Chest
Volume 130, Issue 6, December 2006, Pages 1695-1703
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Original Research: COPD
Pooled Clinical Trial Analysis of Tiotropium Safety

https://doi.org/10.1378/chest.130.6.1695Get rights and content

Background

Marketing approval of pharmaceutical products is often based on data from several thousand subjects or fewer. Evaluation of safety is greatly enhanced by augmenting the safety database with postapproval studies.

Methods

We conducted a pooled analysis of adverse event data from 19 randomized, double-blind, placebo-controlled trials with tiotropium in patients with obstructive lung disease. We computed incidence rates and rate ratios (RRs) for various reported adverse event end points of interest. Patients contributed person-time to the analysis as long as they were in the study until 30 days after treatment (tiotropium, placebo), or until they had the event of interest, whichever came first. Studies were pooled using the Mantel-Haenszel estimator, and we used 95% confidence intervals (CIs) to assess the precision of effect estimates.

Results

The pooled trial population includes 4,435 tiotropium patients and 3,384 placebo patients contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. Dyspnea, dry mouth, COPD exacerbation, and upper respiratory tract infection were the most commonly reported events. There was a higher relative risk of dry mouth in the tiotropium group (RR, 3.60; 95% CI, 2.56 to 5.05). There was a lower risk of dyspnea (RR, 0.64; 95% CI, 0.50 to 0.81) and COPD exacerbation (RR, 0.72; 95% CI, 0.64 to 0.82) in patients receiving tiotropium compared to patients receiving placebo. Other results of interest are as follows: (1) all-cause mortality (RR, 0.76; 95% CI, 0.50 to 1.16); (2) cardiovascular mortality (RR, 0.57; 95% CI, 0.26 to 1.26); and (3) respiratory mortality (RR, 0.71; 95% CI, 0.29 to 1.74). The relative risk of urinary retention was 10.93 (95% CI, 1.26 to 94.88).

Conclusions

Pooling of adverse event data from preapproval and postapproval tiotropium clinical trials increase the precision of effect estimates and supports the present safety profile of tiotropium.

Section snippets

Study Population

Inclusion criteria for entry into the pooled safety database were completed clinical trials in the tiotropium HandiHaler (Boehringer Ingelheim International GmbH; Ingelheim, Germany) project database as of May 2004 with the following characteristics: tiotropium (18 μg qd), placebo-controlled, and parallel-group study design. The 18-μg dosage included in the pooled analysis was chosen because of the relatively smaller amount of data for other doses, and to reflect the use of the approved dose of

Results

The pooled trial population presents information on 7,819 patients from 19 clinical trials, including 4,435 tiotropium-treated patients and 3,384 placebo-treated patients, contributing 2,159 person-years of exposure to tiotropium and 1,662 person-years of exposure to placebo. The distributions of treatment groups according to demographics baseline disease characteristics and duration of exposure are shown in Table 1. The study population was balanced between the tiotropium and placebo groups.

Discussion

Marketing approval of pharmaceutical products is generally based on review of trials often containing several thousand exposed subjects in controlled trials and concluding that a drug has a favorable risk/benefit profile. The evaluation of safety continues beyond the core registration trials and can include phase IV trials, as well as retrospective studies based on claims databases and spontaneous reporting of adverse events. Tiotropium was initially approved and marketed in several countries

ACKNOWLEDGMENT

The authors thank Terry Keyser, Boehringer Ingelheim, Ridgefield, CT, for editorial support in preparation of this article.

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  • Cited by (0)

    Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

    This study was supported by Boehringer Ingelheim Pharmaceuticals Inc. and Pfizer Inc.

    Drs. Kesten and Lanes are employees of Boehringer Ingelheim. Dr. Jara and Mr. Wentworth are consultants for Boehringer Ingelheim.

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