<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/NCT04426214</url>
  </required_header>
  <id_info>
    <org_study_id>PSYCH-2020-28848</org_study_id>
    <nct_id>NCT04426214</nct_id>
  </id_info>
  <brief_title>Neuromodulation and Cognitive Training for Substance Use Disorders</brief_title>
  <official_title>Neuromodulation and Cognitive Training for Substance Use Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Minnesota</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Minnesota</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The relapsing nature of substance use disorder is a major obstacle to successful treatment.&#xD;
      About 70% of those entering treatment will relapse within one year. To improve treatment&#xD;
      outcome, new interventions targeting the underlying brain biomarkers of relapse vulnerability&#xD;
      hold significant promise in reducing this critical public health problem. This study is&#xD;
      testing a new intervention, namely tDCS-Augmented Cognitive Training, to engage these brain&#xD;
      biomarkers to improve cognition and improve treatment outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The relapsing nature of substance use disorder is a major obstacle to successful treatment.&#xD;
      About 70% of those entering treatment will relapse within one year. To improve treatment&#xD;
      outcome, new interventions targeting the underlying brain biomarkers of relapse vulnerability&#xD;
      hold significant promise in reducing this critical public health problem.&#xD;
&#xD;
      Preliminary Data: Using resting functional magnetic resonance imaging (fMRI) we have&#xD;
      identified brain biomarkers that support long-term abstinence. Our cross-sectional and&#xD;
      longitudinal findings provide evidence that higher FC, particularly between NAcc and DLPFC,&#xD;
      is a potential brain biomarker that supports abstinence. Long-term abstinent alcoholics (7&#xD;
      years of abstinence) have higher resting FC between NAcc and DLPFC when compared to controls.&#xD;
      Short-term abstinent alcoholics (11 weeks of abstinence) have intermediate FC (lower than&#xD;
      long-term abstinent alcoholics and higher than controls) (Camchong, Stenger, &amp; Fein, 2013b,&#xD;
      2013c). Further, lower FC between NAcc and DLPFC at 11 weeks of abstinence can be a predictor&#xD;
      of subsequent relapse (with 74% accuracy) (Camchong, Stenger, &amp; Fein, 2013a). Moreover, in a&#xD;
      pilot longitudinal FC study examining resting FC of NAcc at 5 and 13 weeks of abstinence in&#xD;
      individuals with stimulant use disorder, we found that FC between NAcc and DLPFC decreased&#xD;
      from 5 to 13 weeks of abstinence in subsequent relapsers, while it increased in subsequent&#xD;
      abstainers (Camchong et al., 2014). Based on the above, we believe that long-term abstinence&#xD;
      is supported by a compensatory mechanism that mediates proper executive function over reward&#xD;
      (mediated by DLPFC-NAcc FC), a potential brain biomarker that could be an intervention&#xD;
      target. These findings provide a compelling case to explore whether this brain biomarker can&#xD;
      be modulated to enhance patients' ability to remain abstinent. Based on the above literature,&#xD;
      there is a need to investigate non-invasive methods that can be used to increase FC between&#xD;
      DLPFC and NAcc both in stimulant use disorder and alcohol use disorder. Because stimulant use&#xD;
      and alcohol use are a very common incidence in the USA and both are a high burden on society,&#xD;
      the current protocol will recruit both individuals with alcohol and stimulant use disorder.&#xD;
&#xD;
      Existing Literature: Executive functioning, the ability to change maladaptive behavior,&#xD;
      depends on DLPFC input to NAcc (Gruber, Hussain, &amp; O'Donnell, 2009). DLPFC transmits reward&#xD;
      representations to NAcc through glutamatergic projections that guide goal-directed behavior&#xD;
      (Ballard &amp; Knutson, 2009). If DLPFC fails to activate when required, a common observation in&#xD;
      substance use disorder, target neurons in the NAcc core do not receive critical information&#xD;
      needed to select the appropriate outcome, causing acquired maladaptive response patterns to&#xD;
      persist (e.g. drug consumption) (Gruber et al., 2009). Higher FC between DLPFC and NAcc may&#xD;
      be achieved by stimulating DLPFC while subjects perform engaging executive functioning tasks.&#xD;
      Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique&#xD;
      that can modulate brain connectivity. DLPFC stimulation may increase input to NAcc to&#xD;
      facilitate proper selection of goal-directed behavior and may also decrease craving in&#xD;
      individuals with substance use disorder (Boggio et al., 2008). Genetics and treatment&#xD;
      response: A source of treatment response variability could stem from differences between&#xD;
      participants in baseline genetic profiles or epigenetic changes over the course of treatment.&#xD;
      Genetic polymorphisms, especially in genes important for neuroplasticity, may also mediate&#xD;
      neuroplastic changes underlying the effects of tDCS (Chhabra et al., 2016), as has been&#xD;
      demonstrated with gene BDNF (Antal et al., 2010; Fritsch et al., 2010). In light of these&#xD;
      genetic influences on key tenants of our study - i.e. treatment response in alcohol use&#xD;
      disorder and physiological effects of tDCS - we will collect genetic samples from&#xD;
      participants to determine whether genetic or epigenetic variations may affect response to the&#xD;
      cognitive training and tDCS intervention. This information may help inform the development of&#xD;
      more individually-tailored treatment protocols in the future. As this is a secondary aim,&#xD;
      participants will be given the choice in the Consent Form to opt in or out of the genetic&#xD;
      sampling procedure.&#xD;
&#xD;
      Primary Endpoint/Event/Outcome: In a double-blind randomized design, 80 abstinent (3 weeks&#xD;
      abstinent) individuals, 40 with Alcohol Use Disorder (AUD) and 40 with Stimulant Use Disorder&#xD;
      (SUD) recruited from addiction treatment facilities will receive 10 sessions of either (i)&#xD;
      transcranial direct current stimulation (tDCS) to PFC or (ii) sham-tDCS. All subjects will&#xD;
      perform executive functioning tasks during each tDCS intervention (active or sham) to prime&#xD;
      the engagement of the NAcc-PFC brain circuit. We have unpublished preliminary data indicating&#xD;
      that the additional 5 treatment sessions (10 vs. 5) will likely improve outcomes and result&#xD;
      in larger effect sizes. Follow-up interviews will be conducted monthly out to 4 months post&#xD;
      intervention cessation (exact timepoint depending on participant availability) to query&#xD;
      relapse status. We are expanding follow up visits out to 4 months because we have reason to&#xD;
      believe that treatment effects could last up to 6 months post treatment. Tracking outcomes&#xD;
      out to 4 months will be necessary to demonstrate durability of treatment benefits. Dependent&#xD;
      variables will be (i) change in cognitive performance between pre- and post-intervention, and&#xD;
      (ii) relapse status after study participation. The Specific Aims are to determine if the&#xD;
      intervention: (A1) is feasible and safe in individuals with SUD and AUD, (A2) induces&#xD;
      cognitive performance changes, and (A3) is related to relapse status in the months following&#xD;
      study completion. A fourth exploratory aim is to examine relationships between genetic&#xD;
      variants, epigenetic changes and (A2-3).&#xD;
&#xD;
      To evaluate feasibility (A1), withdrawal and retention policies are described in Section&#xD;
      12.0. To evaluate safety (A1), we will use the Treatment Side Effects Questionnaire to record&#xD;
      intervention side effects. Based on our previous alcohol tDCS study and studies from other&#xD;
      research groups, we hypothesize that the intervention will be feasible and safe.&#xD;
&#xD;
      To evaluate cognitive performance changes (A2), we will compare cognitive performance change&#xD;
      from pre-intervention to post-intervention) between active tDCS and sham groups. We&#xD;
      hypothesize that the active tDCS group will have a larger improvement in cognitive&#xD;
      performance than the sham group.&#xD;
&#xD;
      To evaluate relapse status at all monthly follow-up visits, we will administer the Timeline&#xD;
      Follow Back (Sobell and Sobell 1996), questionnaire and saliva/urine samples at each&#xD;
      follow-up. Based on our alcohol pilot study and literature on the effects of tDCS in other&#xD;
      addictions (Lupi et al. 2017; Batista et al. 2015), we hypothesize that the active tDCS group&#xD;
      will have lower relapse rates and longer abstinence periods than the sham group.&#xD;
&#xD;
      Secondary Endpoint(s)/Event(s)/Outcome(s): To determine generalization and durability of&#xD;
      cognitive training, patients will be asked to complete the following tasks at&#xD;
      pre-intervention, post-intervention, and at 2 monthly follow up visits to examine&#xD;
      generalization and durability effects of training: D-KEFS Trail Making Test, D-KEFS Verbal&#xD;
      Fluency, D-KEFS Color Word, Digit-Span (WAIS), and Digit Symbol (WAIS).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">July 16, 2021</start_date>
  <completion_date type="Anticipated">June 30, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</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>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Percent of participants with clean drug screens</measure>
    <time_frame>2 months</time_frame>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">80</enrollment>
  <condition>Stimulant Use</condition>
  <condition>Alcohol Use Disorder</condition>
  <arm_group>
    <arm_group_label>Active tDCS</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Sham tDCS</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>tDCS</intervention_name>
    <description>We will apply tDCS in combination with cognitive training. All participants receive cognitive training, and will be randomized to receive either active or sham tDCS</description>
    <arm_group_label>Active tDCS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Cognitive Training</intervention_name>
    <description>cognitive training on computer</description>
    <arm_group_label>Active tDCS</arm_group_label>
    <arm_group_label>Sham tDCS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Abstinent from any substance or alcohol use (excluding caffeine or nicotine) for a&#xD;
             minimum of 3 weeks at study enrollment&#xD;
&#xD;
          -  Has the intention to remain in their treatment program(s) until the end of the&#xD;
             intervention portion of the study.&#xD;
&#xD;
          -  Able to provide written consent and comply with study procedures.&#xD;
&#xD;
          -  Meets the MINI 7 diagnostic criteria for either stimulant use disorder (SUD) or&#xD;
             alcohol use disorder (AUD).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any medical condition or treatment with neurological sequelae (i.e. stroke, tumor,&#xD;
             HIV)&#xD;
&#xD;
          -  Over 9 months of abstinence from substance use&#xD;
&#xD;
          -  A head injury resulting in a loss of consciousness exceeding 30 minutes (i.e.,&#xD;
             moderate or severe TBI)&#xD;
&#xD;
          -  Presence of a condition that would render study measures difficult or impossible to&#xD;
             administer or interpret&#xD;
&#xD;
          -  Age outside the range of 18 to 65&#xD;
&#xD;
          -  Primary current substance use disorder diagnosis (according to MINI 7 diagnostic&#xD;
             criteria) for a substance other than stimulant or alcohol, except for caffeine or&#xD;
             nicotine (Nicotine use will be recorded but is not exclusionary)&#xD;
&#xD;
          -  Entrance to the treatment program under a court mandate. (i.e. legally incarcerated)&#xD;
&#xD;
          -  History of ECT or cortical energy exposure within the past 6 months, including&#xD;
             participation in any other neuromodulation studies&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kelvin Lim, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Minnesota</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Melanie Stimac</last_name>
    <phone>612-301-2449</phone>
    <email>stima011@umn.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>University of Minnesota Fairview</name>
      <address>
        <city>Minneapolis</city>
        <state>Minnesota</state>
        <zip>55454</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melanie Stimac</last_name>
      <phone>612-301-2449</phone>
      <email>stima011@umn.edu</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 9, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>August 2, 2023</last_update_submitted>
  <last_update_submitted_qc>August 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>tDCS</keyword>
  <keyword>Cognitive Training</keyword>
  <keyword>Plasticity</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Substance-Related Disorders</mesh_term>
    <mesh_term>Alcoholism</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>May 27, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/14/NCT04426214/ICF_000.pdf</document_url>
    </provided_document>
  </provided_document_section>
  <!-- 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/NCT04426214
org study id: PSYCH-2020-28848
nct id: NCT04426214
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
The relapsing nature of substance use disorder is a major obstacle to successful treatment.
      About 70% of those entering treatment will relapse within one year. To improve treatment
      outcome, new interventions targeting the underlying brain biomarkers of relapse vulnerability
      hold significant promise in reducing this critical public health problem. This study is
      testing a new intervention, namely tDCS-Augmented Cognitive Training, to engage these brain
      biomarkers to improve cognition and improve treatment outcomes.
The relapsing nature of substance use disorder is a major obstacle to successful treatment.
      About 70% of those entering treatment will relapse within one year. To improve treatment
      outcome, new interventions targeting the underlying brain biomarkers of relapse vulnerability
      hold significant promise in reducing this critical public health problem.

      Preliminary Data: Using resting functional magnetic resonance imaging (fMRI) we have
      identified brain biomarkers that support long-term abstinence. Our cross-sectional and
      longitudinal findings provide evidence that higher FC, particularly between NAcc and DLPFC,
      is a potential brain biomarker that supports abstinence. Long-term abstinent alcoholics (7
      years of abstinence) have higher resting FC between NAcc and DLPFC when compared to controls.
      Short-term abstinent alcoholics (11 weeks of abstinence) have intermediate FC (lower than
      long-term abstinent alcoholics and higher than controls) (Camchong, Stenger, & Fein, 2013b,
      2013c). Further, lower FC between NAcc and DLPFC at 11 weeks of abstinence can be a predictor
      of subsequent relapse (with 74% accuracy) (Camchong, Stenger, & Fein, 2013a). Moreover, in a
      pilot longitudinal FC study examining resting FC of NAcc at 5 and 13 weeks of abstinence in
      individuals with stimulant use disorder, we found that FC between NAcc and DLPFC decreased
      from 5 to 13 weeks of abstinence in subsequent relapsers, while it increased in subsequent
      abstainers (Camchong et al., 2014). Based on the above, we believe that long-term abstinence
      is supported by a compensatory mechanism that mediates proper executive function over reward
      (mediated by DLPFC-NAcc FC), a potential brain biomarker that could be an intervention
      target. These findings provide a compelling case to explore whether this brain biomarker can
      be modulated to enhance patients' ability to remain abstinent. Based on the above literature,
      there is a need to investigate non-invasive methods that can be used to increase FC between
      DLPFC and NAcc both in stimulant use disorder and alcohol use disorder. Because stimulant use
      and alcohol use are a very common incidence in the USA and both are a high burden on society,
      the current protocol will recruit both individuals with alcohol and stimulant use disorder.

      Existing Literature: Executive functioning, the ability to change maladaptive behavior,
      depends on DLPFC input to NAcc (Gruber, Hussain, & O'Donnell, 2009). DLPFC transmits reward
      representations to NAcc through glutamatergic projections that guide goal-directed behavior
      (Ballard & Knutson, 2009). If DLPFC fails to activate when required, a common observation in
      substance use disorder, target neurons in the NAcc core do not receive critical information
      needed to select the appropriate outcome, causing acquired maladaptive response patterns to
      persist (e.g. drug consumption) (Gruber et al., 2009). Higher FC between DLPFC and NAcc may
      be achieved by stimulating DLPFC while subjects perform engaging executive functioning tasks.
      Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique
      that can modulate brain connectivity. DLPFC stimulation may increase input to NAcc to
      facilitate proper selection of goal-directed behavior and may also decrease craving in
      individuals with substance use disorder (Boggio et al., 2008). Genetics and treatment
      response: A source of treatment response variability could stem from differences between
      participants in baseline genetic profiles or epigenetic changes over the course of treatment.
      Genetic polymorphisms, especially in genes important for neuroplasticity, may also mediate
      neuroplastic changes underlying the effects of tDCS (Chhabra et al., 2016), as has been
      demonstrated with gene BDNF (Antal et al., 2010; Fritsch et al., 2010). In light of these
      genetic influences on key tenants of our study - i.e. treatment response in alcohol use
      disorder and physiological effects of tDCS - we will collect genetic samples from
      participants to determine whether genetic or epigenetic variations may affect response to the
      cognitive training and tDCS intervention. This information may help inform the development of
      more individually-tailored treatment protocols in the future. As this is a secondary aim,
      participants will be given the choice in the Consent Form to opt in or out of the genetic
      sampling procedure.

      Primary Endpoint/Event/Outcome: In a double-blind randomized design, 80 abstinent (3 weeks
      abstinent) individuals, 40 with Alcohol Use Disorder (AUD) and 40 with Stimulant Use Disorder
      (SUD) recruited from addiction treatment facilities will receive 10 sessions of either (i)
      transcranial direct current stimulation (tDCS) to PFC or (ii) sham-tDCS. All subjects will
      perform executive functioning tasks during each tDCS intervention (active or sham) to prime
      the engagement of the NAcc-PFC brain circuit. We have unpublished preliminary data indicating
      that the additional 5 treatment sessions (10 vs. 5) will likely improve outcomes and result
      in larger effect sizes. Follow-up interviews will be conducted monthly out to 4 months post
      intervention cessation (exact timepoint depending on participant availability) to query
      relapse status. We are expanding follow up visits out to 4 months because we have reason to
      believe that treatment effects could last up to 6 months post treatment. Tracking outcomes
      out to 4 months will be necessary to demonstrate durability of treatment benefits. Dependent
      variables will be (i) change in cognitive performance between pre- and post-intervention, and
      (ii) relapse status after study participation. The Specific Aims are to determine if the
      intervention: (A1) is feasible and safe in individuals with SUD and AUD, (A2) induces
      cognitive performance changes, and (A3) is related to relapse status in the months following
      study completion. A fourth exploratory aim is to examine relationships between genetic
      variants, epigenetic changes and (A2-3).

      To evaluate feasibility (A1), withdrawal and retention policies are described in Section
      12.0. To evaluate safety (A1), we will use the Treatment Side Effects Questionnaire to record
      intervention side effects. Based on our previous alcohol tDCS study and studies from other
      research groups, we hypothesize that the intervention will be feasible and safe.

      To evaluate cognitive performance changes (A2), we will compare cognitive performance change
      from pre-intervention to post-intervention) between active tDCS and sham groups. We
      hypothesize that the active tDCS group will have a larger improvement in cognitive
      performance than the sham group.

      To evaluate relapse status at all monthly follow-up visits, we will administer the Timeline
      Follow Back (Sobell and Sobell 1996), questionnaire and saliva/urine samples at each
      follow-up. Based on our alcohol pilot study and literature on the effects of tDCS in other
      addictions (Lupi et al. 2017; Batista et al. 2015), we hypothesize that the active tDCS group
      will have lower relapse rates and longer abstinence periods than the sham group.

      Secondary Endpoint(s)/Event(s)/Outcome(s): To determine generalization and durability of
      cognitive training, patients will be asked to complete the following tasks at
      pre-intervention, post-intervention, and at 2 monthly follow up visits to examine
      generalization and durability effects of training: D-KEFS Trail Making Test, D-KEFS Verbal
      Fluency, D-KEFS Color Word, Digit-Span (WAIS), and Digit Symbol (WAIS).
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Percent of participants with clean drug screens
time frame: 2 months
arm group label: Active tDCS
arm group type: Experimental
arm group label: Sham tDCS
arm group type: Placebo Comparator
intervention type: Device
intervention name: tDCS
description: We will apply tDCS in combination with cognitive training. All participants receive cognitive training, and will be randomized to receive either active or sham tDCS
arm group label: Active tDCS
intervention type: Behavioral
intervention name: Cognitive Training
description: cognitive training on computer
arm group label: Active tDCS
arm group label: Sham tDCS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Kelvin Lim, MD
role: Principal Investigator
affiliation: University of Minnesota
last name: Melanie Stimac
phone: 612-301-2449
email: stima011@umn.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor
mesh term: Substance-Related Disorders
mesh term: Alcoholism
sharing ipd: Undecided
provided document: 