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Clinical Investigations: COPD |

Theophylline for Irreversible Chronic Airflow Limitation*: A Randomized Study Comparing n of 1 Trials to Standard Practice

Jeffrey L. Mahon, MD, MSc; Andreas Laupacis, MD, MSc; Richard V. Hodder, MD, MSc, FCCP; Douglas A. McKim, MD; Nigel A. M. Paterson, MD, FCCP; Thomas E. Wood, MD, MSc, FCCP; Allan Donner, PhD
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*From the Department of Medicine (Drs. Mahon, Paterson, and Wood) and the Department of Epidemiology and Biostatistics (Dr. Donner), University of Western Ontario; and Department of Medicine (Drs. Laupacis, Hodder, and McKim), University of Ottawa. Canada.



Chest. 1999;115(1):38-48. doi:10.1378/chest.115.1.38
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Study objective: To compare quality of life and exercise capacity (primary aim), and drug usage (secondary aim), between groups of patients with irreversible chronic airflow limitation (CAL) who were undergoing theophylline (Theo-Dur; Key Pharmaceuticals; Kenilworth, NJ) therapy guided by n of 1 trials or standard practice.

Design: Randomized study of n of 1 trials vs standard practice.

Setting: Outpatient departments in two tertiary care centers.

Patients: Sixty-eight patients with irreversible CAL who were symptomatic despite the use of inhaled bronchodilators, and who were unsure whether theophylline was helping them following open treatment, were randomized into n of 1 trials (N = 34) or standard practice.

Interventions: The n of 1 trials (single-patient, randomized, double-blind, multiple crossover comparisons of the effect on dyspnea of theophylline vs a placebo) followed published guidelines. Standard practice patients stopped taking theophylline but resumed it if their dyspnea worsened. If their dyspnea then improved, theophylline was continued. In both groups, a decision about continuing or stopping the use of theophylline was made within 3 months of randomization.

Measurements and results: The primary outcomes (the chronic respiratory disease questionnaire [CRQ] and 6-min walk) were measured at baseline, 6 months, and 12 months by personnel blinded to treatment group allocation. No between-group differences (n of 1 minus standard practice) were seen in within-group changes over time (1 year minus baseline) in the CRQ Physical Function score (point estimate on the difference, –2.8; 95% confidence limits [CLs], –8.2, 2.5), CRQ Emotional Function score (point estimate on the difference, 0.5; 95% CLs, –4.7, 5.7), or 6-min walk (point estimate on the difference, 8 m; 95% CLs, –26, 44 m). No differences between groups were seen in the secondary outcome of the proportion of patients taking theophylline at 6 and 12 months. In 7 of 34 n of 1 trial patients (21%), dyspnea improved during theophylline treatment compared with placebo treatment.

Conclusions: Using n of 1 trials to guide theophylline therapy in patients with irreversible CAL did not improve their quality of life or exercise capacity, or reduce drug usage, over 1 year compared to standard practice. Under the objective conditions of an n of 1 trial, 21% of patients with CAL responded to theophylline. There remains a rationale for considering theophylline in patients with irreversible CAL who remain symptomatic despite the use of inhaled bronchodilators, but the use of n of 1 trials to guide this decision did not yield clinically important advantages over standard practice.

Abbreviations:CAL = irreversible chronic airflow limitations; CL = confidence limit; CRQ = chronic respiratory disease questionnaire

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