<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/NCT03811951</url>
  </required_header>
  <id_info>
    <org_study_id>2017-1288</org_study_id>
    <nct_id>NCT03811951</nct_id>
  </id_info>
  <brief_title>Neuro Biomarkers of Smoking Behavior</brief_title>
  <official_title>Neurologic Biomarkers of Smoking Behavior</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Illinois at Chicago</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Illinois at Chicago</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>
      The purpose of this study is to evaluate cognition in smokers and nonsmokers. It involves&#xD;
      administration of intranasal insulin (Novolin R), an investigational medication followed by a&#xD;
      brief non-invasive cognitive test. All participants will receive both Novolin R and placebo&#xD;
      in two separate testing sessions.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This program of research focuses on identifying neurologic biomarkers of smoking behavior in&#xD;
      order to develop individualized smoking cessation aids. The intranasal insulin administered&#xD;
      is an investigational drug and has been granted IND status by the FDA (IND#129432). During&#xD;
      the times of drug effects, the investigators will evaluate a biomarker using computerized&#xD;
      tasks. Non-smokers and smokers will participate in two testing sessions where the biomarker&#xD;
      will be critically evaluated after administration of intranasal insulin and compared to the&#xD;
      cognitive processes elicited by placebo administration.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Different study initiation&#xD;
  </why_stopped>
  <start_date type="Actual">September 12, 2018</start_date>
  <completion_date type="Actual">September 27, 2019</completion_date>
  <primary_completion_date type="Actual">September 27, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>The University of Illinois Hospital and Health Sciences System Investigational Drug Service (IDS) randomizes treatment order to study subjects and prepares drug product and placebo. All other roles, including participant, investigator, and non-IDS study personnel are masked from treatment order.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Go/No-Go Accuracy</measure>
    <time_frame>From time of drug administration to 70 minutes following drug administration, up to 90 minutes</time_frame>
    <description>Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go).&#xD;
Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">4</enrollment>
  <condition>Smoking Cessation</condition>
  <arm_group>
    <arm_group_label>Smokers</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants receive both Novolin R (experimental drug) and 14% NaCl (Sodium Chloride) solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Non-Smokers</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants receive both Novolin R (experimental drug) and 14% NaCl solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Novolin R</intervention_name>
    <description>Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.</description>
    <arm_group_label>Non-Smokers</arm_group_label>
    <arm_group_label>Smokers</arm_group_label>
    <other_name>McKesson Corporation, Novo Nordisk</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 21-40 years&#xD;
&#xD;
          -  Smokers only: Begin smoking within 5 minutes of waking (verified by carbon monoxide&#xD;
             concentrations greater than 10 ppm).&#xD;
&#xD;
          -  Non-smokers only: No self-reported cigarette use in the past 1-year period.&#xD;
&#xD;
          -  Non-smokers only: Carbon monoxide concentration &lt; 6 ppm.&#xD;
&#xD;
          -  Normal vitals (blood pressure &lt; 120/80 mmHg; heart rate between 60 and 100 bpm, body&#xD;
             temperature &lt;37 °C)&#xD;
&#xD;
          -  Point-of-care (POC) blood glucose between 80 and 140 mg/dL&#xD;
&#xD;
          -  Body mass index between 18.5 and 30 kg/m2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Use of non-cigarette tobacco products, e-cigarettes, or smoking cessation treatment&#xD;
&#xD;
          -  Positive urine drug screen test&#xD;
&#xD;
          -  Current pregnancy (urine test-verified) or lactation, or a plan to become pregnant&#xD;
&#xD;
          -  Breath Alcohol Concentration &gt;0.00%&#xD;
&#xD;
          -  Shipley IQ (Intelligence Quotient) test &lt;80&#xD;
&#xD;
          -  Hyposmic or anosmic individuals (identifying less than 10 of 12 smells correctly)&#xD;
&#xD;
          -  Abnormal physical exam of the nares&#xD;
&#xD;
          -  Lifetime DSM-5 (Diagnostic and Statistical Manual of Mental Disorders-5) Axis 1&#xD;
             disorder (except anxiety and depression)&#xD;
&#xD;
          -  Current DSM-5 Axis depression or anxiety disorder&#xD;
&#xD;
          -  Prescription medications&#xD;
&#xD;
          -  Over-the-counter psychotropic medications&#xD;
&#xD;
          -  Use of any medications administered intranasally&#xD;
&#xD;
          -  Allergies to any ingredients in intranasal insulin or placebo&#xD;
&#xD;
          -  Braided hair that would cause noise in EEG recording&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ajna Hamidovic, PharmD, MS</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Illinois at Chicago</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Illinois Department of Pharmacy Practice</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60612</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Benowitz NL, Gourlay SG. Cardiovascular toxicity of nicotine: implications for nicotine replacement therapy. J Am Coll Cardiol. 1997 Jun;29(7):1422-31. doi: 10.1016/s0735-1097(97)00079-x.</citation>
    <PMID>9180099</PMID>
  </reference>
  <reference>
    <citation>de la Monte SM. Intranasal insulin therapy for cognitive impairment and neurodegeneration: current state of the art. Expert Opin Drug Deliv. 2013 Dec;10(12):1699-709. doi: 10.1517/17425247.2013.856877. Epub 2013 Nov 12.</citation>
    <PMID>24215447</PMID>
  </reference>
  <reference>
    <citation>Fehm HL, Perras B, Smolnik R, Kern W, Born J. Manipulating neuropeptidergic pathways in humans: a novel approach to neuropharmacology? Eur J Pharmacol. 2000 Sep 29;405(1-3):43-54. doi: 10.1016/s0014-2999(00)00540-9.</citation>
    <PMID>11033313</PMID>
  </reference>
  <reference>
    <citation>Franken IH, van Strien JW, Kuijpers I. Evidence for a deficit in the salience attribution to errors in smokers. Drug Alcohol Depend. 2010 Jan 15;106(2-3):181-5. doi: 10.1016/j.drugalcdep.2009.08.014. Epub 2009 Sep 24.</citation>
    <PMID>19781864</PMID>
  </reference>
  <reference>
    <citation>Hamidovic A, Khafaja M, Brandon V, Anderson J, Ray G, Allan AM, Burge MR. Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial. Mol Psychiatry. 2017 Oct;22(10):1413-1421. doi: 10.1038/mp.2016.234. Epub 2017 Feb 28.</citation>
    <PMID>28242873</PMID>
  </reference>
  <reference>
    <citation>Kern W, Born J, Schreiber H, Fehm HL. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999 Mar;48(3):557-63. doi: 10.2337/diabetes.48.3.557.</citation>
    <PMID>10078556</PMID>
  </reference>
  <reference>
    <citation>Luijten M, van Meel CS, Franken IH. Diminished error processing in smokers during smoking cue exposure. Pharmacol Biochem Behav. 2011 Jan;97(3):514-20. doi: 10.1016/j.pbb.2010.10.012. Epub 2010 Oct 31.</citation>
    <PMID>21047524</PMID>
  </reference>
  <reference>
    <citation>Nedelcovych MT, Gadiano AJ, Wu Y, Manning AA, Thomas AG, Khuder SS, Yoo SW, Xu J, McArthur JC, Haughey NJ, Volsky DJ, Rais R, Slusher BS. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. ACS Chem Neurosci. 2018 Apr 18;9(4):809-816. doi: 10.1021/acschemneuro.7b00434. Epub 2018 Jan 4.</citation>
    <PMID>29257872</PMID>
  </reference>
  <reference>
    <citation>Ott V, Benedict C, Schultes B, Born J, Hallschmid M. Intranasal administration of insulin to the brain impacts cognitive function and peripheral metabolism. Diabetes Obes Metab. 2012 Mar;14(3):214-21. doi: 10.1111/j.1463-1326.2011.01490.x. Epub 2011 Nov 16.</citation>
    <PMID>21883804</PMID>
  </reference>
  <reference>
    <citation>Rass O, Fridberg DJ, O'Donnell BF. Neural correlates of performance monitoring in daily and intermittent smokers. Clin Neurophysiol. 2014 Jul;125(7):1417-26. doi: 10.1016/j.clinph.2013.12.001. Epub 2013 Dec 11.</citation>
    <PMID>24380760</PMID>
  </reference>
  <reference>
    <citation>Reger MA, Craft S. Intranasal insulin administration: a method for dissociating central and peripheral effects of insulin. Drugs Today (Barc). 2006 Nov;42(11):729-39. doi: 10.1358/dot.2006.42.11.1007675.</citation>
    <PMID>17171192</PMID>
  </reference>
  <reference>
    <citation>Schmid V, Kullmann S, Gfrorer W, Hund V, Hallschmid M, Lipp HP, Haring HU, Preissl H, Fritsche A, Heni M. Safety of intranasal human insulin: A review. Diabetes Obes Metab. 2018 Jul;20(7):1563-1577. doi: 10.1111/dom.13279. Epub 2018 Apr 6.</citation>
    <PMID>29508509</PMID>
  </reference>
  <reference>
    <citation>Shemesh E, Rudich A, Harman-Boehm I, Cukierman-Yaffe T. Effect of intranasal insulin on cognitive function: a systematic review. J Clin Endocrinol Metab. 2012 Feb;97(2):366-76. doi: 10.1210/jc.2011-1802. Epub 2011 Dec 7.</citation>
    <PMID>22162476</PMID>
  </reference>
  <reference>
    <citation>Strachan MW. Insulin and cognitive function in humans: experimental data and therapeutic considerations. Biochem Soc Trans. 2005 Nov;33(Pt 5):1037-40. doi: 10.1042/BST20051037.</citation>
    <PMID>16246040</PMID>
  </reference>
  <reference>
    <citation>West R, Hajek P, Foulds J, Nilsson F, May S, Meadows A. A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. Psychopharmacology (Berl). 2000 Apr;149(3):198-202. doi: 10.1007/s002130000382.</citation>
    <PMID>10823399</PMID>
  </reference>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>November 9, 2018</study_first_submitted>
  <study_first_submitted_qc>January 17, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 22, 2019</study_first_posted>
  <results_first_submitted>November 19, 2020</results_first_submitted>
  <results_first_submitted_qc>March 1, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 2, 2021</results_first_posted>
  <last_update_submitted>March 1, 2021</last_update_submitted>
  <last_update_submitted_qc>March 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Illinois at Chicago</investigator_affiliation>
    <investigator_full_name>Ajna Hamidovic, PharmD, MS</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>Tobacco</keyword>
  <keyword>Cigarettes</keyword>
  <keyword>Nicotine</keyword>
  <keyword>Insulin</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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>November 8, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/51/NCT03811951/ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>January 15, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/51/NCT03811951/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Novolin R First, Then Placebo</title>
          <description>Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 1. Then, participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 2.</description>
        </group>
        <group group_id="P2">
          <title>Placebo First, Then Novolin R</title>
          <description>Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 1. Then, participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 2.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention (1 Day)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (1 Week)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Second Intervention (1 Day)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Novolin R First, Then Placebo</title>
          <description>Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 1. Then, participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 2.</description>
        </group>
        <group group_id="B2">
          <title>Placebo First, Then Novolin R</title>
          <description>Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in session 1. Then, participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in session 2.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
            <count group_id="B2" value="2"/>
            <count group_id="B3" value="4"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24" lower_limit="21" upper_limit="27"/>
                    <measurement group_id="B2" value="24.5" lower_limit="21" upper_limit="28"/>
                    <measurement group_id="B3" value="24.25" lower_limit="21" upper_limit="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>American Indian/Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown/do not want to specify</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Go/No-Go Accuracy</title>
        <description>Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go).&#xD;
Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.</description>
        <time_frame>From time of drug administration to 70 minutes following drug administration, up to 90 minutes</time_frame>
        <population>All the participants were non-smokers</population>
        <group_list>
          <group group_id="O1">
            <title>Smokers</title>
            <description>All participants receive both Novolin R (experimental drug) and 14% NaCl (Sodium Chloride) solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.&#xD;
Novolin R: Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.</description>
          </group>
          <group group_id="O2">
            <title>Non-Smokers</title>
            <description>All participants receive both Novolin R (experimental drug) and 14% NaCl solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.&#xD;
Novolin R: Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.</description>
          </group>
        </group_list>
        <measure>
          <title>Go/No-Go Accuracy</title>
          <description>Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go).&#xD;
Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.</description>
          <population>All the participants were non-smokers</population>
          <units>Milliseconds</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="4"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Run 1 (Insulin)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="70.771" spread="25.82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Run 2 (Placebo)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O2" value="67.693" spread="27.95"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>2 sessions, up to 2 days</time_frame>
      <desc>All-Cause Mortality and Serious Adverse Events were monitored/assessed, but none observed</desc>
      <group_list>
        <group group_id="E1">
          <title>Novolin R (First Intervention)</title>
          <description>Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in first session.</description>
        </group>
        <group group_id="E2">
          <title>Placebo (First Intervention)</title>
          <description>Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in first session.</description>
        </group>
        <group group_id="E3">
          <title>Placebo (Second Intervention)</title>
          <description>Participants received placebo intranasal spray every 3 minutes for the total of 6 sprays in second session.</description>
        </group>
        <group group_id="E4">
          <title>Novolin R (Second Intervention)</title>
          <description>Participants received active ingredients of intranasal insulin, Novolin R, every 3 minutes for the total of 6 sprays in second session.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Nasal Irritation</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Sweating</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Decreased sense of smell, but not total loss</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Partial anosmia (blunted)</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Stinginess</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Hunger</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Sinus Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Burning</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="2"/>
              </event>
              <event>
                <sub_title>Taste</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E4" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Ajna Hamidovic</name_or_title>
      <organization>University of Illinois at Chicago - College of Pharmacy</organization>
      <phone>312-355-1713</phone>
      <email>ahamidov@uic.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03811951
org study id: 2017-1288
nct id: NCT03811951
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to evaluate cognition in smokers and nonsmokers. It involves
      administration of intranasal insulin (Novolin R), an investigational medication followed by a
      brief non-invasive cognitive test. All participants will receive both Novolin R and placebo
      in two separate testing sessions.
This program of research focuses on identifying neurologic biomarkers of smoking behavior in
      order to develop individualized smoking cessation aids. The intranasal insulin administered
      is an investigational drug and has been granted IND status by the FDA (IND#129432). During
      the times of drug effects, the investigators will evaluate a biomarker using computerized
      tasks. Non-smokers and smokers will participate in two testing sessions where the biomarker
      will be critically evaluated after administration of intranasal insulin and compared to the
      cognitive processes elicited by placebo administration.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Diagnostic
masking: Double (Participant, Investigator)
masking description: The University of Illinois Hospital and Health Sciences System Investigational Drug Service (IDS) randomizes treatment order to study subjects and prepares drug product and placebo. All other roles, including participant, investigator, and non-IDS study personnel are masked from treatment order.
measure: Go/No-Go Accuracy
time frame: From time of drug administration to 70 minutes following drug administration, up to 90 minutes
description: Go/No-Go is used to measure a participants capacity for sustained attention and response control. The test requires a participant to perform an action given certain stimuli (e.g., press a button - Go) and inhibit that action under a different set of stimuli (e.g., not press that same button - No-Go).
Average of the 2 runs (run 1 - insulin; run 2 - placebo) were calculated for mean reaction time (+SEM) of smokers and non-smokers on no-go stimuli. The minimum reaction time was 23.08 ms and the maximum reaction time was 97.44 ms. The higher mean value represents slower the reaction time, and the lower mean value represents quicker the reaction time. The higher value means that participants have difficulties with inhibiting a prepotent response. The values do not represent a better or worse outcome.
arm group label: Smokers
arm group type: Experimental
description: All participants receive both Novolin R (experimental drug) and 14% NaCl (Sodium Chloride) solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.
arm group label: Non-Smokers
arm group type: Experimental
description: All participants receive both Novolin R (experimental drug) and 14% NaCl solution (placebo), to be administered in randomly assigned order on two separate testing sessions. During administration of either Novolin R or 14% NaCl, participants will receive 1 spray in each nostril every 3 minutes for a total of 6 sprays. The nasal spray bottle delivers 0.1 ml of liquid per spray. Since the concentration of insulin in Novolin R is 100 IU/mL, six sprays will deliver a 60 IU dose.
intervention type: Drug
intervention name: Novolin R
description: Novolin R is a sterile, clear, aqueous, and colorless solution that contains human insulin (rDNA origin) 100 units/mL, glycerol 16 mg/mL, metacresol 3 mg/mL, zinc chloride approximately 7 mcg/mL and water for injection. The pH (potential Hydrogen) is adjusted to 7.4. Hydrochloric acid 2N (concentration) or sodium hydroxide 2N may be added to adjust pH. Novolin R vials are latex-free. The drug substance is being purchased from McKesson.
arm group label: Non-Smokers
arm group label: Smokers
other name: McKesson Corporation, Novo Nordisk
criteria: 
gender: All
minimum age: 21 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ajna Hamidovic, PharmD, MS
role: Principal Investigator
affiliation: University of Illinois at Chicago
facility: 
country: United States
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PMID: 9180099
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PMID: 24215447
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PMID: 19781864
citation: Hamidovic A, Khafaja M, Brandon V, Anderson J, Ray G, Allan AM, Burge MR. Reduction of smoking urges with intranasal insulin: a randomized, crossover, placebo-controlled clinical trial. Mol Psychiatry. 2017 Oct;22(10):1413-1421. doi: 10.1038/mp.2016.234. Epub 2017 Feb 28.
PMID: 28242873
citation: Kern W, Born J, Schreiber H, Fehm HL. Central nervous system effects of intranasally administered insulin during euglycemia in men. Diabetes. 1999 Mar;48(3):557-63. doi: 10.2337/diabetes.48.3.557.
PMID: 10078556
citation: Luijten M, van Meel CS, Franken IH. Diminished error processing in smokers during smoking cue exposure. Pharmacol Biochem Behav. 2011 Jan;97(3):514-20. doi: 10.1016/j.pbb.2010.10.012. Epub 2010 Oct 31.
PMID: 21047524
citation: Nedelcovych MT, Gadiano AJ, Wu Y, Manning AA, Thomas AG, Khuder SS, Yoo SW, Xu J, McArthur JC, Haughey NJ, Volsky DJ, Rais R, Slusher BS. Pharmacokinetics of Intranasal versus Subcutaneous Insulin in the Mouse. ACS Chem Neurosci. 2018 Apr 18;9(4):809-816. doi: 10.1021/acschemneuro.7b00434. Epub 2018 Jan 4.
PMID: 29257872
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PMID: 21883804
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PMID: 24380760
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PMID: 17171192
citation: Schmid V, Kullmann S, Gfrorer W, Hund V, Hallschmid M, Lipp HP, Haring HU, Preissl H, Fritsche A, Heni M. Safety of intranasal human insulin: A review. Diabetes Obes Metab. 2018 Jul;20(7):1563-1577. doi: 10.1111/dom.13279. Epub 2018 Apr 6.
PMID: 29508509
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PMID: 22162476
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PMID: 16246040
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PMID: 10823399
responsible party type: Principal Investigator
investigator affiliation: University of Illinois at Chicago
investigator full name: Ajna Hamidovic, PharmD, MS
investigator title: Assistant Professor
mesh term: Insulin
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 