<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04449055</url>
  </required_header>
  <id_info>
    <org_study_id>202001387</org_study_id>
    <nct_id>NCT04449055</nct_id>
  </id_info>
  <brief_title>Pilot TMS for Methamphetamine Use Disorder</brief_title>
  <official_title>A Pilot Study of Transcranial Magnetic Stimulation for Treatment of Methamphetamine Use Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Ryan M. Carnahan</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of New Mexico</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Iowa</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a pilot study to test the feasibility of a recruitment strategy and study protocol to&#xD;
      examine the effects of a dual target transcranial magnetic stimulation treatment in&#xD;
      methamphetamine use disorder. The study will test intermittent theta burst stimulation (TBS)&#xD;
      targeting the dorsolateral prefrontal cortex (DLPFC) combined with continuous TBS targeting&#xD;
      the medial prefrontal cortex (MPFC) in people with methamphetamine use disorder (MAUD) who&#xD;
      are engaged in psychosocial treatment. Intermittent TBS targeting the DLPFC is approved by&#xD;
      the Food and Drug Administration for major depressive disorder, and continuous TBS targeting&#xD;
      the MPFC has been studied in cocaine use disorder. We will administer this dual target TBS&#xD;
      daily for 2 weeks, followed by three times weekly for 2 weeks, and monitor depressive&#xD;
      symptoms, anxiety, sleep, craving, quality of life, and methamphetamine use for three months.&#xD;
      Changes in functional connectivity of brain circuits will be evaluated with functional&#xD;
      magnetic resonance imaging (fMRI) before and after treatment. We expect to observe changes in&#xD;
      connectivity between the DLPFC, MPFC, and other regions implicated in addiction and&#xD;
      impulsivity. Furthermore, we will evaluate if baseline differences in functional connectivity&#xD;
      can be used to predict response. Psychological tests focusing on state impulsivity and risk&#xD;
      taking will be administered, and we expect to observe reductions in these characteristics&#xD;
      after treatment. We will test this protocol in 20 patients recruited from clinical care&#xD;
      settings at University of Iowa Hospitals and Clinics, University of New Mexico Health System,&#xD;
      and University of Utah Health to illustrate the feasibility of recruitment and completing the&#xD;
      protocol, to support an external funding proposal.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Overview: This is a single-arm clinical trial, with historical controls as a comparison group&#xD;
      for select outcomes. Subjects with MAUD will receive 16 sessions of dual-target theta burst&#xD;
      stimulation to the DLPFC and MPFC over 4 weeks. We will follow outcomes for 12 weeks.&#xD;
      Outcomes include treatment retention, craving, self-reported MA or stimulant use, urine drug&#xD;
      screen results, depressive symptoms, anxiety symptoms, sleep quality, quality of life,&#xD;
      response inhibition, and functional connectivity. Magnetic resonance imaging (MRI) to measure&#xD;
      functional connectivity and a flanker task to measure response inhibition will be completed&#xD;
      at baseline and four weeks. More detail is provided in the outcome measures section. Subjects&#xD;
      will also complete the Big Five Inventory at baseline, a measure of personality&#xD;
      characteristics, to explore how these relate to outcomes including retention in treatment and&#xD;
      the study.&#xD;
&#xD;
      MR Image Acquisition: MRI will be completed at baseline and after the last TMS session. The&#xD;
      MRI sessions will be conducted using research dedicated MRI scanners at each site. Anatomical&#xD;
      images will include volumetric T1 and T2 weighted images with a 1.0 mm isotropic spatial&#xD;
      resolution. Resting state fMRI will be performed to collect 20 minutes worth of data.&#xD;
&#xD;
      Statistical Analysis:&#xD;
&#xD;
      Retention in the Study and Psychosocial Treatment: We will describe the proportion of&#xD;
      subjects who complete the 4-week TMS treatment period and complete each subsequent monthly&#xD;
      follow-up visit. We will use Kaplan-Meier curves to describe retention in the study and in&#xD;
      psychosocial treatment. If non-retention is common enough, we will use Cox regression to&#xD;
      explore baseline measures as predictors of retention. We anticipate that multivariate&#xD;
      analysis will not be feasible with the sample size.&#xD;
&#xD;
      Symptoms and Impulse Control Measures: Primary analyses for other measures will focus on&#xD;
      changes over the 4-week TMS treatment period. Changes in symptoms evaluated weekly or&#xD;
      biweekly (e.g. craving, depression, affect, anxiety, sleep) will be assessed using&#xD;
      generalized linear mixed models with appropriate distributions. We anticipate a Poisson&#xD;
      distribution for days of MA or other stimulant use and will use a binomial distribution with&#xD;
      a logit link to evaluate changes in positive urine drug screens. Time will be the primary&#xD;
      variable of interest to assess the slopes of change during treatment. Paired t-tests or&#xD;
      Wilcoxon signed-rank tests will be used to evaluate changes in measures completed at baseline&#xD;
      and after 4 weeks of treatment. We will compare measures at baseline and 4 weeks to those at&#xD;
      8 weeks and 12 weeks similarly, but in separate analyses since decay in effects may occur&#xD;
      after TMS ends.&#xD;
&#xD;
      Functional Connectivity Analysis: fMRI functional connectivity analysis will be performed&#xD;
      using a standard analysis pipeline. Functional images will undergo pre-processing including&#xD;
      brain extraction, motion correction, spatial smoothing (6 mm FWHM), and temporal filtering&#xD;
      (.008 Hz &lt; f &lt; 0.08 Hz). Following preprocessing, the fMRI signal will be corrected for&#xD;
      potential sources of noise using image-based estimates and motion correction parameters. The&#xD;
      resulting corrected time-series will be used for all functional connectivity analyses.&#xD;
      Functional connectivity will be measured by extracting time-series data from the&#xD;
      pre-processed imaging data for the regions of interest (ROIs). Multiple ROIs will be examined&#xD;
      and will be defined as spheres (6mm radius) based on coordinate locations previously&#xD;
      published by Yeo and colleagues. Specifically, we will focus on connectivity in the&#xD;
      cingulo-opercular network involved in cognitive control and salience (DLPFC - anterior&#xD;
      insula; DLPFC - anterior cingulate) and reward processing/motivation circuit (MPFC - ventral&#xD;
      striatum). Analyses will be averaged across right and left hemispheres but we will also&#xD;
      explore differences between right and left hemispheres. The time series from the ROIs will be&#xD;
      cross-correlated with the time-series from the other ROIs to determine the strength of&#xD;
      functional connectivity between regions. The resulting Pearson's r will be converted to&#xD;
      Fisher's z scores to improve normality for the statistical analysis. We will treat each ROI&#xD;
      pair connection (DLPFC - anterior insula, DLPFC - anterior cingulate, MPFC - ventral&#xD;
      striatum) as a dependent variable. Primary analyses will use paired t-tests or Wilcoxon&#xD;
      signed-rank tests to compare connectivity at baseline vs. after TMS treatment. We will&#xD;
      explore correlates of connectivity and changes using Pearson or Spearman correlations and&#xD;
      linear regression or mixed models.&#xD;
&#xD;
      Exploratory Analysis: Follow-up exploratory voxel-wise analyses will be conducted for&#xD;
      functional connectivity, which will provide thousands of individual predictors. This will&#xD;
      help confirm findings in large parcel ROI based analysis. We will use the same statistical&#xD;
      models as used for the ROI based analysis described above but at the voxel level. Voxel-wise&#xD;
      data creates a high-dimensional problem in which the number of predictors far exceeds the&#xD;
      number of participants. Machine learning methods, such as random forest will be used to&#xD;
      handle the high-dimensional sub-analyses. Random forest requires a minimum of data&#xD;
      assumptions, automatically accounts for non-linear and interaction effects, and it has proven&#xD;
      useful in identifying useful predictors in high-dimensional contexts.&#xD;
&#xD;
      Comparison with Historical Controls: We will compare retention in psychosocial treatment&#xD;
      programs and positive urine drug screens from chart review with a historical control group of&#xD;
      patients with MA use disorder matched on age, sex, site, and psychosocial treatment modality.&#xD;
      Treatment retention will be compared using a log-rank test. Positive urine drug screens in&#xD;
      each week of follow-up will be compared using generalized estimating equation models with a&#xD;
      logit link, clustered on subject, with participation in the TMS study as the variable of&#xD;
      interest.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 6, 2020</start_date>
  <completion_date type="Actual">March 31, 2022</completion_date>
  <primary_completion_date type="Actual">March 31, 2022</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>Randomized order of TMS site stimulated first</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Retention in the study</measure>
    <time_frame>Baseline to 12 weeks (continuous)</time_frame>
    <description>Time to study dropout (to assess feasibility and tolerability of the protocol)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Retention in psychosocial treatment</measure>
    <time_frame>Baseline to 12 weeks (continuous--assessed weekly)</time_frame>
    <description>Time to discontinuation of psychosocial treatment</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Functional connectivity of the dorsolateral prefrontal cortex and anterior insula</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Functional connectivity of the dorsolateral prefrontal cortex and anterior insula measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional connectivity dorsolateral prefrontal cortex and anterior cingulate cortex</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Functional connectivity of the dorsolateral prefrontal cortex and anterior cingulate cortex measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional connectivity of the medial prefrontal cortex and ventral striatum</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Functional connectivity of the medial prefrontal cortex and ventral striatum measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Flanker Inhibitor Control and Attention Test, Age 12+</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Summary score of accuracy and reaction time (0-10), higher indicates stronger inhibitory control and attention.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Kirby Delay Discounting Questionnaire, 27 item</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Summary score of discounting rate. Scores range from 0.00016 to 0.5, with smaller values indicating a lack of discounting and preference for delayed rewards, and higher values indicating strong discounting and preference for immediate rewards. Higher scores are associated with addictive behaviors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of days of stimulant use in the past week</measure>
    <time_frame>Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Number of days (self-reported)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Urine drug screen positive for stimulant</measure>
    <time_frame>Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks</time_frame>
    <description>Urine dipstick positive or not for stimulants (amphetamine, methamphetamine, cocaine)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief substance craving scale</measure>
    <time_frame>12 weeks</time_frame>
    <description>Summary score of intensity, frequency and length of cravings in the last 24 hours</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Addiction Monitor Use Subscale</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Use subscale. Scores range from 0 to 12 with higher scores indicating more use.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Addiction Monitor Risk Factors Subscale</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Risk factors subscale. Scores range from 0 to 24 with higher scores indicating more risk.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Addiction Monitor Protective Factors Subscale</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Protective factors subscale. Scores range from 0 to 24 with higher scores indicating more protection.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Brief Addiction Monitor Satisfaction with Progress Toward Achieving Recovery Goals</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Item 17, satisfaction with progress toward achieving recovery goals. Scores range from 0 to 4 with higher scores indicating less satisfaction.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Total score. Scores range from 16 to 80 with higher scores indicating more satisfaction. Scores generally reported as a percent of the maximum possible score, such that scores can be calculated with missing responses as long as less than one-third of responses are missing.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient Health Questionnaire--8 item scale</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Total score. Scores range from 0 to 24 with higher scores indicating worse depressive symptoms.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Generalized Anxiety Disorder 7-item scale</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Total score. Scores range from 0 to 21 with higher scores indicating worse anxiety.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of Recovery Capital</measure>
    <time_frame>Baseline, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Total score. Scores range from 0 to 50 with higher scores indicating greater recovery capital.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Positive and Negative Affect Scale Positive Affect Score</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Positive affect score. Scores range from 10 to 50 with higher scores indicating higher positive affect. Higher positive affect is a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Positive and Negative Affect Scale Negative Affect Score</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Negative affect score. Scores range from 10 to 50 with lower scores indicating lower negative affect. Lower negative affect is a better outcome.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pittsburgh Sleep Quality Index</measure>
    <time_frame>Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks</time_frame>
    <description>Total score. Scores range from 0 to 21, with lower scores indicating better sleep quality.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difficulties in Emotion Regulation Scale--Short Form</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Total score. Scores range from 18 to 90 with higher values indicating more difficulty with emotional regulation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>UPPS-P Impulsive Behavior Scale, 59-item revised version</measure>
    <time_frame>Baseline, 4 weeks</time_frame>
    <description>Summary score. Scores range from 59 to 236 with higher scores indicating more impulsive behavior.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">19</enrollment>
  <condition>Stimulant Dependence</condition>
  <condition>Methamphetamine-dependence</condition>
  <condition>Addiction, Drug</condition>
  <arm_group>
    <arm_group_label>DPFC first</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the dorsolateral prefrontal cortex stimulation first.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MPFC first</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the medial prefrontal cortex stimulation first.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial Magnetic Stimulation</intervention_name>
    <description>Participants will undergo 16 treatments consisting of intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex and continuous theta burst stimulation targeting the medial prefrontal cortex, over a 4-week period that coincides with psychosocial treatment for methamphetamine use disorder.</description>
    <arm_group_label>DPFC first</arm_group_label>
    <arm_group_label>MPFC first</arm_group_label>
    <other_name>Theta burst stimulation</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosed with an active methamphetamine use disorder&#xD;
&#xD;
          -  Is engaged in psychosocial treatment or articulates a plan to engage in psychosocial&#xD;
             treatment for methamphetamine use disorder during the study period&#xD;
&#xD;
          -  Age 18 to 60 years&#xD;
&#xD;
          -  Able to consent for treatment and research participation&#xD;
&#xD;
          -  English-speaking&#xD;
&#xD;
          -  Receiving care from UIHC's Addiction Medicine service. This includes patients in the&#xD;
             Crisis Stabilization Unit, seen by the inpatient consultation service, enrolling in&#xD;
             partial hospitalization or intensive outpatient treatment, or seen in the outpatient&#xD;
             Addiction Medicine clinics.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Age less than 18 years&#xD;
&#xD;
          -  Patients that are excluded during TMS assessment including: patients with epilepsy or&#xD;
             seizure disorder, patients with implanted ferromagnetic equipment in their face or&#xD;
             skull near the stimulation target.&#xD;
&#xD;
          -  Current medical treatment with clozapine or stimulants.&#xD;
&#xD;
          -  Current diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, that&#xD;
             is deemed by research team psychiatrists not to have been drug-induced. Psychotic&#xD;
             disorder not associated with drug use per the MINI International Neuropsychiatric&#xD;
             Interview. Psychosis NOS, in remission, or drug-induced psychotic episodes are not&#xD;
             exclusion criteria since these may be related to methamphetamine misuse.&#xD;
&#xD;
          -  Lacks the mental capacity to provide informed consent (i.e. not able to demonstrate&#xD;
             understanding of the risks and benefits of participation)&#xD;
&#xD;
          -  Has a court appointed guardian.&#xD;
&#xD;
          -  Unstable medical illness.&#xD;
&#xD;
          -  Current diagnosis of neurological disorder or neurocognitive disorder.&#xD;
&#xD;
          -  Prior neurosurgical procedure.&#xD;
&#xD;
          -  History of seizure.&#xD;
&#xD;
          -  History of ECT treatment within the past three months.&#xD;
&#xD;
          -  History of any previous TMS treatment.&#xD;
&#xD;
          -  Known inability to complete the protocol, as assessed by asking them if they are able&#xD;
             to make it to all visits for this study without assistance.&#xD;
&#xD;
        MRI Exclusion criteria:&#xD;
&#xD;
          -  Implanted device including pacemaker, coronary stent, defibrillator, or&#xD;
             neurostimulation device that is not MRI-compatible&#xD;
&#xD;
          -  Metal in body including bullets, shrapnel, metal slivers&#xD;
&#xD;
          -  Claustrophobia&#xD;
&#xD;
          -  Uncontrolled high blood pressure&#xD;
&#xD;
          -  Atrial fibrillation&#xD;
&#xD;
          -  Significant heart disease&#xD;
&#xD;
          -  Hemodynamic instability&#xD;
&#xD;
          -  Kidney disease&#xD;
&#xD;
          -  Pregnant&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ryan Carnahan, PharmD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Iowa</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Alison C Lynch, MD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Iowa</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend. 2014 Oct 1;143:11-21. doi: 10.1016/j.drugalcdep.2014.08.003. Epub 2014 Aug 17.</citation>
    <PMID>25176528</PMID>
  </reference>
  <reference>
    <citation>Ma T, Sun Y, Ku Y. Effects of Non-invasive Brain Stimulation on Stimulant Craving in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-Analysis. Front Neurosci. 2019 Oct 18;13:1095. doi: 10.3389/fnins.2019.01095. eCollection 2019.</citation>
    <PMID>31680830</PMID>
  </reference>
  <reference>
    <citation>Zhang JJQ, Fong KNK, Ouyang RG, Siu AMH, Kranz GS. Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis. Addiction. 2019 Dec;114(12):2137-2149. doi: 10.1111/add.14753. Epub 2019 Aug 16.</citation>
    <PMID>31328353</PMID>
  </reference>
  <reference>
    <citation>Makani R, Pradhan B, Shah U, Parikh T. Role of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment of Addiction and Related Disorders: A Systematic Review. Curr Drug Abuse Rev. 2017;10(1):31-43. doi: 10.2174/1874473710666171129225914.</citation>
    <PMID>29189190</PMID>
  </reference>
  <reference>
    <citation>Liang Y, Wang L, Yuan TF. Targeting Withdrawal Symptoms in Men Addicted to Methamphetamine With Transcranial Magnetic Stimulation: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Nov 1;75(11):1199-1201. doi: 10.1001/jamapsychiatry.2018.2383.</citation>
    <PMID>30208372</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>June 23, 2020</study_first_submitted>
  <study_first_submitted_qc>June 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 26, 2020</study_first_posted>
  <last_update_submitted>February 17, 2023</last_update_submitted>
  <last_update_submitted_qc>February 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Iowa</investigator_affiliation>
    <investigator_full_name>Ryan M. Carnahan</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>methamphetamine</keyword>
  <keyword>addiction treatment</keyword>
  <keyword>transcranial magnetic stimulation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Substance-Related Disorders</mesh_term>
    <mesh_term>Behavior, Addictive</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>May 25, 2023</submitted>
    <returned>June 22, 2023</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04449055
org study id: 202001387
nct id: NCT04449055
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
This is a pilot study to test the feasibility of a recruitment strategy and study protocol to
      examine the effects of a dual target transcranial magnetic stimulation treatment in
      methamphetamine use disorder. The study will test intermittent theta burst stimulation (TBS)
      targeting the dorsolateral prefrontal cortex (DLPFC) combined with continuous TBS targeting
      the medial prefrontal cortex (MPFC) in people with methamphetamine use disorder (MAUD) who
      are engaged in psychosocial treatment. Intermittent TBS targeting the DLPFC is approved by
      the Food and Drug Administration for major depressive disorder, and continuous TBS targeting
      the MPFC has been studied in cocaine use disorder. We will administer this dual target TBS
      daily for 2 weeks, followed by three times weekly for 2 weeks, and monitor depressive
      symptoms, anxiety, sleep, craving, quality of life, and methamphetamine use for three months.
      Changes in functional connectivity of brain circuits will be evaluated with functional
      magnetic resonance imaging (fMRI) before and after treatment. We expect to observe changes in
      connectivity between the DLPFC, MPFC, and other regions implicated in addiction and
      impulsivity. Furthermore, we will evaluate if baseline differences in functional connectivity
      can be used to predict response. Psychological tests focusing on state impulsivity and risk
      taking will be administered, and we expect to observe reductions in these characteristics
      after treatment. We will test this protocol in 20 patients recruited from clinical care
      settings at University of Iowa Hospitals and Clinics, University of New Mexico Health System,
      and University of Utah Health to illustrate the feasibility of recruitment and completing the
      protocol, to support an external funding proposal.
Overview: This is a single-arm clinical trial, with historical controls as a comparison group
      for select outcomes. Subjects with MAUD will receive 16 sessions of dual-target theta burst
      stimulation to the DLPFC and MPFC over 4 weeks. We will follow outcomes for 12 weeks.
      Outcomes include treatment retention, craving, self-reported MA or stimulant use, urine drug
      screen results, depressive symptoms, anxiety symptoms, sleep quality, quality of life,
      response inhibition, and functional connectivity. Magnetic resonance imaging (MRI) to measure
      functional connectivity and a flanker task to measure response inhibition will be completed
      at baseline and four weeks. More detail is provided in the outcome measures section. Subjects
      will also complete the Big Five Inventory at baseline, a measure of personality
      characteristics, to explore how these relate to outcomes including retention in treatment and
      the study.

      MR Image Acquisition: MRI will be completed at baseline and after the last TMS session. The
      MRI sessions will be conducted using research dedicated MRI scanners at each site. Anatomical
      images will include volumetric T1 and T2 weighted images with a 1.0 mm isotropic spatial
      resolution. Resting state fMRI will be performed to collect 20 minutes worth of data.

      Statistical Analysis:

      Retention in the Study and Psychosocial Treatment: We will describe the proportion of
      subjects who complete the 4-week TMS treatment period and complete each subsequent monthly
      follow-up visit. We will use Kaplan-Meier curves to describe retention in the study and in
      psychosocial treatment. If non-retention is common enough, we will use Cox regression to
      explore baseline measures as predictors of retention. We anticipate that multivariate
      analysis will not be feasible with the sample size.

      Symptoms and Impulse Control Measures: Primary analyses for other measures will focus on
      changes over the 4-week TMS treatment period. Changes in symptoms evaluated weekly or
      biweekly (e.g. craving, depression, affect, anxiety, sleep) will be assessed using
      generalized linear mixed models with appropriate distributions. We anticipate a Poisson
      distribution for days of MA or other stimulant use and will use a binomial distribution with
      a logit link to evaluate changes in positive urine drug screens. Time will be the primary
      variable of interest to assess the slopes of change during treatment. Paired t-tests or
      Wilcoxon signed-rank tests will be used to evaluate changes in measures completed at baseline
      and after 4 weeks of treatment. We will compare measures at baseline and 4 weeks to those at
      8 weeks and 12 weeks similarly, but in separate analyses since decay in effects may occur
      after TMS ends.

      Functional Connectivity Analysis: fMRI functional connectivity analysis will be performed
      using a standard analysis pipeline. Functional images will undergo pre-processing including
      brain extraction, motion correction, spatial smoothing (6 mm FWHM), and temporal filtering
      (.008 Hz < f < 0.08 Hz). Following preprocessing, the fMRI signal will be corrected for
      potential sources of noise using image-based estimates and motion correction parameters. The
      resulting corrected time-series will be used for all functional connectivity analyses.
      Functional connectivity will be measured by extracting time-series data from the
      pre-processed imaging data for the regions of interest (ROIs). Multiple ROIs will be examined
      and will be defined as spheres (6mm radius) based on coordinate locations previously
      published by Yeo and colleagues. Specifically, we will focus on connectivity in the
      cingulo-opercular network involved in cognitive control and salience (DLPFC - anterior
      insula; DLPFC - anterior cingulate) and reward processing/motivation circuit (MPFC - ventral
      striatum). Analyses will be averaged across right and left hemispheres but we will also
      explore differences between right and left hemispheres. The time series from the ROIs will be
      cross-correlated with the time-series from the other ROIs to determine the strength of
      functional connectivity between regions. The resulting Pearson's r will be converted to
      Fisher's z scores to improve normality for the statistical analysis. We will treat each ROI
      pair connection (DLPFC - anterior insula, DLPFC - anterior cingulate, MPFC - ventral
      striatum) as a dependent variable. Primary analyses will use paired t-tests or Wilcoxon
      signed-rank tests to compare connectivity at baseline vs. after TMS treatment. We will
      explore correlates of connectivity and changes using Pearson or Spearman correlations and
      linear regression or mixed models.

      Exploratory Analysis: Follow-up exploratory voxel-wise analyses will be conducted for
      functional connectivity, which will provide thousands of individual predictors. This will
      help confirm findings in large parcel ROI based analysis. We will use the same statistical
      models as used for the ROI based analysis described above but at the voxel level. Voxel-wise
      data creates a high-dimensional problem in which the number of predictors far exceeds the
      number of participants. Machine learning methods, such as random forest will be used to
      handle the high-dimensional sub-analyses. Random forest requires a minimum of data
      assumptions, automatically accounts for non-linear and interaction effects, and it has proven
      useful in identifying useful predictors in high-dimensional contexts.

      Comparison with Historical Controls: We will compare retention in psychosocial treatment
      programs and positive urine drug screens from chart review with a historical control group of
      patients with MA use disorder matched on age, sex, site, and psychosocial treatment modality.
      Treatment retention will be compared using a log-rank test. Positive urine drug screens in
      each week of follow-up will be compared using generalized estimating equation models with a
      logit link, clustered on subject, with participation in the TMS study as the variable of
      interest.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Randomized order of TMS site stimulated first
primary purpose: Treatment
masking: None (Open Label)
measure: Retention in the study
time frame: Baseline to 12 weeks (continuous)
description: Time to study dropout (to assess feasibility and tolerability of the protocol)
measure: Retention in psychosocial treatment
time frame: Baseline to 12 weeks (continuous--assessed weekly)
description: Time to discontinuation of psychosocial treatment
measure: Functional connectivity of the dorsolateral prefrontal cortex and anterior insula
time frame: Baseline, 4 weeks
description: Functional connectivity of the dorsolateral prefrontal cortex and anterior insula measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.
measure: Functional connectivity dorsolateral prefrontal cortex and anterior cingulate cortex
time frame: Baseline, 4 weeks
description: Functional connectivity of the dorsolateral prefrontal cortex and anterior cingulate cortex measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.
measure: Functional connectivity of the medial prefrontal cortex and ventral striatum
time frame: Baseline, 4 weeks
description: Functional connectivity of the medial prefrontal cortex and ventral striatum measured with fMRI, as defined by the temporal correlation in the blood-oxygen-level-dependent signals of the regions. Higher correlations indicate stronger functional connectivity.
measure: Flanker Inhibitor Control and Attention Test, Age 12+
time frame: Baseline, 4 weeks
description: Summary score of accuracy and reaction time (0-10), higher indicates stronger inhibitory control and attention.
measure: Kirby Delay Discounting Questionnaire, 27 item
time frame: Baseline, 4 weeks
description: Summary score of discounting rate. Scores range from 0.00016 to 0.5, with smaller values indicating a lack of discounting and preference for delayed rewards, and higher values indicating strong discounting and preference for immediate rewards. Higher scores are associated with addictive behaviors.
measure: Number of days of stimulant use in the past week
time frame: Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks
description: Number of days (self-reported)
measure: Urine drug screen positive for stimulant
time frame: Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks
description: Urine dipstick positive or not for stimulants (amphetamine, methamphetamine, cocaine)
measure: Brief substance craving scale
time frame: 12 weeks
description: Summary score of intensity, frequency and length of cravings in the last 24 hours
measure: Brief Addiction Monitor Use Subscale
time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
description: Use subscale. Scores range from 0 to 12 with higher scores indicating more use.
measure: Brief Addiction Monitor Risk Factors Subscale
time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
description: Risk factors subscale. Scores range from 0 to 24 with higher scores indicating more risk.
measure: Brief Addiction Monitor Protective Factors Subscale
time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
description: Protective factors subscale. Scores range from 0 to 24 with higher scores indicating more protection.
measure: Brief Addiction Monitor Satisfaction with Progress Toward Achieving Recovery Goals
time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
description: Item 17, satisfaction with progress toward achieving recovery goals. Scores range from 0 to 4 with higher scores indicating less satisfaction.
measure: Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Total score. Scores range from 16 to 80 with higher scores indicating more satisfaction. Scores generally reported as a percent of the maximum possible score, such that scores can be calculated with missing responses as long as less than one-third of responses are missing.
measure: Patient Health Questionnaire--8 item scale
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Total score. Scores range from 0 to 24 with higher scores indicating worse depressive symptoms.
measure: Generalized Anxiety Disorder 7-item scale
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Total score. Scores range from 0 to 21 with higher scores indicating worse anxiety.
measure: Assessment of Recovery Capital
time frame: Baseline, 4 weeks, 8 weeks, 12 weeks
description: Total score. Scores range from 0 to 50 with higher scores indicating greater recovery capital.
measure: Positive and Negative Affect Scale Positive Affect Score
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Positive affect score. Scores range from 10 to 50 with higher scores indicating higher positive affect. Higher positive affect is a better outcome.
measure: Positive and Negative Affect Scale Negative Affect Score
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Negative affect score. Scores range from 10 to 50 with lower scores indicating lower negative affect. Lower negative affect is a better outcome.
measure: Pittsburgh Sleep Quality Index
time frame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
description: Total score. Scores range from 0 to 21, with lower scores indicating better sleep quality.
measure: Difficulties in Emotion Regulation Scale--Short Form
time frame: Baseline, 4 weeks
description: Total score. Scores range from 18 to 90 with higher values indicating more difficulty with emotional regulation.
measure: UPPS-P Impulsive Behavior Scale, 59-item revised version
time frame: Baseline, 4 weeks
description: Summary score. Scores range from 59 to 236 with higher scores indicating more impulsive behavior.
arm group label: DPFC first
arm group type: Experimental
description: Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the dorsolateral prefrontal cortex stimulation first.
arm group label: MPFC first
arm group type: Experimental
description: Participants in this arm will undergo all study procedures including consent; pre-, during, and post-psychological assessments; pre- and post- MRI and fMRI; 16 treatments of dual target TMS over a 4-week period; and substance use-related assessments to include substance use, withdrawal symptoms, and cravings to use. This arm will receive the medial prefrontal cortex stimulation first.
intervention type: Device
intervention name: Transcranial Magnetic Stimulation
description: Participants will undergo 16 treatments consisting of intermittent theta burst stimulation targeting the dorsolateral prefrontal cortex and continuous theta burst stimulation targeting the medial prefrontal cortex, over a 4-week period that coincides with psychosocial treatment for methamphetamine use disorder.
arm group label: DPFC first
arm group label: MPFC first
other name: Theta burst stimulation
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Ryan Carnahan, PharmD, MS
role: Principal Investigator
affiliation: University of Iowa
last name: Alison C Lynch, MD, MS
role: Principal Investigator
affiliation: University of Iowa
facility: 
country: United States
citation: Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend. 2014 Oct 1;143:11-21. doi: 10.1016/j.drugalcdep.2014.08.003. Epub 2014 Aug 17.
PMID: 25176528
citation: Ma T, Sun Y, Ku Y. Effects of Non-invasive Brain Stimulation on Stimulant Craving in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-Analysis. Front Neurosci. 2019 Oct 18;13:1095. doi: 10.3389/fnins.2019.01095. eCollection 2019.
PMID: 31680830
citation: Zhang JJQ, Fong KNK, Ouyang RG, Siu AMH, Kranz GS. Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis. Addiction. 2019 Dec;114(12):2137-2149. doi: 10.1111/add.14753. Epub 2019 Aug 16.
PMID: 31328353
citation: Makani R, Pradhan B, Shah U, Parikh T. Role of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment of Addiction and Related Disorders: A Systematic Review. Curr Drug Abuse Rev. 2017;10(1):31-43. doi: 10.2174/1874473710666171129225914.
PMID: 29189190
citation: Liang Y, Wang L, Yuan TF. Targeting Withdrawal Symptoms in Men Addicted to Methamphetamine With Transcranial Magnetic Stimulation: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Nov 1;75(11):1199-1201. doi: 10.1001/jamapsychiatry.2018.2383.
PMID: 30208372
responsible party type: Sponsor-Investigator
investigator affiliation: University of Iowa
investigator full name: Ryan M. Carnahan
investigator title: Professor
mesh term: Substance-Related Disorders
mesh term: Behavior, Addictive
sharing ipd: No
submitted: May 25, 2023
returned: June 22, 2023