<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/NCT02988401</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00095554</org_study_id>
    <nct_id>NCT02988401</nct_id>
  </id_info>
  <brief_title>Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis</brief_title>
  <official_title>Intranasal Insulin for Improving Cognitive Function in Multiple Sclerosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Johns Hopkins University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate if giving insulin that is administered in the nostrils (intranasal)&#xD;
      is safe and tolerable for people with multiple sclerosis (MS). It is also being done to&#xD;
      evaluate if intranasal insulin improves cognitive function in people with MS and to evaluate&#xD;
      how it might be working.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic,&#xD;
      central nervous system (CNS) disease characterized by inflammation, demyelination, and&#xD;
      neurodegeneration. One of the most devastating symptoms of this disease is impaired cognitive&#xD;
      function, which is common and present in over 60% of individuals with MS. MS-related&#xD;
      cognitive impairment is associated with lowered quality of life and reduced functional&#xD;
      capacity, including loss of employment, impaired social relationships, compromised driving&#xD;
      safety, and poor adherence to treatment. Impaired cognitive functioning has been observed&#xD;
      early in the disease, sometimes even before diagnosis, and cognitive function has been shown&#xD;
      to decline longitudinally, both over the short- and long-term. Several cognitive domains are&#xD;
      impacted in people with MS, including attention, memory, executive functioning, and&#xD;
      especially processing speed.&#xD;
&#xD;
      To date, multiple pharmacologic interventions have been assessed with disappointing results.&#xD;
      There was no significant difference between treatment and placebo for cognition in randomized&#xD;
      control trials of donepezil, aminopyridines, gingko biloba, and memantine. Psychostimulants&#xD;
      demonstrated some efficacy, but only in secondary outcome measures. Behavioral interventions&#xD;
      show promise but are understudied. Furthermore, cognitive rehabilitation is often time&#xD;
      consuming, costly, and not universally available. Hence, there is an urgent need to identify&#xD;
      or develop novel therapies that can help improve cognitive function in MS.&#xD;
&#xD;
      Intranasal insulin is extremely safe and tolerable in other populations, allowing for&#xD;
      concentrated delivery to the nervous system. An intranasal delivery system provides a&#xD;
      non-invasive way to bypass the blood-brain barrier and allow rapid delivery of a medication&#xD;
      to the CNS via the olfactory and trigeminal perivascular channels.The main advantage of the&#xD;
      delivery system is reducing systemic side effects via limiting a medication's exposure to&#xD;
      peripheral organs and tissues.&#xD;
&#xD;
      Insulin administration has been shown to improve memory and learning in healthy people and in&#xD;
      those with neurodegenerative diseases. Intranasal insulin has been shown to have&#xD;
      neuroprotective and restorative effects in several human clinical trials. Overall, findings&#xD;
      suggest that intranasal insulin not only affects cognitive function acutely, but that over&#xD;
      time, there may be associated structural changes that lead to a more permanent treatment&#xD;
      benefit. Cognitive dysfunction is very common in MS and can be devastating, therefore a&#xD;
      treatment intervention (i.e., intranasal insulin) can help both acutely and longitudinally.&#xD;
&#xD;
      The primary aim of this study is to assess the safety and tolerability of intranasal insulin&#xD;
      in people with MS. The secondary aim is to evaluate if intranasal insulin improves learning&#xD;
      and memory in people with MS. The third aim is to evaluate the impact of intranasal insulin&#xD;
      on measures of oxidative stress, axonal injury, cellular stress, and energy metabolism in MS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 1, 2017</start_date>
  <completion_date type="Actual">December 17, 2021</completion_date>
  <primary_completion_date type="Actual">December 17, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Change in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>This task will be performed at five study visits. The SDMT is one of the most commonly used tests to assess processing speed in the MS population and is included in the Minimal Assessment of Cognitive Function in MS (MACFIMS). Higher scores reflect a better outcome (range 0 to 110). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the SDMTs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events Leading to Study Discontinuation</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention. We report overall adverse events in the relevant section. Here, we report adverse events that led to study discontinuation.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Fingerstick Blood Glucose (Subset)</measure>
    <time_frame>At the baseline visit, monitored twice within the 90 minutes following the first dose administration of study drug</time_frame>
    <description>Fingerstick blood glucose levels were monitored twice within the 90 minutes following the first dose administration of study drug for the first 15 participants.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Cognitive Function as Assessed by the Controlled Oral Word Association Test (COWAT)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>This test measures phonemic fluency. The test scores the number of words a participant can provide that begin with a specified letter within one minute, such that scores range from zero (worst) to an infinite number (better). Total score is sum of three 60-second trials. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the COWAT scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test, Second Edition (CVLT-II)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>This is a verbal learning and memory test. Scores range from zero to 16; a higher number is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the CVLT-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Cognitive Function as Assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>This is a visual, nonverbal test of learning and memory. Scores range from zero to 12; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BVMT-R delayed recall scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Cognitive Function as Assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills. Scores range from zero to 60; higher is better. Herein we present 3-second PASAT results (&quot;PASAT-3&quot;). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include PASAT-3 scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Cognitive Function as Assessed by the Judgement of Line Orientation Test (JLO)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space. Scores range from zero to 30; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include JLO data acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change From Baseline in Cognitive Function as Assessed by the Delis-Kaplan Executive Function System Sorting Test</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>This test measures executive functioning, concept formation, and cognitive flexibility. Scores range from zero to 16; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include DKEFS correct sort scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Assess Depression Severity, as Measured by the Beck Depression Inventory-II (BDI-II)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression. Scores range from zero to 63; higher scores indicate greater depression. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BDI-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the scores.</description>
  </other_outcome>
  <other_outcome>
    <measure>Evaluation of Impact of Study Products on Health Related Quality of Life Using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>FAMS is a self-reported health-related quality-of-life instrument for people with multiple sclerosis. Subjects rate six quality-of-life domains: Mobility, Symptoms, Emotional well-being, General contentment, Thinking/fatigue, and Family/social well-being. Scores range from zero to 176; higher scores indicate better health-related quality of life. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the FAMS scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </other_outcome>
  <other_outcome>
    <measure>Evaluation of How Overall Sleep Quality Impacts People With MS Using a Sleep Questionnaire (Pittsburgh Sleep Quality Index)</measure>
    <time_frame>Up to week 24 visit</time_frame>
    <description>The sleep questionnaire asks subjects to report various aspects related to their sleep routine. Scores range from zero to 21; higher score indicates worse sleep quality. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the PSQIs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
  </other_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">105</enrollment>
  <condition>Multiple Sclerosis, Relapsing-Remitting</condition>
  <condition>Multiple Sclerosis, Secondary Progressive</condition>
  <condition>Multiple Sclerosis, Primary Progressive</condition>
  <arm_group>
    <arm_group_label>Intranasal insulin 20 international units</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intranasal insulin 10 international units</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Intranasal saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Insulin</intervention_name>
    <description>All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
    <arm_group_label>Intranasal insulin 10 international units</arm_group_label>
    <arm_group_label>Intranasal insulin 20 international units</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo (Sterile diluent)</intervention_name>
    <description>All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
    <arm_group_label>Intranasal saline</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Meets 2010 criteria for MS&#xD;
&#xD;
          -  No relapse in past 3 months&#xD;
&#xD;
          -  At least mild cognitive impairment (based off of SDMT/PST score)&#xD;
&#xD;
          -  Capacity to learn and self-administer intranasal insulin/placebo, or presence of a&#xD;
             caregiver with such capacity who is willing to do it for the duration of the trial&#xD;
&#xD;
          -  Untreated/on the same MS therapy for at least 6 months, with no anticipated change in&#xD;
             the next year&#xD;
&#xD;
          -  Willing to prevent pregnancy during study if female of childbearing potential&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current, active major depression&#xD;
&#xD;
          -  No tricyclic antidepressant or anticonvulsant (except carbamazepine, pregabalin or&#xD;
             gabapentin) use within 6 weeks of screening; if on oxybutynin or tolterodine, on&#xD;
             stable dose for &gt; 6 months without plans for changing dose in next year&#xD;
&#xD;
          -  If taking selective serotonin (± norepinephrine) reuptake inhibitors, pregabalin,&#xD;
             gabapentin, sympathomimetic, monoamine oxidase inhibitor, antipsychotic, amantadine,&#xD;
             cholinesterase inhibitor, memantine, modafanil, armodafinil, or evening short-acting&#xD;
             benzodiazepines, on stable dose for 6 weeks or greater&#xD;
&#xD;
          -  Pregnant or nursing&#xD;
&#xD;
          -  THC; illicit drug or alcohol abuse in past 3 months&#xD;
&#xD;
          -  History of diabetes mellitus or insulin resistance&#xD;
&#xD;
          -  Active liver disease, stage IV/V kidney disease or severe metabolic derangements&#xD;
&#xD;
          -  CNS disorder other than MS or headache&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ellen Mowry, MD, MCR</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Scott Newsome, DO</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins University School of Medicine</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, Weinstock-Guttman B. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006 Jul;12(4):549-58. doi: 10.1017/s1355617706060723.</citation>
    <PMID>16981607</PMID>
  </reference>
  <reference>
    <citation>DeLuca J. What we know about cognitive changes in multiple sclerosis. In: LaRocca N, Kalb R, eds. Multiple Sclerosis: Understanding the Cognitive Challenges. New York: Demos Health; 2006: 17-40.</citation>
  </reference>
  <reference>
    <citation>Rao S. Cognitive Function in Patients with Multiple Sclerosis: Impairment and Treatment. IJMSC 2004;1:9-22.</citation>
  </reference>
  <reference>
    <citation>Ruet A, Deloire M, Hamel D, Ouallet JC, Petry K, Brochet B. Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study. J Neurol. 2013 Mar;260(3):776-84. doi: 10.1007/s00415-012-6705-1. Epub 2012 Oct 19.</citation>
    <PMID>23081755</PMID>
  </reference>
  <reference>
    <citation>Strober LB, Christodoulou C, Benedict RH, Westervelt HJ, Melville P, Scherl WF, Weinstock-Guttman B, Rizvi S, Goodman AD, Krupp LB. Unemployment in multiple sclerosis: the contribution of personality and disease. Mult Scler. 2012 May;18(5):647-53. doi: 10.1177/1352458511426735. Epub 2011 Dec 19.</citation>
    <PMID>22183935</PMID>
  </reference>
  <reference>
    <citation>Morrow SA, Drake A, Zivadinov R, Munschauer F, Weinstock-Guttman B, Benedict RH. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010 Oct;24(7):1131-45. doi: 10.1080/13854046.2010.511272. Epub 2010 Sep 8.</citation>
    <PMID>20830649</PMID>
  </reference>
  <reference>
    <citation>Schultheis MT, Weisser V, Ang J, Elovic E, Nead R, Sestito N, Fleksher C, Millis SR. Examining the relationship between cognition and driving performance in multiple sclerosis. Arch Phys Med Rehabil. 2010 Mar;91(3):465-73. doi: 10.1016/j.apmr.2009.09.026.</citation>
    <PMID>20298841</PMID>
  </reference>
  <reference>
    <citation>Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010 Feb 4;4:1-9. doi: 10.2147/ppa.s8230.</citation>
    <PMID>20165593</PMID>
  </reference>
  <reference>
    <citation>Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology. 1991 May;41(5):692-6. doi: 10.1212/wnl.41.5.692.</citation>
    <PMID>1823781</PMID>
  </reference>
  <reference>
    <citation>Amato MP, Razzolini L, Goretti B, Stromillo ML, Rossi F, Giorgio A, Hakiki B, Giannini M, Pasto L, Portaccio E, De Stefano N. Cognitive reserve and cortical atrophy in multiple sclerosis: a longitudinal study. Neurology. 2013 May 7;80(19):1728-33. doi: 10.1212/WNL.0b013e3182918c6f. Epub 2013 Apr 10.</citation>
    <PMID>23576622</PMID>
  </reference>
  <reference>
    <citation>Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001 Oct;58(10):1602-6. doi: 10.1001/archneur.58.10.1602.</citation>
    <PMID>11594918</PMID>
  </reference>
  <reference>
    <citation>Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler. 2013 Nov;19(13):1765-72. doi: 10.1177/1352458513485981. Epub 2013 May 7.</citation>
    <PMID>23652214</PMID>
  </reference>
  <reference>
    <citation>DeLuca J, Barbieri-Berger S, Johnson SK. The nature of memory impairments in multiple sclerosis: acquisition versus retrieval. J Clin Exp Neuropsychol. 1994 Apr;16(2):183-9. doi: 10.1080/01688639408402629.</citation>
    <PMID>8021305</PMID>
  </reference>
  <reference>
    <citation>DeLuca J, Gaudino EA, Diamond BJ, Christodoulou C, Engel RA. Acquisition and storage deficits in multiple sclerosis. J Clin Exp Neuropsychol. 1998 Jun;20(3):376-90. doi: 10.1076/jcen.20.3.376.819.</citation>
    <PMID>9845164</PMID>
  </reference>
  <reference>
    <citation>Thornton AE, Raz N, Tucke KA. Memory in multiple sclerosis: contextual encoding deficits. J Int Neuropsychol Soc. 2002 Mar;8(3):395-409. doi: 10.1017/s1355617702813200.</citation>
    <PMID>11939698</PMID>
  </reference>
  <reference>
    <citation>DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol. 2004 Jun;26(4):550-62. doi: 10.1080/13803390490496641.</citation>
    <PMID>15512942</PMID>
  </reference>
  <reference>
    <citation>Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):661-3. doi: 10.1136/jnnp.67.5.661.</citation>
    <PMID>10519876</PMID>
  </reference>
  <reference>
    <citation>Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, He D, Benedict RH, Goodman A, Rizvi S, Schwid SR, Weinstock-Guttman B, Westervelt HJ, Wishart H. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011 Apr 26;76(17):1500-7. doi: 10.1212/WNL.0b013e318218107a.</citation>
    <PMID>21519001</PMID>
  </reference>
  <reference>
    <citation>Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev. 2001;(4):CD001330. doi: 10.1002/14651858.CD001330.</citation>
    <PMID>11687106</PMID>
  </reference>
  <reference>
    <citation>Lovera JF, Kim E, Heriza E, Fitzpatrick M, Hunziker J, Turner AP, Adams J, Stover T, Sangeorzan A, Sloan A, Howieson D, Wild K, Haselkorn J, Bourdette D. Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial. Neurology. 2012 Sep 18;79(12):1278-84. doi: 10.1212/WNL.0b013e31826aac60. Epub 2012 Sep 5.</citation>
    <PMID>22955125</PMID>
  </reference>
  <reference>
    <citation>Lovera JF, Frohman E, Brown TR, Bandari D, Nguyen L, Yadav V, Stuve O, Karman J, Bogardus K, Heimburger G, Cua L, Remingon G, Fowler J, Monahan T, Kilcup S, Courtney Y, McAleenan J, Butler K, Wild K, Whitham R, Bourdette D. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Jun;16(6):715-23. doi: 10.1177/1352458510367662. Epub 2010 May 18.</citation>
    <PMID>20483885</PMID>
  </reference>
  <reference>
    <citation>Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH. The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial. J Neurol. 2009 Jul;256(7):1095-102. doi: 10.1007/s00415-009-5074-x. Epub 2009 Mar 5.</citation>
    <PMID>19263186</PMID>
  </reference>
  <reference>
    <citation>Mitolo M, Venneri A, Wilkinson ID, Sharrack B. Cognitive rehabilitation in multiple sclerosis: A systematic review. J Neurol Sci. 2015 Jul 15;354(1-2):1-9. doi: 10.1016/j.jns.2015.05.004. Epub 2015 May 9.</citation>
    <PMID>25998261</PMID>
  </reference>
  <reference>
    <citation>Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.</citation>
    <PMID>21911655</PMID>
  </reference>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 7, 2016</study_first_submitted>
  <study_first_submitted_qc>December 7, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 9, 2016</study_first_posted>
  <results_first_submitted>December 16, 2022</results_first_submitted>
  <results_first_submitted_qc>February 10, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">March 10, 2023</results_first_posted>
  <last_update_submitted>February 10, 2023</last_update_submitted>
  <last_update_submitted_qc>February 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Multiple Sclerosis</mesh_term>
    <mesh_term>Multiple Sclerosis, Relapsing-Remitting</mesh_term>
    <mesh_term>Multiple Sclerosis, Chronic Progressive</mesh_term>
    <mesh_term>Sclerosis</mesh_term>
  </condition_browse>
  <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>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>November 20, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT02988401/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 9, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT02988401/SAP_001.pdf</document_url>
    </provided_document>
    <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>July 17, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT02988401/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Intranasal Insulin 20 International Units</title>
          <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="P2">
          <title>Intranasal Insulin 10 International Units</title>
          <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="P3">
          <title>Placebo</title>
          <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="37"/>
                <participants group_id="P2" count="33"/>
                <participants group_id="P3" count="35"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="24"/>
                <participants group_id="P2" count="17"/>
                <participants group_id="P3" count="28"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="13"/>
                <participants group_id="P2" count="16"/>
                <participants group_id="P3" count="7"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Intranasal Insulin 20 International Units</title>
          <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="B2">
          <title>Intranasal Insulin 10 International Units</title>
          <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="B3">
          <title>Placebo</title>
          <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="B4">
          <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="37"/>
            <count group_id="B2" value="33"/>
            <count group_id="B3" value="35"/>
            <count group_id="B4" value="105"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="53.5" spread="10.1"/>
                    <measurement group_id="B2" value="54.4" spread="9.2"/>
                    <measurement group_id="B3" value="49.4" spread="9.2"/>
                    <measurement group_id="B4" value="52.4" spread="9.7"/>
                  </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="20"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="22"/>
                    <measurement group_id="B4" value="65"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="13"/>
                    <measurement group_id="B4" value="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="24"/>
                    <measurement group_id="B4" value="74"/>
                  </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 group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                    <measurement group_id="B2" value="33"/>
                    <measurement group_id="B3" value="35"/>
                    <measurement group_id="B4" value="105"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT)</title>
        <description>This task will be performed at five study visits. The SDMT is one of the most commonly used tests to assess processing speed in the MS population and is included in the Minimal Assessment of Cognitive Function in MS (MACFIMS). Higher scores reflect a better outcome (range 0 to 110). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the SDMTs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Individuals with pre-treatment SDMT were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT)</title>
          <description>This task will be performed at five study visits. The SDMT is one of the most commonly used tests to assess processing speed in the MS population and is included in the Minimal Assessment of Cognitive Function in MS (MACFIMS). Higher scores reflect a better outcome (range 0 to 110). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the SDMTs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
          <population>Individuals with pre-treatment SDMT were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="32"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.145" lower_limit="0.000" upper_limit="0.290"/>
                    <measurement group_id="O2" value="0.207" lower_limit="0.033" upper_limit="0.381"/>
                    <measurement group_id="O3" value="0.163" lower_limit="0.029" upper_limit="0.297"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events Leading to Study Discontinuation</title>
        <description>An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention. We report overall adverse events in the relevant section. Here, we report adverse events that led to study discontinuation.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events Leading to Study Discontinuation</title>
          <description>An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention. We report overall adverse events in the relevant section. Here, we report adverse events that led to study discontinuation.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="37"/>
                <count group_id="O2" value="33"/>
                <count group_id="O3" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Fingerstick Blood Glucose (Subset)</title>
        <description>Fingerstick blood glucose levels were monitored twice within the 90 minutes following the first dose administration of study drug for the first 15 participants.</description>
        <time_frame>At the baseline visit, monitored twice within the 90 minutes following the first dose administration of study drug</time_frame>
        <population>The first 15 participants were included in this safety substudy. One placebo participant was missing the second measurement.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Fingerstick Blood Glucose (Subset)</title>
          <description>Fingerstick blood glucose levels were monitored twice within the 90 minutes following the first dose administration of study drug for the first 15 participants.</description>
          <population>The first 15 participants were included in this safety substudy. One placebo participant was missing the second measurement.</population>
          <units>mg/dL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="5"/>
                <count group_id="O2" value="5"/>
                <count group_id="O3" value="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>First timepoint</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="97.8" spread="13.4"/>
                    <measurement group_id="O2" value="95.8" spread="15.5"/>
                    <measurement group_id="O3" value="90.0" spread="18.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Second timepoint</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                    <count group_id="O2" value="5"/>
                    <count group_id="O3" value="4"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="88.4" spread="8.8"/>
                    <measurement group_id="O2" value="92.2" spread="15.5"/>
                    <measurement group_id="O3" value="87.8" spread="11.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Cognitive Function as Assessed by the Controlled Oral Word Association Test (COWAT)</title>
        <description>This test measures phonemic fluency. The test scores the number of words a participant can provide that begin with a specified letter within one minute, such that scores range from zero (worst) to an infinite number (better). Total score is sum of three 60-second trials. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the COWAT scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Cognitive Function as Assessed by the Controlled Oral Word Association Test (COWAT)</title>
          <description>This test measures phonemic fluency. The test scores the number of words a participant can provide that begin with a specified letter within one minute, such that scores range from zero (worst) to an infinite number (better). Total score is sum of three 60-second trials. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the COWAT scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="37"/>
                <count group_id="O2" value="31"/>
                <count group_id="O3" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.090" lower_limit="-0.112" upper_limit="0.292"/>
                    <measurement group_id="O2" value="0.070" lower_limit="-0.162" upper_limit="0.303"/>
                    <measurement group_id="O3" value="0.021" lower_limit="-0.174" upper_limit="0.216"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test, Second Edition (CVLT-II)</title>
        <description>This is a verbal learning and memory test. Scores range from zero to 16; a higher number is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the CVLT-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test, Second Edition (CVLT-II)</title>
          <description>This is a verbal learning and memory test. Scores range from zero to 16; a higher number is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the CVLT-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="31"/>
                <count group_id="O3" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.082" lower_limit="0.015" upper_limit="0.149"/>
                    <measurement group_id="O2" value="0.021" lower_limit="-0.057" upper_limit="0.100"/>
                    <measurement group_id="O3" value="0.020" lower_limit="-0.043" upper_limit="0.082"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Cognitive Function as Assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall</title>
        <description>This is a visual, nonverbal test of learning and memory. Scores range from zero to 12; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BVMT-R delayed recall scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Cognitive Function as Assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall</title>
          <description>This is a visual, nonverbal test of learning and memory. Scores range from zero to 12; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BVMT-R delayed recall scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="29"/>
                <count group_id="O3" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.027" lower_limit="-0.020" upper_limit="0.074"/>
                    <measurement group_id="O2" value="0.059" lower_limit="0.006" upper_limit="0.113"/>
                    <measurement group_id="O3" value="0.030" lower_limit="-0.015" upper_limit="0.075"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Cognitive Function as Assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT)</title>
        <description>The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills. Scores range from zero to 60; higher is better. Herein we present 3-second PASAT results (&quot;PASAT-3&quot;). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include PASAT-3 scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Cognitive Function as Assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT)</title>
          <description>The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills. Scores range from zero to 60; higher is better. Herein we present 3-second PASAT results (&quot;PASAT-3&quot;). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include PASAT-3 scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="29"/>
                <count group_id="O3" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.372" lower_limit="0.180" upper_limit="0.563"/>
                    <measurement group_id="O2" value="0.363" lower_limit="0.136" upper_limit="0.591"/>
                    <measurement group_id="O3" value="0.212" lower_limit="0.027" upper_limit="0.398"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Cognitive Function as Assessed by the Judgement of Line Orientation Test (JLO)</title>
        <description>Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space. Scores range from zero to 30; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include JLO data acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Cognitive Function as Assessed by the Judgement of Line Orientation Test (JLO)</title>
          <description>Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space. Scores range from zero to 30; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include JLO data acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="29"/>
                <count group_id="O3" value="35"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.031" lower_limit="-0.109" upper_limit="0.046"/>
                    <measurement group_id="O2" value="0.047" lower_limit="-0.044" upper_limit="0.139"/>
                    <measurement group_id="O3" value="-0.005" lower_limit="-0.079" upper_limit="0.069"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change From Baseline in Cognitive Function as Assessed by the Delis-Kaplan Executive Function System Sorting Test</title>
        <description>This test measures executive functioning, concept formation, and cognitive flexibility. Scores range from zero to 16; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include DKEFS correct sort scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline assessment were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Change From Baseline in Cognitive Function as Assessed by the Delis-Kaplan Executive Function System Sorting Test</title>
          <description>This test measures executive functioning, concept formation, and cognitive flexibility. Scores range from zero to 16; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include DKEFS correct sort scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline assessment were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="35"/>
                <count group_id="O2" value="29"/>
                <count group_id="O3" value="32"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.001" lower_limit="-0.112" upper_limit="0.111"/>
                    <measurement group_id="O2" value="0.027" lower_limit="-0.104" upper_limit="0.159"/>
                    <measurement group_id="O3" value="0.002" lower_limit="-0.114" upper_limit="0.118"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Assess Depression Severity, as Measured by the Beck Depression Inventory-II (BDI-II)</title>
        <description>The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression. Scores range from zero to 63; higher scores indicate greater depression. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BDI-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the scores.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline questionnaire were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Assess Depression Severity, as Measured by the Beck Depression Inventory-II (BDI-II)</title>
          <description>The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression. Scores range from zero to 63; higher scores indicate greater depression. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BDI-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the scores.</description>
          <population>Participants who completed a baseline questionnaire were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="25"/>
                <count group_id="O3" value="27"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.022" lower_limit="-0.152" upper_limit="0.108"/>
                    <measurement group_id="O2" value="-0.019" lower_limit="-0.179" upper_limit="0.140"/>
                    <measurement group_id="O3" value="-0.045" lower_limit="-0.183" upper_limit="0.094"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Evaluation of Impact of Study Products on Health Related Quality of Life Using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS)</title>
        <description>FAMS is a self-reported health-related quality-of-life instrument for people with multiple sclerosis. Subjects rate six quality-of-life domains: Mobility, Symptoms, Emotional well-being, General contentment, Thinking/fatigue, and Family/social well-being. Scores range from zero to 176; higher scores indicate better health-related quality of life. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the FAMS scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed a baseline questionnaire were included.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Evaluation of Impact of Study Products on Health Related Quality of Life Using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS)</title>
          <description>FAMS is a self-reported health-related quality-of-life instrument for people with multiple sclerosis. Subjects rate six quality-of-life domains: Mobility, Symptoms, Emotional well-being, General contentment, Thinking/fatigue, and Family/social well-being. Scores range from zero to 176; higher scores indicate better health-related quality of life. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the FAMS scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed a baseline questionnaire were included.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="36"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="34"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.056" lower_limit="-0.277" upper_limit="0.389"/>
                    <measurement group_id="O2" value="0.051" lower_limit="-0.357" upper_limit="0.459"/>
                    <measurement group_id="O3" value="0.240" lower_limit="-0.087" upper_limit="0.567"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Evaluation of How Overall Sleep Quality Impacts People With MS Using a Sleep Questionnaire (Pittsburgh Sleep Quality Index)</title>
        <description>The sleep questionnaire asks subjects to report various aspects related to their sleep routine. Scores range from zero to 21; higher score indicates worse sleep quality. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the PSQIs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
        <time_frame>Up to week 24 visit</time_frame>
        <population>Participants who completed the baseline assessment were eligible for inclusion.</population>
        <group_list>
          <group group_id="O1">
            <title>Intranasal Insulin 20 International Units</title>
            <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O2">
            <title>Intranasal Insulin 10 International Units</title>
            <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
          <group group_id="O3">
            <title>Placebo</title>
            <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Evaluation of How Overall Sleep Quality Impacts People With MS Using a Sleep Questionnaire (Pittsburgh Sleep Quality Index)</title>
          <description>The sleep questionnaire asks subjects to report various aspects related to their sleep routine. Scores range from zero to 21; higher score indicates worse sleep quality. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the PSQIs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.</description>
          <population>Participants who completed the baseline assessment were eligible for inclusion.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
                <count group_id="O3" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.026" lower_limit="-0.091" upper_limit="0.039"/>
                    <measurement group_id="O2" value="0.035" lower_limit="-0.035" upper_limit="0.105"/>
                    <measurement group_id="O3" value="-0.045" lower_limit="-0.110" upper_limit="0.021"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>AEs and SAEs were collected from the point of randomization until a participant terminated from the study. Unresolved AEs, as well as SAEs, were followed for an added 30 days after study completion. Up to 48 weeks overall.</time_frame>
      <desc>Adverse events were captured through mixed methods. Subjects were provided with a diary in which to record adverse events. Serious adverse events that were catalogued as such due to hospital admission were also captured systematically if the admission occurred within our hospital system through automated reports to the PI. Other times, the adverse events were captured non-systematically, such as through ad hoc reports to study team members.</desc>
      <group_list>
        <group group_id="E1">
          <title>Intranasal Insulin 20 International Units</title>
          <description>Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="E2">
          <title>Intranasal Insulin 10 International Units</title>
          <description>Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Insulin: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
        <group group_id="E3">
          <title>Placebo</title>
          <description>Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.&#xD;
Placebo (Sterile diluent): All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <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="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Chest pain</sub_title>
                <counts group_id="E1" events="5" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Small bowel obstruction</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Urinary Tract Infection</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Perirectal abscess</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Zoster ophthalmicus</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Worsening of neurological symptoms</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Multiple sclerosis relapse</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Non-epileptic seizure</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</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="24" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="18" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="18" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Fracture</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Weakness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="5" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Memory impairment</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Nightmare</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Rhinorrhea</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="35"/>
              </event>
              <event>
                <sub_title>Sore throat</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="37"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="33"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="35"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>
    <limitations_and_caveats>This study faced major disruptions due to the COVID-19 pandemic. Per IRB, all in-person research activities were halted from mid-March until mid-July 2020. Remote study activities were conducted, where possible. 13 participants who were in the active treatment phase of the study stopped study drug early per DSMB. After re-opening, per IRB request, in-person study visits were restricted to the minimum needed for the main study goals. Thus, there is greater than anticipated missingness.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Ellen Mowry</name_or_title>
      <organization>Johns Hopkins University</organization>
      <phone>4106141522</phone>
      <email>Emowry1@jhmi.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/NCT02988401
org study id: IRB00095554
nct id: NCT02988401
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This study will evaluate if giving insulin that is administered in the nostrils (intranasal)
      is safe and tolerable for people with multiple sclerosis (MS). It is also being done to
      evaluate if intranasal insulin improves cognitive function in people with MS and to evaluate
      how it might be working.
Cognitive impairment is common in and devastating to people with MS. MS is a common, chronic,
      central nervous system (CNS) disease characterized by inflammation, demyelination, and
      neurodegeneration. One of the most devastating symptoms of this disease is impaired cognitive
      function, which is common and present in over 60% of individuals with MS. MS-related
      cognitive impairment is associated with lowered quality of life and reduced functional
      capacity, including loss of employment, impaired social relationships, compromised driving
      safety, and poor adherence to treatment. Impaired cognitive functioning has been observed
      early in the disease, sometimes even before diagnosis, and cognitive function has been shown
      to decline longitudinally, both over the short- and long-term. Several cognitive domains are
      impacted in people with MS, including attention, memory, executive functioning, and
      especially processing speed.

      To date, multiple pharmacologic interventions have been assessed with disappointing results.
      There was no significant difference between treatment and placebo for cognition in randomized
      control trials of donepezil, aminopyridines, gingko biloba, and memantine. Psychostimulants
      demonstrated some efficacy, but only in secondary outcome measures. Behavioral interventions
      show promise but are understudied. Furthermore, cognitive rehabilitation is often time
      consuming, costly, and not universally available. Hence, there is an urgent need to identify
      or develop novel therapies that can help improve cognitive function in MS.

      Intranasal insulin is extremely safe and tolerable in other populations, allowing for
      concentrated delivery to the nervous system. An intranasal delivery system provides a
      non-invasive way to bypass the blood-brain barrier and allow rapid delivery of a medication
      to the CNS via the olfactory and trigeminal perivascular channels.The main advantage of the
      delivery system is reducing systemic side effects via limiting a medication's exposure to
      peripheral organs and tissues.

      Insulin administration has been shown to improve memory and learning in healthy people and in
      those with neurodegenerative diseases. Intranasal insulin has been shown to have
      neuroprotective and restorative effects in several human clinical trials. Overall, findings
      suggest that intranasal insulin not only affects cognitive function acutely, but that over
      time, there may be associated structural changes that lead to a more permanent treatment
      benefit. Cognitive dysfunction is very common in MS and can be devastating, therefore a
      treatment intervention (i.e., intranasal insulin) can help both acutely and longitudinally.

      The primary aim of this study is to assess the safety and tolerability of intranasal insulin
      in people with MS. The secondary aim is to evaluate if intranasal insulin improves learning
      and memory in people with MS. The third aim is to evaluate the impact of intranasal insulin
      on measures of oxidative stress, axonal injury, cellular stress, and energy metabolism in MS.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Change in Cognitive Function as Assessed by the Symbol Digit Modalities Test (SDMT)
time frame: Up to week 24 visit
description: This task will be performed at five study visits. The SDMT is one of the most commonly used tests to assess processing speed in the MS population and is included in the Minimal Assessment of Cognitive Function in MS (MACFIMS). Higher scores reflect a better outcome (range 0 to 110). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the SDMTs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.
measure: Number of Participants With Adverse Events Leading to Study Discontinuation
time frame: Up to week 24 visit
description: An adverse event will be defined as any occurrence or worsening of an undesirable or unintended sign, symptom (or abnormal laboratory test), or disease temporally associated with the use of a medicinal product or intervention, whether or not it is considered related to the product/intervention. We report overall adverse events in the relevant section. Here, we report adverse events that led to study discontinuation.
measure: Fingerstick Blood Glucose (Subset)
time frame: At the baseline visit, monitored twice within the 90 minutes following the first dose administration of study drug
description: Fingerstick blood glucose levels were monitored twice within the 90 minutes following the first dose administration of study drug for the first 15 participants.
measure: Change From Baseline in Cognitive Function as Assessed by the Controlled Oral Word Association Test (COWAT)
time frame: Up to week 24 visit
description: This test measures phonemic fluency. The test scores the number of words a participant can provide that begin with a specified letter within one minute, such that scores range from zero (worst) to an infinite number (better). Total score is sum of three 60-second trials. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the COWAT scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Change From Baseline in Cognitive Function as Assessed by the California Verbal Learning Test, Second Edition (CVLT-II)
time frame: Up to week 24 visit
description: This is a verbal learning and memory test. Scores range from zero to 16; a higher number is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the primary analyses include the CVLT-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Change From Baseline in Cognitive Function as Assessed by the Brief Visuospatial Memory Test - Revised (BVMT-R) Delayed Recall
time frame: Up to week 24 visit
description: This is a visual, nonverbal test of learning and memory. Scores range from zero to 12; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BVMT-R delayed recall scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Change in Cognitive Function as Assessed by the Rao-version of the Paced Auditory Serial Addition Test (PASAT)
time frame: Up to week 24 visit
description: The Rao-version of the PASAT evaluates processing speed, working memory, and basic addition skills. Scores range from zero to 60; higher is better. Herein we present 3-second PASAT results ("PASAT-3"). In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include PASAT-3 scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the SDMT.
measure: Change From Baseline in Cognitive Function as Assessed by the Judgement of Line Orientation Test (JLO)
time frame: Up to week 24 visit
description: Judgment of Line Orientation Test measures a person's ability to match the angle and orientation of lines in space. Scores range from zero to 30; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include JLO data acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Change From Baseline in Cognitive Function as Assessed by the Delis-Kaplan Executive Function System Sorting Test
time frame: Up to week 24 visit
description: This test measures executive functioning, concept formation, and cognitive flexibility. Scores range from zero to 16; higher is better. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include DKEFS correct sort scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Assess Depression Severity, as Measured by the Beck Depression Inventory-II (BDI-II)
time frame: Up to week 24 visit
description: The BDI-II is a 21-question multiple-choice self-report inventory test for measuring the severity of depression. Scores range from zero to 63; higher scores indicate greater depression. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the BDI-II scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the scores.
measure: Evaluation of Impact of Study Products on Health Related Quality of Life Using the Functional Assessment of Multiple Sclerosis Questionnaire (FAMS)
time frame: Up to week 24 visit
description: FAMS is a self-reported health-related quality-of-life instrument for people with multiple sclerosis. Subjects rate six quality-of-life domains: Mobility, Symptoms, Emotional well-being, General contentment, Thinking/fatigue, and Family/social well-being. Scores range from zero to 176; higher scores indicate better health-related quality of life. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the FAMS scores acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
measure: Evaluation of How Overall Sleep Quality Impacts People With MS Using a Sleep Questionnaire (Pittsburgh Sleep Quality Index)
time frame: Up to week 24 visit
description: The sleep questionnaire asks subjects to report various aspects related to their sleep routine. Scores range from zero to 21; higher score indicates worse sleep quality. In order to account for all contributed data (even for those who did not complete the study but contributed some post-randomization data in the active study phase), the analyses include the PSQIs acquired within the active treatment phase (from baseline to week 24 visit). We then calculated and report the average change per week in the score.
arm group label: Intranasal insulin 20 international units
arm group type: Experimental
description: Subjects will administer 20 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.
arm group label: Intranasal insulin 10 international units
arm group type: Experimental
description: Subjects will administer 10 I.U. of insulin in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.
arm group label: Intranasal saline
arm group type: Placebo Comparator
description: Subjects will administer a sterile diluent containing inactive ingredients in the nostrils using a ViaNaseTM controlled particle dispersion nasal device two times/day (BID) for 24 weeks.
intervention type: Drug
intervention name: Insulin
description: All patients will receive either insulin or placebo using the Vianase III N2B device during the first 24 weeks of the study.
arm group label: Intranasal insulin 10 international units
arm group label: Intranasal insulin 20 international units
intervention type: Drug
intervention name: Placebo (Sterile diluent)
description: All patients will receive either insulin or placebo using Vianase III N2B device during the first 24 weeks of the study.
arm group label: Intranasal saline
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Ellen Mowry, MD, MCR
role: Principal Investigator
affiliation: Johns Hopkins University
last name: Scott Newsome, DO
role: Principal Investigator
affiliation: Johns Hopkins University
facility: 
country: United States
citation: Benedict RH, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, Weinstock-Guttman B. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS). J Int Neuropsychol Soc. 2006 Jul;12(4):549-58. doi: 10.1017/s1355617706060723.
PMID: 16981607
citation: DeLuca J. What we know about cognitive changes in multiple sclerosis. In: LaRocca N, Kalb R, eds. Multiple Sclerosis: Understanding the Cognitive Challenges. New York: Demos Health; 2006: 17-40.
citation: Rao S. Cognitive Function in Patients with Multiple Sclerosis: Impairment and Treatment. IJMSC 2004;1:9-22.
citation: Ruet A, Deloire M, Hamel D, Ouallet JC, Petry K, Brochet B. Cognitive impairment, health-related quality of life and vocational status at early stages of multiple sclerosis: a 7-year longitudinal study. J Neurol. 2013 Mar;260(3):776-84. doi: 10.1007/s00415-012-6705-1. Epub 2012 Oct 19.
PMID: 23081755
citation: Strober LB, Christodoulou C, Benedict RH, Westervelt HJ, Melville P, Scherl WF, Weinstock-Guttman B, Rizvi S, Goodman AD, Krupp LB. Unemployment in multiple sclerosis: the contribution of personality and disease. Mult Scler. 2012 May;18(5):647-53. doi: 10.1177/1352458511426735. Epub 2011 Dec 19.
PMID: 22183935
citation: Morrow SA, Drake A, Zivadinov R, Munschauer F, Weinstock-Guttman B, Benedict RH. Predicting loss of employment over three years in multiple sclerosis: clinically meaningful cognitive decline. Clin Neuropsychol. 2010 Oct;24(7):1131-45. doi: 10.1080/13854046.2010.511272. Epub 2010 Sep 8.
PMID: 20830649
citation: Schultheis MT, Weisser V, Ang J, Elovic E, Nead R, Sestito N, Fleksher C, Millis SR. Examining the relationship between cognition and driving performance in multiple sclerosis. Arch Phys Med Rehabil. 2010 Mar;91(3):465-73. doi: 10.1016/j.apmr.2009.09.026.
PMID: 20298841
citation: Patti F. Optimizing the benefit of multiple sclerosis therapy: the importance of treatment adherence. Patient Prefer Adherence. 2010 Feb 4;4:1-9. doi: 10.2147/ppa.s8230.
PMID: 20165593
citation: Rao SM, Leo GJ, Ellington L, Nauertz T, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. II. Impact on employment and social functioning. Neurology. 1991 May;41(5):692-6. doi: 10.1212/wnl.41.5.692.
PMID: 1823781
citation: Amato MP, Razzolini L, Goretti B, Stromillo ML, Rossi F, Giorgio A, Hakiki B, Giannini M, Pasto L, Portaccio E, De Stefano N. Cognitive reserve and cortical atrophy in multiple sclerosis: a longitudinal study. Neurology. 2013 May 7;80(19):1728-33. doi: 10.1212/WNL.0b013e3182918c6f. Epub 2013 Apr 10.
PMID: 23576622
citation: Amato MP, Ponziani G, Siracusa G, Sorbi S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch Neurol. 2001 Oct;58(10):1602-6. doi: 10.1001/archneur.58.10.1602.
PMID: 11594918
citation: Lacy M, Hauser M, Pliskin N, Assuras S, Valentine MO, Reder A. The effects of long-term interferon-beta-1b treatment on cognitive functioning in multiple sclerosis: a 16-year longitudinal study. Mult Scler. 2013 Nov;19(13):1765-72. doi: 10.1177/1352458513485981. Epub 2013 May 7.
PMID: 23652214
citation: DeLuca J, Barbieri-Berger S, Johnson SK. The nature of memory impairments in multiple sclerosis: acquisition versus retrieval. J Clin Exp Neuropsychol. 1994 Apr;16(2):183-9. doi: 10.1080/01688639408402629.
PMID: 8021305
citation: DeLuca J, Gaudino EA, Diamond BJ, Christodoulou C, Engel RA. Acquisition and storage deficits in multiple sclerosis. J Clin Exp Neuropsychol. 1998 Jun;20(3):376-90. doi: 10.1076/jcen.20.3.376.819.
PMID: 9845164
citation: Thornton AE, Raz N, Tucke KA. Memory in multiple sclerosis: contextual encoding deficits. J Int Neuropsychol Soc. 2002 Mar;8(3):395-409. doi: 10.1017/s1355617702813200.
PMID: 11939698
citation: DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol. 2004 Jun;26(4):550-62. doi: 10.1080/13803390490496641.
PMID: 15512942
citation: Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999 Nov;67(5):661-3. doi: 10.1136/jnnp.67.5.661.
PMID: 10519876
citation: Krupp LB, Christodoulou C, Melville P, Scherl WF, Pai LY, Muenz LR, He D, Benedict RH, Goodman A, Rizvi S, Schwid SR, Weinstock-Guttman B, Westervelt HJ, Wishart H. Multicenter randomized clinical trial of donepezil for memory impairment in multiple sclerosis. Neurology. 2011 Apr 26;76(17):1500-7. doi: 10.1212/WNL.0b013e318218107a.
PMID: 21519001
citation: Solari A, Uitdehaag B, Giuliani G, Pucci E, Taus C. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev. 2001;(4):CD001330. doi: 10.1002/14651858.CD001330.
PMID: 11687106
citation: Lovera JF, Kim E, Heriza E, Fitzpatrick M, Hunziker J, Turner AP, Adams J, Stover T, Sangeorzan A, Sloan A, Howieson D, Wild K, Haselkorn J, Bourdette D. Ginkgo biloba does not improve cognitive function in MS: a randomized placebo-controlled trial. Neurology. 2012 Sep 18;79(12):1278-84. doi: 10.1212/WNL.0b013e31826aac60. Epub 2012 Sep 5.
PMID: 22955125
citation: Lovera JF, Frohman E, Brown TR, Bandari D, Nguyen L, Yadav V, Stuve O, Karman J, Bogardus K, Heimburger G, Cua L, Remingon G, Fowler J, Monahan T, Kilcup S, Courtney Y, McAleenan J, Butler K, Wild K, Whitham R, Bourdette D. Memantine for cognitive impairment in multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Jun;16(6):715-23. doi: 10.1177/1352458510367662. Epub 2010 May 18.
PMID: 20483885
citation: Morrow SA, Kaushik T, Zarevics P, Erlanger D, Bear MF, Munschauer FE, Benedict RH. The effects of L-amphetamine sulfate on cognition in MS patients: results of a randomized controlled trial. J Neurol. 2009 Jul;256(7):1095-102. doi: 10.1007/s00415-009-5074-x. Epub 2009 Mar 5.
PMID: 19263186
citation: Mitolo M, Venneri A, Wilkinson ID, Sharrack B. Cognitive rehabilitation in multiple sclerosis: A systematic review. J Neurol Sci. 2015 Jul 15;354(1-2):1-9. doi: 10.1016/j.jns.2015.05.004. Epub 2015 May 9.
PMID: 25998261
citation: Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A, Arbuckle M, Callaghan M, Tsai E, Plymate SR, Green PS, Leverenz J, Cross D, Gerton B. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: a pilot clinical trial. Arch Neurol. 2012 Jan;69(1):29-38. doi: 10.1001/archneurol.2011.233. Epub 2011 Sep 12.
PMID: 21911655
responsible party type: Sponsor
mesh term: Multiple Sclerosis
mesh term: Multiple Sclerosis, Relapsing-Remitting
mesh term: Multiple Sclerosis, Chronic Progressive
mesh term: Sclerosis
mesh term: Insulin
sharing ipd: No
provided document: 
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: This study faced major disruptions due to the COVID-19 pandemic. Per IRB, all in-person research activities were halted from mid-March until mid-July 2020. Remote study activities were conducted, where possible. 13 participants who were in the active treatment phase of the study stopped study drug early per DSMB. After re-opening, per IRB request, in-person study visits were restricted to the minimum needed for the main study goals. Thus, there is greater than anticipated missingness.
point of contact: 