Effect of inhaled corticosteroid tapering in obese T2-low asthma patients on asthma control and quality of life: an investigator-initiated, multicenter, non-inferiority, open label crossover trial with open label extension

Asthma is a heterogeneous disease with increasing attention in the past years
forits endotypes. Obesity-related asthma is an endotype with often a high
burden of disease without noticeable T2 inflammation, the so-called T2 low
endotype. However, their is no distinction between the treament of the
differenct astma endotypes. ICS remains the cornerstone of asthma treatment in
both primary and secondary care. Despite ICS treatment, the asthma control
often remains poor in patients without T2 inflammation. Previous research from
the FGV shows that weight loss does improve asthma control. Recent large-scale
research from Erasmus MC shows that ICS can have adverse systemic effects and
are associated with a higher BMI, larger waist circumference and other
determinants of the metabolic syndrome. In addition, obese people use
corticosteroids two to three times more often, which makes losing weight
difficult. Nonetheless, both national- and international guidelines continue to
adviese treatment with ICS for all astma patients. This is mainly due to lack
of research in T2 low asthma. For example, to date, there are no good
randomized studies demonstrating effectiveness of ICS in this specific group of
T2-low asthma patients with obesity.

Primary Objective
To demonstrate that ICS can be safely withdrawn in T2-low asthma patients with
obesity in secondary care (i.e. without loss of asthma control).

Secondary Objectives
1. To determine predictive factors for successful ICS withdrawal.
2. To determine the effect of ICS withdrawal on determents of Metabolic
Syndrome using physical examination (such as weight an blood pressure), blood-
and hair tests (e.g. endocrine markers of metabolic syndrome and steroid levels)
3. To describe the effect of ICS on inflammatory biomarkers (e.g. proteomics
and genomics) and physical parameters (e.g. lung function) in T2-low asthma.
4. To detect whether the T2-low status changes over time and during an
exacerbation (i.e. detecting T2-hidden or false negative patients)
5. To further complement T2-phenotyping using exhaled molecular compounds
analyses (i.e. electronic nose or eNose) which gives inside in potential early
biomarkers for low steroid efficacy.

An investigator-initiated multicenter non-inferiority open label randomized
crossover study with open-label extension.

- inclusion and randomisation into arm A and arm B

Run in:
- Fluticason 1000mcg per day plus Fenoterol/*ipratropium as needed for 4 weeks
- In case of progressive dyspneu, but no exacerbation: IOS/FeNO/Spiro and
restart of LABA, after 2 weeks IOS/FeNO/Spiro/blood tests and eindpoint
reached: end of trial

Arm A:
- 14 weeks fluticason 1000mcg/day

Arm B:
- 2 weeks fluticason 500mcg/day
- 2 weeks fluticason 250mcg/day
- 10 weeks no ICS

----- CROSSOVER -----

Arm A:
- 2 weeks fluticason 500mcg/day
- 2 weeks fluticason 250mcg/day
- 10 weeks no ICS

Arm B:
- 14 weeks fluticason 1000mcg/day

----- START EXTENSION-----

No study arms. Patients with sustained asthma control after ICS tapering may
continue in a controlled extension study to study long term benefits of being
ICS naïve. (Metabolic and endocrine parameters.)

Geen studie armen. Patiënten die succesvol hebben afgebouwd kunnen in een
gecontroleerde setting 2 jaar meedoen aan de extensie studie. (Dit geeft
informatie over zowel de lange termijn astma controle, alsook lange termijn
voordelen van het stoppen met ICS op metabole en endocriene determinanten.)

The study requires the patients to visit the outpatient more often than usual
(after inclusion 4 visits in 9 months). Additionally, patients wil lbe asked
to complete a short questionnaire weekly, using an online application. In this
application, patients will report the frequency of Fenoterol/*ipratropium use
(escape medication). The patients will be instructed to contact the local
investigator in case of worsening of asthma symptoms. In case of a significant
increase of the ACQ (>= 0.5 points for >= 4 days) or in case of frequent use of
escape medication (>6 inhalations of Fenoterol/*ipratropium per day), a consult
by telephone will be scheduled. When the investigator suspects an exacerbation,
the patient will be asked to visit the hospital, where the patient will receive
usual care. In case of a second intermediate/severe exacerbation, the patient
van no longer participate in the study and its extension.

During the visits at the outpatient clinic, some tests will be performed, only
the vena puncture is (minimally) invasive.