Asthma is characterized by changes in eicosanoids metabolism, especially high production of bronchoconstrictive cysteinyl leukotrienes (CystLTBs) and leukotriene B4 (LTB4). Recent studies have also demonstrated a relative low production of lipoxin A4, an endogenous lipid mediator resulting from lipo-oxygenase action, distinct from CystLTBs, with anti-inflammatory properties, in bronchial epithelial cells and lung macrophages of severe asthma patients, leading to imbalance between pro-resolving and pro-inflammatory eicosanoids production in airways. Such data suggest that aspirin, that induces lipoxins production, could restore lipoxins deficit in severe asthma. Interest for aspirin is also supported by data obtained in asthma patients with aspirin intolerance (Aspirin induced asthma, AIA) : in this particular group of patients, aspirin treatment significantly improves nasal symptoms, quality of life, asthma and rhinitis scores, and reduces need for hospitalizations, nasal surgery and oral steroids use. Potential effect of aspirin in patients with uncontrolled asthma without aspirin intolerance, who presented changes in arachidonic acid pathway close to those observed in AIA, is not established.

The aim of the study is to assess whether long term aspirin treatment could improve asthma control, compared to placebo, in patients with uncontrolled disease and nasal polyposis, whatever their aspirin tolerance level.

Asthma concerns about 7% of the French adult population. About 10% of them have uncontrolled disease, despite high doses of inhaled steroids combined with long acting beta 2 agonists and adequate management of aggravating factors. They account for considerable asthma morbidity, mortality and costs. New treatments are needed for these patients.

Asthma is characterized by changes in eicosanoids metabolism, especially high production of bronchoconstrictive cysteinyl leukotrienes and LTB4. Recent studies have also demonstrated a relative low production of lipoxin A4, an endogenous lipid mediator resulting from lipo-oxygenase action, distinct from CystLTBs, with anti-inflammatory properties, in bronchial epithelial cells and lung macrophages of severe asthma patients, leading to imbalance between pro-resolving and pro-inflammatory eicosanoids production in airways. Such data suggest that aspirin, that induces lipoxins production, could restore lipoxins deficit in severe asthma, as demonstrated in other models.

Interest for aspirin is also supported by data obtained in asthma patients with aspirin intolerance (Aspirin induced asthma, AIA), who are characterized by a severe difficult-to-treat respiratory disease frequently associated with nasal polyposis, overproduction of leukotrienes and increased expression of leukotriene receptors. In this particular group of patients, aspirin treatment significantly improves nasal symptoms, quality of life, asthma and rhinitis scores, and reduces need for hospitalizations and nasal surgery. A reduction in oral steroids use was observed in most series. In this group of patients, aspirin also induced a decrease in interleukin 4 (IL-4) and Matrix metallopeptidase 9 (MMP-9) levels in sputum in asthma patients thus providing another explanation for anti inflammatory effect of aspirin in asthma. Patients treated with higher doses of aspirin (650 mg BID) had more favorable courses than those treated with lower doses.Aspirin desensitization is considered as a cost-effective therapeutic intervention in patients with moderate-to-severe AIA However, some of these studies, coming mostly from the same team, can be criticized for methodological reasons, low evidence, small series, and weak asthma characterization.

Potential effect of aspirin in patients with uncontrolled asthma without aspirin intolerance, who presented changes in arachidonic acid pathway close to those observed in AIA, is not established. Because similar changes in eicosanoid metabolism are described in nasal polyps mucosa, a pathology frequently associated with asthma, we hypothesize that patients with nasal polyps and asthma could be a specific target for aspirin treatment.

Aspirin is a cheap treatment, compared with biotherapies developed for severe asthma.

Hypothesis The investigators propose to compare the effect aspirin (600 mg twice daily) versus placebo, given during six months, on asthma control in patients with uncontrolled asthma and nasal polyposis, whatever their aspirin level of tolerance, in a randomized, double blind, placebo-controlled trial.

Study objectives Primary objective To assess whether long term aspirin treatment could improve asthma control, compared to placebo, in patients with uncontrolled disease and nasal polyposis, whatever their aspirin tolerance level.

Secondary objectives

To assess the effect of long term aspirin treatment compared to placebo, in patients with uncontrolled disease and nasal polyposis, on the following criteria:

• lung function
• number of exacerbations
• time to the first exacerbation
• oral and inhaled steroid use and doses
• Nasal symptoms
• Nasal sinus symptoms severity
• quality of life
• Lipoxin A4, cysteinyl leukotrienes (cystLT) and LTB4 levels in sputum
• Reactions during oral aspirin challenge
• Gastro-intestinal and other bleedings

Study design This is a multicentric, randomized, placebo-controlled, double-blinded phase III clinical trial.

Inclusion Criteria:

• Age : 18 to 75 years old
• Patients receiving inhaled steroids (>1000 µg/d beclomethasone or equivalent) combined with long acting beta agonist at a stable dose for at least 1 month and montelukast for at least 2 weeks.
• Patients receiving Proton Pump Inhibitors for at least 2 weeks
• Uncontrolled asthma defined by an ACQ 6 score≥1.5 at baseline
• Recurrent chronic rhinosinusitis with nasal polyposis diagnosed by nasal endoscopy by an otorhinolaryngologist
• Evidence of reversibility of airway obstruction defined as an increase of FEV1 of 12% or greater and at least 200 ml after Short Acting Beta Agonists (SABA) administration OR after oral corticoid test or an increase of CVF of 12% or greater and at least 200 ml after Short Acting Beta Agonists (SABA) administration or after oral corticoid test OR a variation in FEV1 of more than 200 ml and 12% between 2 follow-up visits OR variation of the Peak Expiratory Flow Rate (PEF) with a delta PEF over the day / average PEF over 2 weeks > 10% OR a positive methacholine bronchial challenge test: decrease in FEV1 by more than 20% for a dose < 1600 µg documented once during medical history
• FEV1>1.5l and 60% of predicted value at inclusion
• Never smoked or non-smoker for at least 6 months, with a smoking history of no more than 10 pack-years
• Written informed consent
• Efficient contraception, other than an intrauterine device (IUD), for women of reproductive age

Exclusion Criteria:

• Evidence of another clinically significant, active pulmonary disorder (bronchiectasis, chronic obstructive pulmonary disease (COPD), …) that could influence asthma control evaluation
• Patient treated regularly with aspirin or NSAID for another pathology
• Hypersensitive response to lansoprazole
• treatment by nelfinavir or other HIV protease inhibitors for which absorption depends on gastric pH (atazanavir...)
• Asthma exacerbation within the 4 weeks prior to inclusion (as defined by an oral corticotherapy for more than 48h or a 2-fold increase of oral corticoid intake )
• Pregnancy or breast feeding
• Recent myocardial infarction within the 6 months prior to inclusion
• immunodeficiency
• Patients receiving bet-blockers
• Contra-indication for aspirin : history of gastro-intestinal or cerebral bleeding, active gastric or duodenal ulcer, major surgery within the 4 weeks prior to inclusion, treatment with methotrexate, probenecid, selective serotonin re-uptake inhibitor, diuretic, angiotensin-converting-enzyme inhibitor, angiotensin receptor inhibitor or anti-platelet drug, ,any hemorrhagic risk according to the investigator, heart, liver or kidney failure, hyperuricemia, phenylketonuria.
• Major surgery planned during the 6 month study period
• under security or legal protection measures
• patient intolerant to lactose or other excipient
• Patient with intra-uterine device
• patient who has not given written consent
• Non affiliation to a social security scheme (beneficiary or assignee)

Secondary exclusion criteria :

-Patients who will require epinephrine injection or transfer to ICU or patients who do not reach the maximum dose of 600mg during aspirin challenge-desensitization will stop the study and not be randomized