<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/NCT03244488</url>
  </required_header>
  <id_info>
    <org_study_id>150929</org_study_id>
    <nct_id>NCT03244488</nct_id>
  </id_info>
  <brief_title>Mental Ability Challenge Study in Adults With and Without HIV</brief_title>
  <official_title>Cholinergic Correlates of Impaired Cognitive Ability in HIV-Associated Neurocognitive Disorders</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      It is estimated that by 2016, nearly 50% of HIV-positive individuals in the US will be aged&#xD;
      50 or older, and up to 60% of those will experience some degree of cognitive impairment as&#xD;
      they age. The purpose of this study is to evaluate the contribution of the neuronal&#xD;
      cholinergic receptor system to the cognitive impairments seen in adults aging with chronic&#xD;
      HIV Infection. By using anti-cholinergic challenge drugs to reversibly &quot;stress&quot; cognitive&#xD;
      functioning, the investigators hope to understand whether the presence of the HIV virus in&#xD;
      the brain impairs the neural system necessary for normal cognition, more than would be&#xD;
      expected from normal cognitive aging.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study is intended to evaluate the involvement of the neuronal cholinergic receptor&#xD;
      system in the accelerated cognitive aging profile seen in adults living with chronic HIV-1&#xD;
      infection. It is estimated by the CDC that by the year 2016, nearly 50% of the US'&#xD;
      HIV-positive population will be 50 or older. The HIV-1 virus is known to enter the CNS very&#xD;
      rapidly after initial infection, and cause a pattern of persistent neural inflammation, which&#xD;
      is deleterious to neurons and glia. This damage is believed to be the basis of cognitive&#xD;
      impairment associated with long-term chronic HIV infection, known as HIV-Associated&#xD;
      Neurocognitive Disorders (HAND). Successful introduction of Anti-Retroviral Treatment (ART)&#xD;
      has greatly reduced the likelihood of progressing to the most severe category of HAND&#xD;
      (HIV-Associated Dementia), however the mild and moderate forms (Asymptomatic Neurocognitive&#xD;
      Impairment and Mild Neurocognitive Disorder, respectively) are still fairly common even in&#xD;
      adults declared &quot;virally suppressed&quot;, with little to no detectable peripheral viral DNA/RNA.&#xD;
      Prior studies have shown that over the lifetime, more than 50% of adults diagnosed with HIV&#xD;
      will experience some degree of cognitive impairment as they age. Some of these changes may be&#xD;
      due to cholinergic dysfunction. The acetylcholinergic receptor system is necessary for normal&#xD;
      cognitive performance, and is active during working memory, executive functioning, attention,&#xD;
      and learning tasks. It has been shown that as the human brain ages, cognitive ability begins&#xD;
      to decline, and correlates with declining acetylcholinergic activity. The cholinergic theory&#xD;
      of cognitive aging postulates that this loss of activity at cholinergic receptors with age is&#xD;
      at least partly responsible for poorer cognitive performance in aging. I will use this model&#xD;
      to examine the impact of HIV infection on cholinergic system functioning. This study will use&#xD;
      a well-established anti-cholinergic drug challenge model to evaluate cognitive performance in&#xD;
      domains of cognitive functioning relevant to cholinergic functioning. Under conditions of&#xD;
      temporary muscarinic or nicotinic blockade, or a combination of both, I aim to explore the&#xD;
      contribution of putative cholinergic receptor dysfunction to the observed symptoms of HAND. I&#xD;
      also intend to determine whether age and HIV-status interact to produce an accelerated&#xD;
      pattern of cholinergic cognitive aging that would indicate that older adults with HIV are at&#xD;
      higher risk for more rapid cognitive aging than HIV-negative individuals. If successful, the&#xD;
      outcome of this study would support the future exploration of novel pro-cholinergic&#xD;
      medications to treat cognitive symptoms of HAND, which may improve quality of life for adults&#xD;
      living with chronic HIV infection, as they survive into old age.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 2015</start_date>
  <completion_date type="Actual">December 2018</completion_date>
  <primary_completion_date type="Actual">December 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Crossover</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Cognitive Outcome - Lower verbal memory score</measure>
    <time_frame>2 hours</time_frame>
    <description>Cognitive performance will be more significantly impaired by study medications in HIV-positive participants relative to HIV-negative participants, indicating impairment of cholinergic neurotransmitter system.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Age and HIV-Status Interaction - Slower CRTreaction time</measure>
    <time_frame>2 hours</time_frame>
    <description>Older age and positive HIV status will interact to more significantly impair cognitive performance as measured by reaction time on the Choice Reaction Time task under the influence of study medications, than either variable alone.</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">22</enrollment>
  <condition>HIV-1-infection</condition>
  <condition>Aging, Premature</condition>
  <condition>Cognitive Impairment</condition>
  <condition>Memory Impairment</condition>
  <condition>HIV-Associated Cognitive Motor Complex</condition>
  <arm_group>
    <arm_group_label>HIV-Positive</arm_group_label>
    <description>Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>HIV-Negative</arm_group_label>
    <description>Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Scopolamine Injectable Product</intervention_name>
    <description>2.5 or 5 mcg/kg of scopolamine via IV</description>
    <arm_group_label>HIV-Negative</arm_group_label>
    <arm_group_label>HIV-Positive</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Mecamylamine Pill</intervention_name>
    <description>10 or 20mg of mecamylamine orally</description>
    <arm_group_label>HIV-Negative</arm_group_label>
    <arm_group_label>HIV-Positive</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples collected from all participants for routine screening labs and APOE genotyping.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        HIV-Positive Healthy older adults and HIV-Negative Healthy older adults&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. 35 years of age or older;&#xD;
&#xD;
          2. HIV-Positive (must be on ART's for at least 6 months, most recent viral load (within 6&#xD;
             months) &lt;50, CD4+ count &gt;200, must be diagnosed HIV-positive at least 5 years) or&#xD;
             HIV-Negative, At-Risk Individuals&#xD;
&#xD;
          3. Able and willing to give written informed consent&#xD;
&#xD;
          4. Negative urine pregnancy test&#xD;
&#xD;
          5. Adequate visual and auditory acuity to allow neuropsychological testing.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Unmanaged HIV Infection, identified by no current medication regimen or the presence&#xD;
             of one or more AIDS-defining conditions&#xD;
&#xD;
          2. Fagerstrom cigarettes per day (CPD) score of '2' indicating heavy use of nicotine&#xD;
&#xD;
          3. An ART regimen including a Protease Inhibitor Medication&#xD;
&#xD;
          4. A documented history of cardiac disease or abnormal ECG at Screening&#xD;
&#xD;
          5. Current alcohol or substance abuse, particularly intravenously&#xD;
&#xD;
          6. Current use of psychoactive medications (antipsychotics, benzodiazepines, etc.)&#xD;
&#xD;
          7. Current Axis I or Axis II psychiatric disorder&#xD;
&#xD;
          8. History of myocardial infarction in the past year or unstable or severe cardiovascular&#xD;
             disease&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37212</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 9, 2017</study_first_posted>
  <last_update_submitted>February 21, 2019</last_update_submitted>
  <last_update_submitted_qc>February 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University Medical Center</investigator_affiliation>
    <investigator_full_name>Asante Kamkwalala</investigator_full_name>
    <investigator_title>Graduate Research Assistant</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>AIDS Dementia Complex</mesh_term>
    <mesh_term>Aging, Premature</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mecamylamine</mesh_term>
    <mesh_term>Scopolamine</mesh_term>
    <mesh_term>Butylscopolammonium Bromide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03244488
org study id: 150929
nct id: NCT03244488
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
It is estimated that by 2016, nearly 50% of HIV-positive individuals in the US will be aged
      50 or older, and up to 60% of those will experience some degree of cognitive impairment as
      they age. The purpose of this study is to evaluate the contribution of the neuronal
      cholinergic receptor system to the cognitive impairments seen in adults aging with chronic
      HIV Infection. By using anti-cholinergic challenge drugs to reversibly "stress" cognitive
      functioning, the investigators hope to understand whether the presence of the HIV virus in
      the brain impairs the neural system necessary for normal cognition, more than would be
      expected from normal cognitive aging.
This study is intended to evaluate the involvement of the neuronal cholinergic receptor
      system in the accelerated cognitive aging profile seen in adults living with chronic HIV-1
      infection. It is estimated by the CDC that by the year 2016, nearly 50% of the US'
      HIV-positive population will be 50 or older. The HIV-1 virus is known to enter the CNS very
      rapidly after initial infection, and cause a pattern of persistent neural inflammation, which
      is deleterious to neurons and glia. This damage is believed to be the basis of cognitive
      impairment associated with long-term chronic HIV infection, known as HIV-Associated
      Neurocognitive Disorders (HAND). Successful introduction of Anti-Retroviral Treatment (ART)
      has greatly reduced the likelihood of progressing to the most severe category of HAND
      (HIV-Associated Dementia), however the mild and moderate forms (Asymptomatic Neurocognitive
      Impairment and Mild Neurocognitive Disorder, respectively) are still fairly common even in
      adults declared "virally suppressed", with little to no detectable peripheral viral DNA/RNA.
      Prior studies have shown that over the lifetime, more than 50% of adults diagnosed with HIV
      will experience some degree of cognitive impairment as they age. Some of these changes may be
      due to cholinergic dysfunction. The acetylcholinergic receptor system is necessary for normal
      cognitive performance, and is active during working memory, executive functioning, attention,
      and learning tasks. It has been shown that as the human brain ages, cognitive ability begins
      to decline, and correlates with declining acetylcholinergic activity. The cholinergic theory
      of cognitive aging postulates that this loss of activity at cholinergic receptors with age is
      at least partly responsible for poorer cognitive performance in aging. I will use this model
      to examine the impact of HIV infection on cholinergic system functioning. This study will use
      a well-established anti-cholinergic drug challenge model to evaluate cognitive performance in
      domains of cognitive functioning relevant to cholinergic functioning. Under conditions of
      temporary muscarinic or nicotinic blockade, or a combination of both, I aim to explore the
      contribution of putative cholinergic receptor dysfunction to the observed symptoms of HAND. I
      also intend to determine whether age and HIV-status interact to produce an accelerated
      pattern of cholinergic cognitive aging that would indicate that older adults with HIV are at
      higher risk for more rapid cognitive aging than HIV-negative individuals. If successful, the
      outcome of this study would support the future exploration of novel pro-cholinergic
      medications to treat cognitive symptoms of HAND, which may improve quality of life for adults
      living with chronic HIV infection, as they survive into old age.
observational model: Case-Crossover
time perspective: Cross-Sectional
measure: Cognitive Outcome - Lower verbal memory score
time frame: 2 hours
description: Cognitive performance will be more significantly impaired by study medications in HIV-positive participants relative to HIV-negative participants, indicating impairment of cholinergic neurotransmitter system.
measure: Age and HIV-Status Interaction - Slower CRTreaction time
time frame: 2 hours
description: Older age and positive HIV status will interact to more significantly impair cognitive performance as measured by reaction time on the Choice Reaction Time task under the influence of study medications, than either variable alone.
arm group label: HIV-Positive
description: Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.
arm group label: HIV-Negative
description: Patients will be administered each of 4 possible treatments: high dose (5 mcg/kg) scopolamine, high dose (20 mg) mecamylamine, a low dose combination (2.5mcg/kg and 10 mg) of scopolamine and mecamylamine, or placebo.
intervention type: Drug
intervention name: Scopolamine Injectable Product
description: 2.5 or 5 mcg/kg of scopolamine via IV
arm group label: HIV-Negative
arm group label: HIV-Positive
intervention type: Drug
intervention name: Mecamylamine Pill
description: 10 or 20mg of mecamylamine orally
arm group label: HIV-Negative
arm group label: HIV-Positive
Blood samples collected from all participants for routine screening labs and APOE genotyping.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 35 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University Medical Center
investigator full name: Asante Kamkwalala
investigator title: Graduate Research Assistant
mesh term: AIDS Dementia Complex
mesh term: Aging, Premature
mesh term: Mecamylamine
mesh term: Scopolamine
mesh term: Butylscopolammonium Bromide
sharing ipd: No