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Theta-Burst Stimulation as a Treatment for Reducing Cocaine Use

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ClinicalTrials.gov Identifier: NCT02927236
Recruitment Status : Recruiting
First Posted : October 7, 2016
Last Update Posted : November 12, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Drug Abuse (NIDA) )

October 6, 2016
October 7, 2016
November 12, 2018
October 6, 2016
December 21, 2020   (Final data collection date for primary outcome measure)
  • Main Study -to characterize cue reactivity, reward processing, executive control, intrinsic network connectivity, and cardiac (specifically soft plaques) differences between healthy controls and cocaine dependent participants at baseline, during... [ Time Frame: Each of the 39 study visits ]
  • Pilot - To establish tolerability of 3 daily iTBS sessions with an inter-session interval of at least 60 minutes in cocaine dependent participants. This Pilot is also designed for gathering preliminary data on the effectiveness of iTBS as a trea... [ Time Frame: Each of the 10 iTBS sessions ]
  • Main Study -to characterize cue reactivity, reward processing, executive control, intrinsic network connectivity, and cardiac (specifically soft plaques) differences between healthy controls and cocaine dependent participants at baseline, during... [ Time Frame: Each of the 39 study visits ]
  • Pilot - To establish tolerability of 3 daily iTBS sessions with an inter-session interval of 60 minutes in cocaine depedent participants. This Pilot is also designed for gathering preliminary data on the effectiveness of iTBS as a treatment for ... [ Time Frame: Each of the 10 iTBS sessions ]
Complete list of historical versions of study NCT02927236 on ClinicalTrials.gov Archive Site
To evaluate iTBS as an efficacious treatment for CD. More iTBS treatment sessions (n = 30) than the FDA approved depression rTMS protocol is anticipated to increase the likelihood of affecting change in cocaine use. [ Time Frame: Study visits ]
Same as current
Not Provided
Not Provided
 
Theta-Burst Stimulation as a Treatment for Reducing Cocaine Use
Theta-Burst Stimulation as a Treatment for Reducing Cocaine Use

Background:

More effective treatments for people with cocaine use disorder are needed. Researchers want to understand the parts of the brain involved in the disorder. Transcranial magnetic stimulation (TMS) stimulates parts of the brain. A form of TMS called intermittent theta-burst stimulation (iTBS) may help reduce cocaine use. Researchers want to learn how the brain might change with treatment.

Objectives:

To test if iTBS can reduce cocaine use. Also, to learn how cocaine changes the heart and the brain.

Eligibility:

Healthy, right-handed adults ages 18-60 who do or do not have cocaine use disorder.

Design:

Participants will be screened with:

  • Questionnaires
  • Medical history
  • Physical exam
  • Blood and urine tests
  • Alcohol breath tests

In the pilot study, 10 participants with cocaine use disorder will have 10 treatment days over 2 weeks. Half will be inpatient and half will be outpatient. They will have 2 follow-up visits. Treatment includes:

  • iTBS: A coil is placed on the head. A brief electrical current passes through the coil. They view cocaine-related images during each session. Sessions are videotaped.
  • Repeat of screening tests

    • In the main study, participants will be randomly assigned to have either real or fake iTBS.
    • Participants with cocaine use disorder will join an incentive program to quit.
    • Participants will have 39 visits over 6 months. These include:
  • Repeat of screening tests
  • MRIs at 5 visits: Participants lie on a table that slides into a cylinder that takes pictures of the brain. They respond to images while in the scanner.
  • iTBS at 10 visits (5 days a week for 2 weeks)

Participants will be contacted throughout the study to discuss iTBS treatment and drug use.

Objectives: Illicit drug use affects tens of millions of Americans and costs nearly $200 billion annually in health care costs and lost productivity. Cocaine dependence accounts for 25% of reported lifetime drug dependence though few successfully abstain with treatment. For efforts toward positive long-term outcomes, it is imperative to identify risk factors of poor outcomes, specialized treatments, neural mechanisms that change with treatment, and predictive measures of treatment outcomes. Substance abusers are known to have dysregulation in cue reactivity, reward processing, executive control, and intrinsic network connectivity. Non-invasive brain stimulation (NIBS) has proven effective at reducing drug craving in nicotine, alcohol, and cocaine users. Here, intermittent theta-burst stimulation (iTBS), a type a NIBS, delivered to left dorsolateral prefrontal cortex (dlPFC) is implemented to modulate substance abuse related circuit dysregulations and assess effectiveness of iTBS in promoting abstinence.

Study population: Recruitment from the Baltimore, Maryland area will take place for this protocol. For the Pilot, 20 cocaine dependent (CD) individuals will be recruited. For the Clinical Trial, 50 healthy adults (HC) and 100 CD individuals will be recruited. All of the HC group will receive both active- and sham-iTBS in a within-subject crossover design. Half of the CD group will receive active-iTBS and half will receive sham-iTBS. The Clinical Trial groups will be matched on demographic measures (e.g., age, IQ, sex).

Design: The Pilot is designed to be a tolerability pilot where iTBS parameters are assessed in CD participants. The first half of the Pilot participants will be inpatient (for initial close observations) and the second half will be outpatient (closely reflecting the clinical trial). Throughout the Pilot, clinical measures will be collected and participants closely monitored. The general outline for the Clinical Trial is to characterize the treatment cohort (vs. HC) and assess effectiveness of iTBS over the left dlPFC in reducing cocaine use. The iTBS intervention consists of 30 sessions over a 2-week (10 treatment days) period as an add-on to a treatment-as-usual, contingency management. Structural and functional magnetic resonance imaging, neural measures of cue reactivity, reward processing, executive control, intrinsic network connectivity along with cardiac measures will be collected to identify differences between CD and HC participants at baseline. In CD participants, neural and cardiac measure along with cocaine use will be tracked longitudinally to assess changes with treatment. Contingency management will continue for 13 weeks and a 3-month follow-up will be scheduled. The Clinical Trial includes 39 visits.

Outcome parameters: Two main comparisons are of interest. First, baseline differences in neural and cardiac measures between CD and HC participants will be identified. CD participants are expected to show dysregulations in these functions, relative to HC participants. Second, neural plasticity related to these functions due to iTBS treatment and reduction in cocaine use will be measured. The active-iTBS intervention is expected to be effective in reducing cocaine use, relative to the sham-iTBS intervention. Normalization of circuit dysregulation is hypothesized to be associated with reduction of cocaine use. Overall, the current protocol is designed to test whether iTBS to left dlPFC is efficacious in reducing cocaine use.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Cocaine Dependence
Device: TMS
TBS is a type of TMS protocol.To administer the iTBS treatment, a MagVenture MagPro 100 with MagOption (MagVenture Inc, Alpharetta, GA) machine equipped with a figure-8 coil will be used.
  • Experimental: Pilot
    P1 is designed to establish safety and tolerability criteria for administering iTBS to treatment seeking cocaine users, initially as in-patient followed by an out-patient cohort
    Intervention: Device: TMS
  • Experimental: Cocaine-Active
    Designed to implement the iTBS administration parameters established from P1 with a larger sample of treatment seeking CD participants. Though the schedule may change slightly based on the outcome of the pilot, a schedule of 3 daily iTBS sessions with a 20 minute interval between administrations is planned and used throughout the design.
    Intervention: Device: TMS
  • Sham Comparator: Cocaine-Sham
    To test the efficacy of iTBS.
    Intervention: Device: TMS
  • Healthy Control-Main
    Population comparison of acute experimental iTBS.
    Intervention: Device: TMS
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
210
170
December 31, 2021
December 21, 2020   (Final data collection date for primary outcome measure)
  • INCLUSION CRITERIA - TOLERABILITY PILOT:

    1. Be able to give valid informed consent.
    2. Be 18 - 60 years of age.

      1. Justification: Many neural processes change with age, and these changes could introduce unwanted variability in both behavioral and MRI signals.
      2. Screening tool: Self-report. Government-issued forms of identification (e.g. driver s license, birth certificate)

        3 .Right-handed.

      1. Justification: Differences in hemispheric dominance could confound iTBS administration and MRI measurements.
      2. Screening tool: Edinburgh Handedness Inventory.

    4. Be in good health.

    1. Justification: Many illnesses may alter neural functioning as well as fMRI signals.
    2. Screening tools: Medical Assessment, Medical History and Physical Examination. Medical assessments include: Vital Signs, EKG, oral HIV test, height/weight measurements, urinalysis, and blood sample. Tests on the blood sample include CBC, complete metabolic profile, TSH, ESR, syphilis test, and HIV (if needed to confirm a positive salivary test for HIV). The following individual laboratory results will independently disqualify individuals: Cholesterol >250 mg/dl, Hemoglobin < 10 g/dl, WBC < 2400/microliter, LFTs > 3 X upper normal limit, HCG positive, Casual serum glucose > 200 mg/dl, Urine protein > 1+, HIV positive. (Serum glucose over 140 mg/dl will be followed up with a fasting serum glucose assessment. Those with fasting glucose below 100 mg/dl may be considered for the protocol. Others will be rejected and referred for work-up.) Liver function will be evaluated with aspartate aminotransferase (AST) and alanine transaminase (ALT). A greater than 3 x upper normal limit for AST or ALT will disqualify individuals. MAI reserves the right to exclude at less extreme lab values if clinical judgment warrants exclusion.

      5. Absence of a specific learning disability, ADHD or cognitive impairment

    1. Justification: Participants must be able to perform a cognitively challenging task to a high standard.
    2. Screening tool: Adult ADHD Self-Report Scale with follow up clinical interview, Wechsler Abbreviated Scale of Intelligence (WASI), History of placement in special education classes for a learning problem.

      6. Participants will meet DSM-5 criteria for current moderate to severe substance (i.e., cocaine) use disorder, without a period of continuous abstinence lasting a one-month period over the last year, other than in a controlled environment.

    1. Justification: cocaine use disorder, in regular users, is the focus of this protocol.
    2. Screening tool: Potential diagnoses will be evaluated by a counselor using any one or more of the following: Drug Use Survey, SCID Screen Patient Questionnaire, Mini International Neuropsychiatric Interview (M.I.N.I), Addiction Severity Index, and Brief Cocaine Cessation Motivation Assessment. The interviewer will supplement SCID with questions to assess for DSM-5 substance use disorders. The MAI may be consulted in this determination.

EXCLUSION CRITERIA - TOLERABILITY PILOT:

  1. History of any neurological disorder that would increase seizure risk from iTBS such as stroke, brain lesions, previous neurosurgery, any history of seizure or fainting episode of unknown cause, or head trauma resulting in loss of consciousness, lasting over 30 minutes or with sequela lasting longer than one month.

    1. Justification: Stroke, vascular lesions or head trauma can lower the seizure threshold, and are therefore contra-indications for iTBS. Fainting episodes or syncope of unknown cause could indicate an undiagnosed condition associated with seizures.
    2. Screening tool: TMS safety Screen, Medical History and clinical MRI/MRA scan.
  2. Current DSM-5 moderate-severe substance use disorder on a substance other than cocaine, nicotine, marijuana, or opiates (provided they are currently stable on Suboxone) or meeting withdrawal criteria for alcohol or a sedative/hypnotic/anxiolytic, or tolerance criteria in an individual using 3 or more days/week, regardless of diagnosis. Individuals will be considered stable on

    Suboxone if they have been on a stable dose for at least 2-weeks prior to consenting to 17-DA-N002 and have provided at least 3 urine specimens negative for illicit opioids over the same 2-week period (10 business days) with at least one test collected within two business days of the start of the period, one collected within three business days of the end of the period and one collected at

    least two days from either of the other two specimens. Urine results may be gathered at NIDA as part of screening or be provided by the Suboxone prescriber. Communication between the Suboxone provider and the MAI (or covering Staff Clinician) will be ongoing to establish continued illicit opioid abstinence between participant clearance and consent to 17-DA-N002. Individuals must be receiving their Suboxone as take-home doses from an external (i.e., non-NIDA-IRP) provider.

    1. Justification: While use of multiple substances is the norm and some use will be allowed, the focus of the current protocol is on cocaine. However, participants with tolerance or withdrawal symptoms to alcohol or a sedative/hypnotic/anxiolytic will be at increased risk of a seizure from iTBS and will therefore be excluded. Individuals receiving Suboxone and struggling with cocaine use are an ecologically valid population in the greater Baltimore area and do not increase risk of seizure.
    2. Screening tool: Drug Use Survey and SCID Screen Patient Questionnaire or M.I.N.I). The interviewer will supplement SCID with questions to assess for DSM-5 substance use disorders. Potential diagnoses will be further evaluated with a clinical interview with a counselor.
  3. First-degree family history of any neurological disorder with a potentially hereditary basis, including migraines, epilepsy, or multiple sclerosis.

    1. ustification: Neurological disorders can lower the seizure threshold, and are therefore contra-indications for iTBS. First-degree family history of certain neurological disorders with a hereditary component increases the risk of the participant having an undiagnosed condition that is associated with lowered seizure threshold.
    2. Screening tool: TMS safety screening, Medical History.
  4. Cardiac pacemakers, neural stimulators, implantable defibrillator, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object in the body that precludes iTBS administration.

    1. Justification: Certain metal in the body is a contra-indication for iTBS administration, as this method involves exposure to a relatively strong static magnetic field that can move magnetic material not securely bound and rapidly alternating magnetic fields that can generate heat and current in metal contained in the body.
    2. Screening tool: Medical History, TMS safety screen.
  5. Noise-induced hearing loss or tinnitus.

    1. Justification: individuals with noise-induced hearing problems may be particularly vulnerable to the acoustic noise generated by iTBS equipment.
    2. Screening tools: TMS safety screening.
  6. Current use (any use in the past 4 weeks, daily use for more than a week within past 6 months) of any investigational drug or of any medications with psychotropic (e.g., benzodiazepines), anti or pro-convulsive action, or anti-coagulants. This will be determined at the discretion of the MAI.

    1. Justification: The use of certain medications or drugs can lower seizure threshold during use or withdrawal and is therefore contra-indicated for iTBS. Such medications may also alter neural functioning independent of the individual s drug use or the effects of the iTBS and thus add more variability to our data.
    2. Screening tools: MRI safety screening questionnaire, Medical history, Medical Assessments: Urine toxicology analyzes for presence of a broad range of prescription and nonprescription drugs.
  7. Lifetime history of schizophrenia, bipolar disorder, mania, or hypomania.

    1. Justification: The population of interest here is a healthy population with no psychiatric disorders other than substance use disorders. In participants with bipolar disorder, mania or hypomania, there is a small chance that iTBS can trigger (hypo)manic symptoms. As some degree of depressive symptoms is common in cocaine dependence and may result from the drug use, mild unipolar depression will not be exclusionary.
    2. Screening tools: SCID Screen Patient Questionnaire or M.I.N.I. Potential diagnoses will be further evaluated by a counselor.
  8. History of myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, mitral valve prolapse, or any heart condition currently under medical care.

    1. Justifications: the risk of iTBS for individuals with a heart condition is unknown and advanced cardiovascular disease is incompatible with the goal of studying subclinical CAD. These conditions are also likely to add considerable additional variability to the data.
    2. Screening tool: physical assessment (EKG), medical history.
  9. Pregnant or lactating women or women with reproductive potential who engage in heterosexual sex that may lead to pregnancy and not using a medically acceptable form of contraception (such as birth control pills, condoms, or a diaphragm with spermicide).

    1. Justification: it is unknown whether iTBS poses a risk to fetuses.
    2. Screening tool: Urine and/or serum pregnancy tests, and clinical interview.
  10. Participation in any NIBS session (excluding the current protocol) less than two weeks ago. No NIBS exposure for treatment purposes in the last 6 months.

    1. Justification: in order to avoid possible carry-over effects from previous exposure to NIBS prior to participation in the proposed intervention, we will not enroll participants who have received any NIBS in the two weeks preceding enrollment or treatment with NIBS modality with the last 6 months preceding enrollment.
    2. Screening tool: TMS safety screen.

INCLUSION AND EXCLUSION - MAIN STUDY:

The same inclusion and exclusion criteria will be used as in the Pilot with the exception of:

  1. CD participants, and not HC participants, will meet current DSM-5 criteria for current moderate to severe substance (i.e., cocaine) use disorder and currently seeking treatment.

    1. Justification: cocaine use disorder is the focus of this protocol.
    2. Screening tool: Drug Use Survey and SCID Screen Patient Questionnaire. The interviewer will supplement SCID with questions to assess for DSM-5 substance use disorders. Potential diagnoses will be further evaluated by a counselor.
  2. Treatment seeking CD participants will be recruited.

    1. Justification: The population of interest is CD dependent individuals motivated to reduce or eliminate their cocaine use.
    2. Screening tools: Cocaine use, Pattern, and Withdrawal Questionnaire.
  3. HC participants will not currently meet DSM-5 criteria for moderate to severe substance use disorder (excluding nicotine), and in the past, will not meet DSM-5 criteria for moderate to severe substance use disorder for cannabis or alcohol in the past 5 years or ever for other illicit substances. HC will not meet current tolerance or withdrawal criteria for alcohol or sedative/hypnotics/anxiolytics. Urine toxicology positive for any illicit substance inconsistent with history given will also be exclusionary.

    1. Justification: The population of interest is a healthy control population with no substance use disorder. Current use of illicit substances or alcohol could impact on seizure threshold and is therefore contra-indicated for iTBS.
    2. Screening tools: SCID Screen Patient Questionnaire. The interviewer will supplement SCID with questions to assess for DSM-5 substance use disorders. Potential diagnoses will be further evaluated by a counsellor, Drug Use Survey (DUS), Substance Use Disorder Evaluation, Medical Assessments: urine qualitative drug screen is performed for cocaine, THC, benzo, morphine/opiates, MDMA, amphetamine /methamphetamine, methadone, buprenorphine, PCP, and oxycodone.
  4. Participation in any NIBS session less than two weeks prior to admission (including the Pilot of this protocol but excluding ongoing participation in the Clinical Trial of the current protocol). No NIBS exposure for treatment purposes in the last 6 months.

    1. Justification: in order to avoid possible carry-over effects from previous exposure to NIBS prior to participation in the proposed intervention, we will not enroll participants who have received any NIBS in the two weeks preceding enrollment or treatment with NIBS modality with the last 6 months preceding enrollment. Also, because the current scientific goals of this protocol is to assess the effectiveness of 30 iTBS sessions in relation to treating CD, participants who received iTBS sessions in the Pilot will be excluded.
    2. Screening tool: TMS safety screening questionnaire.
Sexes Eligible for Study: All
18 Years to 60 Years   (Adult)
No
Contact: Elliot Stein, Ph.D. (443) 740-2650 estein@mail.nih.gov
United States
 
 
NCT02927236
999917002
17-DA-N002
Not Provided
Not Provided
Not Provided
National Institutes of Health Clinical Center (CC) ( National Institute on Drug Abuse (NIDA) )
National Institute on Drug Abuse (NIDA)
Not Provided
Principal Investigator: Elliot Stein, Ph.D. National Institute on Drug Abuse (NIDA)
National Institutes of Health Clinical Center (CC)
November 8, 2018

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