To investigate the effect of dabigatran etexilate on airway inflammation, hemostasis and asthma control in patients with severe asthma.
ID
Source
Brief title
Condition
- Bronchial disorders (excl neoplasms)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoint will be the change from baseline in percentage of eosinophils
in induced sputum as a marker of anti-inflammatory activity after 3 months
treatment with dabigatran etexilate.
Secondary outcome
Secondary endpoints will be changes from baseline in asthma control, lung
function, exhaled nitric oxide, and changes in markers of hemostasis and
inflammation in blood and induced sputum.
Background summary
In many patients with severe refractory asthma airway inflammation is
insufficiently suppressed by inhaled corticosteroids alone and these patients
require chronic oral corticosteroids to maintain asthma control. High levels of
glucocorticoids, either endogenous or exogenous, have been shown to induce
hypercoagulability and an increased risk of venous thromboembolism. In
addition, asthma itself has also been associated with a prothrombotic state,
and preliminary data from our group have shown an increased risk of pulmonary
embolism in patients with severe asthma that was associated with chronic oral
corticosteroid use and frequent asthma exacerbations.
Anticoagulants, such as inhaled heparin and low molecular weight heparin have
been shown to attenuate airway inflammation in patients with allergic asthma.
These data suggest that the interaction between coagulation and inflammation is
important in disease severity, therapy resistance and thromboembolic
complications in patients with severe asthma. Although all anticoagulants have
some antiinflammatory properties, dabigatran etexilate seem the most
appropriate given its mode of action, safety profile and availability.
Study objective
To investigate the effect of dabigatran etexilate on airway inflammation,
hemostasis and asthma control in patients with severe asthma.
Study design
a single-center, randomized, parallel, double-blind, placebo-controlled trial
Intervention
Patients will be randomized to receive dabigatran etexilate (once daily 220 mg
orally) or identical placebo for 12 weeks.
Study burden and risks
For patients with severe, refractory asthma, there are hardly any therapeutic
options except oral corticosteroids that are associated with serious long-term
side effects. This study will investigate whether anticoagulant treatment may
have beneficial effects in these patients in terms of reduction of the
procoagulant and inflammatory state, and better asthma control (by ACQ).
Adverse effects of anticoagulants are well documented and limited with a
prophylactic dose. Dabigatran etexilate is a new oral thrombininhibitor with a
similar bleeding risk as that of low molecular weight heparins. Since a
prophylactic dose will be administered in the present study, we believe that
the potential benefits of participating in this study largely outweigh the
potential risks of this treatment for patients with severe refractory asthma.
Meibergdreef 9
Amsterdam 1105 AZ
NL
Meibergdreef 9
Amsterdam 1105 AZ
NL
Listed location countries
Age
Inclusion criteria
• Age >= 18 years
• Non-smoking patients, or patients who stopped smoking more than 12 months ago and KCO >= 90% pred.
• Able to give written and dated informed consent prior to any study-specific procedures
• All patients have previous evidence of variable airways obstruction within the last 5 yrs, as documented by at least one of the following:
*- Reversibility in forced expiratory volume in one second (FEV1) of >=9% predicted after 4 puffs of
a 100 µg salbutamol dose-aerosol, administered via a spacer.
*- A mean diurnal variation in peak expiratory flow (PEF) >=15% (highest PEF*lowest PEF) per
mean PEF on >=4 days per week for a minimum of 2 weeks.
*- An increase in FEV1 of >=400 mL after a course of prednisolone 0.5 mg•kg*1•day*1 for 14
days.
*- A provocative concentration causing a 20% fall in FEV1 with histamine or methacholine <8
mg/mL.
• On stable doses of oral and inhaled corticosteroids during the previous 4 weeks and during the study.
• No other clinically significant abnormality on history and clinical examination
• Severe asthma according to the criteria of the International Consensus of the Innovative Medicine Initiative (IMI)
• High- and ultrahigh dose of ICS (Fluticasone >=1000 µg/day or equivalent drug) with continuous use of oral corticosteroids (>=5 mg/day).
• Sputum eosinophil count > 3% of the total cell count.
Exclusion criteria
• Women who are pregnant or lactating or who have a positive urine pregnancy test at screening
• Ongoing use of tobacco products of any kind.
• Ex-smoking patients with reduced diffusion capacity: KCO < 90% pred.
• Use of omalizumab during the last 6 months before randomization
• Use of heparin, LMWH, NSAID or vitamin K antagonists.
• Any bleeding diathesis
• History of acute intracranial disease or haemorrhagic stroke
• Major surgery, trauma, uncontrolled hypertension, or myocardial infarction in the past 3 months
• Gastrointestinal or urogenital bleeding, or ulcer disease in the past 6 months
• Severe liver disease
• Alanine or aspartate aminotransferase concentrations greater than two times the upper limit of
the normal range in the past month
• Severe renal insufficiency (creatinine clearance less than 30 mL/min)
• Active malignant disease
• Participation in any clinical investigational drug treatment protocol within the preceding 30 days
• Unwillingness or inability to comply with the study protocol for any other reason
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
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-005406-30-NL |
| CCMO | NL38698.018.11 |