AR antagonist [ Time Frame: Baseline to 1 week ]
    Change in fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose
Original Other Pre-specified Outcome Measures
 (submitted: April 15, 2019)
  • Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis impulsive action [ Time Frame: 1 day ]
    Impulsivity as measured by Go/NoGo task with placebo dose vs Mirtazapine dose
  • Effective connectivity involved in the 5-HT2AR:5-HT2CR homeostasis cue reactivity [ Time Frame: 1 day ]
    Cue reactivity as measured by Attentional bias task with placebo dose vs Mirtazapine dose
  • Explore interactions between other 5-HT2CR SNPs and brain activation during attentional bias task after a 5- HT2AR antagonist [ Time Frame: 1 day ]
    fMRI activation with other 5-HT2CR SNPs during Attentional bias task with placebo dose vs Mirtazapine dose
  • Explore interactions between other 5-HT2CR SNPs and brain activation during Go/NoGo (impulsivity) task after a 5- HT2AR antagonist [ Time Frame: 1 day ]
    fMRI activation with other 5-HT2CR SNPs during Go/NoGo (impulsivity) task with placebo dose vs Mirtazapine dose
 
Descriptive Information
Brief Title  ICMJE 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
Official Title  ICMJE 5-HT2AR: 5HT2CR Balance in Brain Connectivity in Cocaine Dependence
Brief Summary This project will evaluate the role of the 5-HT2CR:5-HT2AR balance in impulsive action and cue reactivity in cocaine-dependent subjects as compared to non-drug using controls.
Detailed Description The overall goal of this project is to evaluate the role of molecular interactions between 5-HT2AR and 5-HT2CR in behavioral phenotypes that confer risk for cocaine dependence and relapse. Specifically, this project will evaluate the role of the 5-HT2CR:5-HT2AR balance in impulsive action and cue reactivity in cocaine-dependent subjects as compared to non-drug using controls. Brain and behavioral responses to the 5-HT2AR blocking medication mirtazapine will be compared between subjects who have high and low functioning of the 5-HT2CR based on presence of a specific, functionally-relevant single nucleotide polymorphism (SNP) of the 5-HT2CR (Cys23Ser). The 5-HT2CR Cys23Ser SNP is thought to decrease the function of the protein and a preliminary observation indicates cocaine-dependent subjects carrying the CC genotype (Ser23 protein variant) display significantly higher cue reactivity. For Aims 1 and 2, two fMRI analysis methods will be used: 1) a voxelwise whole brain analysis; 2) a region of interest analysis based on proposed integrative circuitry shown in the model below. Because neuroimaging studies have shown that performance of impulsive action tasks and exposure to cocaine-associated cues (cue reactivity paradigms) activate brain regions in brain circuits in humans, impulsive action and cue reactivity may be engendered in related pathways. To explore this hypothesis, researchers will employ functional magnetic resonance imaging (fMRI)-based dynamic causal modeling (DCM) to ascertain the causal influences of one brain region over another. Employing DCM, researchers will uncover the effective connectivity within nodes of the neurocircuitry involved in impulsive action and cue reactivity. This project will parallel preclinical work studying the relationship between 5-HT2AR and 5-HT2CR on impulsive action and cue reactivity.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE Cocaine Dependence
Intervention  ICMJE
  • Drug: Mirtazapine 15 MG Oral Tablet
    15mg of mirtazapine oral table prior to scan
    Other Name: Remeron
  • Other: Placebo oral capsule
    Oral placebo consisting of dextrose in gelatin capsule prior to scan
    Other Name: Dextrose placebo in gelatin capsule
Study Arms  ICMJE
  • Cocaine-dependent
    Participants who use and are dependent on cocaine
    Interventions:
    • Drug: Mirtazapine 15 MG Oral Tablet
    • Other: Placebo oral capsule
  • Non-drug
    Participants who are not drug users
    Interventions:
    • Drug: Mirtazapine 15 MG Oral Tablet
    • Other: Placebo oral capsule
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: April 15, 2019)
100
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 30, 2019
Estimated Primary Completion Date December 30, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

Cocaine Dependent Subjects

  1. Be English-speaking volunteers
  2. Be aged between 18 and 60 years
  3. Meet DSM-5 criteria for cocaine dependence
  4. Have a self-reported history of using cocaine
  5. Have hematology and chemistry laboratory tests that are within reference limits ( 10%) with the following exceptions: hemoglobin and hematocrit within normal limits (for fMRI).
  6. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant abnormalities
  7. Have a medical history and physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the principal investigator.
  8. Have no metal fragments or other bodily metal (e.g., pacemaker) or significant claustrophobia that would put the subjects at risk for MRI scanning.

Non-Drug Using Controls

  1. Be English-speaking volunteers
  2. Be aged between 18 and 60 years
  3. Have no past history of Psychiatric or non-Psychiatric medical disorders which could affect the central nervous system as assessed by SCID and physical examination.
  4. Have hematology and chemistry laboratory tests that are within reference limits ( 10%), with the following exceptions: hemoglobin and hematocrit within normal limits (for fMRI)
  5. Have a baseline EKG that demonstrates clinically normal sinus rhythm, clinically normal conduction, and no clinically significant abnormalities
  6. Have a medical history and brief physical examination demonstrating no clinically significant contraindications for study participation, in the judgment of the admitting physician and the Principal investigator.
  7. Have no metal fragments or other bodily metal (pacemaker) or significant claustrophobia that would put the subjects at risk for MRI scanning

Exclusion Criteria:

Cocaine Dependent Subjects

  1. Have any history or evidence suggestive of seizure disorder or brain injury.
  2. Have any previous medically adverse reaction to mirtazapine or other antidepressants.
  3. Have neurological or psychiatric disorders, such as (a) psychosis, bipolar illness or major depression as assessed by SCID; (b) organic brain disease or dementia assessed by clinical interview; (c) history of any psychiatric disorder that would require ongoing treatment or that would make study compliance difficult; and (d) history of suicide attempts within the past 3 months and/or current suicidal ideation/plan.
  4. Have evidence of uncontrolled clinically significant heart disease or hypertension, as determined by the PI.
  5. Have evidence of non-psychiatric medical illness including neuroendocrine, autoimmune, renal, hepatic, or active infectious disease.
  6. Use of any medications or drugs that can affect the central nervous system other than cocaine, marijuana, alcohol caffeine and nicotine.
  7. Have a positive HIV test.
  8. Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, weekly during the study, and at the end of study participation.
  9. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study.

Non-Drug Using Controls

  1. Meet DSM-5 criteria for any current or past Axis I disorder.
  2. Meet DSM-5 criteria for an Axis II diagnosis of Borderline or Antisocial Personality Disorder.
  3. Have any history or evidence suggestive of seizure disorder or brain injury.
  4. Have any previous medically adverse reaction to mirtazapine or other antidepressants.
  5. Have evidence of uncontrolled clinically significant heart disease or hypertension, as determined by the PI.
  6. Have evidence of medical illness including neuroendocrine, autoimmune, renal, hepatic, or active infectious disease.
  7. Use of any medications or drugs that can affect the central nervous system other than caffeine or nicotine.
  8. Have a positive HIV test.
  9. Be pregnant or nursing. Other females must either be unable to conceive (i.e., surgically sterilized, sterile, or postmenopausal) or be using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or spermicide). All females must provide negative pregnancy urine tests before study entry, weekly during the study, and at the end of study participation.
  10. Have any other illness, condition, or use of psychotropic medications, which in the opinion of the PI and/or the admitting physician would preclude safe and/or successful completion of the study.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Lori KeyserMarcus, PhD 804-828-4164 lori.keysermarcus@vcuhealth.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03921151
Other Study ID Numbers  ICMJE HM15289
P20DA024157-04S1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Virginia Commonwealth University
Study Sponsor  ICMJE Virginia Commonwealth University
Collaborators  ICMJE
  • The University of Texas Medical Branch, Galveston
  • National Institute on Drug Abuse (NIDA)
Investigators  ICMJE
Principal Investigator: Frederick Moeller, M.D. Virginia Commonwealth University
PRS Account Virginia Commonwealth University
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP