<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/NCT02985515</url>
  </required_header>
  <id_info>
    <org_study_id>201608163</org_study_id>
    <nct_id>NCT02985515</nct_id>
  </id_info>
  <brief_title>Steroid Nasal Irrigation for Flavor Evaluation and Detection Study</brief_title>
  <acronym>SNIFFED</acronym>
  <official_title>Steroid Nasal Irrigation for Flavor Evaluation and Detection (SNIFFED) Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to examine the efficacy of a 12-week smell training&#xD;
      intervention for participants with olfactory dysfunction following an infection of the upper&#xD;
      respiratory tract.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Olfactory dysfunction affects up to fifteen percent of the general population and can cause&#xD;
      significant psychosocial distress including decreased appetite, reduced self-hygiene, and&#xD;
      mood disturbances.&#xD;
&#xD;
      This study aims to study the efficacy of smell training for patients with olfactory&#xD;
      dysfunction following a viral upper respiratory tract infection. Eligible participants will&#xD;
      complete a 30-day course of budesonide nasal saline irrigation. Participants who do not show&#xD;
      improvement in their olfaction based on composite smell and taste tests will be eligible to&#xD;
      receive a baseline resting-state fMRI (rs-fMRI) and complete a 12-week smell training&#xD;
      intervention program. Smell training involves participants smelling 4 odors (phenyl ethyl&#xD;
      alcohol, eucalyptus, lemon, and eugenol) twice a day for 12 weeks. Following completion of&#xD;
      smell training, participants will undergo repeat smell and taste tests as well as rs-fMRI to&#xD;
      ascertain the efficacy of smell training.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 28, 2016</start_date>
  <completion_date type="Actual">November 20, 2019</completion_date>
  <primary_completion_date type="Actual">November 20, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <intervention_model_description>This is a prospective cohort, pre- and post-intervention study</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training.</measure>
    <time_frame>12 weeks</time_frame>
    <description>Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p&lt;0.05 was considered to be significant.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment</measure>
    <time_frame>30 days</time_frame>
    <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Subjective Response to Smell Training Intervention</measure>
    <time_frame>12 weeks</time_frame>
    <description>Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of Olfactory Network in Healthy Controls to Study Participants</measure>
    <time_frame>1 week</time_frame>
    <description>Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P &lt; .05 was considered statistically significant.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training</measure>
    <time_frame>12 weeks</time_frame>
    <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pre and Post Difference in QOD-NS After Smell Training</measure>
    <time_frame>12 weeks</time_frame>
    <description>The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">51</enrollment>
  <condition>Olfactory Disorder</condition>
  <arm_group>
    <arm_group_label>Budesonide Nasal Irrigation</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>30-day run-in course of budesonide nasal irrigation.&#xD;
1-month supply of budesonide capsules, an 8-oz sinus rinse bottle, and a 1-month supply of commercially prepared isotonic salt packets.&#xD;
Participants were instructed to dissolve 2 budesonide capsules (0.5mg per capsule) into the sinus rinse bottle along with the saline mixture and then irrigate both nasal cavities once daily.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Budesonide Nasal Irrigation + Smell Training</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Budesonide nasal irrigation + smell training for 12 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Baseline olfaction testing and rs-fMRI</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Smell training</intervention_name>
    <description>Participants will be provided with 4 vials of essential odors. Participants will sniff each scent for 20-30 seconds, twice daily, for 12 weeks. The participant will take 30 seconds of rest between each scent. All participants will undergo this smell training regimen for 12 weeks.</description>
    <arm_group_label>Budesonide Nasal Irrigation + Smell Training</arm_group_label>
    <other_name>Olfactory Training</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 18 and 70&#xD;
&#xD;
          -  Anosmia or hyposmia (UPSIT &lt;34 (male), UPSIT &lt;34 (female); Sniffin' Sticks threshold&#xD;
             below 5.5)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to understand English&#xD;
&#xD;
          -  Current smoker or history of smoking within the past 6 months&#xD;
&#xD;
          -  Current nasal polyps&#xD;
&#xD;
          -  Exposure to head and or/neck radiation&#xD;
&#xD;
          -  Exposure to chemotherapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jay F Piccirillo, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF, Kimmelman CP, Brightman VJ, Snow JB Jr. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch Otolaryngol Head Neck Surg. 1991 May;117(5):519-28. doi: 10.1001/archotol.1991.01870170065015.</citation>
    <PMID>2021470</PMID>
  </reference>
  <reference>
    <citation>Doty RL, Frye RE, Agrawal U. Internal consistency reliability of the fractionated and whole University of Pennsylvania Smell Identification Test. Percept Psychophys. 1989 May;45(5):381-4. doi: 10.3758/bf03210709.</citation>
    <PMID>2726398</PMID>
  </reference>
  <reference>
    <citation>Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. 'Sniffin' sticks': olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses. 1997 Feb;22(1):39-52. doi: 10.1093/chemse/22.1.39.</citation>
    <PMID>9056084</PMID>
  </reference>
  <reference>
    <citation>Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. &quot;Sniffin' sticks&quot;: screening of olfactory performance. Rhinology. 1996 Dec;34(4):222-6.</citation>
    <PMID>9050101</PMID>
  </reference>
  <reference>
    <citation>Coldwell SE, Mennella JA, Duffy VB, Pelchat ML, Griffith JW, Smutzer G, Cowart BJ, Breslin PA, Bartoshuk LM, Hastings L, Victorson D, Hoffman HJ. Gustation assessment using the NIH Toolbox. Neurology. 2013 Mar 12;80(11 Suppl 3):S20-4. doi: 10.1212/WNL.0b013e3182872e38.</citation>
    <PMID>23479539</PMID>
  </reference>
  <reference>
    <citation>Bartoshuk LM, Duffy VB, Hayes JE, Moskowitz HR, Snyder DJ. Psychophysics of sweet and fat perception in obesity: problems, solutions and new perspectives. Philos Trans R Soc Lond B Biol Sci. 2006 Jul 29;361(1471):1137-48. doi: 10.1098/rstb.2006.1853.</citation>
    <PMID>16815797</PMID>
  </reference>
  <reference>
    <citation>Pepino MY, Finkbeiner S, Beauchamp GK, Mennella JA. Obese women have lower monosodium glutamate taste sensitivity and prefer higher concentrations than do normal-weight women. Obesity (Silver Spring). 2010 May;18(5):959-65. doi: 10.1038/oby.2009.493. Epub 2010 Jan 14.</citation>
    <PMID>20075854</PMID>
  </reference>
  <reference>
    <citation>Cicerale S, Breslin PA, Beauchamp GK, Keast RS. Sensory characterization of the irritant properties of oleocanthal, a natural anti-inflammatory agent in extra virgin olive oils. Chem Senses. 2009 May;34(4):333-9. doi: 10.1093/chemse/bjp006. Epub 2009 Mar 8.</citation>
    <PMID>19273462</PMID>
  </reference>
  <reference>
    <citation>Keast RS, Roper J. A complex relationship among chemical concentration, detection threshold, and suprathreshold intensity of bitter compounds. Chem Senses. 2007 Mar;32(3):245-53. doi: 10.1093/chemse/bjl052. Epub 2007 Jan 13.</citation>
    <PMID>17220518</PMID>
  </reference>
  <reference>
    <citation>Cowart BJ. Relationships between taste and smell across the adult life span. Ann N Y Acad Sci. 1989;561:39-55. doi: 10.1111/j.1749-6632.1989.tb20968.x. No abstract available.</citation>
    <PMID>2735688</PMID>
  </reference>
  <reference>
    <citation>Hummel T, Rissom K, Reden J, Hahner A, Weidenbecher M, Huttenbrink KB. Effects of olfactory training in patients with olfactory loss. Laryngoscope. 2009 Mar;119(3):496-9. doi: 10.1002/lary.20101.</citation>
    <PMID>19235739</PMID>
  </reference>
  <reference>
    <citation>Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer's disease. J Neurol Sci. 2013 Oct 15;333(1-2):19-24. doi: 10.1016/j.jns.2013.06.033. Epub 2013 Aug 5.</citation>
    <PMID>23927938</PMID>
  </reference>
  <reference>
    <citation>Tepper BJ, Christensen CM, Cao J. Development of brief methods to classify individuals by PROP taster status. Physiol Behav. 2001 Jul;73(4):571-7. doi: 10.1016/s0031-9384(01)00500-5.</citation>
    <PMID>11495661</PMID>
  </reference>
  <reference>
    <citation>Pekala K, Chandra RK, Turner JH. Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2016 Mar;6(3):299-307. doi: 10.1002/alr.21669. Epub 2015 Dec 1.</citation>
    <PMID>26624966</PMID>
  </reference>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>December 3, 2016</study_first_submitted>
  <study_first_submitted_qc>December 6, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 7, 2016</study_first_posted>
  <results_first_submitted>April 14, 2021</results_first_submitted>
  <results_first_submitted_qc>November 3, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">November 4, 2022</results_first_posted>
  <last_update_submitted>November 3, 2022</last_update_submitted>
  <last_update_submitted_qc>November 3, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Anosmia</keyword>
  <keyword>Hyposmia</keyword>
  <keyword>Intranasal Steroid Irrigation</keyword>
  <keyword>Olfactory Neuroplasticity</keyword>
  <keyword>Olfactory training</keyword>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>May 22, 2019</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT02985515/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Adults 18 to 70 years of age with clinically diagnosed or self reported postviral olfactory loss of 3 months or longer were eligible to participate.&#xD;
For the control group, adults with normal smell function were eligible to participate.</recruitment_details>
      <pre_assignment_details>PVOD participants first underwent 30-day trial period of budesonide nasal irrigation. If they did not experience improvement in their smell to the normal range as measured by UPSIT and Sniffin'Sticks, they continued budesonide nasal irrigation plus 12-weeks of smell intervention. Resting-state fMRI was obtained before and after smell intervention.&#xD;
For the participants in the Control Group, one time fs-MRI and questionnaire completion only.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Controls</title>
          <description>Healthy volunteers with normal smell function. Participants in the Control Group completed UPSIT, MRI, and Questionnaires one time and were finished with study participation.</description>
        </group>
        <group group_id="P2">
          <title>Budesonide Nasal Irrigation</title>
          <description>30-day run-in course of budesonide nasal irrigation.&#xD;
1-month supply of budesonide capsules, an 8-oz sinus rinse bottle, and a 1-month supply of commercially prepared isotonic salt packets.&#xD;
Participants were instructed to dissolve 2 budesonide capsules (0.5mg per capsule) into the sinus rinse bottle along with the saline mixture and then irrigate both nasal cavities once daily.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Olfaction Testing</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Protocol Violation</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
        <period>
          <title>Smell Training</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Baseline data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group</population>
      <group_list>
        <group group_id="B1">
          <title>Budesonide Nasal Irrigation</title>
          <description>Participants will first undergo a 30-day trial of budesonide nasal saline irrigation. If there is no subsequent improvement in olfaction, participants will undergo a 12-week smell training intervention.&#xD;
Budesonide nasal irrigation: Eligible participants will be provided with a &quot;NeilMed&quot; Sinus Rinse Regular Bottle Kit and a one-month supply of USP Grade Sodium Chloride &amp; Sodium Bicarbonate Mixture commercially prepared packets. Participants will need to purchase distilled water or boil tap water for five minutes for use with the saline irrigation. The contents of two capsules (0.5mg budesonide each) will be dissolved into &quot;NeilMed&quot; Sinus Rinse Regular Bottle along with the saline rinse. Both nasal cavities will be irrigated once daily for 30 days.&#xD;
Smell training: Participants who do not have objective improvement in their olfaction after the trial of budesonide irrigation will have a baseline resting-state fMRI (rs-fMRI) and undergo 12 weeks of smell training. Smell training involves the participants smelling 4 vials of essential odors (clove, lemon, eucalyptus, rose) twice a day for 12 weeks. Following smell training, participants will have their smell ability re-evaluated and a second rs-fMRI performed.</description>
        </group>
        <group group_id="B2">
          <title>Control Group</title>
          <description>Control participants sex and age matched (±5 years) to participants with PVOD had normal smell as determined by UPSIT and were recruited for baseline neuroimaging. Individuals with MRI contraindications were excluded.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="23"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="43"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 participants remained after 8 were removed for protocol violations. The remaining 23 participants showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training.&#xD;
20 participants in the Control Group.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="20"/>
                    <count group_id="B3" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="35"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Additionally, 7 participants were removed from the final analysis due to motion artifact on MRI leaving a total of 16 participants in the final analysis.</population>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="20"/>
                    <count group_id="B3" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62" lower_limit="30" upper_limit="70"/>
                    <measurement group_id="B2" value="61.5" lower_limit="30" upper_limit="69"/>
                    <measurement group_id="B3" value="62" lower_limit="30" upper_limit="70"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Additionally, 7 participants were removed from the final analysis due to motion artifact on MRI leaving a total of 16 participants in the final analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="20"/>
                    <count group_id="B3" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="15"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Additionally, 7 participants were removed from the final analysis due to motion artifact on MRI leaving a total of 16 participants in the final analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="20"/>
                    <count group_id="B3" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <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_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_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="21"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="39"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown 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_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Additionally, 7 participants were removed from the final analysis due to motion artifact on MRI leaving a total of 16 participants in the final analysis.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="20"/>
                    <count group_id="B3" value="43"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="43"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Duration of smell loss</title>
          <description>Baseline duration of smell loss was not obtained from the control group as all 20 participants in the control group had normal smell.</description>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group</population>
          <units>months</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12" lower_limit="3" upper_limit="240"/>
                    <measurement group_id="B3" value="12" lower_limit="3" upper_limit="240"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>UPSIT</title>
          <description>University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. A score below 5 is highly suggestive of malingering. Possible scores range from 0 to 40 with higher scores indicating better sense of smell.</description>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="19.5" lower_limit="7" upper_limit="36"/>
                    <measurement group_id="B3" value="35" lower_limit="10" upper_limit="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>TDI</title>
          <description>Like UPSIT, the Sniffin' Sticks test is a reliable and validated tool to assess olfactory function. Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.&#xD;
Baseline TDI was not obtained from the control group as all 20 participants had normal smell.</description>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18" lower_limit="7" upper_limit="30.5"/>
                    <measurement group_id="B3" value="18" lower_limit="7" upper_limit="30.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>VAS sense of smell</title>
          <description>Baseline subjective sense of smell was measured using visual analogue sense of smell with scores ranging from 0 to 100. 0 represented no sense of smell and 100 represented best possible sense of smell.&#xD;
As all participants in the control group had normal sense of smell, baseline VAS was not measured.</description>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0.1095" lower_limit="0" upper_limit="0.5"/>
                    <measurement group_id="B3" value="0.1095" lower_limit="0" upper_limit="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>QOD-NS score</title>
          <description>The Questionnaire for Olfactory Dysfunction-Negative Statements (QOD-NS) is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (scores range from 0 to 51), with higher scores reflective of more impaired quality of life.&#xD;
As all participants in the control group had both objective and subjective normal sense of smell, QOD-NS was not ascertained in the control group.</description>
          <population>A total of 31 PVOD participants were in the Budesonide Nasal Irrigation group. Of the 31 participants, 23 remained after 8 were removed for protocol violations. The remaining 23 showed no improvement after the 30 days of budesonide nasal irrigation and therefore continued on the study and received 12 weeks of smell training. Data were only *collected* for 23 participants in the Budesonide Nasal Irrigation Arm/Group.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="23"/>
                    <count group_id="B2" value="0"/>
                    <count group_id="B3" value="23"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10.55" lower_limit="3.42" upper_limit="16.53"/>
                    <measurement group_id="B3" value="10.55" lower_limit="3.42" upper_limit="16.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training.</title>
        <description>Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p&lt;0.05 was considered to be significant.</description>
        <time_frame>12 weeks</time_frame>
        <population>Of the total 23 participants who completed smell training and rs-fMRI, 7 were excluded from analysis because of excessive artifact. Thus, the final study included a total of 16 participants. A set of 164 regions of interest(ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing. The CONN toolbox is an open source Matlab/SPM software that integrates pre-processing, display, and analysis of rs-fMRI data.</population>
        <group_list>
          <group group_id="O1">
            <title>Smell Training</title>
            <description>Participants will first undergo a 30-day trial of budesonide nasal saline irrigation. If there is no subsequent improvement in olfaction, participants will undergo a 12-week smell training intervention.&#xD;
Smell training: Eligible participants will be provided with a &quot;NeilMed&quot; Sinus Rinse Regular Bottle Kit and a one-month supply of USP Grade Sodium Chloride &amp; Sodium Bicarbonate Mixture commercially prepared packets. Participants will need to purchase distilled water or boil tap water for five minutes for use with the saline irrigation. The contents of two capsules (0.5mg budesonide each) will be dissolved into &quot;NeilMed&quot; Sinus Rinse Regular Bottle along with the saline rinse. Both nasal cavities will be irrigated once daily for 30 days.&#xD;
Participants who do not have objective improvement in their olfaction after the trial of budesonide irrigation will have a baseline resting-state fMRI (rs-fMRI) and undergo 12 weeks of smell training. Smell training involves the participants smelling 4 vials of essential odors twice a day for 12 weeks. Following smell training, participants will have their smell ability re-evaluated and a second rs-fMRI performed.</description>
          </group>
        </group_list>
        <measure>
          <title>Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training.</title>
          <description>Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p&lt;0.05 was considered to be significant.</description>
          <population>Of the total 23 participants who completed smell training and rs-fMRI, 7 were excluded from analysis because of excessive artifact. Thus, the final study included a total of 16 participants. A set of 164 regions of interest(ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing. The CONN toolbox is an open source Matlab/SPM software that integrates pre-processing, display, and analysis of rs-fMRI data.</population>
          <units>Regions of interest</units>
          <param>Number</param>
          <units_analyzed>Regions of interest</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Regions of interest</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="187"/>
              </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>
        <type>Secondary</type>
        <title>Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment</title>
        <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
        <time_frame>30 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Budesonide Nasal Irrigation</title>
            <description>Participants will first undergo a 30-day trial of budesonide nasal saline irrigation. If there is no subsequent improvement in olfaction, participants will undergo a 12-week smell training intervention.&#xD;
Budesonide nasal irrigation: Eligible participants will be provided with a &quot;NeilMed&quot; Sinus Rinse Regular Bottle Kit and a one-month supply of USP Grade Sodium Chloride &amp; Sodium Bicarbonate Mixture commercially prepared packets. Participants will need to purchase distilled water or boil tap water for five minutes for use with the saline irrigation. The contents of two capsules (0.5mg budesonide each) will be dissolved into &quot;NeilMed&quot; Sinus Rinse Regular Bottle along with the saline rinse. Both nasal cavities will be irrigated once daily for 30 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment</title>
          <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>UPSIT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.5" lower_limit="5" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TDI</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="17.5" lower_limit="7" upper_limit="27.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Subjective Response to Smell Training Intervention</title>
        <description>Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Smell Training</title>
            <description>Smell training: Participants had no improvement in olfaction underoing 30-days of budesonide nasal saline irrigation underwent 12-week smell training intervention. Participants were given 4 vials of essential oils (clove, lemon, eucalyptus, rose) to smell twice a day for 12 weeks. Participants underwent a baseline resting-state (rs-fMRI) prior to smell intervention. Following smell training, participants had their smell ability re-evaluated and a second rs-fMRI performed.</description>
          </group>
        </group_list>
        <measure>
          <title>Subjective Response to Smell Training Intervention</title>
          <description>Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="23.8" lower_limit="9" upper_limit="83.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Comparison of Olfactory Network in Healthy Controls to Study Participants</title>
        <description>Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P &lt; .05 was considered statistically significant.</description>
        <time_frame>1 week</time_frame>
        <population>A set of 164 regions of interest (ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing.</population>
        <group_list>
          <group group_id="O1">
            <title>Control Group</title>
            <description>20 participants sex and age matched (+/- 5 years) to participants with PVOD with normal smell as determined by UPSIT were recruited for baseline neuroimaging.</description>
          </group>
        </group_list>
        <measure>
          <title>Comparison of Olfactory Network in Healthy Controls to Study Participants</title>
          <description>Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P &lt; .05 was considered statistically significant.</description>
          <population>A set of 164 regions of interest (ROIs) from the CONN toolbox were used, supplemented with 23 ROIs determined by prior studies to be associated with olfactory processing.</population>
          <units>Regions of interest</units>
          <param>Number</param>
          <units_analyzed>Regions of interest</units_analyzed>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
              </count_list>
            </analyzed>
            <analyzed>
              <units>Regions of interest</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="187"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training</title>
        <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Smell Training</title>
            <description>Smell training:&#xD;
Participants who do not have objective improvement in their olfaction after the trial of budesonide irrigation will have a baseline resting-state fMRI (rs-fMRI) and undergo 12 weeks of smell training. Smell training involves the participants smelling 4 vials of essential odors (clove, lemon, eucalyptus, rose) twice a day for 12 weeks. Following smell training, participants will have their smell ability re-evaluated and a second rs-fMRI performed.</description>
          </group>
        </group_list>
        <measure>
          <title>Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training</title>
          <description>Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.&#xD;
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell.&#xD;
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score &gt;30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>UPSIT</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19" lower_limit="9" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>TDI</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="18.3" lower_limit="7" upper_limit="34.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Pre and Post Difference in QOD-NS After Smell Training</title>
        <description>The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life.</description>
        <time_frame>12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Smell Training</title>
            <description>Smell training:&#xD;
Participants who do not have objective improvement in their olfaction after the trial of budesonide irrigation will have a baseline resting-state fMRI (rs-fMRI) and undergo 12 weeks of smell training. Smell training involves the participants smelling 4 vials of essential odors (clove, lemon, eucalyptus, rose) twice a day for 12 weeks. Following smell training, participants will have their smell ability re-evaluated and a second rs-fMRI performed.</description>
          </group>
        </group_list>
        <measure>
          <title>Pre and Post Difference in QOD-NS After Smell Training</title>
          <description>The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life.</description>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.4" lower_limit="0" upper_limit="17.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Up through 13 months</time_frame>
      <desc># who underwent budesonide nasal irrigation at risk for serious adverse events:31; All participants who underwent the 12-weeks of smell training are included because all underwent 30-day trial of budesonide nasal irrigation. If improved, participation ended.If no improvement, they underwent 12-weeks of smell training intervention. # of controls at risk for serious adverse events:20; Adverse Events were not collected separately in the Smell Training portion from the Budesonide Nasal Irrigation.</desc>
      <group_list>
        <group group_id="E1">
          <title>Control Group</title>
          <description>20 participants sex and age matched (+/- 5 years) to participants with PVOD with normal smell as determined by UPSIT were recruited for baseline neuroimaging.</description>
        </group>
        <group group_id="E2">
          <title>Budesonide Nasal Irrigation</title>
          <description>Adults 18 to 70 years of age with clinically diagnosed or self-reported postviral olfactory loss of 3 months underwent 30-day trial of budesonide nasal irrigation. If they improved, study participation ended. If they had no improvement in sense of smell after a 30-day trial of budesonide nasal irrigation, they then underwent 12-weeks of smell training intervention. All participants who underwent the 12-weeks of smell training intervention are included this adverse event group. Adverse Events were not collected separately in the Smell Training portion of the study from the Budesonide Nasal Irrigation but instead collected as a whole.</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="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </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="20"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cavernoma</sub_title>
                <description>Incidental MRI finding</description>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>pleomorphic adenoma</sub_title>
                <description>Incidental MRI finding</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>extra-axial meningiomas</sub_title>
                <description>Incidental MRI finding</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="31"/>
              </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>Pawina JIramongkolchai, MD</name_or_title>
      <organization>Washington University in St. Louis</organization>
      <phone>314-393-2455</phone>
      <email>pawina@wustl.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/NCT02985515
org study id: 201608163
nct id: NCT02985515
lead sponsor: 
has dmc: Yes
The purpose of this research study is to examine the efficacy of a 12-week smell training
      intervention for participants with olfactory dysfunction following an infection of the upper
      respiratory tract.
Olfactory dysfunction affects up to fifteen percent of the general population and can cause
      significant psychosocial distress including decreased appetite, reduced self-hygiene, and
      mood disturbances.

      This study aims to study the efficacy of smell training for patients with olfactory
      dysfunction following a viral upper respiratory tract infection. Eligible participants will
      complete a 30-day course of budesonide nasal saline irrigation. Participants who do not show
      improvement in their olfaction based on composite smell and taste tests will be eligible to
      receive a baseline resting-state fMRI (rs-fMRI) and complete a 12-week smell training
      intervention program. Smell training involves participants smelling 4 odors (phenyl ethyl
      alcohol, eucalyptus, lemon, and eugenol) twice a day for 12 weeks. Following completion of
      smell training, participants will undergo repeat smell and taste tests as well as rs-fMRI to
      ascertain the efficacy of smell training.
allocation: Non-Randomized
intervention model: Parallel Assignment
intervention model description: This is a prospective cohort, pre- and post-intervention study
primary purpose: Treatment
masking: None (Open Label)
measure: Pre- and Post-intervention Difference in Functional Connectivity Before and After Smell Training.
time frame: 12 weeks
description: Baseline and post-intervention connectivity within and between regions of interest in the olfactory and olfactory related networks using resting state fMRI will be obtained. Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons. p<0.05 was considered to be significant.
measure: Pre- and Post-intervention Difference in Smell Testing Before and After Budesonide Treatment
time frame: 30 days
description: Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores indicating better sense of smell.
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score >30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.
measure: Subjective Response to Smell Training Intervention
time frame: 12 weeks
description: Participants subjective sense of smell following intervention is measured using a visual analogue scale from 0 to 100 with 0 representing no sense of smell and 100 representing best possible sense of smell.
measure: Comparison of Olfactory Network in Healthy Controls to Study Participants
time frame: 1 week
description: Baseline functional connectivity within and between the olfactory and associated networks of healthy controls will be compared to that of study participants prior to smell intervention treatment as measured by rs-fMRI.Resting-state connectivity was analyzed using the CONN toolbox version 18b (https://web.conn-toolbox.org/) and SPM12, version 7487 (Wellcome Trust Centre for Neuroimaging). Functional connectivity values (Fisher z-transformed Pearson correlation coefficients) were compared using a paired, 2-tailed t test and corrected for multiple comparisons . P < .05 was considered statistically significant.
measure: Pre- and Post-intervention Difference in Smell Testing Before and After Smell Training
time frame: 12 weeks
description: Objective pre- and post-intervention differences of participant performance on the UPSIT and Sniffin Sticks tests before and after budesonide saline nasal irrigation.
University of Pennsylvania Identification Test (UPSIT) consists of 4 odor-impregnated booklets that participants scratch and sniff to identify various odors, and scores account for differences in sex. Hyposmia is defined as a score of 19 to 34 for females and 19 to 33 for males. Anosmia for either sex is defined as a score below 18. Possible scores range from 0 to 40 with higher scores representing better sense of smell.
Sniffin' Sticks are odor-encapsulated markers that are used to measure odor detection threshold, discrimination, and identification (TDI). Normosmia is defined as a TDI score >30.5. An increase by 5.5 points or more from baseline is considered meaningful improvement. Possible scores range from 1 to 48 with higher values indicating better sense of smell.
measure: Pre and Post Difference in QOD-NS After Smell Training
time frame: 12 weeks
description: The QOD-NS is a validated 17-item questionnaire that pertains to olfactory-specific quality of life domains adversely impacted by olfactory dysfunction and is inversely scored (maximum score of 51), with higher scores reflective of more impaired quality of life.
arm group label: Budesonide Nasal Irrigation
arm group type: No Intervention
description: 30-day run-in course of budesonide nasal irrigation.
1-month supply of budesonide capsules, an 8-oz sinus rinse bottle, and a 1-month supply of commercially prepared isotonic salt packets.
Participants were instructed to dissolve 2 budesonide capsules (0.5mg per capsule) into the sinus rinse bottle along with the saline mixture and then irrigate both nasal cavities once daily.
arm group label: Budesonide Nasal Irrigation + Smell Training
arm group type: Experimental
description: Budesonide nasal irrigation + smell training for 12 weeks
arm group label: Controls
arm group type: No Intervention
description: Baseline olfaction testing and rs-fMRI
intervention type: Behavioral
intervention name: Smell training
description: Participants will be provided with 4 vials of essential odors. Participants will sniff each scent for 20-30 seconds, twice daily, for 12 weeks. The participant will take 30 seconds of rest between each scent. All participants will undergo this smell training regimen for 12 weeks.
arm group label: Budesonide Nasal Irrigation + Smell Training
other name: Olfactory Training
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jay F Piccirillo, MD
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
citation: Deems DA, Doty RL, Settle RG, Moore-Gillon V, Shaman P, Mester AF, Kimmelman CP, Brightman VJ, Snow JB Jr. Smell and taste disorders, a study of 750 patients from the University of Pennsylvania Smell and Taste Center. Arch Otolaryngol Head Neck Surg. 1991 May;117(5):519-28. doi: 10.1001/archotol.1991.01870170065015.
PMID: 2021470
citation: Doty RL, Frye RE, Agrawal U. Internal consistency reliability of the fractionated and whole University of Pennsylvania Smell Identification Test. Percept Psychophys. 1989 May;45(5):381-4. doi: 10.3758/bf03210709.
PMID: 2726398
citation: Hummel T, Sekinger B, Wolf SR, Pauli E, Kobal G. 'Sniffin' sticks': olfactory performance assessed by the combined testing of odor identification, odor discrimination and olfactory threshold. Chem Senses. 1997 Feb;22(1):39-52. doi: 10.1093/chemse/22.1.39.
PMID: 9056084
citation: Kobal G, Hummel T, Sekinger B, Barz S, Roscher S, Wolf S. "Sniffin' sticks": screening of olfactory performance. Rhinology. 1996 Dec;34(4):222-6.
PMID: 9050101
citation: Coldwell SE, Mennella JA, Duffy VB, Pelchat ML, Griffith JW, Smutzer G, Cowart BJ, Breslin PA, Bartoshuk LM, Hastings L, Victorson D, Hoffman HJ. Gustation assessment using the NIH Toolbox. Neurology. 2013 Mar 12;80(11 Suppl 3):S20-4. doi: 10.1212/WNL.0b013e3182872e38.
PMID: 23479539
citation: Bartoshuk LM, Duffy VB, Hayes JE, Moskowitz HR, Snyder DJ. Psychophysics of sweet and fat perception in obesity: problems, solutions and new perspectives. Philos Trans R Soc Lond B Biol Sci. 2006 Jul 29;361(1471):1137-48. doi: 10.1098/rstb.2006.1853.
PMID: 16815797
citation: Pepino MY, Finkbeiner S, Beauchamp GK, Mennella JA. Obese women have lower monosodium glutamate taste sensitivity and prefer higher concentrations than do normal-weight women. Obesity (Silver Spring). 2010 May;18(5):959-65. doi: 10.1038/oby.2009.493. Epub 2010 Jan 14.
PMID: 20075854
citation: Cicerale S, Breslin PA, Beauchamp GK, Keast RS. Sensory characterization of the irritant properties of oleocanthal, a natural anti-inflammatory agent in extra virgin olive oils. Chem Senses. 2009 May;34(4):333-9. doi: 10.1093/chemse/bjp006. Epub 2009 Mar 8.
PMID: 19273462
citation: Keast RS, Roper J. A complex relationship among chemical concentration, detection threshold, and suprathreshold intensity of bitter compounds. Chem Senses. 2007 Mar;32(3):245-53. doi: 10.1093/chemse/bjl052. Epub 2007 Jan 13.
PMID: 17220518
citation: Cowart BJ. Relationships between taste and smell across the adult life span. Ann N Y Acad Sci. 1989;561:39-55. doi: 10.1111/j.1749-6632.1989.tb20968.x. No abstract available.
PMID: 2735688
citation: Hummel T, Rissom K, Reden J, Hahner A, Weidenbecher M, Huttenbrink KB. Effects of olfactory training in patients with olfactory loss. Laryngoscope. 2009 Mar;119(3):496-9. doi: 10.1002/lary.20101.
PMID: 19235739
citation: Stamps JJ, Bartoshuk LM, Heilman KM. A brief olfactory test for Alzheimer's disease. J Neurol Sci. 2013 Oct 15;333(1-2):19-24. doi: 10.1016/j.jns.2013.06.033. Epub 2013 Aug 5.
PMID: 23927938
citation: Tepper BJ, Christensen CM, Cao J. Development of brief methods to classify individuals by PROP taster status. Physiol Behav. 2001 Jul;73(4):571-7. doi: 10.1016/s0031-9384(01)00500-5.
PMID: 11495661
citation: Pekala K, Chandra RK, Turner JH. Efficacy of olfactory training in patients with olfactory loss: a systematic review and meta-analysis. Int Forum Allergy Rhinol. 2016 Mar;6(3):299-307. doi: 10.1002/alr.21669. Epub 2015 Dec 1.
PMID: 26624966
responsible party type: Sponsor
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 