<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/NCT03281694</url>
  </required_header>
  <id_info>
    <org_study_id>HP-0009999</org_study_id>
    <nct_id>NCT03281694</nct_id>
  </id_info>
  <brief_title>The Use of AVL-3288 to Potentiate the Attention-Enhancing Effects of Low-Dose Nicotine</brief_title>
  <official_title>The Use of AVL-3288 to Potentiate the Attention-Enhancing Effects of Low-Dose Nicotine</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Maryland, Baltimore</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Maryland, Baltimore</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Single-center, randomized, double-blind, placebo-controlled, proof-of-principle study to&#xD;
      evaluate potential cognitive benefits of a single oral dose of AVL-3288 (3 mg) in the&#xD;
      presence and absence of transdermal nicotine (7 mg/24 hrs) in healthy non-smokers, while&#xD;
      monitoring the safety and tolerability of AVL-3288.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine have been shown to enhance&#xD;
      cognitive performance, especially functions in the attention domain. Efforts have been made&#xD;
      to develop similar compounds as therapeutic agents for disorders such as schizophrenia or&#xD;
      Alzheimer's disease. Over the last two decades, drug development has invested into novel&#xD;
      nAChR agonists. Effects have generally been in the expected direction, but tended to be of&#xD;
      small magnitude. A potential way of increasing the effect size ceiling is by co-administering&#xD;
      a nAChR positive allosteric modulator (PAM). PAMs generally do not activate the nAChR on&#xD;
      their own but bind to a second, modulatory site and facilitate agonist-induced responses. The&#xD;
      present study is aimed at testing the effects of AVL-3288, a PAM selective for the α7 nAChR&#xD;
      subtype that is thought to be of particular relevance for cognition in schizophrenia, on&#xD;
      cognitive task performance, and on nicotine-induced improvements in cognitive task&#xD;
      performance, in healthy adult non-smokers.&#xD;
&#xD;
      The aim of the present study is to provide the proof-of-principle that the&#xD;
      attention-enhancing effects of the prototypical nAChR agonist nicotine can be potentiated by&#xD;
      an α7 nAChR PAM (AVL-3288). Potentiation of nAChR agonist effects by PAMs have been shown in&#xD;
      preclinical behavioral assays. The availability of AVL-3288 as a safe pure nAChR PAM for&#xD;
      human research allows testing the hypothesis that nicotine and AVL-3288 will have additive or&#xD;
      synergistic effects, such that the attention-enhancing effects of nicotine and AVL-3288&#xD;
      combined will be greater than the effects of either drug alone.&#xD;
&#xD;
      AVL-3288 has shown preclinical efficacy in rat paradigms of attention and memory, including&#xD;
      models of cognitive dysfunction1-3. A human study in healthy adults reported no adverse&#xD;
      effects associated with AVL-3288, tested at doses of 3, 10, and 30 mg. Some of the&#xD;
      participants tested with 3 mg were smokers, some on nicotine replacement.&#xD;
&#xD;
      The present study will adopt a repeated measures design, in which a single group of 24&#xD;
      healthy non-smokers will complete 4 test sessions, in each of which they perform the same&#xD;
      three cognitive paradigms. In each session, a skin patch will be administered 5 hrs prior to&#xD;
      testing, and a solution (3 mL) will be administered by mouth 1 hr prior to testing. The skin&#xD;
      patch is either a 7 mg/24 hrs nicotine patch or a placebo patch. The solution either contains&#xD;
      AVL-3288 (3 mg) or is inactive diluent only. Over the 4 test sessions, each participant will&#xD;
      be tested with Placebo + Placebo, Nicotine + Placebo, Placebo + AVL-3288, and Nicotine +&#xD;
      AVL-3288, in a 2x2 factorial design. The sequence of test conditions will be only known to&#xD;
      the statistician and pharmacist and counterbalanced across subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Drug supplier did not come through.&#xD;
  </why_stopped>
  <start_date type="Anticipated">May 2018</start_date>
  <completion_date type="Anticipated">February 2019</completion_date>
  <primary_completion_date type="Anticipated">February 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>The study will be double-blind. Only the statistician performing randomization and the dispensing pharmacist will know the sequence of test conditions.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Spatial Attentional Resource Allocation Task reaction time</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>average reaction time of trials with a signal detection response</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Spatial Attentional Resource Allocation Task omission errors</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>percentage of trials on which no response was registered</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rapid Visual Information Processing Task signal detection</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>signal detection index based on hit rate and false alarm rate</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Rapid Visual Information Processing Task reaction time</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>average reaction time on trials with a correct response</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change Detection Task accuracy</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>% of correct responses</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change Detection reaction time</measure>
    <time_frame>5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day</time_frame>
    <description>average reaction time across trials</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Vital signs: blood pressure</measure>
    <time_frame>hourly for 8 hours on each test day</time_frame>
    <description>mm Hg</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Vital signs: heart rate</measure>
    <time_frame>hourly for 8 hours on each test day</time_frame>
    <description>beats per minute</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ECG</measure>
    <time_frame>Before and 4 hours after ingestion of oral solution on each test day</time_frame>
    <description>QTc interval</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Cognitive Change</condition>
  <arm_group>
    <arm_group_label>Nicotine - AVL-3288 Interaction Study</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Over four different test days, all participants will be tested with Placebo, Nicotine, AVL-3288, and Nicotine + AVL-3288, in a counterbalanced sequence.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>placebo skin patch and placebo oral solution</description>
    <arm_group_label>Nicotine - AVL-3288 Interaction Study</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nicotine</intervention_name>
    <description>nicotine skin patch (7 mg/24 hrs) and placebo oral solution</description>
    <arm_group_label>Nicotine - AVL-3288 Interaction Study</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AVL-3288</intervention_name>
    <description>placebo skin patch and AVL-3288 oral solution (3 mg)</description>
    <arm_group_label>Nicotine - AVL-3288 Interaction Study</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nicotine + AVL-3288</intervention_name>
    <description>nicotine skin patch (7 mg/24 hrs) and AVL-3288 oral solution (3 mg)</description>
    <arm_group_label>Nicotine - AVL-3288 Interaction Study</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Aged 21-50 years.&#xD;
&#xD;
          -  Male or female willing to use qualified methods of contraception for the study&#xD;
             duration and up to 2 months after its end. Qualified methods are: intrauterine device,&#xD;
             condoms, oral contraceptives, surgical sterilization of the subject or the partner at&#xD;
             least one year in advance, or postmenopausal status of the female defined as at least&#xD;
             two years without menstruation.&#xD;
&#xD;
          -  No exposure to any nicotine-containing product in the last year.&#xD;
&#xD;
          -  Smoked no more that 40 cigarettes, cigars or cigarillos in lifetime.&#xD;
&#xD;
          -  Normal or corrected to normal vision (at least 20/80).&#xD;
&#xD;
          -  Body weight 110-220 lbs.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding.&#xD;
&#xD;
          -  DSM Axis I mood, anxiety or psychotic disorder.&#xD;
&#xD;
          -  Drug or alcohol abuse or dependence currently or in the last 2 years.&#xD;
&#xD;
          -  Cardiovascular or cerebrovascular disease, such as history of myocardial infarction&#xD;
             and ischemia, heart failure, angina, stroke, severe arrhythmias, or EKG abnormalities&#xD;
             (see below).&#xD;
&#xD;
          -  Uncontrolled hypertension (resting systolic BP &gt;150 or diastolic &gt;95 mm Hg).&#xD;
&#xD;
          -  Hypotension (resting systolic BP below 90 or diastolic below 60).&#xD;
&#xD;
          -  Significant kidney or liver impairment.&#xD;
&#xD;
          -  Moderate to severe asthma.&#xD;
&#xD;
          -  Type I diabetes.&#xD;
&#xD;
          -  Gastrointestinal illness.&#xD;
&#xD;
          -  Use of any prescription or over-the-counter medication except birth control or&#xD;
             non-steroidal antiinflammatory drugs on an as-needed basis.&#xD;
&#xD;
          -  History of or current neurological illnesses, such as stroke, seizure disorders,&#xD;
             neurodegenerative diseases, or organic brain syndrome.&#xD;
&#xD;
          -  Learning disability, mental retardation, or any other condition that impedes&#xD;
             cognition.&#xD;
&#xD;
          -  Any surgeries requiring full anesthesia scheduled within 2 weeks of any of the study&#xD;
             test sessions.&#xD;
&#xD;
          -  Inability to perform the Rapid Visual Information Processing Task.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>September 2017</verification_date>
  <study_first_submitted>September 6, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 13, 2017</study_first_posted>
  <last_update_submitted>September 11, 2019</last_update_submitted>
  <last_update_submitted_qc>September 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">September 13, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Maryland, Baltimore</investigator_affiliation>
    <investigator_full_name>Robert Buchanan</investigator_full_name>
    <investigator_title>Professor, Director Maryland Psychiatric Research Center</investigator_title>
  </responsible_party>
  <keyword>nicotine</keyword>
  <keyword>positive allosteric modulator</keyword>
  <keyword>attention</keyword>
  <keyword>cognition</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Nicotine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Study data will be made available, in de-identified form, to Anvyl LLC (Irvine, CA).</ipd_description>
  </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/NCT03281694
org study id: HP-0009999
nct id: NCT03281694
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Single-center, randomized, double-blind, placebo-controlled, proof-of-principle study to
      evaluate potential cognitive benefits of a single oral dose of AVL-3288 (3 mg) in the
      presence and absence of transdermal nicotine (7 mg/24 hrs) in healthy non-smokers, while
      monitoring the safety and tolerability of AVL-3288.
Nicotinic acetylcholine receptor (nAChR) agonists such as nicotine have been shown to enhance
      cognitive performance, especially functions in the attention domain. Efforts have been made
      to develop similar compounds as therapeutic agents for disorders such as schizophrenia or
      Alzheimer's disease. Over the last two decades, drug development has invested into novel
      nAChR agonists. Effects have generally been in the expected direction, but tended to be of
      small magnitude. A potential way of increasing the effect size ceiling is by co-administering
      a nAChR positive allosteric modulator (PAM). PAMs generally do not activate the nAChR on
      their own but bind to a second, modulatory site and facilitate agonist-induced responses. The
      present study is aimed at testing the effects of AVL-3288, a PAM selective for the α7 nAChR
      subtype that is thought to be of particular relevance for cognition in schizophrenia, on
      cognitive task performance, and on nicotine-induced improvements in cognitive task
      performance, in healthy adult non-smokers.

      The aim of the present study is to provide the proof-of-principle that the
      attention-enhancing effects of the prototypical nAChR agonist nicotine can be potentiated by
      an α7 nAChR PAM (AVL-3288). Potentiation of nAChR agonist effects by PAMs have been shown in
      preclinical behavioral assays. The availability of AVL-3288 as a safe pure nAChR PAM for
      human research allows testing the hypothesis that nicotine and AVL-3288 will have additive or
      synergistic effects, such that the attention-enhancing effects of nicotine and AVL-3288
      combined will be greater than the effects of either drug alone.

      AVL-3288 has shown preclinical efficacy in rat paradigms of attention and memory, including
      models of cognitive dysfunction1-3. A human study in healthy adults reported no adverse
      effects associated with AVL-3288, tested at doses of 3, 10, and 30 mg. Some of the
      participants tested with 3 mg were smokers, some on nicotine replacement.

      The present study will adopt a repeated measures design, in which a single group of 24
      healthy non-smokers will complete 4 test sessions, in each of which they perform the same
      three cognitive paradigms. In each session, a skin patch will be administered 5 hrs prior to
      testing, and a solution (3 mL) will be administered by mouth 1 hr prior to testing. The skin
      patch is either a 7 mg/24 hrs nicotine patch or a placebo patch. The solution either contains
      AVL-3288 (3 mg) or is inactive diluent only. Over the 4 test sessions, each participant will
      be tested with Placebo + Placebo, Nicotine + Placebo, Placebo + AVL-3288, and Nicotine +
      AVL-3288, in a 2x2 factorial design. The sequence of test conditions will be only known to
      the statistician and pharmacist and counterbalanced across subjects.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
masking description: The study will be double-blind. Only the statistician performing randomization and the dispensing pharmacist will know the sequence of test conditions.
measure: Spatial Attentional Resource Allocation Task reaction time
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: average reaction time of trials with a signal detection response
measure: Spatial Attentional Resource Allocation Task omission errors
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: percentage of trials on which no response was registered
measure: Rapid Visual Information Processing Task signal detection
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: signal detection index based on hit rate and false alarm rate
measure: Rapid Visual Information Processing Task reaction time
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: average reaction time on trials with a correct response
measure: Change Detection Task accuracy
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: % of correct responses
measure: Change Detection reaction time
time frame: 5 hrs after patch application (=1 hr after ingestion of oral solution) on each test day
description: average reaction time across trials
measure: Vital signs: blood pressure
time frame: hourly for 8 hours on each test day
description: mm Hg
measure: Vital signs: heart rate
time frame: hourly for 8 hours on each test day
description: beats per minute
measure: ECG
time frame: Before and 4 hours after ingestion of oral solution on each test day
description: QTc interval
arm group label: Nicotine - AVL-3288 Interaction Study
arm group type: Other
description: Over four different test days, all participants will be tested with Placebo, Nicotine, AVL-3288, and Nicotine + AVL-3288, in a counterbalanced sequence.
intervention type: Drug
intervention name: Placebo
description: placebo skin patch and placebo oral solution
arm group label: Nicotine - AVL-3288 Interaction Study
intervention type: Drug
intervention name: Nicotine
description: nicotine skin patch (7 mg/24 hrs) and placebo oral solution
arm group label: Nicotine - AVL-3288 Interaction Study
intervention type: Drug
intervention name: AVL-3288
description: placebo skin patch and AVL-3288 oral solution (3 mg)
arm group label: Nicotine - AVL-3288 Interaction Study
intervention type: Drug
intervention name: Nicotine + AVL-3288
description: nicotine skin patch (7 mg/24 hrs) and AVL-3288 oral solution (3 mg)
arm group label: Nicotine - AVL-3288 Interaction Study
criteria: 
gender: All
minimum age: 21 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Principal Investigator
investigator affiliation: University of Maryland, Baltimore
investigator full name: Robert Buchanan
investigator title: Professor, Director Maryland Psychiatric Research Center
mesh term: Nicotine
sharing ipd: Yes
ipd description: Study data will be made available, in de-identified form, to Anvyl LLC (Irvine, CA).