Chest
Volume 119, Issue 5, May 2001, Pages 1347-1356
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Clinical Investigations
COPD
In Patients With COPD, Treatment With a Combination of Formoterol and Ipratropium Is More Effective Than a Combination of Salbutamol and Ipratropium: A 3-Week, Randomized, Double-Blind, Within-Patient, Multicenter Study

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Study objectives:

To compare the efficacy of adding formoterol or salbutamol to regular ipratropium bromide treatment in COPD patients whose conditions were suboptimally controlled with ipratropium bromide alone.

Design:

A randomized, double-blind, double-dummy, two-period, crossover clinical trial.

Setting:

Twenty-four clinics and university medical centers in nine countries.

Patients:

One hundred seventy-two patients with baseline FEV1 ≤ 65% predicted, with FEV1 reversibility to salbutamol not exceeding the normal variability of the measurement, and symptomatic despite regular treatment with ipratropium bromide.

Interventions:

Each patient received two treatments in random order: either inhaled formoterol dry powder, 12 μg bid, in addition to ipratropium bromide, 40 μg qid for 3 weeks, followed by salbutamol, 200 μg qid, in addition to ipratropium, 40 μg qid for 3 weeks, or vice versa.

Measurements and results:

Efficacy end points included morning premedication peak expiratory flow (PEF) during the last week of treatment (primary end point), the area under the curve (AUC) for FEV1 measured for 6 h after morning dose on the last day of treatment, and symptom scores (from daily diary recordings). Morning PEF and the AUC for FEV1 were significantly better for formoterol/ipratropium than for salbutamol/ipratropium (p = 0.0003 and p < 0.0001, respectively). The formoterol/ipratropium combination also induced a greater improvement in mean total symptom scores (p = 0.0042). The safety profile of the two treatments was comparable.

Conclusions:

In COPD patients requiring combination bronchodilator treatment, the addition of formoterol to regular ipratropium treatment is more effective than the addition of salbutamol.

Section snippets

Study Design

This was a randomized, multicenter, double-blind, double-dummy, two-period, crossover clinical trial comparing the clinical benefits of adding either formoterol (Foradil Aerolizer; Novartis; Basel, Switzerland), 12 μg bid via dry-powder inhaler, or salbutamol (Ventolin; Glaxo Smith Kline; Uxbridge, UK), 200 μg qid via pressurized metered-dose inhaler (100 μg/puff), to ipratropium bromide (Atrovent; Boehringer Ingelheim; Ingelheim, Germany), 40 μg qid via pressurized metered-dose inhaler (20

Study Patients

A total of 252 patients were screened, and 172 patients were randomized to each treatment sequence as reported in Table 1. Of the randomized patients, 159 completed the study and 13 withdrew prematurely, all during the first treatment period. Four patients were discontinued due to adverse events, and all these discontinuations occurred during treatment with the salbutamol/ipratropium combination. Four patients withdrew their consent, two patients were unavailable for follow-up, two patients

Discussion

The results of this randomized, double-blind, crossover study indicate that the addition of formoterol, 12 μg bid, to treatment with ipratropium bromide, 40 μg qid, is more effective than the addition of salbutamol, 200 μg qid, in patients with COPD who require combined bronchodilator therapy.

Mean morning premedication PEF increased significantly more during treatment with formoterol/ipratropium than during treatment with salbutamol/ipratropium. The change from baseline in the ITT-1 population,

Appendix

Participants: J. Almeida, MD, Porto, Portugal; S. Boucher, MD, Quebec, Canada; J. Castillo, MD, Sevilla, Spain; S. Centanni, MD, Milano, Italy; J. Cordoso, MD, Lisbon, Portugal; M. C. De Salvo, MD, Buenos Aires, Argentina; C. G. Di Bartolo, MD, Buenos Aires, Argentina; A. D'Urzo, MD, Toronto, Canada; A. Eivindson, MD, Arendal, Norway; D. Gorecka, MD, Warsaw, Poland; C. Gratziou, MD, Athens, Greece; J. Kottakis, MD, Horsham, UK; J. Kozielski, MD, Zabrze, Poland; G. Krammer, MSc, Basel,

ACKNOWLEDGMENT

We are grateful to Professor Paul W. Jones for the QoL results.

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  • Cited by (0)

    This study was supported by a research grant from Novartis Pharma A.G., Basel, Switzerland. According to their statements, the authors and all study investigators have not made any financial arrangement whereby the value of the compensation could be influenced by the outcome of the study; have not received significant payments from the sponsor of other sorts, excluding the costs for conducting the study; do not have a proprietary or financial interest in

    the test product such as patent, trademark, copyright, or licensing agreements; do not hold a significant equity interest in the sponsor of the study (exceeding $50,000 [US]). John Kottakis, MD, and Guenter Rapatz, MSc, hold permanent positions with Novartis Pharmaceuticals.

    A complete list of participants is located in the Appendix

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