Aspirin for Uncontrolled Asthma
Condition: Uncontrolled Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 3

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Aspirin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Aspirin 600 mg (2 tablets of 300 mg) twice daily for 6 months; Placebo (2 tablets) twice daily for 6 months
Other intervention name(s): acetylsalicylic acid
Intervention MeSH terms: Aspirin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: asthma, aspirin