Stepping Down of Asthma Medication in Controlled Asthma
Stepping Down of Asthma Medication in Controlled Asthma
Background:

 The most common asthma drugs, namely inhaled glucocorticoids (ICS) and long-acting beta-2
 sympathomimetic drugs (LABA) carry a risk of adverse effects, some of which being potentially
 severe. Therefore, current guidelines for asthma management recommend that, after a period of
 symptom control, a reduction of the dose and cessation of the ICSs and LABAs should be
 attempted. However, reduction in asthma medications sometimes leads to an exacerbation of
 asthma. Therefore both physicians and asthmatics are often reluctant to reduce or stop asthma
 medications and asthma over-medication often occurs. A test that could identify those
 asthmatics who probably would tolerate asthma medication reduction would be useful.

 Objectives:

 1. To investigate whether airway responsiveness to hypertonic saline can predict the
 outcome of asthma treatment reduction in subjects with controlled asthma.

 2. To get an estimate about how large a proportion of Finnish asthmatic patients use their
 medications with unnecessarily high doses or would even manage well without any asthma
 medications.

 Study hypothesis:

 1. Airway responsiveness to hypertonic saline can predict the outcome of asthma treatment
 reduction

 2. Most of the Finnish asthmatic patients use their medications with unnecessarily high
 doses

 Methods:

 This is a prospective study in which the physician responsible for the subject management and
 medications is blinded from the saline challenge results and the nurse performing the saline
 challenges is blinded from medications 70 asthmatic patients with both inhaled ICS and LABA
 will be recruited. Asthma must be well controlled (Juniper's Asthma Control Questionnaire
 score equal or less than 0.75 ).

 The asthma medications will be reduced in three steps, in six weeks' intervals, up to total
 cessation of asthma drugs or up to asthma exacerbation. The criteria for asthma exacerbation
 are strictly defined. First step: LABA will be discontinued. The ICS is continued. Second
 step: medium to high daily ICS dose is reduced to low daily dose. Third step: The low ICS
 dose will be stopped. Before each reduction, saline challenge will be performed. Asthma diary
 is kept throughout the study and the subjects will be provided a direct telephone number to a
 respiratory physician during all hours of day.
Stepping down of asthma medication in controlled asthma

 Principal investigator:

 Heikki Koskela, MD. Kuopio University Hospital, Unit for Medicine and Clinical Research,
 Division of Pulmonary Medicine

 The study will be started during the year 2012 and will continue for 36 months.

 Background

 In Finland, asthma is the second most important disorder justifying special reimbursement of
 asthma medication, thus causing large expenses to the society.

 Inhaled corticosteroids (ICS) are the mainstay of modern asthma therapy. When a medium-dose
 ICS fail to achieve asthma control, they can be combined with long-acting B2-agonist
 bronchodilators (LABA). Unfortunately, potential side effects of ICSs and LABAs are common
 with increased frequency with increased dozing. The most common side effects of ICS are
 benign, like sore and dry throat but also include serious adverse effects like growth
 retardation in children and adrenal insufficiency. LABAs, in turn can increase the risks of
 severe asthma exacerbations and even asthma-related deaths. Therefore, current guidelines for
 asthma management recommend that, after a period of symptom control, a reduction of the dose
 and cessation of the ICSs and LABAs should be attempted. There are two recommend strategies:
 The international Global initiative for asthma (GINA) guideline recommends reduction of the
 ICS dose first, with subsequent LABA cessation. On the contrary, the American Food and Drug
 Administration (FDA) recommends cessation of LABAs first. In the present study we follow the
 FDA recommendations.

 At present there is limited experimental data on the optimal timing, sequence, and magnitude
 of treatment reductions in asthma. Usually, the decision for treatment reduction is based on
 the absence of symptoms for a certain period of time. However, even asthmatic subjects with
 minimal symptoms may suffer from asthma exacerbation after treatment reduction. Consequently,
 both physicians and asthmatics are often reluctant to reduce or stop asthma medications. Very
 probably this is a major reason for the fact that a great proportion of asthmatic subjects
 use unnecessarily high doses of asthma medications and multiple preparations. For example, in
 Finland combination preparations containing both LABA and ICS are more commonly prescribed
 than preparations containing only ICS (Finnish Social Insurance Institution statistics 2010).
 Very probably many asthmatics would do well even without any asthma medications: In an
 Italian study with stable asthmatics, all asthma medication could be stopped in 73 % of the
 subjects.

 There has been a great interest to find a biomarker that could identify asthmatic subjects
 that would tolerate treatment reduction without exacerbation and those in whom the reduction
 should not be tried. The following biomarkers have been evaluated to predict asthma
 exacerbation after ICS dose reduction/cessation: Airway challenges with histamine, mannitol,
 hypertonic saline, and adenosine as well as measurements of exhaled nitric oxide and sputum
 eosinophils. In adult subjects, the hypertonic airway challenges (mannitol, hypertonic
 saline) and the adenosine challenge have usually performed best in this respect. However,
 none of these biomarkers have been able to predict the outcome of the ICS treatment reduction
 accurately enough to become part of the clinical routine. To our knowledge, there are no
 studies that have tried to predict asthma exacerbation after LABA cessation.

 Hypertonic airway challenges have long been used to assess airways' tendency to constrict in
 response to external stimuli (=airway responsiveness). Asthmatic subjects are well known to
 be hyperresponsive to the bronchoconstrictive effect of hypertonic aerosols. During the
 recent years we have shown that asthmatic subjects are hypersensitive also to the
 cough-provoking effect of hypertonic aerosols. Furthermore, treatment with ICS decreases the
 sensitivity to the cough-provoking effect of hypertonic aerosols. Among asthmatics, cough
 responsiveness to hypertonic saline correlates closely with a well validated asthma control
 questionnaire. The bronchoconstrictive response and the cough response to hypertonicity are
 two separate phenomena and therefore provide additional information about the state of the
 subject's airways. The two responses can be measured during a single challenge.

 The cough response to hypertonic aerosols has never been evaluated whether it can predict the
 outcome of asthma treatment reduction in subjects with stable asthma. It is possible that
 analysis of both the bronchoconstrictive and the cough response might predict the asthma
 exacerbation better than analysis of only one of the responses.

 The study objectives

 Subjects: 70 well-controlled asthmatic patients with both LABA and ICS.

 The main objectives of the study:

 1. To investigate whether hypertonic saline bronchoconstrictive responsiveness can predict
 the outcome of asthma treatment reduction in subjects with stable asthma.

 2. To investigate whether hypertonic saline cough responsiveness can predict the outcome of
 asthma treatment reduction in subjects with stable asthma.

 3. To investigate whether the two responses together have a stronger predictive power than
 the responses separately.

 The secondary objective is to get an estimate about how large a proportion of Finnish stable
 asthmatic patients use their medications with unnecessarily high doses or would even manage
 well without any asthma medications.

 Methods

 Study design

 This is a prospective study in which the physician responsible for the subject management and
 medications is blinded from the saline challenge results and the nurse performing the saline
 challenges is blinded from medications. The study includes two periods: A two-week run-in
 period during which the subjects continue their regular asthma medications and their asthma
 control is ensured. After that, the stepping down of the asthma medication is started and
 continued until both ICS and LABA treatments have been stopped or until asthma exacerbation
 has occurred. The effect of every reduction is observed for six weeks before proceeding to
 the following step. If the medication is insufficient, an asthma exacerbation is very likely
 to take place within this time period. In previous studies, the exacerbations have taken
 place mean 16 - 17 days after steroid reduction.

 First step: LABA will be discontinued. The use of ICS is continued, using the same dosage,
 preparation, and inhaler as before.

 Second step: In subjects with a daily ICS dose of more than 500 ug of beclomethasone or
 equivalent (="medium to high dose"), the ICS dose is reduced to 500 ug of beclomethasone or
 equivalent ( = "low daily dose") according to GINA, see table 1. The reduced ICS dose will be
 administered with the same preparation and inhaler as before.

 Third step: In subjects with a daily ICS dose of less or equal to 500 ug of beclomethasone or
 equivalent ( = "low daily dose") the ICS will be stopped.

 Non-permitted medications

 The use of any asthma drug apart from ICS and LABAs can be continued throughout the study.
 However, on the study days the subject should not use any asthma drugs before the visit to
 the outpatient clinic. All medications to other illnesses will be continued throughout the
 study.

 Detailed description of the study

 Day 1. The subject will be interviewed (nurse) and the baseline questionnaire and asthma
 control questionnaire 19 will be filled in. The suitability of the subject for the study is
 evaluated according to the above-mentioned criteria. Written, informed consent is obtained.
 If skin allergy tests have not been performed before, it will be performed now. The use of
 asthma diary is instructed. It will be used throughout the study. A two-week diary monitoring
 with PEF values will be performed.

 Asthma diary:

 Every morning and evening: The number of rescue bronchodilating drug doses taken. Three peak
 flow (PEF) recordings before taking any asthma medication.

 Plus every morning: Awakenings at night due to asthma symptoms

 Day 2. The diary will be reviewed (physician). The subject will be included in the study if
 his/her asthma is well controlled, defined as asthma control questionnaire (ACQ) score equal
 or less than 0.75. The final ACQ score can be determined after the saline challenge since it
 includes spirometry and forced expiratory volume in one second (FEV1) information is utilised
 when calculating the ACQ score. If the subject is included, a written asthma medication
 reduction plan is made, one copy is given to the subject and another is stored in the subject
 file. The threshold value for significant PEF reduction is calculated (see below). The
 subject is told about the signs and symptoms of asthma exacerbation and an action plan is
 made. The saline challenge will be performed (nurse) as described below. The first step-down
 in the medication is performed (LABA cessation).

 Definition of asthma exacerbation, at least one of the following:

 -  awakening at two consecutive nights due to asthma symptoms

 -  PEF less than 3 standard deviations from the mean PEF value obtained during the run-in
 period on three consecutive days 20

 -  bronchodilator use more than once a day on three consecutive days.

 -  whenever the subjects feels that his/her asthma symptoms have clearly increased

 Individually adjusted definition of asthma exacerbation is written in the asthma diary

 Action plan in case of exacerbation: The telephone numbers of the study physicians are given
 to the subject and she/he can contact them during the office hours. The telephone number of
 the respiratory physician in charge is given in case of an exacerbation occurring outside the
 office hours. The exacerbation will be treated according to the standard clinical practice,
 depending on the physician's judgement. An asthma exacerbation indicates end of the study.
 The contacted physician informs the research nurse about the exacerbation. The nurse marks
 down the date of exacerbation. The research nurse asks the patient to visit the outpatient
 clinic after two weeks. The subject will visit the study physician and the permanent asthma
 medication will be instructed.

 Action plan is written in the asthma diary

 Days 3, 4 and 5. The ACQ will be filled in and the diary will be reviewed (physician). If no
 exacerbations have occurred since the last step-down, the next step-down is made. The
 hypertonic saline challenge will be performed (nurse). However, if the previous step-down was
 steroid cessation, the study ends.

 Hypertonic saline challenge

 This test will be performed as we have previously described with some modifications:
 Spirometry is performed three times. After that the subject inhales isotonic
 phosphate-buffered saline for two minutes via a high-output ultrasonic nebuliser, using tidal
 breathing. The coughs occurring during the inhalation and two minutes after it will be
 counted up. The number of these "spontaneous" coughs will be subtracted from the coughs
 provoked by each hypertonic solution. After two minutes from the end of inhalation, the
 spirometry will be performed twice. The better of the two recorded FEV1 values will be used
 as the reference value when calculating the saline-induced bronchoconstriction. Subsequently,
 they inhale hypertonic phosphate-buffered saline solutions with osmolalities of 600, 900,
 1200, 1500, 1800 and 2100 milliosmoles (mOsm) /kg. The challenge will be stopped if either if
 a 15 % fall in FEV1 is recorded or if the final solution has been inhaled or if the patient
 feels severe discomfort. The cough response to saline will be calculated as the provocative
 osmolality to induce 15 cumulative coughs. The bronchoconstrictive response will be
 calculated as the provocative osmolality to induce 15 % fall in FEV1. If the patient feels
 dyspnoea or if the FEV1 falls equal or more than 15 % from baseline, Ventoline Evohaler two
 doses a 0.1 mg /Volumatic will be administered. After 15 minutes from that, spirometry will
 be performed twice.

 Ethics

 According to international studies, asthma patients often overmedicate themselves, thus being
 exposed to unnecessary side effects and expenses. Also, due to the vast amount of asthma
 patients, unnecessary asthma medication causes large expenses to the society. Therefore, the
 present study is indicated. It is evident that a proportion of the subjects will experience
 asthma exacerbation during the study. However, they have full-time contact to a respiratory
 physician. In the study setting, the asthma medication reduction takes place in a much more
 controlled fashion than in everyday clinical practice.

 A permission of the Institutional Ethics Committee has been received (Number 118//2011, dated
 29.11.2011).

 The time table and financing

 The study will be started during the year 2012 and will continue for 36 months. The
 investigators seek funding from the Finnish government research funding (VTR) and from
 private foundations.

 Investigators and affiliations

 Principal investigator: Heikki Koskela, MD, respiratory physician, Kuopio University
 Hospital, Unit of Medicine and Clinical Research, Department of Respiratory Medicine

 Minna Purokivi, MD, respiratory physician, Kuopio University Hospital, Unit of Medicine and
 Clinical Research, Department of Respiratory Medicine

 Jouko Kokkarinen, MD, respiratory physician, Kuopio University Hospital, Unit of Medicine and
 Clinical Research, Department of Respiratory Medicine

 Merja Esselström, registered nurse, MD, Kuopio University Hospital, Unit of Medicine and
 Clinical Research, Department of Respiratory Medicine

 Kirsi Kontra, Pharm. Lic. Kuopio University Hospital, Department of Pharmacy

 Analysis of the results, publication plan

 The analysis will consist of three parts, one publication will be written about each.

 1. The ability of the saline challenge to predict an exacerbation after cessation of LABA
 will be assessed by comparing the responses to saline between those who tolerated the
 first reduction (=LABA cessation) and those who did not tolerate it, utilising unpaired
 T-tests. Suitable cut-off values for saline responses will be sought and after that, the
 sensitivity and specificity of the saline responses to predict an asthma exacerbation
 after LABA cessation are defined.

 2. The subjects who tolerated the LABA reduction will undergo reductions 2 and 3. The
 ability of the saline test to predict an exacerbation after reduction/cessation of ICS
 will be assessed by comparing the results to saline between those who tolerated the
 second and the third reduction (= ICS reduction and ICS cessation) and those who did not
 tolerate it, utilising unpaired T-tests. Suitable cut-off values for saline responses
 will be sought and after that, the sensitivity and specificity of the saline responses
 to predict an asthma exacerbation after ICS reduction are defined.

 3. In addition, the proportion of the subjects who tolerated asthma medication
 reduction/cessation will be calculated and reported.
Inclusion Criteria:70 adult (over 18 years) subjects with the following features

 -  doctor's diagnosis of asthma and right to special reimbursement from anti-asthma
 medication expenses according to Finnish Social Insurance Institute criteria (code 203
 in the social insurance card)

 -  asthma diagnosis confirmed at least two years previously

 -  regular treatment with inhaled corticosteroids and long-acting beta-agonists for at
 least 6 months

 -  no changes in regular anti-asthma medication within 6 months

 -  asthma is well controlled (all conditions must be fulfilled):

 -  No courses of oral corticosteroids due to asthma within one year

 -  No hospital admissions due to asthma within one year

 -  Juniper's Asthma Control Questionnaire score equal or less than 0.75

 Exclusion Criteria:

 -  the presence of another chronic respiratory disease in addition to asthma. Such
 diseases include moderate to severe polypotic chronic rhinosinusitis, chronic
 obstructive pulmonary disease, sarcoidosis, and cystic fibrosis

 -  presence of severe co-morbidity

 -  history of smoking more than 10 pack-years

 -  pregnancy