Asthma Chronic Clinical Trial
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
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 [CióÅ‚kowski 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.
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