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

doi:10.1378/chest.115.1.38

Chest

Volume 115, Issue 1, January 1999, Pages 38-48

https://doi.org/10.1378/chest.115.1.38 Get rights and content

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.

Section snippets

Protocol

Our rationale for studying theophylline for irreversible CAL was twofold: (1) prescription of theophylline for CAL meets the prerequisites for n of 1 trials19, 20 (CAL is chronic and relatively stable, the action of theophylline starts and ends within several days, and the efficacy of theophylline in a specific patient with CAL is often in doubt); and (2) successful n of 1 trials of theophylline for CAL have been reported.²² Approval by institutional review boards was obtained, and all patients

Interventions

The n of 1 trials followed published guidelines (Fig 1).²³ Patients identified daily activities during which they could become dyspneic. These activities were incorporated into a diary, in which the severity of dyspnea was rated on a 7-point Likert scale. For example, if dyspnea while climbing stairs was identified, the question read “How short of breath were you today when you were climbing stairs?,” with response options of 1 (extremely short of breath), 2 (very short of breath), 3 (quite a

Outcome Measures and Sample Size

The chronic respiratory disease questionnaire (CRQ), 6-min walk, FEV₁, and FVC were assessed at baseline, 6 months, and 12 months in both the n of 1 trial and standard practice groups. The CRQ is a valid, responsive, quality-of-life index specific for CAL9, 26 that measures four domains. These domains can be combined into larger domains of Physical Function (combining dyspnea and fatigue) and Emotional Function (combining emotional function and mastery).⁹ The 6-min walk has been used to measure

Analysis

Two-way analyses of variance, accounting for the randomization strata and n of 1 trial or standard practice therapy, were performed. The effects of interest were the changes from baseline at 6 and 12 months in the CRQ Physical and Emotional Function scores and in the 6-min walk. The primary analysis compared all n of 1 trial patients to all standard practice patients. A prespecified secondary analysis compared n of 1 trial patients to standard practice patients within the prior-theophylline-use

Assignment and Masking

Patients were individually randomized at each site to either n of 1 trials or standard practice. Computer-generated sequences were provided to the sites in sequentially numbered, opaque, sealed envelopes. Opening the envelope constituted randomization and was done by the study physicians immediately before patients began the n of 1 or standard practice trials. Personnel measuring the CRQ and 6-min walk were unaware of the treatment group allocation, and patients were instructed to maintain this

Participant Flow and Follow-up

Seven patients placed openly on theophylline were not randomized because of side effects (five patients) or a perceived improvement in dyspnea (two patients) such that they did not want to stop taking theophylline (Fig 3). Sixty-eight patients were randomized to n of 1 trials or standard practice (34 patients each). The baseline characteristics of the groups appeared to be well matched (Table 1). Seven randomized patients (three n of 1 trial patients and four standard practice patients) were

Discussion

When determining therapy in single patients, the objectivity of n of 1 trials makes them an appealing alternative to the standard approach of open, before-after trials. Despite this, n of 1 trials are rarely used, for two reasons. First, they make extra demands of patients and physicians. Second, randomized studies have not shown that n of 1 trials improve clinical outcomes over standard practice. The present study is the largest such randomized study to date and did not confirm our main

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: This work was supported by the Ontario Ministry of Health, grant no.04348F. Astra Pharma Incorporated (Mississauga, Ontario) provided themedication used in this study.

View full text

Chest

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

Study objective

Design

Setting

Patients

Interventions

Measurements and results

Conclusions

Section snippets

Protocol

Interventions

Outcome Measures and Sample Size

Analysis

Assignment and Masking

Participant Flow and Follow-up

Discussion

Chest

Chest

Chest

Chest

Chest

Chest

Chest

Controlled Clin Trials

Controlled Clin Trials

Lancet

Is theophylline obsolete?

Chest

Guidelines for the assessment and management of chronic obstructive pulmonary disease

Can Med Assoc J

Treatment of chronic obstructive pulmonary disease with orally administered theophylline. A double blind controlled study

JAMA

Efficacy of theophylline in “irreversible” airflow obstruction

Ann Int Med

Sustained-release theophylline reduces dysnea in nonreversible obstructive airway disease

Am Rev Respir Dis

Bronchodilators in chronic airflow limitation

Am Rev Respir Dis

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