AIMTo discover the molecular, cellular and structural airway targets of BT and link these to severe asthma phenotypes and outcome.OBJECTIVES1. To identify molecular and cellular targets of BT therapy and related changes in airway remodelling. 2. To…
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint is the difference in change in ASM mass as determined by the
percentage of ASM surface area in airway biopsies between the immediate BT
group and the delayed BT group = control group (n=20/group)
Secondary outcome
Secondary endpoints are BT-induced changes in:
1. ASM mass as determined by percentage/absolute ASM surface area or distance
of reticular basement membrane (RBM) to ASM layer in endobronchial biopsies.
2. mucosal endobronchial biopsy and induced sputum inflammatory cell
density/counts (eosinophils and neutrophils);
3. OCT- and rEBUS-determined changes in structural airway remodelling as
measured by changes in lumen area (Ai) and airway wall thickness (Aaw) and
composition (Figure 4);
4. Clinical outcome parameters including pulmonary function tests (pre-and post
bronchodilator FEV1, PC20 methacholine (PC20 Meth), FeNO and airway-resistance
(sRaw)/-compliance(sGaw)/-mechanics (FOT) parameters, asthma control
questionnaire (ACQ), asthma related quality of life questionnaire (AQLQ),
health care utilization (number of severe asthma exacerbations, emergency room
visits, hospital and intensive care unit (ICU) admissions).
Statistical analyses performed on these secondary endpoints are:
A. comparative between BT treatment and control groups (n=20/group) if not a
primary endpoint;
B. paired before and after BT analyses in all BT treated subjects (n=40) and;
C. comparative between BT-treated and untreated (right middle lobe RML) areas
of the lung in all BT-treated subjects (n=40) if applicable for that endpoint:
Correlation/responder analyses between baseline factors and endpoints and
predefined subgroup analyses.
Background summary
RATIONALE
Approximately 5% of asthma patients suffer from severe asthma that is
characterized by frequent asthma exacerbations resulting in significant
morbidity and excessive utilization of health care resources. Therefore, there
is a strong need for improved therapeutic strategies for these patients.
Insight in the pathogenesis and molecular pathways active in severe asthma is
crucial to reach this goal. Bronchial Thermoplasty (BT) is a novel, innovative
device-based treatment of severe asthma that is based on local, radiofrequent
energy delivery in larger airways during bronchoscopy. Although proven
effective on clinical outcomes in recent randomized trials, the mechanism that
determines BT effective is largely unknown.
HYPOTHESIS
BT-induced clinical improvement in severe asthma is a consequence of reduction
in airway smooth muscle (ASM) mass and (immunomodulatory) function,
inflammation, neural innervation and/or vascular integrity resulting in altered
airway remodelling. BT target identification and severe asthma phenotyping are
critical for improved patient selection for BT and fundamental to discovering
novel, specific signalling pathways active in severe asthma.
Study objective
AIM
To discover the molecular, cellular and structural airway targets of BT and
link these to severe asthma phenotypes and outcome.
OBJECTIVES
1. To identify molecular and cellular targets of BT therapy and related changes
in airway remodelling.
2. To link objective 1 to in vivo Optical Coherence Tomography (OCT)- and
radial endobronchial ultrasound (rEBUS)-detected BT-induced changes in airway
remodelling in severe asthma.
3. To phenotype and monitor severe asthma before and after BT by clinical
parameters including induced sputum, bronchial hyper-responsiveness (BHR, PC20
methacoline), forced expiratory volume in 1 second (FEV1) and fractional
exhaled nitric oxide (FeNO) and molecular parameters including RNA-derived
transcriptomes extracted from severe asthma biopsies/brushes; results are
compared to mild asthmatic and healthy controls.
Key Objective 1. and 2. will be linked to clinical outcome parameters.
Study design
The investigator-initiated TASMA trial aims to integrate the expertise of the
AMC Amsterdam in severe asthma, basic research and lung physiology with the
expertise in Interventional Pulmonology in AMC Amsterdam, UMCG Groningen,
Thoraxklinik, Heidelberg, Germany and Royal Brompton, London, United Kingdom.
This study recruits 40 severe asthma patients for BT at 4 sites in Europe
(n=9-12/center: AMC, Amsterdam; UMCG, Groningen. Thoraxklinikum Heidelberg,
Germany, Royal Brompton Hospital, London, United Kingdom). This number of
patients is based on the previously described discriminative power of primary
and secondary endpoints used for key objectives 1 to 3. Each site will enrol
9-12 patients, after the patient has been diagnosed with severe asthma,
fulfilled in- and exclusion criteria and has provided informed consent to
participate in the study. In- and exclusion criteria are described separately
in *study population/enrolment and patient selection* in the protocol. Patients
will be screened and phenotyped by demographic data, medical history, body mass
index (BMI), atopy, routine blood analyses including blood eosinophils, induced
sputum, chest X-ray, HR-CT of the chest, asthma control questionnaire (ACQ) and
pulmonary function tests (spirometry including FEV1, body plethysmography,
methacholine challenge test (PC20 Mch) and fractional exhaled nitric oxide
(FeNO)).
The study has a two-armed, randomized design with immediate BT treatment in the
first group and delayed BT treatment in the control group (n= 20 / group). This
strategy will generate power for controlled (between group) BT target
identification including ASM mass and clinical outcome analysis including PC20,
FEV1, asthma symptoms/quality of life (ACQ, AQLQ) and health care utilization
including frequency of emergency room visits, hospital admissions, severe
asthma exacerbation frequency (secondary endpoints) with maximal power for
paired analyses before and after BT (n =40).
After informed consent followed by standard BT screening patients will be
randomized to an immediate and delayed BT-treatment group. The delayed BT group
serves first as a control group in between BT and control group analyses
(n=20/group) and second to increase the sample size of active treatment in
paired analyses before and after BT (n=40). Standard screening to determine a
patient suitable for BT includes a single bronchoscopy for detection of gross
airway abnormalities, high-resolution computer tomography of the chest (HR-CT)
including expiration phase, sputum induction, standard pulmonary function and
blood testing before BT. Standard BT will be performed using the Alair system
(Boston Scientific, USA) and therefore patients will undergo 3 bronchoscopy
procedures with BT at least 3 weeks apart within a 2 months period. Standard BT
follow-up afterwards includes routine blood analysis, pulmonary function tests
and HR-CT at 24 weeks. For research purposes, we ask patients to undergo a
maximum of 2 extra bronchoscopies: 1 bronchoscopy in the immediate BT group
(24 weeks after BT) or 2 bronchoscopy in the delayed BT group (3 weeks before
and 24 weeks after BT). These bronchoscopies are on top of a single standard
screening bronchoscopy before randomisation and BT during which airway sampling
and OCT/rEBUS imaging is performed along with sputum induction, pulmonary
function tests, questionnaires and venous blood sampling (see Table 1 and
Figure 0.). Off protocol follow-up of patients will be offered by standard
follow-up procedures yearly after BT treatment for 5 years.
Intervention
Bronchial Thermoplasty by the Alair system (Boston Scientific, USA). 1
(immediate BT group n=20) of 2 (delayed BT group n=20) additional
bronchoscopies for airway-sampling and -imaging.
Study burden and risks
This study has a two-fold purpose: 1. to unravel the targets of BT in severe
asthma (how does it work?) which is fundamental for better patient selection
(who benefits most?) and further improvement of BT technology and novel asthma
therapy development (how to treat better?). These objectives can only be
achieved by linking patient-reported outcomes to airway structure/function,
which is the principal aim of the study proposed. 2. to investigate clinical
outcome analyses. These gaps in scientific knowledge and important questions
are identified and articulated in the national and international severe asthma
guidelines and need to be addressed for further application of BT in severe
asthma. The proposed TASMA study is designed to fill these gaps and as such is
critical for a broader application of this novel endoscopic treatment in severe
asthma with possible lifelong benefit. The study protocol is judged
methodologically Very Good (2x) or Excellent (4x) by six international experts.
Two grants - Dutch Lung Foundation and ZonMw - are obtained to execute this
study. The patient benefit of study participation is that he/she is offered a
novel severe asthma treatment that is proven effective and safe with potential
lifelong benefit but unfortunately not regularly available yet. For research
purpose patients will be randomised to an immediate and delayed BT group
(n=20/group). The delayed BT group first serves as a control group and to
increase the sample size of the active treatment group. For this reason we ask
half of the patients to wait for 24 weeks for getting actual BT treatment. In
addition we ask patients to undergo a maximum of 2 extra bronchoscopies: 1
bronchoscopy in the immediate BT group (24 weeks after BT) or 2 bronchoscopy
in the delayed BT group (3 weeks before and 24 weeks after BT). These
bronchoscopies are on top of a single standard screening bronchoscopy before
randomisation and BT during which airway sampling and OCT/rEBUS imaging is
performed along with sputum induction, pulmonary function tests, questionnaires
and venous blood sampling (see Table 1 and Figure 0.). The bronchoscopies will
be performed under conscious sedation (midazolam or propofol) to minimize
patient discomfort. Previous experiences in research bronchoscopies in severe
asthma patients by our group and others have proven these procedures to be
safe. To our opinion the burden of either 1 or 2 additional bronchoscopies
including airway sampling/imaging, sputum induction, pulmonary function test
and questionnaires and postponing the actual BT treatment in half of the
patients is justified by the scientific insights that can be obtained in this
important trial in which a novel severe asthma treatment is offered that is
otherwise not available.
Meibergdreef 9
Amsterdam 1105AZ
NL
Meibergdreef 9
Amsterdam 1105AZ
NL
Listed location countries
Age
Inclusion criteria
symptomatic severe asthma despite optimal inhalation therapy
FEV1<= or >50% (stabilized on ICS/ABA) or post-bronchodilator FEV1 <= or > 60%
non-smokers
Exclusion criteria
age <18 or >65 years
other respiratory tract disease than asthma including bronchiectasis, infection
use of immunosuppressive therapy other than prednisolone <20mg/day
use of anticoagulants
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| CCMO | NL45394.018.13 |