<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/NCT02252289</url>
  </required_header>
  <id_info>
    <org_study_id>154768</org_study_id>
    <secondary_id>P2SKP3_151971/1</secondary_id>
    <nct_id>NCT02252289</nct_id>
  </id_info>
  <brief_title>Fluctuation of Airway Function in Children With Asthma</brief_title>
  <official_title>Fluctuation of Airway Function in Children With Asthma Phenotype as a Predictor of Outcome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Imperial College London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Royal Brompton &amp; Harefield NHS Foundation Trust</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Swiss National Science Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Imperial College London</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      It is increasingly recognised that asthma is not a single disease but that there are many&#xD;
      different phenotypes. Much of the work that we have previously carried out has focussed on&#xD;
      differentiating children with difficult asthma (those whose asthma control improves with&#xD;
      attention to the basics of asthma management such as adherence) from those with severe&#xD;
      therapy resistant asthma (ongoing poor control despite high dose treatment and attention to&#xD;
      the basics. Our collaborators in Basel, Switzerland have demonstrated that serial&#xD;
      measurements of lung function (peak flow) in adults can characterise the severe asthma&#xD;
      phenotype and its stability in adults with asthma. We plan to carry out twice daily peak flow&#xD;
      measurement sin children with asthma using an electronic peak flow meter. We will analyse&#xD;
      peak flow patterns in children with severe therapy resistant asthma (STRA), difficult asthma&#xD;
      (DA) and mild to moderate asthma. We will also investigate the relationship between peak flow&#xD;
      variations and symptoms, recorded in a daily diary and medication use, recorded by an&#xD;
      electronic measuring device which attaches to the child's own inhaler (Smart-inhaler).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Many children present with poorly controlled asthma despite high intensity treatment&#xD;
      including high doses of inhaled steroids. A number of these children will get better once the&#xD;
      basics of asthma management are addressed (such as adherence, allergen avoidance, smoking&#xD;
      cessation). The remainder will need further escalation of treatment (with attendant side&#xD;
      effects) and more invasive, investigations. Adults with severe asthma have been found to have&#xD;
      differences in the fluctuation patterns of peak flow compared to mild asthmatics. This study&#xD;
      will enable us to evaluate whether the same is true in children, enabling us to improve the&#xD;
      way we identify children with difficult asthma (DA) and severe therapy resistant asthma&#xD;
      (STRA) and whether the difficult asthma: DA group are in fact more similar to the&#xD;
      mild/moderate group.&#xD;
&#xD;
      Asthma exacerbations are a serious and concerning problem in children with asthma. This study&#xD;
      will enable us to assess whether mathematical modelling of fluctuation patterns can enable us&#xD;
      to predict n asthma attack and therefore intervene before it becomes severe or even life&#xD;
      threatening. This study will also enable us to investigate the relationship between symptoms,&#xD;
      peak flow patterns, exacerbations and adherence to inhaled corticosteroids (ICS) as measured&#xD;
      by electronic recording devices (Smart-inhalers).&#xD;
&#xD;
      This is an observational cohort study. If the child and their family are happy to participate&#xD;
      in the study the first study visit can take place immediately. If they would like time to&#xD;
      consider the study it can be deferred until their next routine attendance at the hospital.&#xD;
&#xD;
      Study visit 1:&#xD;
&#xD;
      Information will be collected relating to past medical history, asthma history and current&#xD;
      medications (this information may also be obtained from the case notes).&#xD;
&#xD;
      The following standardised questionnaires will be used: Asthma Control Test, children &gt;12&#xD;
      years (ACT) or Childhood Asthma Control Test, children 6-11years (cACT) (usually completed as&#xD;
      part of a routine clinical visit); Mini Paediatric Asthma Quality of Life Questionnaire&#xD;
      (PAQLQ); Medicines Adherence Rating Scale (MARS); Beliefs about Medicines Questionnaire&#xD;
      (BMQ).&#xD;
&#xD;
      Study procedures:&#xD;
&#xD;
      Lung function (included as part of a routine clinic visit), bronchodilator reversibility&#xD;
      (lung function repeated after administration of salbutamol), exhaled nitric oxide.&#xD;
&#xD;
      The child and their family will be issued with a paper diary, electronic peak flow meter&#xD;
      (PIKO) and electronic monitoring device for their inhaler (Smart-inhaler) and shown how to&#xD;
      use these.&#xD;
&#xD;
      Between visits:&#xD;
&#xD;
      Children will be asked to measure their peak flow twice daily (morning and evening) and&#xD;
      record their symptoms in a diary. Their parents will also be asked to complete the diary.&#xD;
      They will be contacted by the study investigator to check whether there are any technical&#xD;
      problems and as a reminder to make the peak flow measurements and complete the diary.&#xD;
&#xD;
      Visit 2, approximately 12 weeks later (from 8 to 16 weeks)&#xD;
&#xD;
      The second study visit will be scheduled at the time of a planned hospital appointment. This&#xD;
      will largely be a repeat of visit 1:&#xD;
&#xD;
      Information will be collected relating to asthma control and exacerbations since visit 1. The&#xD;
      following standardised questionnaires will be used: Asthma Control Test, children &gt;12 years&#xD;
      (ACT) or Childhood Asthma Control Test, children 6-11years (cACT) (usually completed as part&#xD;
      of a routine clinical visit); Mini Paediatric Asthma Quality of Life Questionnaire (PAQLQ)&#xD;
&#xD;
      Study procedures:&#xD;
&#xD;
      Lung function (included as part of a routine clinic visit), bronchodilator reversibility&#xD;
      (lung function repeated after administration of salbutamol), exhaled nitric oxide.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2014</start_date>
  <completion_date type="Actual">August 2015</completion_date>
  <primary_completion_date type="Actual">August 2015</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Individual variability in peak expiratory flow</measure>
    <time_frame>3 months</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Individual variability in FEV1</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Exacerbations (severe and moderate)</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Asthma control (asthma control test (ACT) scores )</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ICS dose</measure>
    <time_frame>3 months</time_frame>
    <description>Dose of inhaled corticosteroids</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Asthma related quality of life (paediatric quality of life PAQLQ scores)</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lung function (FEV1, bronchodilator reversibility)</measure>
    <time_frame>3 months</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adherence</measure>
    <time_frame>3 months</time_frame>
    <description>Adherence as measured by Smart-inhaler data which will be downloaded at the follow up visit</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">120</enrollment>
  <condition>Asthma</condition>
  <arm_group>
    <arm_group_label>Problematic severe asthmatics</arm_group_label>
    <description>Approximately 75 Children aged 5 to 17 years with problematic severe asthma (PSA). Two groups of PSA children will be recruited: those who have already been assessed as part of the Difficult Asthma protocol and classified as DA (difficult asthma)/ STRA (severe therapy resistant asthma) (training set) and those newly referred to the protocol (validation set).&#xD;
Previous enrolment or new referral to the Royal Brompton Hospital Difficult Asthma Protocol.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group of moderate asthmatics</arm_group_label>
    <description>A control group of 30 children aged 5 to 17 years with mild to moderate asthma.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Children with problematic severe asthma (PSA) will be identified from clinical records and&#xD;
        the existing clinical database which records all those who have been assessed as part of&#xD;
        the Difficult Asthma (DA) protocol. Children newly referred to the DA protocol will be&#xD;
        identified by notification from Clinical Nurse Specialists (CNSs) who receive the&#xD;
        referrals. Children with mild-moderate asthma will be identified from clinical records&#xD;
        only.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Parent / guardian must be able to give written informed consent prior to participation&#xD;
             in the study, which includes ability to comply with the requirements and restrictions&#xD;
             listed in the consent form. Informed consent must be obtained prior to undertaking any&#xD;
             study procedures.&#xD;
&#xD;
          -  Assent should be obtained from all children in the study where appropriate.&#xD;
&#xD;
          -  Male or female subject aged between 5 - 17 years inclusive at screening.&#xD;
&#xD;
          -  The parent / guardian, or where appropriate the child must be able to read,&#xD;
             comprehend, and write at a sufficient level to complete study related materials.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. As a result of medical interview, physical examination or screening investigation the&#xD;
             physician responsible considers the child unfit for the study.&#xD;
&#xD;
          2. Those who, in the opinion of the investigator, have a risk of non-compliance with&#xD;
             study procedures.&#xD;
&#xD;
          3. Significant alternative diagnoses that may mimic or complicate asthma, in particular&#xD;
             dysfunctional breathing, panic attacks, and overt psychosocial problems (if these are&#xD;
             thought to be the major problem rather than in addition to severe asthma)&#xD;
&#xD;
          4. Significant other primary pulmonary disorders in particular cystic fibrosis,&#xD;
             interstitial lung disease&#xD;
&#xD;
          5. Participants with bronchiectasis should only be excluded if this is thought to be the&#xD;
             major pulmonary disorder rather than in addition to severe asthma&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Louise Fleming, MD, MBChB</last_name>
    <role>Principal Investigator</role>
    <affiliation>Senior Lecturer Paediatric Respiratory Medicine, Imperial College London</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Royal Brompton Hospital</name>
      <address>
        <city>London</city>
        <zip>SW36NP</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <reference>
    <citation>Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray JJ, Pendergraft TB. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004 Jan;113(1):59-65. doi: 10.1016/j.jaci.2003.09.008.</citation>
    <PMID>14713908</PMID>
  </reference>
  <reference>
    <citation>Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, Rosenzweig JC, Manjunath R. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007 Apr;119(4):817-25. doi: 10.1016/j.jaci.2006.12.662. Epub 2007 Mar 13.</citation>
    <PMID>17353040</PMID>
  </reference>
  <reference>
    <citation>Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in children with asthma. Qual Life Res. 1996 Feb;5(1):35-46. doi: 10.1007/BF00435967.</citation>
    <PMID>8901365</PMID>
  </reference>
  <reference>
    <citation>Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ, Halm EA. Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol. 2009 Oct;103(4):325-31. doi: 10.1016/s1081-1206(10)60532-7.</citation>
    <PMID>19852197</PMID>
  </reference>
  <reference>
    <citation>Menckeberg TT, Bouvy ML, Bracke M, Kaptein AA, Leufkens HG, Raaijmakers JA, Horne R. Beliefs about medicines predict refill adherence to inhaled corticosteroids. J Psychosom Res. 2008 Jan;64(1):47-54. doi: 10.1016/j.jpsychores.2007.07.016.</citation>
    <PMID>18157999</PMID>
  </reference>
  <reference>
    <citation>Frey U, Brodbeck T, Majumdar A, Taylor DR, Town GI, Silverman M, Suki B. Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature. 2005 Dec 1;438(7068):667-70. doi: 10.1038/nature04176.</citation>
    <PMID>16319891</PMID>
  </reference>
  <reference>
    <citation>Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, Wilson NM, Bush A. The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child. 2009 Oct;94(10):780-4. doi: 10.1136/adc.2008.152140. Epub 2009 Jun 21.</citation>
    <PMID>19546102</PMID>
  </reference>
  <verification_date>February 2016</verification_date>
  <study_first_submitted>September 26, 2014</study_first_submitted>
  <study_first_submitted_qc>September 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 30, 2014</study_first_posted>
  <last_update_submitted>February 19, 2016</last_update_submitted>
  <last_update_submitted_qc>February 19, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 22, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Asthma</keyword>
  <keyword>children</keyword>
  <keyword>fluctuation analysis</keyword>
  <keyword>exacerbations</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <pending_results>
    <submitted>July 22, 2019</submitted>
    <returned>August 29, 2019</returned>
    <submitted>October 10, 2019</submitted>
    <submission_canceled>October 10, 2019</submission_canceled>
    <submitted>February 9, 2021</submitted>
    <returned>March 5, 2021</returned>
    <submitted>January 18, 2022</submitted>
    <returned>March 16, 2022</returned>
  </pending_results>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02252289
org study id: 154768
secondary id: P2SKP3_151971/1
nct id: NCT02252289
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
It is increasingly recognised that asthma is not a single disease but that there are many
      different phenotypes. Much of the work that we have previously carried out has focussed on
      differentiating children with difficult asthma (those whose asthma control improves with
      attention to the basics of asthma management such as adherence) from those with severe
      therapy resistant asthma (ongoing poor control despite high dose treatment and attention to
      the basics. Our collaborators in Basel, Switzerland have demonstrated that serial
      measurements of lung function (peak flow) in adults can characterise the severe asthma
      phenotype and its stability in adults with asthma. We plan to carry out twice daily peak flow
      measurement sin children with asthma using an electronic peak flow meter. We will analyse
      peak flow patterns in children with severe therapy resistant asthma (STRA), difficult asthma
      (DA) and mild to moderate asthma. We will also investigate the relationship between peak flow
      variations and symptoms, recorded in a daily diary and medication use, recorded by an
      electronic measuring device which attaches to the child's own inhaler (Smart-inhaler).
Many children present with poorly controlled asthma despite high intensity treatment
      including high doses of inhaled steroids. A number of these children will get better once the
      basics of asthma management are addressed (such as adherence, allergen avoidance, smoking
      cessation). The remainder will need further escalation of treatment (with attendant side
      effects) and more invasive, investigations. Adults with severe asthma have been found to have
      differences in the fluctuation patterns of peak flow compared to mild asthmatics. This study
      will enable us to evaluate whether the same is true in children, enabling us to improve the
      way we identify children with difficult asthma (DA) and severe therapy resistant asthma
      (STRA) and whether the difficult asthma: DA group are in fact more similar to the
      mild/moderate group.

      Asthma exacerbations are a serious and concerning problem in children with asthma. This study
      will enable us to assess whether mathematical modelling of fluctuation patterns can enable us
      to predict n asthma attack and therefore intervene before it becomes severe or even life
      threatening. This study will also enable us to investigate the relationship between symptoms,
      peak flow patterns, exacerbations and adherence to inhaled corticosteroids (ICS) as measured
      by electronic recording devices (Smart-inhalers).

      This is an observational cohort study. If the child and their family are happy to participate
      in the study the first study visit can take place immediately. If they would like time to
      consider the study it can be deferred until their next routine attendance at the hospital.

      Study visit 1:

      Information will be collected relating to past medical history, asthma history and current
      medications (this information may also be obtained from the case notes).

      The following standardised questionnaires will be used: Asthma Control Test, children >12
      years (ACT) or Childhood Asthma Control Test, children 6-11years (cACT) (usually completed as
      part of a routine clinical visit); Mini Paediatric Asthma Quality of Life Questionnaire
      (PAQLQ); Medicines Adherence Rating Scale (MARS); Beliefs about Medicines Questionnaire
      (BMQ).

      Study procedures:

      Lung function (included as part of a routine clinic visit), bronchodilator reversibility
      (lung function repeated after administration of salbutamol), exhaled nitric oxide.

      The child and their family will be issued with a paper diary, electronic peak flow meter
      (PIKO) and electronic monitoring device for their inhaler (Smart-inhaler) and shown how to
      use these.

      Between visits:

      Children will be asked to measure their peak flow twice daily (morning and evening) and
      record their symptoms in a diary. Their parents will also be asked to complete the diary.
      They will be contacted by the study investigator to check whether there are any technical
      problems and as a reminder to make the peak flow measurements and complete the diary.

      Visit 2, approximately 12 weeks later (from 8 to 16 weeks)

      The second study visit will be scheduled at the time of a planned hospital appointment. This
      will largely be a repeat of visit 1:

      Information will be collected relating to asthma control and exacerbations since visit 1. The
      following standardised questionnaires will be used: Asthma Control Test, children >12 years
      (ACT) or Childhood Asthma Control Test, children 6-11years (cACT) (usually completed as part
      of a routine clinical visit); Mini Paediatric Asthma Quality of Life Questionnaire (PAQLQ)

      Study procedures:

      Lung function (included as part of a routine clinic visit), bronchodilator reversibility
      (lung function repeated after administration of salbutamol), exhaled nitric oxide.
observational model: Cohort
time perspective: Prospective
measure: Individual variability in peak expiratory flow
time frame: 3 months
measure: Individual variability in FEV1
time frame: 3 months
measure: Exacerbations (severe and moderate)
time frame: 3 months
measure: Asthma control (asthma control test (ACT) scores )
time frame: 3 months
measure: ICS dose
time frame: 3 months
description: Dose of inhaled corticosteroids
measure: Asthma related quality of life (paediatric quality of life PAQLQ scores)
time frame: 3 months
measure: Lung function (FEV1, bronchodilator reversibility)
time frame: 3 months
measure: Adherence
time frame: 3 months
description: Adherence as measured by Smart-inhaler data which will be downloaded at the follow up visit
arm group label: Problematic severe asthmatics
description: Approximately 75 Children aged 5 to 17 years with problematic severe asthma (PSA). Two groups of PSA children will be recruited: those who have already been assessed as part of the Difficult Asthma protocol and classified as DA (difficult asthma)/ STRA (severe therapy resistant asthma) (training set) and those newly referred to the protocol (validation set).
Previous enrolment or new referral to the Royal Brompton Hospital Difficult Asthma Protocol.
arm group label: Control group of moderate asthmatics
description: A control group of 30 children aged 5 to 17 years with mild to moderate asthma.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 5 Years
maximum age: 17 Years
healthy volunteers: No
last name: Louise Fleming, MD, MBChB
role: Principal Investigator
affiliation: Senior Lecturer Paediatric Respiratory Medicine, Imperial College London
facility: 
country: United Kingdom
citation: Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray JJ, Pendergraft TB. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol. 2004 Jan;113(1):59-65. doi: 10.1016/j.jaci.2003.09.008.
PMID: 14713908
citation: Liu AH, Zeiger R, Sorkness C, Mahr T, Ostrom N, Burgess S, Rosenzweig JC, Manjunath R. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol. 2007 Apr;119(4):817-25. doi: 10.1016/j.jaci.2006.12.662. Epub 2007 Mar 13.
PMID: 17353040
citation: Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in children with asthma. Qual Life Res. 1996 Feb;5(1):35-46. doi: 10.1007/BF00435967.
PMID: 8901365
citation: Cohen JL, Mann DM, Wisnivesky JP, Home R, Leventhal H, Musumeci-Szabo TJ, Halm EA. Assessing the validity of self-reported medication adherence among inner-city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol. 2009 Oct;103(4):325-31. doi: 10.1016/s1081-1206(10)60532-7.
PMID: 19852197
citation: Menckeberg TT, Bouvy ML, Bracke M, Kaptein AA, Leufkens HG, Raaijmakers JA, Horne R. Beliefs about medicines predict refill adherence to inhaled corticosteroids. J Psychosom Res. 2008 Jan;64(1):47-54. doi: 10.1016/j.jpsychores.2007.07.016.
PMID: 18157999
citation: Frey U, Brodbeck T, Majumdar A, Taylor DR, Town GI, Silverman M, Suki B. Risk of severe asthma episodes predicted from fluctuation analysis of airway function. Nature. 2005 Dec 1;438(7068):667-70. doi: 10.1038/nature04176.
PMID: 16319891
citation: Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, Wilson NM, Bush A. The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child. 2009 Oct;94(10):780-4. doi: 10.1136/adc.2008.152140. Epub 2009 Jun 21.
PMID: 19546102
responsible party type: Sponsor
mesh term: Asthma
sharing ipd: No
submitted: July 22, 2019
returned: August 29, 2019
submitted: October 10, 2019
submission canceled: October 10, 2019
submitted: February 9, 2021
returned: March 5, 2021
submitted: January 18, 2022
returned: March 16, 2022