The Effect of Montelukast in Patients With Chronic Cough and Bronchial Hyperreactivity
Condition: Cough; Bronchial Hyperreactivity
MeSH terms: Cough; Bronchial Hyperreactivity
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose is to determine whether montelukast during 6 weeks has superior antitussive
      effects (measured with the LCQ) compared with placebo in patients with cough lasting > 8
      weeks and enhanced bronchial hyperreactivity.
    

Detailed description: 
      Chronic cough is a frequent problem in general practice and one of the most common reasons
      for referral to a respiratory clinic. Prospective studies have shown that the vast majority
      of cases of chronic cough are due to one or more of three conditions: rhinitis/postnasal drip
      syndrome, asthma and gastro-oesophageal reflux disease. Other significant causes of chronic
      cough include postviral (post-infectious) cough, and eosinophilic bronchitis. In only a
      minority of the patients with a chronic cough no cause can be found. This is called
      idiopathic cough.

      Analysis and treatment of patients with chronic cough often proved to be difficult and
      disappointing. Nevertheless, centers in which a comprehensive diagnostic and therapeutic
      protocol was implemented reported excellent results. Therefore the first cough clinic is
      started in The Isala Klinieken, Zwolle/The Netherlands in 2004.

      Asthmatic cough is often accompanied by the more typical symptoms of dyspnoea and wheezing.
      In a subgroup of asthmatics, however, cough is the sole or predominant symptom. This
      condition is termed cough-variant asthma (CVA). Cough due to CVA usually improves within the
      first week of inhaled bronchodilator therapy, however, complete resolution of cough may
      require up to 8 weeks of combination therapy with inhaled bronchodilators and
      corticosteroids. A subgroup of CVA patients with severe, refractory cough may require
      systemic (oral) steroids, alone or followed by inhaled therapy.

      Leukotrienes are contributing significantly to the pathobiology of asthma. These 'pathways of
      asthma' could be suppressed by leukotriene inhibitors. Multiple clinical trials have
      demonstrated the ability of the leukotriene modifiers to improve symptoms, pulmonary function
      and bronchial hyperresponsiveness in chronic asthma, as well as in exercise-induced and
      aspirin-induced asthma. Until recently, the antitussive effects of this drug class had not
      been investigated properly. Spector and Tan concluded in a pilot trial with only 14 patients
      that 10 mg montelukast seems to be effective in CVA. However, nowadays in care of asthma,
      montelukast is widely used in a dosage of 10 mg. Therefore we intend to study the effects of
      montelukast on chronic cough (VAS-cough-score) on a wider patient population; is montelukast
      superior to placebo in the treatment of patients with chronic cough and a demonstrated
      bronchial hyperreactivity?

      Aim of the study:

      The purpose is to determine whether montelukast during 6 weeks has superior antitussive
      effects (measured with the VAS cough) compared with placebo in patients with cough lasting >
      8 weeks and enhanced bronchial hyperreactivity.

      Study design:

      Montelukast trial: prospective single-centre, double blind randomised trial.

      In the montelukast study 84 patients between 18 and 90 years old, referred to the cough
      outpatient clinic with chronic cough and enhanced bronchial hyperreactivity will be recruited
      after informed consent is obtained.

      Patients will be randomised (for gender, age, smoking, duration of symptoms and the use of
      inhaled corticosteroids) to 6- week treatment with 10 mg daily montelukast or placebo. Before
      randomisation all patients have to fill in the Visual Analogue Scale (VAS) for detection of
      the degree of cough in the last 24 hours and the dutch version of the Leicester Cough
      Questionnaire (LCQ) for the detection of illness specific quality of life. Adverse events
      will be noted in this period. Finally, both groups will be compared.

      Inhaled corticosteroids may be continued during the study at a constant dose. Nasal,
      ophthalmologic and dermatological steroids are allowed according to individual needs, but
      their dose should be kept constant throughout the trial.

      H1 blockers, nasal anticholinergics as well as nasal or ophthalmologic preparations of
      nedocromil or cromoglycate are permitted for treatment of allergic rhinitis.

      Study population:

      Patients between 18 and 90 years old, referred to the cough outpatient clinic with chronic
      cough and enhanced bronchial hyperreactivity.

      Intervention:

      Patients between 16 and 90 years old, referred to the cough outpatient clinic with chronic
      cough and enhanced bronchial hyperreactivity will receive daily montelukast 10 mg or placebo
      during 6 weeks.

      Main study endpoint :

      1. Difference in cough VAS scores; montelukast vs placebo.

      Secondary study endpoints:

        1. Difference in average score on the Leicester Cough Questionaire (LCQ) between the two
           treatment groups; montelukast vs placebo.

        2. Comparison of the adverse events of montelukast vs placebo.

      Randomisation:

      Patients will be randomised by a computer minimisation program for the following factors:
      gender, age, smoking, duration of symptoms and the use of inhaled corticosteroids.

      Statistical analysis:

      The primary analysis will be on an intention-to-treat basis. The mean change in the primary
      endpoint (LCQ total and domain scores) after 6 weeks between the groups will be analysed
      using an unpaired t-test. This test will also be used to analyse differences after 6 weeks in
      secondary endpoints (VAS cough score).

      Since both the primary and secondary endpoints in the study will be measured more than two
      times (repeatedly measured) the course of these scores over time will be tested using
      MANOVA-analysis. To test for differences in proportions (proportion of patients with adverse
      events) the Chi2 -test will be used. Data analyses will be performed using SPSS version 12.

      Burden, risks and advantages associated with participation:

      Side effects have been reported in 10 % of the cases; mostly of headache and abdominal pain.
      Also gastrointestinal problems, allergic reactions, psychiatric disorders, liver, and
      haematological disorders could occur.

      Interactions: Montelukast is metabolised by CYP3A4. Concomitant use of CYP3A4 inducing
      medication like fenytoïne, phenobarbital, or rifampicin must be prevented.

      Medication metabolised by CYP2C8 must also be avoided, because in vitro studies have shown
      that montelukast is an powerful CYP2C8 inhibitor.

      Benefits: superior resolution of cough compared to placebo.
    

Intervention name(s): montelukast; placebo
Intervention type(s): Drug; Drug
Intervention description(s): montelukast, 8 weeks, once daily, 10 milligrams; placebo
Other intervention name(s): singulair
Intervention MeSH terms: Montelukast
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: cough; hyperreactivity; montelukast