Clinical Trial Details
— Status: Enrolling by invitation
Administrative data
| NCT number |
NCT05853809 |
| Other study ID # |
2020-00919 |
| Secondary ID |
|
| Status |
Enrolling by invitation |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
April 1, 2023 |
| Est. completion date |
June 1, 2025 |
Study information
| Verified date |
May 2023 |
| Source |
Region Stockholm |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Asthma is a chronic inflammatory respiratory disease that affects people of all ages and of
both sexes. It is a common disease and is present in 8-10 % of the population. Despite drug
treatment, many patients have poor control of their asthma with an impact on quality of life
and restriction of daily activities. The purpose of this study in primary care is to
investigate if measurement of airway inflammation (FeNO) can improve the treatment results
and the overall care of adult patients with asthma. The main question in the study is whether
the use of FeNO measurements can reduce the number of deterioration periods. The study is
conducted under real clinical conditions where the effect of the intervention is measured
(pragmatic intervention study). Eight to twelve primary health care centers with functional
asthma / COPD clinics are selected within the Stockholm County and are randomly assigned to
two groups with four to six primary health care centers each, an active group and a control
group (cluster randomization). Instruments for FeNO measurements are made available to the
active group and this group is also trained on FeNO measurements and how the value should be
interpreted and used to control the treatment, while the control group continues to take care
of their asthma patients as usual. The study can lead to improved treatment decisions and
patients gaining an increased understanding of their asthma by being informed on the actual
degree of inflammation in the airways. Optimized treatment can provide better asthma control
with increased quality of life and fewer periods of deterioration, which results in reduced
burden on healthcare and lower costs for patients and society.
Description:
Cluster-Randomized Asthma FeNO Trial (CRAFT)
Clinical effect of FeNO measurement for asthma treatment in primary care: A real-world
cluster-randomised controlled trial
Jörgen Syk, Hanna Sandelowsky, Björn Stridh, Kjell Alving
Overview of the field
The prevalence of asthma has increased in the last decades and seems to be increasing among
children in Sweden also in the 21st century. A study performed by the Institute of
Environmental Medicine at the Karolinska Institute, in collaboration with the National Board
of Health and Welfare, showed that the prevalence of physician-diagnosed asthma increased
between the years 2003 and 2011: from 6.1% to 9.5% among four-year-olds and from 6.4% to 8.9%
among twelve-year-olds [1]. This likely portends a continued increase of the asthma
prevalence among the adult population as well. The reason for the increase of allergy and
asthma is likely to be multifactorial and therefore difficult to counteract at a societal
level. Instead, healthcare must be developed to effectively diagnose and treat the increasing
number of patients.
In the early 2000s, major hope was placed in combination inhalers (corticosteroid +
long-acting beta-2 agonist) within asthma care, and prescription of these increased
dramatically. However, studies have shown that the proportion of patients with controlled
asthma has not increased after the introduction of such inhalers [2, 3], while the costs for
asthma medication have increased drastically instead. Within the last ten years, the need has
been identified for better characterisation of patients with asthma symptoms, as the asthma
disease is heterogeneous and also varies over time. Particular interest has been raised in
biomarkers like the fraction of exhaled nitric oxide, FeNO, and blood eosinophil levels
(B-Eos) [4-6].
Currently, FeNO is the most commonly used clinical biomarker of asthma, although the method
is not established within Swedish primary care. However, the British authority NICE (National
Institute of Health and Care Excellence) states, in its 2017 guidelines on asthma, that FeNO
should be used in asthma diagnosing and in treatment follow-up for patients with remaining
symptoms despite treatment with inhaled corticosteroids (ICS) [7]. FeNO is a marker of type-2
inflammation in the airways, more specifically of mechanisms induced by interleukin (IL)-4
and IL-13. Dupilumab, a biological drug blocking the effect of IL-4/IL-13, has recently been
approved within the EU as add-on maintenance treatment in severe asthma, but only for
patients with detectable persistent type-2 inflammation, i.e., elevated FeNO and/or B-Eos.
FeNO, unlike B-Eos, correlates strongly with the degree of hyperreactivity to methacholine
and mannitol [8], and elevated FeNO is a reliable predictor of clinical response to use of
ICS [9]. FeNO usually decreases with use of ICS, except in cases of high allergen exposure
[10, 11]. The FeNO value may thus be a very good starting point in the dialogue between a
physician and a patient regarding treatment adherence and environmental aspects, such as
exposure to furred pets.
Preliminary results
Our application is preceded by many years' research activity within the field by the group.
We began with a pilot study at a primary healthcare centre to test a treatment algorithm
guided by FeNO values. We could show that FeNO drops to normal levels following increased use
of ICS, so long as allergen exposure is not too high [11].
Strengthened by these results, we moved on to a multi-centre study (NOAK) within primary
care, with the Stockholm County Council as the main financier [12]. In this study, 187 adult
patients with allergic asthma were randomised to an active group (FeNO-guided treatment) or a
control group (usual care, mainly guideline-based) at 17 healthcare centres in central and
southern Sweden. The patients were followed for 12 months, with 5 visits to their healthcare
centre. The treatment was stepped up in the same way in both groups and included ICS and
anti-leukotrienes. In this study, we could show a significantly larger improvement of asthma
control (Juniper Asthma Control Questionnaire) and a decrease in the number of moderately
severe exacerbations in the FeNO-guided group as compared with the control group, without any
increase in average drug use. Internationally, several similar studies have been performed,
and meta-analyses, including the NOAK study on the adult side, have shown a significantly
better effect on asthma exacerbations with FeNO-guided treatment, in both children and adults
[13]. However, our study is the only one thus far performed within primary care. Furthermore,
in a post hoc analysis of the NOAK study, we could also show that the levels of total IgE and
IgE antibodies against, for example, furred pets, decreased over the course of 12 months with
optimised treatment [14]. The decrease of IgE correlated with decrease of FeNO, and with
improved asthma control and asthma-related quality of life.
As indicated above, FeNO may provide important information to the physician about the
patient's treatment adherence and possible effects of allergen exposure. Further, reporting
the FeNO value to the patient may increase the patient's awareness about his/her disease,
possibly leading to change in behaviour. These are aspects of FeNO measurements that cannot
be captured in a randomized, controlled trial such as the NOAK study described above.
Therefore, we are now planning for a real-world cluster-randomized, controlled study within
primary health care, to be able to catch also these aspects of FeNO measurements. Only one
previous study has aimed at such study design [15]. However, due to the lack of FeNO-naïve
allergy clinics in the area, true cluster-randomization could not be done, leading to
baseline bias, and the study was partly negative. In Stockholm County, this will not
constitute a problem since no single primary health care center use FeNO measurements today
in this region.
Aim The overall aim of this real-world, cluster-randomised study is to investigate if use of
FeNO measurements in primary care, to guide anti-inflammatory treatment, can improve
treatment outcome and care of adult patients with asthma.
Research questions All research questions relate to use of FeNO measurements in primary care
for monitoring of anti-inflammatory treatment in individuals aged ≥ 18 years with
asthma/suspected asthma.
Primary research question
- Can use of FeNO measurements decrease the number of exacerbations?
Secondary research questions
- Can use of FeNO measurements improve asthma control as measured using the Asthma Control
Test (ACT) questionnaire?
- Can use of FeNO measurements improve lung function, measured using spirometry, as
regards FEV1 (forced expiratory volume in one second) and FEV1 in percent of expected
(reference values from Hedenström)?
- Can use of FeNO measurements decrease the use of short-acting β2 receptor agonists
(salbutamol, terbutaline and formoterol)?
- Can use of FeNO measurements decrease the total cost of drugs for asthma treatment?
The study could lead to more certain asthma diagnoses, better treatment adherence and more
optimised anti-inflammatory treatment. If the study can indicate positive effects for
patients with asthma in regular clinical practice in primary care, the results may lead to
changed national recommendations on asthma patient care (Swedish National Board of Health and
Wellfare).
Work plan Study design: The study is devised as a real-world cluster randomised intervention
study. Healthcare centres within Stockholm County with at least 7,000 listed patients, which
use the medical record system TakeCare and have a certified asthma/COPD facility, can
participate in the study. Eligible Healthcare centres should also on a routine basis transfer
data to the Swedish National Airway Register. The power calculation for the study in this
application is based on the NOAK study, with exacerbation frequency as the primary outcome
measure. In a trial with 6 clusters per arm, the total minimum sample size was determined to
be 636 (on average 53 patients per cluster), to obtain 80% power (alpha=0.05), and to detect
a 10 per cent unit reduction in exacerbation rate. The participating healthcare centres will
be randomised to two equal-sized groups, one intervention group and one control group, and
will be followed for two years.
Intervention: Physicians, nurses and other staff at the healthcare centres in the
intervention group will get a two-hour education on what FeNO is, how a FeNO measurement is
performed, and how FeNO values can be interpreted and used to guide anti-inflammatory
treatment. A web-based FeNO Interpretation Aid to assist in determining if a value is
elevated or not, with individual tailoring based on gender, age and height, will be provided.
We have previously shown that reference equations can be developed using Lambda-Mu-Sigma
models, similar to Global Lung Function Initiative [16]. In The FeNO Interpretation Aid we
will use data from both the US (NHANES) and Sweden. A follow-up meeting, approximately one
hour in length, is planned for one month after the education, to enable evaluation and
provide the opportunity to ask questions. The healthcare centres in the control group will
continue to care for their asthma patients as usual.
For the patients in the intervention group, the study means that they will have to perform a
FeNO measurement for the asthma/COPD nurse in connection with an asthma-related visit to the
healthcare centre, when this is considered justified. A FeNO measurement involves a maximal
inhalation, followed by an even exhalation for ten seconds into a FeNO measuring device. The
results are shown on a display after about one minute. The asthma/COPD nurse enters the
result of a FeNO measurement into the patient's medical record. The treating physician can
then assess the result and decide on any change to the anti-inflammatory treatment.
Data collection: Approval from the ethics board and written approval from each centre's
manager are required. The asthma/COPD nurses extract medical record data after one and two
years, in accordance with items 1-6 below, from the healthcare centres' medical record system
TakeCare using the data collection program MedRave4. The data collected are exported to Excel
on the asthma/COPD nurses' computers and all personal data are erased.
1. Number of patients aged ≥ 18 years, with a diagnosis of asthma in the past year, plus
their gender and age.
2. Number of recorded exacerbation diagnoses.
3. Points on the Asthma Control Test questionnaire.
4. Spirometry results (FEV1 in litres and in percent of expected value).
5. Results of FeNO measurements performed (active centers).
Data on filled prescriptions, to calculate drug use and costs, will be collected at the
healthcare centre level through the follow-up portal GUPS, which can be accessed online
through the portal Janusinfo (www.janusinfo.se) under drug statistics. With the approval of
the GUPS system owner and the healthcare centre's manager, data for each individual
healthcare centre can be collected. These data can be connected to diagnosis using the
so-called VAL database, for which we can get assistance from the Drug and Therapeutics
Committee in Region Stockholm. From the Swedish National Airway Register the following
variables will be collected: Date of examination, Sex, Age, Asthma diagnosis (year), Allergy
diagnosis (year), Height, Weight, Body Mass Index, Smoke habits, Spirometry measures, Number
of asthma exacerbations last 12 months, Number of hospitalizations because of asthma last 12
months, Received patient asthma education, Asthma Control Test score, Asthma severity, FeNO
value, Objective allergy testing (year), Respiratory allergy, Asthma or Allergy medication
categories and Other Allergy manifestations. Descriptive data on the healthcare centres, such
as the number of listed patients, operative form, asthma/COPD facilities, further education,
and socio-demographics, are collected through interviews with the asthma/COPD nurses. After
this, analyses and statistical processing can be performed.
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