<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/NCT04490239</url>
  </required_header>
  <id_info>
    <org_study_id>Intranasal Heparin</org_study_id>
    <nct_id>NCT04490239</nct_id>
  </id_info>
  <brief_title>Intranasal Heparin Tolerability Study</brief_title>
  <official_title>Intranasal Heparin Tolerability Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Joshua Sharp</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Mississippi, Oxford</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators are investigating the tolerability of Heparin Sodium (porcine) administered&#xD;
      topically via a nasal spray. This agent is being investigated as a potential prophylactic&#xD;
      treatment to prevent infection by SARS(severe acute respiratory syndrome)-CoV-2, the novel&#xD;
      coronavirus that causes COVID-19. Heparin Sodium (porcine) is an FDA-approved anticoagulant&#xD;
      drug administered by injection. Recent work from multiple groups have found that heparin can&#xD;
      prevent the infection of cells by SARS-CoV-2, indicating a possible use as a topical&#xD;
      anti-viral. Numerous studies in both rodent models and humans have shown that heparin&#xD;
      administered via a pulmonary or intranasal route enters the blood stream in negligible&#xD;
      amounts, suggesting intranasal administration of heparin should be safe even at very large&#xD;
      doses. Data from mouse models indicate that repeated daily nasal administration of heparin&#xD;
      had no adverse effects in mice over a two week period (including weight loss, nose bleeds,&#xD;
      loss of sense of smell, nasal discharge, or decreased blood clotting time). However, no data&#xD;
      of repeated nasal administration of heparin in humans is available.&#xD;
&#xD;
      The investigators will test nasal administration of FDA-approved heparin sodium (porcine),&#xD;
      originally formulated for injection. The formulations the investigators will be testing&#xD;
      consist of heparin, sodium chloride, and 1% benzyl alcohol as a preservative bottled in a&#xD;
      nasal sprayer dispensing 0.1 mL(millilitres) per spray. The investigation is planned in two&#xD;
      phases. A single-dose phase will test the acute tolerability of the drug. In this phase,&#xD;
      subjects will be administered 0.1 mL of Heparin Sodium in each nostril formulated at one of&#xD;
      two doses: Day 1 will test a formulation of 5000 U(units)/mL, and Day 2 will test a&#xD;
      formulation of 10000 U(units) /mL. After each dose, subjects will be tested for systemic&#xD;
      exposure via blood aPTT tests and platelet count, as well as for local topical toxicity via&#xD;
      examination for epistaxis and anosmia, along with any other adverse events. In the chronic&#xD;
      phase, subjects will be administered the highest dose that was tolerated in the acute phase&#xD;
      daily for fourteen days. Subjects will be tested for aPTT and platelet count, as well as&#xD;
      epistaxis, anosmia and any other adverse events.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Objectives&#xD;
&#xD;
      This exploratory clinical trial is designed to assess tolerability of increasing doses of&#xD;
      intranasally administered heparin sodium in saline solution. Baseline values for aPTT and&#xD;
      complete blood count will be obtained from six subjects. Heparin will be administered in&#xD;
      increasing concentrations using one 0.1 mL(millilitre) spray per nostril (0.2 ml total) on a&#xD;
      daily basis. Major signs of toxicity will be clinically relevant changes in aPTT time,&#xD;
      clinically relevant decrease in platelet count, signs of anosmia 30 minutes after&#xD;
      administration, or epistaxis. Dosing will start at 1000 units of heparin administered (500&#xD;
      units in each nostril) and then escalated to 2000 units. Should a clinically relevant aPTT&#xD;
      prolongation (&gt;50% increase from subject baseline) or decrease in platelet count (below&#xD;
      clinical lab normal limit) be observed at either dose, the study will be halted and a series&#xD;
      of lower doses evaluated.&#xD;
&#xD;
      Study Overview&#xD;
&#xD;
      Description of Design of Study&#xD;
&#xD;
      This study is a single center, prospective, Phase 0 exploratory tolerability trial. A total&#xD;
      of 6 healthy subjects (3 M and 3 F) will be enrolled into the study. This study will evaluate&#xD;
      the acute and multi-day (14 days) tolerability of intranasally administered heparin.&#xD;
&#xD;
      Test Article&#xD;
&#xD;
      Investigational Product&#xD;
&#xD;
      The study will assess the single and multi-dose tolerability of intranasal administration of&#xD;
      an aliquot of an FDA-approved heparin sodium injection (5,000 USP units/mL or 10,000 USP&#xD;
      units/mL) to deliver 1000U (units) or 2000U of heparin sodium. Doses will be prepared and&#xD;
      administered as follows:&#xD;
&#xD;
      1000 U = (2 x 0.1 mL(milliliter) of 5000U(units)/mL or one spray of 500 U in each nostril)&#xD;
      2000 U = (2 x 0.1 mL of 10000U/mL or one spray of 1000 U in each nostril)&#xD;
&#xD;
      The test article will be administered by transferring (4 mL) of sterile heparin sodium&#xD;
      injection (5,000 USP units/mL or 10,000 USP units/mL) at ambient room temperature into&#xD;
      intranasal spray bottles, one for each individual subject.&#xD;
&#xD;
      The test article will be administered within 4 weeks of preparation, and the remainder&#xD;
      discarded after study completion.&#xD;
&#xD;
      Supplier The test article (Heparin Sodium USP) will be obtained from appropriate commercial&#xD;
      sources.&#xD;
&#xD;
      Safety Assessments&#xD;
&#xD;
      Safety assessments will be completed as part of this single and multi-dose, pharmacokinetic&#xD;
      study. Safety will be assessed prior to test article administration and at 24 post dose, in&#xD;
      the acute phase. For safety assessments during the chronic phase, safety assessments will be&#xD;
      assessed prior to test article administration , day 14 and day 15-post study. Test subject&#xD;
      will be called every three (3) days for updates and subjective reports (adverse events),&#xD;
      during 14 day, daily dose phase. Subject safety will be assessed by monitoring adverse&#xD;
      events, clinical laboratory tests, vital signs, and physical examinations.&#xD;
&#xD;
      Laboratory parameters will be evaluated during screening and daily, to include the following:&#xD;
&#xD;
        -  Complete Blood Count (WBC, RBC(red blood cell count), Hematocrit, Hemoglobin, MCV (mean&#xD;
           corpuscular volume), Platelet Count)&#xD;
&#xD;
        -  PT(prothrombin time)/INR (international normalized ratio) Baseline and post study&#xD;
&#xD;
        -  Serum/Urine hCG ( human chorionic gonadotropin)baseline and predose&#xD;
&#xD;
        -  Activated Partial Thromboplastin Time (aPTT)&#xD;
&#xD;
      Clinical Adverse Events&#xD;
&#xD;
      Clinical Adverse Events will be monitored throughout the study. However, such events are not&#xD;
      anticipated during this trial due to the low systemic exposure of the test article being&#xD;
      administered. However, local side effects of intranasal heparin, such as epistaxis or nasal&#xD;
      congestion may result.&#xD;
&#xD;
      For any abnormal lab values, test subjects will be evaluated for any sign and symptoms, and&#xD;
      labs will be redrawn, until stabilized or returned to baseline. Subjects will be referred to&#xD;
      the primary physician for any continued care required.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 9, 2020</start_date>
  <completion_date type="Actual">November 18, 2020</completion_date>
  <primary_completion_date type="Actual">November 18, 2020</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This study will evaluate the acute and multi-day (14 days) tolerability of intranasally administered heparin. Two doses will be tested in the acute phase: 1000 U/day, then 2000 U/day. In the multi-day phase, the highest tolerated dose from the acute phase will be tested over a 14-day period of daily self-administration.</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1</measure>
    <time_frame>24 hours after a 1000 U intranasal dose of heparin</time_frame>
    <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2</measure>
    <time_frame>24 hours after 2000 U dose intranasal heparin</time_frame>
    <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14</measure>
    <time_frame>Day 14, chronic phase</time_frame>
    <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15</measure>
    <time_frame>24 hours after the last 2000 U dose of the chronic phase</time_frame>
    <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percent Change in Platelet Count From Pre-dose Baseline</measure>
    <time_frame>Pre-dose baseline, Day 14 chronic phase</time_frame>
    <description>Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Incidents of Epistaxis, Acute Phase</measure>
    <time_frame>Day 0 through Day 2, acute phase</time_frame>
    <description>Number of incidents of blood coming from the nose during the acute phase</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Incidents of Epistaxis, Chronic Phase</measure>
    <time_frame>Day 1 through Day 15, chronic phase</time_frame>
    <description>Blood coming from the nose or pink tinged nasal secretions</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14</measure>
    <time_frame>Day 14, Chronic Phase</time_frame>
    <description>Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Other Adverse Effects, Acute Phase</measure>
    <time_frame>Day 0 through Day 2, acute phase</time_frame>
    <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Other Adverse Effects, Chronic Phase</measure>
    <time_frame>Day 1 through Day 15, chronic phase</time_frame>
    <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">6</enrollment>
  <condition>Covid19</condition>
  <arm_group>
    <arm_group_label>Experimental Arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intranasal heparin sodium (porcine)</intervention_name>
    <description>Intranasal heparin sodium</description>
    <arm_group_label>Experimental Arm</arm_group_label>
    <other_name>NDC (National Drug Code) 0409-2721-30</other_name>
    <other_name>NDC 0409-2723-01</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Normal, healthy adults aged 18 to 65 years&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Allergy to Heparin&#xD;
&#xD;
          -  Currently taking any prescription blood thinners or anti-coagulants, or currently&#xD;
             taking any intranasal medication&#xD;
&#xD;
          -  Known history of anemia, thrombocytopenia, or other blood disorder&#xD;
&#xD;
          -  Autoimmune disorders&#xD;
&#xD;
          -  Known history of Neurologic/Psychiatric disorders&#xD;
&#xD;
          -  Report of an active infection&#xD;
&#xD;
          -  Subject is pregnant or breast-feeding, or is expecting to conceive during the study.&#xD;
&#xD;
        NOTE: Subjects will be instructed to abstain from alcohol for the duration of the study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Bill Gurley, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Mississippi Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>The University of Mississippi National Center for Natural Products Research</name>
      <address>
        <city>University</city>
        <state>Mississippi</state>
        <zip>38677-1848</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Tandon R, Sharp JS, Zhang F, Pomin VH, Ashpole NM, Mitra D, Jin W, Liu H, Sharma P, Linhardt RJ. Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives. bioRxiv. 2020 Jul 28:2020.06.08.140236. doi: 10.1101/2020.06.08.140236. Preprint.</citation>
    <PMID>32577638</PMID>
  </reference>
  <verification_date>April 2021</verification_date>
  <study_first_submitted>July 20, 2020</study_first_submitted>
  <study_first_submitted_qc>July 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 29, 2020</study_first_posted>
  <results_first_submitted>December 15, 2020</results_first_submitted>
  <results_first_submitted_qc>April 26, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">April 28, 2021</results_first_posted>
  <last_update_submitted>April 27, 2021</last_update_submitted>
  <last_update_submitted_qc>April 27, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Mississippi, Oxford</investigator_affiliation>
    <investigator_full_name>Joshua Sharp</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Heparin</mesh_term>
    <mesh_term>Calcium heparin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data that underlie the results reported, after deidentification</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_time_frame>Beginning 3 months and ending 36 months following publication</ipd_time_frame>
    <ipd_access_criteria>Proposals should be directed to jsharp@olemiss.edu. To gain access, requestors will need to sign a data access agreement.</ipd_access_criteria>
  </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>September 1, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/39/NCT04490239/Prot_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Experimental Arm</title>
          <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>1000 U Acute (One Dose, Day 1)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>2000 U Acute (One Dose, Day 3)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>2000 U Chronic (Daily, 14 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Experimental Arm</title>
          <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="6"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31" lower_limit="18" upper_limit="61"/>
                  </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="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1</title>
        <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin</description>
        <time_frame>24 hours after a 1000 U intranasal dose of heparin</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1</title>
          <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin</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="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>participants with normal aPTT (24-33 sec)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>participants with abnormal aPTT (&lt;24 sec or &gt;33 sec)</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2</title>
        <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin</description>
        <time_frame>24 hours after 2000 U dose intranasal heparin</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2</title>
          <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin</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="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Participants with normal aPTT (24-33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Participants with abnormal aPTT (&lt;24 sec or &gt;33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14</title>
        <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin</description>
        <time_frame>Day 14, chronic phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14</title>
          <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin</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="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Participants with normal aPTT (24-33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Participants with abnormal aPTT (&lt;24 sec or &gt;33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15</title>
        <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin</description>
        <time_frame>24 hours after the last 2000 U dose of the chronic phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15</title>
          <description>A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin</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="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Participants with normal aPTT (24-33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Participants with abnormal aPTT (&lt;24 sec or &gt;33 sec)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Percent Change in Platelet Count From Pre-dose Baseline</title>
        <description>Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</description>
        <time_frame>Pre-dose baseline, Day 14 chronic phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Percent Change in Platelet Count From Pre-dose Baseline</title>
          <description>Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</description>
          <units>percent change from baseline</units>
          <param>Mean</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.2" lower_limit="-3.2" upper_limit="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Incidents of Epistaxis, Acute Phase</title>
        <description>Number of incidents of blood coming from the nose during the acute phase</description>
        <time_frame>Day 0 through Day 2, acute phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Incidents of Epistaxis, Acute Phase</title>
          <description>Number of incidents of blood coming from the nose during the acute phase</description>
          <units>Reported incidents</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Incidents of Epistaxis, Chronic Phase</title>
        <description>Blood coming from the nose or pink tinged nasal secretions</description>
        <time_frame>Day 1 through Day 15, chronic phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Incidents of Epistaxis, Chronic Phase</title>
          <description>Blood coming from the nose or pink tinged nasal secretions</description>
          <units>Reported incidents</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14</title>
        <description>Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</description>
        <time_frame>Day 14, Chronic Phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14</title>
          <description>Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.</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="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Participants with normal platelet counts (150,000 - 450,000 platelets/uL)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Participants with abnormal platelet counts (&lt;150,000 or &gt;450,000 platelets/uL)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Other Adverse Effects, Acute Phase</title>
        <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation</description>
        <time_frame>Day 0 through Day 2, acute phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Other Adverse Effects, Acute Phase</title>
          <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation</description>
          <units>Reported incidents</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Other Adverse Effects, Chronic Phase</title>
        <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing</description>
        <time_frame>Day 1 through Day 15, chronic phase</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Experimental Arm</title>
            <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
          </group>
        </group_list>
        <measure>
          <title>Other Adverse Effects, Chronic Phase</title>
          <description>Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing</description>
          <units>Reported incidents</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From date of first dose in acute phase through sixteen days after last dose in chronic phase; 38 days total</time_frame>
      <desc>Adverse event collection was obtained by vital sign measurement, INR measurements from blood collection, and subject self-reporting</desc>
      <group_list>
        <group group_id="E1">
          <title>Experimental Arm</title>
          <description>Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.&#xD;
Acute phase:&#xD;
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.&#xD;
Chronic phase:&#xD;
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.&#xD;
Intranasal heparin sodium (porcine): Intranasal heparin sodium</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Mild nasal irritation lasting less than 1 min after administration</sub_title>
                <description>Mild nasal irritation immediately after administration, lasting less than one minute. Includes mild burning sensation in the nose, itchiness and sneezing.</description>
                <counts group_id="E1" events="7" subjects_affected="2" subjects_at_risk="6"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <description>Incidents of mild nose bleeds and/or pink tinged nasal secretions (NOTE: affected subject disclosed prior history of epistaxis not initially disclosed during screening)</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="6"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Joshua Sharp</name_or_title>
      <organization>University of Mississippi</organization>
      <phone>662-915-1758</phone>
      <email>jsharp@olemiss.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/NCT04490239
org study id: Intranasal Heparin
nct id: NCT04490239
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The investigators are investigating the tolerability of Heparin Sodium (porcine) administered
      topically via a nasal spray. This agent is being investigated as a potential prophylactic
      treatment to prevent infection by SARS(severe acute respiratory syndrome)-CoV-2, the novel
      coronavirus that causes COVID-19. Heparin Sodium (porcine) is an FDA-approved anticoagulant
      drug administered by injection. Recent work from multiple groups have found that heparin can
      prevent the infection of cells by SARS-CoV-2, indicating a possible use as a topical
      anti-viral. Numerous studies in both rodent models and humans have shown that heparin
      administered via a pulmonary or intranasal route enters the blood stream in negligible
      amounts, suggesting intranasal administration of heparin should be safe even at very large
      doses. Data from mouse models indicate that repeated daily nasal administration of heparin
      had no adverse effects in mice over a two week period (including weight loss, nose bleeds,
      loss of sense of smell, nasal discharge, or decreased blood clotting time). However, no data
      of repeated nasal administration of heparin in humans is available.

      The investigators will test nasal administration of FDA-approved heparin sodium (porcine),
      originally formulated for injection. The formulations the investigators will be testing
      consist of heparin, sodium chloride, and 1% benzyl alcohol as a preservative bottled in a
      nasal sprayer dispensing 0.1 mL(millilitres) per spray. The investigation is planned in two
      phases. A single-dose phase will test the acute tolerability of the drug. In this phase,
      subjects will be administered 0.1 mL of Heparin Sodium in each nostril formulated at one of
      two doses: Day 1 will test a formulation of 5000 U(units)/mL, and Day 2 will test a
      formulation of 10000 U(units) /mL. After each dose, subjects will be tested for systemic
      exposure via blood aPTT tests and platelet count, as well as for local topical toxicity via
      examination for epistaxis and anosmia, along with any other adverse events. In the chronic
      phase, subjects will be administered the highest dose that was tolerated in the acute phase
      daily for fourteen days. Subjects will be tested for aPTT and platelet count, as well as
      epistaxis, anosmia and any other adverse events.
Study Objectives

      This exploratory clinical trial is designed to assess tolerability of increasing doses of
      intranasally administered heparin sodium in saline solution. Baseline values for aPTT and
      complete blood count will be obtained from six subjects. Heparin will be administered in
      increasing concentrations using one 0.1 mL(millilitre) spray per nostril (0.2 ml total) on a
      daily basis. Major signs of toxicity will be clinically relevant changes in aPTT time,
      clinically relevant decrease in platelet count, signs of anosmia 30 minutes after
      administration, or epistaxis. Dosing will start at 1000 units of heparin administered (500
      units in each nostril) and then escalated to 2000 units. Should a clinically relevant aPTT
      prolongation (>50% increase from subject baseline) or decrease in platelet count (below
      clinical lab normal limit) be observed at either dose, the study will be halted and a series
      of lower doses evaluated.

      Study Overview

      Description of Design of Study

      This study is a single center, prospective, Phase 0 exploratory tolerability trial. A total
      of 6 healthy subjects (3 M and 3 F) will be enrolled into the study. This study will evaluate
      the acute and multi-day (14 days) tolerability of intranasally administered heparin.

      Test Article

      Investigational Product

      The study will assess the single and multi-dose tolerability of intranasal administration of
      an aliquot of an FDA-approved heparin sodium injection (5,000 USP units/mL or 10,000 USP
      units/mL) to deliver 1000U (units) or 2000U of heparin sodium. Doses will be prepared and
      administered as follows:

      1000 U = (2 x 0.1 mL(milliliter) of 5000U(units)/mL or one spray of 500 U in each nostril)
      2000 U = (2 x 0.1 mL of 10000U/mL or one spray of 1000 U in each nostril)

      The test article will be administered by transferring (4 mL) of sterile heparin sodium
      injection (5,000 USP units/mL or 10,000 USP units/mL) at ambient room temperature into
      intranasal spray bottles, one for each individual subject.

      The test article will be administered within 4 weeks of preparation, and the remainder
      discarded after study completion.

      Supplier The test article (Heparin Sodium USP) will be obtained from appropriate commercial
      sources.

      Safety Assessments

      Safety assessments will be completed as part of this single and multi-dose, pharmacokinetic
      study. Safety will be assessed prior to test article administration and at 24 post dose, in
      the acute phase. For safety assessments during the chronic phase, safety assessments will be
      assessed prior to test article administration , day 14 and day 15-post study. Test subject
      will be called every three (3) days for updates and subjective reports (adverse events),
      during 14 day, daily dose phase. Subject safety will be assessed by monitoring adverse
      events, clinical laboratory tests, vital signs, and physical examinations.

      Laboratory parameters will be evaluated during screening and daily, to include the following:

        -  Complete Blood Count (WBC, RBC(red blood cell count), Hematocrit, Hemoglobin, MCV (mean
           corpuscular volume), Platelet Count)

        -  PT(prothrombin time)/INR (international normalized ratio) Baseline and post study

        -  Serum/Urine hCG ( human chorionic gonadotropin)baseline and predose

        -  Activated Partial Thromboplastin Time (aPTT)

      Clinical Adverse Events

      Clinical Adverse Events will be monitored throughout the study. However, such events are not
      anticipated during this trial due to the low systemic exposure of the test article being
      administered. However, local side effects of intranasal heparin, such as epistaxis or nasal
      congestion may result.

      For any abnormal lab values, test subjects will be evaluated for any sign and symptoms, and
      labs will be redrawn, until stabilized or returned to baseline. Subjects will be referred to
      the primary physician for any continued care required.
allocation: N/A
intervention model: Sequential Assignment
intervention model description: This study will evaluate the acute and multi-day (14 days) tolerability of intranasally administered heparin. Two doses will be tested in the acute phase: 1000 U/day, then 2000 U/day. In the multi-day phase, the highest tolerated dose from the acute phase will be tested over a 14-day period of daily self-administration.
primary purpose: Prevention
masking: None (Open Label)
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 1
time frame: 24 hours after a 1000 U intranasal dose of heparin
description: A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 1000 U intranasal dose of heparin
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Acute Phase Day 2
time frame: 24 hours after 2000 U dose intranasal heparin
description: A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin collected 24 hours after a 2000 U intranasal dose of heparin
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 14
time frame: Day 14, chronic phase
description: A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained immediately after the 14 consecutive day of daily 2000 U dose of intranasal heparin
measure: Number of Participants With Normal or Abnormal Activated Partial Thromboplastin Time (aPTT), Chronic Phase Day 15
time frame: 24 hours after the last 2000 U dose of the chronic phase
description: A measurement of blood clotting ability; tests for systemic bioavailability of intranasal heparin obtained 24 hours after the 14 consecutive day of daily 2000 U dose of intranasal heparin
measure: Percent Change in Platelet Count From Pre-dose Baseline
time frame: Pre-dose baseline, Day 14 chronic phase
description: Indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.
measure: Number of Incidents of Epistaxis, Acute Phase
time frame: Day 0 through Day 2, acute phase
description: Number of incidents of blood coming from the nose during the acute phase
measure: Number of Incidents of Epistaxis, Chronic Phase
time frame: Day 1 through Day 15, chronic phase
description: Blood coming from the nose or pink tinged nasal secretions
measure: Number of Participants With Normal or Abnormal Platelet Counts, Chronic Phase Day 14
time frame: Day 14, Chronic Phase
description: Abnormally low platelet counts indicative of heparin-induced thrombocytopenia, a serious adverse side effect of systemically bioavailable heparin, measured immediately after the last 2000 U intranasal dose of the chronic phase.
measure: Other Adverse Effects, Acute Phase
time frame: Day 0 through Day 2, acute phase
description: Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation
measure: Other Adverse Effects, Chronic Phase
time frame: Day 1 through Day 15, chronic phase
description: Reports of mild, short-lived nasal irritation immediately after administration including mild burning sensation, itchiness or sneezing
arm group label: Experimental Arm
arm group type: Experimental
description: Subjects will be administered heparin sodium (porcine) bottled in a nasal sprayer with a volume per spray of 0.1 mL.
Acute phase:
On day 1, each subject will be administered 0.1 mL per nostril of 5000 U/mL heparin sodium (porcine), for a total dose of 1000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.
On day 2, each subject will be administered 0.1 mL per nostril of 10000 U/mL heparin sodium (porcine), for a total dose of 2000 U. Vital signs, blood work, and follow-up clinical observation will be used to detect adverse effects.
Chronic phase:
The highest acute dose that has no impact on aPTT or INR will be used for the chronic phase of this study. Each subject will be administered a daily dose for fourteen days. The first and last dose will be administered in the clinic; all other doses will be self-administered by subjects at home at the same time of day using a dosing diary to keep records.
intervention type: Drug
intervention name: Intranasal heparin sodium (porcine)
description: Intranasal heparin sodium
arm group label: Experimental Arm
other name: NDC (National Drug Code) 0409-2721-30
other name: NDC 0409-2723-01
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Bill Gurley, PhD
role: Principal Investigator
affiliation: University of Mississippi Medical Center
facility: 
country: United States
citation: Tandon R, Sharp JS, Zhang F, Pomin VH, Ashpole NM, Mitra D, Jin W, Liu H, Sharma P, Linhardt RJ. Effective Inhibition of SARS-CoV-2 Entry by Heparin and Enoxaparin Derivatives. bioRxiv. 2020 Jul 28:2020.06.08.140236. doi: 10.1101/2020.06.08.140236. Preprint.
PMID: 32577638
responsible party type: Sponsor-Investigator
investigator affiliation: University of Mississippi, Oxford
investigator full name: Joshua Sharp
investigator title: Associate Professor
mesh term: Heparin
mesh term: Calcium heparin
sharing ipd: Yes
ipd description: Individual participant data that underlie the results reported, after deidentification
ipd info type: Study Protocol
ipd time frame: Beginning 3 months and ending 36 months following publication
ipd access criteria: Proposals should be directed to jsharp@olemiss.edu. To gain access, requestors will need to sign a data access agreement.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 