Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05040997 |
| Other study ID # |
3999 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 1, 2021 |
| Est. completion date |
May 9, 2023 |
Study information
| Verified date |
September 2021 |
| Source |
Fondazione Policlinico Universitario Agostino Gemelli IRCCS |
| Contact |
Matteo Bonini, MD, PhD |
| Phone |
+390630156011 |
| Email |
matteo.bonini[@]unicatt.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Rationale Although the majority of asthma patients can be effectively treated with currently
available medications, a substantial subset remains severe, causing a considerable proportion
of resource expenditure. Severe asthma is now widely accepted to be a heterogeneous syndrome
consisting of multiple phenotypes identified by specific biomarkers and targeted by tailored
biological therapies. However, much remains unclear regarding the best approaches to manage
these patients, or concerning the pathophysiological mechanisms underlying the disease.
Small airways (SA) are defined as those airways with an internal diameter <2 mm. In patients
affected by asthma, it has been reported that SA are the predominant site of airflow
resistance. Peripheral airways are thickened in asthma due to chronic inflammation in the
epithelium, submucosa and muscle area. It has been suggested that the outer wall is more
inflamed than the inner wall, with a higher number of lymphocytes, eosinophils, and
neutrophils associated to an increased mRNA expression of interleukin-4 (IL-4), IL-5 and
eotaxin. Moreover, it is well documented that SA inflammation and dysfunction contributes
significantly to the clinical impact of asthma and that 50-60% of asthmatics have a SA
involvement across all disease severities. An important question is whether SA disease in
asthma is variable among distinct asthma phenotypes and whether it occurs in all patients.
Cluster analyses have been recently used to identify specific asthma phenotypes, but markers
of SA function have not been investigated. However, evidence is accumulating to support the
concept that SA dysfunction and inflammation may contribute to distinct asthma phenotypes.
Recent findings indicate that SA are significantly affected in severe asthma and that their
involvement is associated with worse disease outcomes. It has been reported that patients
with asthma and a history of frequent exacerbations per year had a significant SA involvement
Furthermore, peripheral airways significantly contribute not only to the level of asthma
control, but also to patients' quality of life and perception of symptoms. At last more
thickened SA and higher numbers of eosinophils are detectable in subjects with fatal asthma.
The assessment of SA represents a big challenge and requires qualified expertise and
sophisticated techniques including body plethysmography, single and multiple breath nitrogen
washout, impulse oscillometry (IOS), fraction exhaled NO at multiflow, sputum induction and
high-resolution chest CT (HRCT). Such procedures can either provide functional information on
the degree/extent of ventilation heterogeneity and air trapping or facilitate the
understanding of the inflammatory and remodeling processes. These measures are not usually
part of the evaluation of asthmatic patients and in the monitoring of the effects of drugs
recommended for severe asthma.
Mepolizumab represents an innovative weapon for the treatment of severe eosinophilic asthma.
In most of these patients the drug controls inflammation, improves lung function, ameliorates
clinical symptoms, reduces exacerbations and has a marked steroid-sparing effect. However,
there is still a significant proportion of non-responders and a lack of validated predictive
biomarkers in such subpopulation. In regard to this, very limited findings are available
about the effect of mepolizumab on SA. At the best of our knowledge, the only paper available
in literature, addressing the topic, is the study of Farah and co-workers. The authors found
that an early improvement in SA function was associated with better asthma control and
represented a significant contributor to the therapeutic response. However, the study was
conducted in a limited cohort of patients, assessing SA only through multi breath nitrogen
washout, and not considering the relationship between SA disease and levels of
peripheral/sputum eosinophils. Also, a study was recently initiated at the Hopitaux de Paris
to evaluate airway remodelling during mepolizumab treatment (REMOMEPO, NCT03797404).
A better definition of severe asthma phenotypes and endotypes, as well as the identification
of novel disease targets and biomarkers to predict treatment response and monitor efficacy
and safety of biological drugs over time, would favor a Precision Medicine approach
translating in both improved disease management and reduced healthcare costs and social
burdens. This is considered a crucial unmet need and further research in the field is
strongly recommended by international guidelines, respiratory scientific societies,
healthcare systems and regulatory boards.
Description:
Study hypothesis We hypothesize that mepolizumab has a significant beneficial effect on small
airways disease in severe asthmatics and that the evaluation of small airways before and
during treatment may represent a distinctive marker of response and a novel target for a
preferential use of this drug vs other biologics available for severe eosinophilic asthmatic
patients.
Study objectives
- To evaluate a wide panel of validated small airways endpoints in eosinophilic severe
asthmatics before mepolizumab treatment
- To evaluate longitudinal changes of these endpoints at different time points during
mepolizumab treatment
- To relate small airways endpoints recorded at baseline and their changes over time to
other functional, laboratory, clinical and patient reported outcomes
Study center The study will be conducted at the Asthma Center of the Fondazione Policlinico
Universitario A. Gemelli, IRCCS, Respiratory, Allergy and ENT Physicians closely and
sinergically collaborate in the framework of the Asthma Center with shared clinical and
research activities aimed to an optimal management of asthma and its comorbidities, as well
as with regular meetings for multidisciplinary clinical case discussion and collective
decisions on treatment strategies. The Asthma Center is part of the Italian Severe Asthma
Network (SANI) and will be soon one of the coordinating centers for the newborn Italian
Mild-Moderate Asthma Network (MANI), therefore representing a center of excellence and
reference at a national level, with easy and wide access to the study population.
Study design Asthmatic patients referred to the Asthma Center and eligible for starting
Mepolizumab, after having optimized adherence, inhalation technique and comorbidity
management following multidisciplinary assessment, will enter a single-site oservational
prospective longitudinal cohort study. Subjects will be monitored for 12 months and SA
endpoints will be recorded at the beginning of the biological therapy (T0) and after 3,6,12
months (T3, T6, T12). SA endpoints will be also related to other functional, clinical and
patient reported outcomes.
Study population Male and female subjects addressed to the Asthma Center, aged ≥12 yrs with
severe asthma as defined by ATS/ERS guidelines (≥12months high-dose ICS + additional
controller treatments), ≥2 exacerbations (corticosteroid and/or ED visit and/or
hospitalization in the previous 12 months), blood eosinophil ≥150 cells/µl at study entrance
or ≥300cells/µl historically and a smoking history <2 pack/year.
Study drug Mepolizumab 100mg via subcoutaneous administration
Study procedures
The following methodologies will be included in the study:
Clinical history, Demographics and questionnaires (i.e. ACT, ACQ, ACQLQ) Pulmonary function
tests (i.e. spirometry, body plethysmography, single- and multi-breath nitrogen washout,
impulse oscillometry) Airway inflammatory markers (i.e. fraction exhaled nitric oxide - FeNO)
Allergy tests (i.e. skin-prick tests and immunoassays for total and specific serum IgE)
Biological sampling (i.e. blood and sputum eosinophils)
Study endpoints The following endpoints relating to small airways involvement will be
considered: R5, R20, X5, AX, RF, FEF25-75, TLC, RV, Raw, Gaw, DLCO, KCO, LCI
