Theophylline in Chronic Obstructive Pulmonary Disease
Condition: COPD
MeSH terms: Pulmonary Disease, Chronic Obstructive
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This will be a prospective randomized double-blinded parallel group clinical trial evaluating
      the short-term effects of theophylline therapy on exercise duration and lung function in
      patients with chronic obstructive pulmonary disease already receiving both tiotropium and a
      long-acting beta-agonist (salmeterol or formoterol).
    

Detailed description: 
      Objective:

      The primary objectives of this study is to assess the effects of 4 weeks of theophylline
      therapy on exercise performance and lung function in patients with COPD already receiving
      combination inhaled long-acting bronchodilator therapy.

      Background:

      The latest Canadian COPD guidelines recommend the use of long-acting bronchodilators in
      patients who continue to experience symptoms despite as-needed use of short-acting
      bronchodilators. Unfortunately, patients with severe COPD may continue to experience symptoms
      despite use of both long-acting beta-agonists and anticholinergics. For these patients, the
      Canadian guidelines recommend a trial of theophylline. Studies have shown that theophylline
      can reduce symptoms and improve exercise performance, however, the use of theophylline is
      limited by its narrow therapeutic window and multiple drug interactions. Despite
      recommendations, it remains unknown whether theophylline provides any additional benefit for
      COPD patients already receiving combined long-acting bronchodilator therapy. No study has
      evaluated the effect of theophylline in patients already receiving both long-acting
      beta-agonist and long-acting anticholinergic therapy.

      Methods:

      This will be a prospective randomized double-blinded parallel group clinical trial evaluating
      the short-term effects of theophylline therapy on exercise duration and lung function in
      patients already receiving both tiotropium and a long-acting beta-agonist (salmeterol or
      formoterol). Twenty-four patients with moderate to severe COPD who are already using
      tiotropium and long-acting beta agonists will be randomized to receive either: a) 4 weeks of
      oral theophylline dosed to achieve therapeutic blood levels, or b) 4 weeks of identical
      placebo therapy. Only patients with stable COPD (no exacerbations nor changes in medications
      over the last 2 months) and no contraindications to exercise testing or theophylline use will
      be enrolled. All patients will undergo baseline pulmonary function testing and incremental
      and constant load exercise testing prior to randomization. PFTs and constant load exercise
      testing will be repeated after 4 weeks of therapy. Patients will be instructed to report
      adverse events and will have their theophylline dose adjusted to ensure therapeutic bloods
      levels (55-110 umol/L), prior to repeat testing.

      Outcome Measurements:

      The primary outcome of interest will be the effect of theophylline on exercise duration
      during constant load (75% maximum) exercise testing. The study will be powered to detect a
      20% greater improvement in exercise duration for the theophylline-treated group. Secondary
      outcome measures will include changes in spirometry (FEV1) and lung volumes.

      Anticipated results:

      Exercise duration (on constant load exercise testing) was chosen as the primary endpoint of
      this study because it has been shown to be a reproducible and highly responsive measure for
      physiologic benefit in COPD. It is unknown whether theophylline will provide any additional
      increase in exercise duration, when added to a combined long-acting bronchodilator regimen.
      If an improvement is found with theophylline, a follow-up study of larger size and longer
      duration will be required to investigate whether this benefit will translate into
      improvements in clinical outcomes such as quality of life or frequency of exacerbations.
      Alternatively, if no improvement can be detected, the current COPD treatment recommendation
      should be re-evaluated.
    

Intervention name(s): Theophylline
Intervention type(s): Drug
Intervention description(s): Patients assigned to study group, will receive slow-release theophylline at a dose of 10 mg/kg, titrated to blood levels between 55-110 umol/L, for a period of 4 weeks.
Patients assigned to placebo group will receive identical-appearing placebo tablets for the same period of time.
Intervention MeSH terms: Theophylline
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Chronic Obstructive Pulmonary Disease; Theophylline; Exercise testing