Effect of Ipratropium on Acute Bronchitis in Subjects Without Underlying Lung Disease
Condition: Bronchitis
MeSH terms: Bronchitis; Lung Diseases; Acute Disease
Study type: Interventional

Summary: 
      ABSTRACT CONTEXT: Inappropriate antibiotic prescriptions for acute bronchitis is a major
      public health concern because of antibiotic resistance. Effective therapies for managing the
      symptoms of acute bronchitis are lacking, however.

      OBJECTIVE: Determine if patients with acute bronchitis have better symptom control when
      treated with inhaled ipratropium.

      DESIGN, SETTING, PARTICIPANTS: COUGH STOP was a randomized, double blind, placebo controlled
      trial comparing ipratropium with placebo in acute bronchitis. Subjects were referred by their
      primary care provider or from urgent care clinics at a single institution. Subjects had been
      diagnosed with acute bronchitis and had no significant co-morbidities.

      INTERVENTION: Subjects received ipratropium or placebo inhalers, administering 2 puffs four
      times daily. A structured telephone interview took place 2, 4, and 8 days after enrollment.
      Medical records were reviewed at 60 days.

      OUTCOME: The primary endpoint was improvement in cough symptomology; secondary endpoints
      included subsequent antibiotic prescriptions and "well being."
    

Detailed description: 
      METHODS

      COUGH STOP was an investigator-initiated study. We conducted a prospective, randomized,
      double blind, placebo controlled trial to test the hypothesis that ipratropium would improve
      cough symptoms in otherwise healthy subjects with acute bronchitis. Subjects were enrolled
      between October 9th 2002 and November 1 2003, and were included if they had a cough with or
      without sputum production for less than 30 days duration; were age 18 through 65; and were
      willing to follow up by phone for a brief interview at 2, 4, and 8 days after enrollment.
      Subjects were excluded if they had a history of COPD; asthma; or other lung disease; had
      localized lung findings on exam to suggest pneumonia or asthma; chest X-ray (if done) with
      evidence of pneumonia; purulent nasal discharge or other evidence of bacterial sinus
      infection; evidence of streptococcal pharyngitis; temperature greater than 101.5 in the
      preceding 72 hours; treatment of a respiratory tract infection in the last 30 days;
      pregnancy; breast feeding; actively trying to become pregnant; history of heart failure;
      history of renal failure or insufficiency with a creatinine greater than 2.0 mg/dl; history
      of psychiatric illness other than minor depression; currently incarcerated; or were unwilling
      to sign the consent form.

      The study was reviewed and approved by the IRB for our facility, and approved by the FDA by
      way of an IND application. Subjects were either referred to one of the study investigators by
      a practicing physician or nurse practitioner at our facility, or were enrolled by a member of
      our team directly. Subjects were given a copy of the consent form, asked to review it and ask
      questions. Those who signed the consent form were randomly assigned to treatment with
      ipratropium or placebo metered dose inhaler (MDI). The assignment key was maintained by the
      pharmacy and by one of the investigators who had no interaction with the subjects or the data
      collection process. Subjects received training on how to use an MDI with a spacer device from
      a member of the study team. Subjects were instructed to take two puffs from the study MDI
      four times a day for the next 8 days. After the first 8 days they were instructed to use the
      study MDI on an as needed basis if they thought it was benefiting them.

      During a structured enrollment interview subjects were asked the following questions: How
      long have you been coughing (number of days)? What other symptoms do you have? Are you
      producing sputum? Do you smoke? Are you coughing at night? If "Yes," is it interrupting your
      sleep? Have you stopped working/daily activities? Are you having fevers? If "Yes," how high
      are they? What over-the-counter medications are you using?

      During the follow up telephone interviews, on days 2, 4, and 8 after enrollment, subjects
      were asked a similar but shorter set of questions: Are you still coughing? Is your cough
      better, worse, the same? Are you producing sputum? Is your sputum production better, worse,
      the same? Are you coughing at night? If "Yes," is it interrupting your sleep? Have you
      returned to work/daily activities? Has your sense of well being returned? Are you having
      fevers? If "Yes," how high are they? Are you having any side effects with the medication? If
      "Yes," what are they? Are you having any problems using your inhaler? If "Yes," please
      describe. What over-the-counter medications are you using? Subjects were not given any
      medical advice during the follow up interviews and were advised to address any medical
      questions with their primary care physician.

      Medical records were reviewed after two months of enrollment for, frequency of return clinic
      visits, medication prescriptions, especially antibiotics, and complications related to study
      enrollment. Subjects who had either a subsequent antibiotic prescription or clinic visit for
      respiratory complaints in the 60 days following study enrollment had an audit of their
      medical records. Subjects who were prescribed antibiotics in this period had their records
      reviewed for the following: which antibiotic was prescribed; how long after enrollment it was
      prescribed; and why it was prescribed. This data was collected in a separate database and
      reviewed in a blinded fashion by the entire research team for inclusion in the final
      analysis. All decisions were unanimous, and based on the following factors: the diagnosis at
      the time of the prescription was consistent with that of an upper respiratory tract infection
      (URI); the antibiotic prescribed was consistent with treatment for URI; in cases where the
      diagnosis at the time of prescription could not be determined, the subject was included in
      the secondary analysis if the antibiotic prescribed was consistent with treatment of a URI.
      Subjects were excluded from the analysis if their diagnosis at the time of the prescription
      was not consistent with URI or if the antibiotic prescribed was not consistent with treatment
      of a URI.

      Similarly, subjects who had clinic visits in the subsequent sixty-days had their records
      audited. Data was again collected in a separate database and reviewed in a blinded fashion by
      the entire team. Again, all decisions were unanimous, and criteria for inclusion were that
      the diagnosis at the time of the visit was consistent with that of a URI.

      Statistical Analysis Power analysis indicated that a sample size of approximately 100
      subjects in the treatment and control arms would be sufficient to detect a 33% reduction of
      cough frequency in the experimental arm receiving ipratropium, assuming a =.05 and b =.20,
      using a two- tailed z-statistic. Calculation of standard effect size for this power analysis
      was based upon extrapolation from Hueston's and Melbye's data13 15 on albuterol and fenoterol
      use in acute bronchitis, assuming a similar effect of ipratropium. Effect size for this
      calculation was based upon published values of relative risk in the references. Power
      analysis was not performed for other outcome variables.

      Data was analyzed on an intention-to-treat basis, according to randomized assignment. The
      ipratropium and placebo arms were compared for: self-reported cough severity [same, better,
      worse]; cough duration [present, not present] for days 2, 4, 8; , well-being [well, not-well]
      for days 2, 4, 8; work absence [attended work, did not work] for days 2, 4, 8. Proportions
      and rates for non-continuous grouped variables were compared using chi-square test. Normally
      distributed continuous variables, such as cough duration, were compared between treatment
      arms using a two-tailed t-test.
    

Intervention name(s): ipratropium
Intervention type(s): Drug
Intervention MeSH terms: Ipratropium
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Bronchitis; Acute bronchitis; Ipratropium; Cough; Metered dose inhaler; Antibiotic prescriptions; Sputum production