<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/NCT03788057</url>
  </required_header>
  <id_info>
    <org_study_id>NITLD</org_study_id>
    <nct_id>NCT03788057</nct_id>
  </id_info>
  <brief_title>Inflammatory Indices in Predicting the Failure of Inhaled Corticosteroids Reduction in Young Participants With Asthma</brief_title>
  <official_title>Evaluation of the Usefulness of Induced Sputum Eosinophilia, eNO and Bronchial Hyperresponsiveness in Predicting the Failure of Inhaled Corticosteroids Dose Reduction in Children and Adolescents With Stable Asthma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute for Tuberculosis and Lung Diseases, Poland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Rzeszow</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Regional Public Hospital in Lesko, Poland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>National Institute for Tuberculosis and Lung Diseases, Poland</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      A prospective, observational, interventional, single-blind study (blinded for a clinician in&#xD;
      the field of inflammatory parameters).&#xD;
&#xD;
      The aim of the study is evaluation of the usefulness of induced sputum eosinophilia and other&#xD;
      inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature, bronchial&#xD;
      hyperresponsiveness] in predicting the failure of treatment reduction with inhaled&#xD;
      corticosteroids (ICS) in stable asthma in children and adolescents.&#xD;
&#xD;
      In participants with a stable course of the asthma (confirmed in the run -in period), every 3&#xD;
      months the dose of ICS is halved (according to GINA guidelines) until the control is lost or&#xD;
      the lowest daily ICS dose is reached (200 mcg, calculated as budesonide equivalent).&#xD;
      Throughout the treatment reduction period, the participants run an observation card (clinical&#xD;
      symptoms) and peak expiratory flow rate (PEFR) measurements. Clinical evaluation is performed&#xD;
      every month, with spirometry, exhaled NO and exhaled breath temperature measurements. Before&#xD;
      the reduction and then one month after the change of treatment, the hyperresponsiveness&#xD;
      measurement is carried out with the sputum induction (combined method using hypertonic&#xD;
      saline), and 2 months after the change of treatment with the exercise challenge test.&#xD;
&#xD;
      In the case of loss of asthma control, beta-mimetic will be administered (temporarily) and&#xD;
      return to dose of ICS before reduction or further increase of treatment is planned. In severe&#xD;
      asthma exacerbations, oral steroids will be considered.&#xD;
&#xD;
      The study is observational: treatment is modified according to GINA guidelines based on&#xD;
      clinical data as part of routine medical care. Only difference compared do standard care is&#xD;
      supplementary inflammation evaluation (exhaled NO, sputum eosinophilia, bronchial&#xD;
      hyperreactivity).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Introduction Guidelines for the treatment of asthma recommend the use of the smallest dose of&#xD;
      inhaled steroid (ICS), which allows to maintain control of the symptoms of the disease. The&#xD;
      GINA 2006 guidelines proposed (and later editions it upheld) that in the case of symptom&#xD;
      control by monotherapy with ICS, to reduce their dose every 3 months, up to the lowest dose&#xD;
      administered once a day, which should be used for one year before taking possible decision to&#xD;
      stop it.&#xD;
&#xD;
      There are no clear of simple and sensitive indicators that would allow detection of a&#xD;
      threatening loss of control before the clinical symptoms worsen.&#xD;
&#xD;
      Aim of the study Evaluation of the usefulness of induced sputum eosinophilia and other&#xD;
      inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature (EBT), bronchial&#xD;
      hyperresponsiveness] in predicting the failure of treatment reduction with inhaled&#xD;
      corticosteroids in stable asthma in children and adolescents.&#xD;
&#xD;
      Subjects Participants aged 12-18 years with stable asthma (mild or moderate), treated in the&#xD;
      Allergy Clinic of the Hospital in Lesko with medium doses in ICS. The severity of asthma was&#xD;
      initially determined in accordance with the GINA criteria and verified during several years&#xD;
      of observation by the assessment of clinical symptoms, functional examinations and the dose&#xD;
      of inhaled steroids controlling the disease.&#xD;
&#xD;
      Project description A prospective, observational, single-blind study (blinded for a clinician&#xD;
      in the field of inflammatory parameters). Clinician takes decision about possible reduction&#xD;
      of ICS dose basing on clinical data only - is not aware of the results of the inflammatory&#xD;
      parameters measurement.&#xD;
&#xD;
      The study is consisting of two periods:&#xD;
&#xD;
      First period (run - in):&#xD;
&#xD;
      A four-week run - in period in which clinical symptoms and the use of short acting beta2&#xD;
      agonists (SABA) and PEFR are monitored. At the end of this period, in participants with&#xD;
      stable disease the following parameters are measured: eNO, EBT, spirometry, and sputum&#xD;
      induction with hyperosmolar saline in combination with the hyperresponsiveness. Before the&#xD;
      reduction of treatment on another day, an exercise challenge test is also performed.&#xD;
&#xD;
      The criteria for the stability of asthma in the run - in period are:&#xD;
&#xD;
        -  symptoms no more than 3 times a week&#xD;
&#xD;
        -  SABA use less than 3 times a week&#xD;
&#xD;
        -  without night wake up&#xD;
&#xD;
        -  PEFR variability below 20%&#xD;
&#xD;
        -  FEV1 above 80% of predicted&#xD;
&#xD;
      Second period of the study - reduction of anti-inflammatory therapy. In participants with&#xD;
      previously stable course of the asthma (confirmed in the run -in period), the control of&#xD;
      asthma is monitored regularly throughout the observation period. All participants run an&#xD;
      observation card (clinical symptoms) and PEFR measurements. Monthly spirometry, exhaled NO&#xD;
      and exhaled breath temperature measurements are performed. Every 3 months and one month after&#xD;
      the change of treatment (i.e in months 0, 1, 3, 4, 6 and 7), the hyperresponsiveness&#xD;
      measurement is carried out with the sputum induction (combined method, [7]). Two months after&#xD;
      the dose change (months 2, 5, 8) the exercise challenge test is carried out.&#xD;
&#xD;
      Every 3 months control of the asthma symptoms is evaluated taking account the clinical data,&#xD;
      and possible change of ICS dose is considered. Results of bronchial reactivity measurements&#xD;
      and sputum cytology are not known to clinician who decide on a possible ICS dose change - he&#xD;
      is blinded to the results of tests and the therapeutic decision is based solely on clinical&#xD;
      evaluation.&#xD;
&#xD;
      In participants with a stable course of the disease over past 3 months, the dose of ICS is&#xD;
      halved, in accordance with GINA guidelines. In the case of loss of asthma control,&#xD;
      appropriate treatment modifications are administered and the patient is withdrawn from the&#xD;
      study.&#xD;
&#xD;
      Participation in the study is continued until asthma control is lost or the lowest daily dose&#xD;
      is reached (200 mcg, calculated as budesonide equivalent) - without losing asthma control at&#xD;
      next visit.&#xD;
&#xD;
      Measurements&#xD;
&#xD;
        1. Daily clinical evaluation by the patient:&#xD;
&#xD;
             -  symptoms score according to the Santanello questionnaire&#xD;
&#xD;
             -  PEFR measurement&#xD;
&#xD;
        2. Every month&#xD;
&#xD;
             -  Asthma Control Test&#xD;
&#xD;
             -  spirometry [forced expiratory flow in 1st second (FEV1), forced vital capacity&#xD;
                (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25-75)]&#xD;
&#xD;
             -  eNO measurement&#xD;
&#xD;
             -  exhaled breath temperature measurement (EBT)&#xD;
&#xD;
        3. every 3 months&#xD;
&#xD;
             -  quality of life test (QoL, Polish version of the questionnaire), i.e. months 3, 6,&#xD;
                9&#xD;
&#xD;
             -  cytological evaluation of induced sputum (i.e. months 0, 1, 3, 4, 6, 7)&#xD;
&#xD;
             -  assessment of bronchial hyperresponsiveness:&#xD;
&#xD;
                  -  one month after the ICS dose reduction and then before each subsequent dose&#xD;
                     reduction in ICS ((i.e. months 0, 1, 3, 4, 6, 7) - during the sputum induction&#xD;
                     with hyperosmolar salt (combined method)&#xD;
&#xD;
                  -  2 months after each treatment reduction (i.e. months 2, 5, 8): exercise&#xD;
                     challenge test (6-minute free-running test monitored by pulse)&#xD;
&#xD;
      Criteria for loss of control [1, 6] - any of the following:&#xD;
&#xD;
        -  use of bronchodilators&gt; 5 times a week&#xD;
&#xD;
        -  the need for treatment with oral corticosteroids&#xD;
&#xD;
        -  PEFR decrease above 20% for 2 consecutive days, compared to the average run-in period In&#xD;
           the case of loss of asthma control, beta-mimetic will be administered (temporarily) and&#xD;
           return to the chronic administration of the previous, twice higher dose of ICS is&#xD;
           restored (or further increase of treatment). In severe exacerbations, inclusion of oral&#xD;
           steroids will be considered.&#xD;
&#xD;
      Criteria for discontinuation of participation in the study&#xD;
&#xD;
        1. Loss of asthma control (treatment strategy: beta-mimetic temporarily, return to dose of&#xD;
           ICS before reduction or further increase of treatment; in severe exacerbations,&#xD;
           inclusion of oral steroids).&#xD;
&#xD;
        2. Lack of adherence to the recommendations or failure to report.&#xD;
&#xD;
      The staff of the center has experience in the production of sputum induction in participants&#xD;
      with asthma [Ciółkowski J, Mazurek H, Stasiowska B. Evaluation of step - down therapy from an&#xD;
      inhaled steroid to montelukast in childhood asthma. Allergologia et immunopathologia (Madr.),&#xD;
      2014: Jul - Aug; 42 (4): 282 - 288].&#xD;
&#xD;
      The test will be performed in conditions ensuring patient safety, with the availability of an&#xD;
      anaesthesiologist and anti-shock kit.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 1, 2016</start_date>
  <completion_date type="Anticipated">October 2019</completion_date>
  <primary_completion_date type="Anticipated">March 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>A prospective, observational, interventional, single blind study. Clinician takes decision about possible reduction of ICS dose basing on clinical data only - is not aware of the results of the inflammatory parameters measurement.</intervention_model_description>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Clinician takes decision about possible change in treatment basing on clinical data only - is not aware of the results of the inflammatory parameters measurements</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>The percentage of patients with loss of asthma control</measure>
    <time_frame>at 9 months</time_frame>
    <description>Criteria for loss of control (any of the following):&#xD;
use of bronchodilators &gt; 5 times a week&#xD;
the need for treatment with oral corticosteroids&#xD;
PEFR decrease &gt;20% for 2 consecutive days, compared to the average run-in period</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in sputum eosinophilia</measure>
    <time_frame>at 1, 3, 4, 6 and 7 month</time_frame>
    <description>eosinophil percentage in induced sputum compared to baseline</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Change in airway hyperresponsiveness to hypertonic saline</measure>
    <time_frame>at 1, 3, 4, 6 and 7 month</time_frame>
    <description>Airway hyperresponsiveness to hypertonic saline measured using combined method (together with sputum induction) and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in airway hyperresponsiveness (exercise)</measure>
    <time_frame>at 2, 5 and 8 month</time_frame>
    <description>Airway hyperresponsiveness measured using an exercise challenge test and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in exhaled NO</measure>
    <time_frame>months 1 - 8</time_frame>
    <description>Measured every month and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in exhaled breath temperature (EBT)</measure>
    <time_frame>months 1 - 8</time_frame>
    <description>Measured every month and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in FEV1</measure>
    <time_frame>months 1 - 8</time_frame>
    <description>Measured every month and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in FVC</measure>
    <time_frame>months 1 - 8</time_frame>
    <description>Measured every month and compared to baseline</description>
  </other_outcome>
  <other_outcome>
    <measure>Change in FEF25-75</measure>
    <time_frame>months 1 - 8</time_frame>
    <description>Measured every month and compared to baseline</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Asthma Chronic</condition>
  <arm_group>
    <arm_group_label>stable asthma</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>In patients with previously stable course of the asthma, every 3 months the symptoms are evaluated and the dose of ICS is customized - in accordance with the GINA guidelines. This decision is based solely on clinical data (control of symptoms) and is the same as in patients not participating in the study.&#xD;
In patients participating in the study, inflammatory parameters are also measured (sputum eosinophilia, eNO, EBT, bronchial reactivity), but results are not known to clinician taking decision about possible ICS dose reduction.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>ICS dose reduction</intervention_name>
    <description>If control of symptoms is maintained (evaluation based on clinical symptoms solely), every 3 months the dose of ICS is halved according to GINA guidelines, until the control is lost or the lowest daily dose is reached (200 mcg, calculated as budesonide equivalent).&#xD;
In the case of loss of asthma control, beta-mimetic will be administered (temporarily) and return to the chronic administration of the previous, twice higher dose of ICS is restored (or further increase of treatment). In severe exacerbations, inclusion of oral steroids will be considered.</description>
    <arm_group_label>stable asthma</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  mild or moderate asthma with a stable course of at least 3 months:&#xD;
&#xD;
               -  symptoms less than 4x per week,&#xD;
&#xD;
               -  use of SABA below 3x a week,&#xD;
&#xD;
               -  night awakening below 1x per week,&#xD;
&#xD;
               -  FEV1&gt; 80% of predicted&#xD;
&#xD;
               -  no dose change in ICS or use of systemic steroids from 3 months&#xD;
&#xD;
          -  good adherence to treatment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  infection or exacerbation of asthma requiring the use of systemic steroids (or changes&#xD;
             in the dose of inhaled steroids) in the last 3 months before the study&#xD;
&#xD;
          -  other chronic lung diseases or general diseases affecting the respiratory system&#xD;
&#xD;
          -  tobacco smoking&#xD;
&#xD;
          -  FEV1 below 80% of the predicted value&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>12 Years</minimum_age>
    <maximum_age>18 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Henryk Mazurek, MD, PhD</last_name>
    <phone>+48 602440286</phone>
    <email>hmazurek@igrabka.edu.pl</email>
  </overall_contact>
  <location>
    <facility>
      <name>The Regional Public Hospital in Lesko, Poland</name>
      <address>
        <city>Lesko</city>
        <zip>38-600</zip>
        <country>Poland</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Janusz Ciółkowski, MD</last_name>
      <phone>+48134698071</phone>
      <email>ciolkowski.janusz@gmail.com</email>
    </contact>
  </location>
  <location_countries>
    <country>Poland</country>
  </location_countries>
  <results_reference>
    <citation>www.ginasthma.org</citation>
  </results_reference>
  <results_reference>
    <citation>Zacharasiewicz A, Wilson N, Lex C, Erin EM, Li AM, Hansel T, Khan M, Bush A. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med. 2005 May 15;171(10):1077-82. doi: 10.1164/rccm.200409-1242OC. Epub 2005 Feb 11.</citation>
    <PMID>15709050</PMID>
  </results_reference>
  <results_reference>
    <citation>Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002 Nov 30;360(9347):1715-21. doi: 10.1016/S0140-6736(02)11679-5.</citation>
    <PMID>12480423</PMID>
  </results_reference>
  <results_reference>
    <citation>Fleming L, Wilson N, Regamey N, Bush A. Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax. 2012 Mar;67(3):193-8. doi: 10.1136/thx.2010.156836. Epub 2011 Aug 8.</citation>
    <PMID>21825081</PMID>
  </results_reference>
  <results_reference>
    <citation>Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, Cartier A, Hussack P, Goldsmith CH, Laviolette M, Parameswaran K, Hargreave FE. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006 Mar;27(3):483-94. doi: 10.1183/09031936.06.00137704.</citation>
    <PMID>16507847</PMID>
  </results_reference>
  <results_reference>
    <citation>Li AM, Tsang TW, Lam HS, Sung RY, Chang AB. Predictors for failed dose reduction of inhaled corticosteroids in childhood asthma. Respirology. 2008 May;13(3):400-7. doi: 10.1111/j.1440-1843.2007.01222.x.</citation>
    <PMID>18399863</PMID>
  </results_reference>
  <results_reference>
    <citation>Prieto L, Bruno L, Gutierrez V, Uixera S, Perez-Frances C, Lanuza A, Ferrer A. Airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide measurements: predictive value as markers for reducing the dose of inhaled corticosteroids in asthmatic subjects. Chest. 2003 Oct;124(4):1325-33. doi: 10.1378/chest.124.4.1325.</citation>
    <PMID>14555562</PMID>
  </results_reference>
  <results_reference>
    <citation>Deykin A, Lazarus SC, Fahy JV, Wechsler ME, Boushey HA, Chinchilli VM, Craig TJ, Dimango E, Kraft M, Leone F, Lemanske RF, Martin RJ, Pesola GR, Peters SP, Sorkness CA, Szefler SJ, Israel E; Asthma Clinical Research Network, National Heart, Lung, and Blood Institute/NIH. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005 Apr;115(4):720-7. doi: 10.1016/j.jaci.2004.12.1129.</citation>
    <PMID>15805990</PMID>
  </results_reference>
  <results_reference>
    <citation>Belda J, Parameswaran K, Lemiere C, Kamada D, O'Byrne PM, Hargreave FE. Predictors of loss of asthma control induced by corticosteroid withdrawal. Can Respir J. 2006 Apr;13(3):129-33. doi: 10.1155/2006/189127.</citation>
    <PMID>16642226</PMID>
  </results_reference>
  <results_reference>
    <citation>Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med. 2000 Jan;161(1):64-72. doi: 10.1164/ajrccm.161.1.9809100.</citation>
    <PMID>10619799</PMID>
  </results_reference>
  <results_reference>
    <citation>Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, Koskela H, Brannan JD, Freed R, Andersson M, Chan HK, Woolcock AJ. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med. 2001 Feb;163(2):406-12. doi: 10.1164/ajrccm.163.2.9912091.</citation>
    <PMID>11179114</PMID>
  </results_reference>
  <results_reference>
    <citation>Cabral AL, Vollmer WM, Barbirotto RM, Martins MA. Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study. Ann Allergy Asthma Immunol. 2009 Sep;103(3):206-11. doi: 10.1016/S1081-1206(10)60183-4.</citation>
    <PMID>19788017</PMID>
  </results_reference>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 25, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 27, 2018</study_first_posted>
  <last_update_submitted>December 25, 2018</last_update_submitted>
  <last_update_submitted_qc>December 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 27, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Asthma</mesh_term>
  </condition_browse>
  <!-- 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/NCT03788057
org study id: NITLD
nct id: NCT03788057
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
A prospective, observational, interventional, single-blind study (blinded for a clinician in
      the field of inflammatory parameters).

      The aim of the study is evaluation of the usefulness of induced sputum eosinophilia and other
      inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature, bronchial
      hyperresponsiveness] in predicting the failure of treatment reduction with inhaled
      corticosteroids (ICS) in stable asthma in children and adolescents.

      In participants with a stable course of the asthma (confirmed in the run -in period), every 3
      months the dose of ICS is halved (according to GINA guidelines) until the control is lost or
      the lowest daily ICS dose is reached (200 mcg, calculated as budesonide equivalent).
      Throughout the treatment reduction period, the participants run an observation card (clinical
      symptoms) and peak expiratory flow rate (PEFR) measurements. Clinical evaluation is performed
      every month, with spirometry, exhaled NO and exhaled breath temperature measurements. Before
      the reduction and then one month after the change of treatment, the hyperresponsiveness
      measurement is carried out with the sputum induction (combined method using hypertonic
      saline), and 2 months after the change of treatment with the exercise challenge test.

      In the case of loss of asthma control, beta-mimetic will be administered (temporarily) and
      return to dose of ICS before reduction or further increase of treatment is planned. In severe
      asthma exacerbations, oral steroids will be considered.

      The study is observational: treatment is modified according to GINA guidelines based on
      clinical data as part of routine medical care. Only difference compared do standard care is
      supplementary inflammation evaluation (exhaled NO, sputum eosinophilia, bronchial
      hyperreactivity).
Introduction Guidelines for the treatment of asthma recommend the use of the smallest dose of
      inhaled steroid (ICS), which allows to maintain control of the symptoms of the disease. The
      GINA 2006 guidelines proposed (and later editions it upheld) that in the case of symptom
      control by monotherapy with ICS, to reduce their dose every 3 months, up to the lowest dose
      administered once a day, which should be used for one year before taking possible decision to
      stop it.

      There are no clear of simple and sensitive indicators that would allow detection of a
      threatening loss of control before the clinical symptoms worsen.

      Aim of the study Evaluation of the usefulness of induced sputum eosinophilia and other
      inflammatory indices [exhaled nitric oxide (NO), exhaled breath temperature (EBT), bronchial
      hyperresponsiveness] in predicting the failure of treatment reduction with inhaled
      corticosteroids in stable asthma in children and adolescents.

      Subjects Participants aged 12-18 years with stable asthma (mild or moderate), treated in the
      Allergy Clinic of the Hospital in Lesko with medium doses in ICS. The severity of asthma was
      initially determined in accordance with the GINA criteria and verified during several years
      of observation by the assessment of clinical symptoms, functional examinations and the dose
      of inhaled steroids controlling the disease.

      Project description A prospective, observational, single-blind study (blinded for a clinician
      in the field of inflammatory parameters). Clinician takes decision about possible reduction
      of ICS dose basing on clinical data only - is not aware of the results of the inflammatory
      parameters measurement.

      The study is consisting of two periods:

      First period (run - in):

      A four-week run - in period in which clinical symptoms and the use of short acting beta2
      agonists (SABA) and PEFR are monitored. At the end of this period, in participants with
      stable disease the following parameters are measured: eNO, EBT, spirometry, and sputum
      induction with hyperosmolar saline in combination with the hyperresponsiveness. Before the
      reduction of treatment on another day, an exercise challenge test is also performed.

      The criteria for the stability of asthma in the run - in period are:

        -  symptoms no more than 3 times a week

        -  SABA use less than 3 times a week

        -  without night wake up

        -  PEFR variability below 20%

        -  FEV1 above 80% of predicted

      Second period of the study - reduction of anti-inflammatory therapy. In participants with
      previously stable course of the asthma (confirmed in the run -in period), the control of
      asthma is monitored regularly throughout the observation period. All participants run an
      observation card (clinical symptoms) and PEFR measurements. Monthly spirometry, exhaled NO
      and exhaled breath temperature measurements are performed. Every 3 months and one month after
      the change of treatment (i.e in months 0, 1, 3, 4, 6 and 7), the hyperresponsiveness
      measurement is carried out with the sputum induction (combined method, [7]). Two months after
      the dose change (months 2, 5, 8) the exercise challenge test is carried out.

      Every 3 months control of the asthma symptoms is evaluated taking account the clinical data,
      and possible change of ICS dose is considered. Results of bronchial reactivity measurements
      and sputum cytology are not known to clinician who decide on a possible ICS dose change - he
      is blinded to the results of tests and the therapeutic decision is based solely on clinical
      evaluation.

      In participants with a stable course of the disease over past 3 months, the dose of ICS is
      halved, in accordance with GINA guidelines. In the case of loss of asthma control,
      appropriate treatment modifications are administered and the patient is withdrawn from the
      study.

      Participation in the study is continued until asthma control is lost or the lowest daily dose
      is reached (200 mcg, calculated as budesonide equivalent) - without losing asthma control at
      next visit.

      Measurements

        1. Daily clinical evaluation by the patient:

             -  symptoms score according to the Santanello questionnaire

             -  PEFR measurement

        2. Every month

             -  Asthma Control Test

             -  spirometry [forced expiratory flow in 1st second (FEV1), forced vital capacity
                (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25-75)]

             -  eNO measurement

             -  exhaled breath temperature measurement (EBT)

        3. every 3 months

             -  quality of life test (QoL, Polish version of the questionnaire), i.e. months 3, 6,
                9

             -  cytological evaluation of induced sputum (i.e. months 0, 1, 3, 4, 6, 7)

             -  assessment of bronchial hyperresponsiveness:

                  -  one month after the ICS dose reduction and then before each subsequent dose
                     reduction in ICS ((i.e. months 0, 1, 3, 4, 6, 7) - during the sputum induction
                     with hyperosmolar salt (combined method)

                  -  2 months after each treatment reduction (i.e. months 2, 5, 8): exercise
                     challenge test (6-minute free-running test monitored by pulse)

      Criteria for loss of control [1, 6] - any of the following:

        -  use of bronchodilators> 5 times a week

        -  the need for treatment with oral corticosteroids

        -  PEFR decrease above 20% for 2 consecutive days, compared to the average run-in period In
           the case of loss of asthma control, beta-mimetic will be administered (temporarily) and
           return to the chronic administration of the previous, twice higher dose of ICS is
           restored (or further increase of treatment). In severe exacerbations, inclusion of oral
           steroids will be considered.

      Criteria for discontinuation of participation in the study

        1. Loss of asthma control (treatment strategy: beta-mimetic temporarily, return to dose of
           ICS before reduction or further increase of treatment; in severe exacerbations,
           inclusion of oral steroids).

        2. Lack of adherence to the recommendations or failure to report.

      The staff of the center has experience in the production of sputum induction in participants
      with asthma [Ciółkowski J, Mazurek H, Stasiowska B. Evaluation of step - down therapy from an
      inhaled steroid to montelukast in childhood asthma. Allergologia et immunopathologia (Madr.),
      2014: Jul - Aug; 42 (4): 282 - 288].

      The test will be performed in conditions ensuring patient safety, with the availability of an
      anaesthesiologist and anti-shock kit.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: A prospective, observational, interventional, single blind study. Clinician takes decision about possible reduction of ICS dose basing on clinical data only - is not aware of the results of the inflammatory parameters measurement.
primary purpose: Diagnostic
masking: None (Open Label)
masking description: Clinician takes decision about possible change in treatment basing on clinical data only - is not aware of the results of the inflammatory parameters measurements
measure: The percentage of patients with loss of asthma control
time frame: at 9 months
description: Criteria for loss of control (any of the following):
use of bronchodilators > 5 times a week
the need for treatment with oral corticosteroids
PEFR decrease >20% for 2 consecutive days, compared to the average run-in period
measure: Change in sputum eosinophilia
time frame: at 1, 3, 4, 6 and 7 month
description: eosinophil percentage in induced sputum compared to baseline
measure: Change in airway hyperresponsiveness to hypertonic saline
time frame: at 1, 3, 4, 6 and 7 month
description: Airway hyperresponsiveness to hypertonic saline measured using combined method (together with sputum induction) and compared to baseline
measure: Change in airway hyperresponsiveness (exercise)
time frame: at 2, 5 and 8 month
description: Airway hyperresponsiveness measured using an exercise challenge test and compared to baseline
measure: Change in exhaled NO
time frame: months 1 - 8
description: Measured every month and compared to baseline
measure: Change in exhaled breath temperature (EBT)
time frame: months 1 - 8
description: Measured every month and compared to baseline
measure: Change in FEV1
time frame: months 1 - 8
description: Measured every month and compared to baseline
measure: Change in FVC
time frame: months 1 - 8
description: Measured every month and compared to baseline
measure: Change in FEF25-75
time frame: months 1 - 8
description: Measured every month and compared to baseline
arm group label: stable asthma
arm group type: Other
description: In patients with previously stable course of the asthma, every 3 months the symptoms are evaluated and the dose of ICS is customized - in accordance with the GINA guidelines. This decision is based solely on clinical data (control of symptoms) and is the same as in patients not participating in the study.
In patients participating in the study, inflammatory parameters are also measured (sputum eosinophilia, eNO, EBT, bronchial reactivity), but results are not known to clinician taking decision about possible ICS dose reduction.
intervention type: Other
intervention name: ICS dose reduction
description: If control of symptoms is maintained (evaluation based on clinical symptoms solely), every 3 months the dose of ICS is halved according to GINA guidelines, until the control is lost or the lowest daily dose is reached (200 mcg, calculated as budesonide equivalent).
In the case of loss of asthma control, beta-mimetic will be administered (temporarily) and return to the chronic administration of the previous, twice higher dose of ICS is restored (or further increase of treatment). In severe exacerbations, inclusion of oral steroids will be considered.
arm group label: stable asthma
criteria: 
gender: All
minimum age: 12 Years
maximum age: 18 Years
healthy volunteers: No
last name: Henryk Mazurek, MD, PhD
phone: +48 602440286
email: hmazurek@igrabka.edu.pl
facility: 
status: Recruiting
contact: 
country: Poland
citation: www.ginasthma.org
citation: Zacharasiewicz A, Wilson N, Lex C, Erin EM, Li AM, Hansel T, Khan M, Bush A. Clinical use of noninvasive measurements of airway inflammation in steroid reduction in children. Am J Respir Crit Care Med. 2005 May 15;171(10):1077-82. doi: 10.1164/rccm.200409-1242OC. Epub 2005 Feb 11.
PMID: 15709050
citation: Green RH, Brightling CE, McKenna S, Hargadon B, Parker D, Bradding P, Wardlaw AJ, Pavord ID. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002 Nov 30;360(9347):1715-21. doi: 10.1016/S0140-6736(02)11679-5.
PMID: 12480423
citation: Fleming L, Wilson N, Regamey N, Bush A. Use of sputum eosinophil counts to guide management in children with severe asthma. Thorax. 2012 Mar;67(3):193-8. doi: 10.1136/thx.2010.156836. Epub 2011 Aug 8.
PMID: 21825081
citation: Jayaram L, Pizzichini MM, Cook RJ, Boulet LP, Lemiere C, Pizzichini E, Cartier A, Hussack P, Goldsmith CH, Laviolette M, Parameswaran K, Hargreave FE. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006 Mar;27(3):483-94. doi: 10.1183/09031936.06.00137704.
PMID: 16507847
citation: Li AM, Tsang TW, Lam HS, Sung RY, Chang AB. Predictors for failed dose reduction of inhaled corticosteroids in childhood asthma. Respirology. 2008 May;13(3):400-7. doi: 10.1111/j.1440-1843.2007.01222.x.
PMID: 18399863
citation: Prieto L, Bruno L, Gutierrez V, Uixera S, Perez-Frances C, Lanuza A, Ferrer A. Airway responsiveness to adenosine 5'-monophosphate and exhaled nitric oxide measurements: predictive value as markers for reducing the dose of inhaled corticosteroids in asthmatic subjects. Chest. 2003 Oct;124(4):1325-33. doi: 10.1378/chest.124.4.1325.
PMID: 14555562
citation: Deykin A, Lazarus SC, Fahy JV, Wechsler ME, Boushey HA, Chinchilli VM, Craig TJ, Dimango E, Kraft M, Leone F, Lemanske RF, Martin RJ, Pesola GR, Peters SP, Sorkness CA, Szefler SJ, Israel E; Asthma Clinical Research Network, National Heart, Lung, and Blood Institute/NIH. Sputum eosinophil counts predict asthma control after discontinuation of inhaled corticosteroids. J Allergy Clin Immunol. 2005 Apr;115(4):720-7. doi: 10.1016/j.jaci.2004.12.1129.
PMID: 15805990
citation: Belda J, Parameswaran K, Lemiere C, Kamada D, O'Byrne PM, Hargreave FE. Predictors of loss of asthma control induced by corticosteroid withdrawal. Can Respir J. 2006 Apr;13(3):129-33. doi: 10.1155/2006/189127.
PMID: 16642226
citation: Jatakanon A, Lim S, Barnes PJ. Changes in sputum eosinophils predict loss of asthma control. Am J Respir Crit Care Med. 2000 Jan;161(1):64-72. doi: 10.1164/ajrccm.161.1.9809100.
PMID: 10619799
citation: Leuppi JD, Salome CM, Jenkins CR, Anderson SD, Xuan W, Marks GB, Koskela H, Brannan JD, Freed R, Andersson M, Chan HK, Woolcock AJ. Predictive markers of asthma exacerbation during stepwise dose reduction of inhaled corticosteroids. Am J Respir Crit Care Med. 2001 Feb;163(2):406-12. doi: 10.1164/ajrccm.163.2.9912091.
PMID: 11179114
citation: Cabral AL, Vollmer WM, Barbirotto RM, Martins MA. Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to-severe asthma: a prospective, 5-month study. Ann Allergy Asthma Immunol. 2009 Sep;103(3):206-11. doi: 10.1016/S1081-1206(10)60183-4.
PMID: 19788017
responsible party type: Sponsor
mesh term: Asthma