Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05792592 |
| Other study ID # |
4253 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
February 15, 2022 |
| Est. completion date |
June 16, 2024 |
Study information
| Verified date |
March 2023 |
| Source |
Fondazione Policlinico Universitario Agostino Gemelli IRCCS |
| Contact |
Matteo Bonini, Prof. |
| Phone |
06030156011 |
| Email |
matteo.bonini[@]policlinicogemelli.it |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
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 airway (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 expression of interleukin-4 (IL-4), interleukin-5
(IL-5) and eotaxin. Moreover, it is well documented that SA inflammation and dysfunction
contribute 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 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.
In addition, a number of clinical trials have in recent years demonstrated the efficacy of
biologics in severe asthma. Omalizumab, a humanized anti-Imunoglobulin E monoclonal antibody
(mAb) has been well recognized as an important option for treating allergic asthma as an add-
on therapy for uncontrolled disease.
Three anti-IL-5 therapies are currently available for the treatment of severe asthma,
including Mepolizumab, Reslizumab, and Benralizumab.
The newest biologic agent to be approved is Dupilumab that is a human mAb that targets the
subunit of the IL-4 receptor.
Biologics represent an innovative strategy for the treatment of severe asthma. In most
patients with SAD these drugs control inflammation, improve lung function, ameliorate
clinical symptoms, reduce exacerbations and have 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 biologics therapy on SA.
Description:
Study hypothesis We hypothesize that biological therapy 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 one over other biological therapies currently available for severe
asthmatic patients.
Study objectives
- To evaluate small airway endpoints in severe asthmatics before starting biologic
treatment.
- To evaluate longitudinal changes of these endpoints at different time points during
biologic treatment.
- To relate small airway endpoints recorded at baseline and their changes over time to
other functional, laboratory, clinical and patient-reported outcomes.
- To make comparisons for subgroups identified on the basis of the type of the biological
drug used.
Study center
The study will be conducted at the Asthma Center of Fondazione Policlinico Universitario
Agostino Gemelli. Asthma Clinic evaluates approximately 1000 asthmatic patients per year;
furthermore, it is part of the Italian Severe Asthma Network (SANI) and 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 This is a 24-month, single-site observational retrospective and prospective
longitudinal cohort study involving asthmatic patients referred to the Asthma Center and
eligible for starting one of the biological therapy currently available. The patient will be
considered eligible only after having optimized adherence, inhalation technique, comorbidity
management and following a multidisciplinary assessment. Subjects will be monitored for 12
months and SA endpoints as well as other functional, clinical, laboratory and
patient-reported outcomes will be recorded at the beginning of the biological therapy (T0)
and after 3,6,12 months (T3, T6, T12). Values and changes in SA endpoints will be also
related to other functional, clinical and patient-reported outcomes.
Study procedures
The following study procedures will be performed in the framework of the standard care for
severe asthmatic patients:
- Clinical history;
- Demographics data (such as age, sex, race et.)
- Questionnaires (i.e. Asthma Control Test [ACT], Asthma Control Questionnaire [ACQ],
Asthma Quality of Life Questionnaire [AQLQ])
- Pulmonary function tests (i.e. spirometry [Forced Expiratory volume in 1 second
(FEV1),Forced Vital Capacity (FVC), FEV1/FVC, body plethysmography [Residual Volume
(RV), Total Lung Capacity (TLC), RV/TLC, impulse oscillometry as resistance at 5 and 20
Hz (R5, R20).
- 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).
- Imaging (i.e. chest XR and HRCT)
Study endpoints The primary endpoint will be represented by the R5-R20 parameter registered
through impulsoscillometry. Baseline values and changes over the one-year follow-up period at
preplanned timepoints (i.e. 3, 6, and 12 months) will be recorded. According to literature
evidence, baseline values ≥0.07 support the evidence of small airways dysfunction.
Secondary endpoints will be represented by indirect parameters of SA involvement (i.e. TLC,
RV, TLC/RV, FEF25-75). Baseline values and changes over the one-year follow-up period at
preplanned timepoints (i.e. 3, 6, and 12 months) will be recorded.
Variations in primary and secondary endpoints will be also related to changes in functional
parameters (i.e FEV1), clinical parameters (exacerbation rate), inflammatory markers (FeNO)
and patients' questionnaire scores (ACT, AQLQ, ACQ). Established minimal clinically important
difference (MCID) thresholds will be taken into consideration for correlation analyses.
Statistical analysis Statistical analysis will be performed using a statistical software.
Data will be tested for normality and will be expressed as mean (SD) or median (IQR).
Comparative analysis will be performed using parametric and non-parametric methods as
appropriate. Single and multiple linear regression analyses will be run to determine
correlation between small airway endpoints and clinical, functional, laboratory, and
patients' reported outcomes. A p-value≥0.05 will be considered statistically significant.
Most appropriate statistical analyses and models will be anyway chosen and run, following the
advice of statisticians at the institutional Department of Public Health. Considering the
"R5-R20 Delta", measured through impulse oscillometry, as the primary endpoint for the study,
and aiming for a minimal difference of 0.02 (according to literature data), in order to have
an a error of 0.5 and a study power of 80%, at least 54 subjects will have to be enrolled in
the study. Documentation will be stored for a minimum of 10 years after the completion of the
study, including the follow-up period.
Study significance and innovation Systems biology approaches are establishing the links
between disease pathways/mechanisms, and clinical/physiologic features. Validation of these
pathways may contribute to better defining severe asthma endotypes and treatable mechanisms.
Precision medicine approaches are necessary to link treatable mechanisms with treatable
traits and biomarkers derived from clinical, physiologic, inflammatory, molecular and genetic
variables. A deep and proper assessment of airway samples along with non-invasive biomarkers
may have a highly relevant translational significance and enable better knowledge and
management of severe asthma.
Risk analysis No major difficulties are expected in view of the study's observational design.
No additional costs will be held.
