Clinical Trial Details
— Status: Completed
Administrative data
NCT number |
NCT01961154 |
Other study ID # |
KUH5801124 |
Secondary ID |
|
Status |
Completed |
Phase |
N/A
|
First received |
October 9, 2013 |
Last updated |
August 31, 2016 |
Start date |
October 2012 |
Est. completion date |
July 2015 |
Study information
Verified date |
August 2016 |
Source |
Kuopio University Hospital |
Contact |
n/a |
Is FDA regulated |
No |
Health authority |
Finland: Ethics Committee |
Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.