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Clinical InvestigationsCOPDTheophylline for Irreversible Chronic Airflow Limitation: A Randomized Study Comparing n of 1 Trials to 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
References (32)
Theophylline is no more obsolete than “two puffs qid” of current beta-2 agonists
Chest
(1990)- et al.
Effects of theophylline on breathlessness in patients with chronic airflow limitation
Chest
(1982) - et al.
Efficacy of inhaled metaproterenol and orally-administered theophylline in patients with chronic airflow limitation
Chest
(1986) - et al.
Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease
Chest
(1992) - et al.
Is oral theophylline effective in combination with both inhaled antichinergic agent and inhaled beta 2-agonist in the treatment of stable COPD?
Chest
(1993) - et al.
Effects of theophylline withdrawl in severe chronic obstructive pulmonary disease
Chest
(1993) - et al.
The additive effect of theophylline on a high-dose combination of inhaled salbutamol and ipratropium bromide in stable COPD
Chest
(1995) - et al.
N of 1 randomized trials for investigating new drugs
Controlled Clin Trials
(1990) - et al.
Measurement of health status. Ascertaining the minimal clinically important difference
Controlled Clin Trials
(1989) - et al.
The ethics of n of 1 trials
Lancet
(1995)
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
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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.