Comparison of the Efficacy, Tolerability, and Safety of Formoterol Dry Powder and Oral, Slow-Release Theophylline in the Treatment of COPD

doi:10.1378/chest.121.4.1058

Chest

Volume 121, Issue 4, April 2002, Pages 1058-1069

https://doi.org/10.1378/chest.121.4.1058 Get rights and content

Study objective

To compare the efficacy, tolerability, and safety of therapy with formoterol and oral slow-release theophylline (THEO) in patients with COPD.

Design

A randomized, parallel-group study, with double-blind arms for formoterol and placebo (PL) and an open arm for oral slow-release THEO administered in individual doses on the basis of plasma concentrations.

Setting

Eighty-one centers worldwide.

Patients

Eight hundred fifty-four patients with symptomatic COPD.

Intervention

Comparison of twice-daily inhaled formoterol dry powder (12 or 24 μg), PL, and THEO (individualized doses) over 12 months.

Measurements and results

Compared to PL, doses of formoterol and THEO both significantly improved the area under the curve for FEV₁ measured over a period of 12 h following the morning dose of study medication at 3 and 12 months (p < 0.001 for all comparisons). Therapy with formoterol, 12 μg, was significantly more effective than that with THEO (p ≤ 0.026). Formoterol significantly reduced the percentage of “bad days” (ie, days with at least two individual symptom scores ≥ 2 and/or a reduction in peak expiratory flow from a baseline of > 20%; p ≤ 0.035 vs PL and THEO), and the use of salbutamol rescue medication (p ≤ 0.003 vs PL) over the whole treatment period, while the effect of THEO was similar to that of PL. Therapy with formoterol and THEO was more effective than PL at improving quality of life for > 12 months (p ≤ 0.030). Treatment-related adverse events and discontinuations were more frequent among patients receiving THEO than among those receiving formoterol.

Conclusions

Long-term treatment with inhaled formoterol dry powder is more effective and better tolerated than treatment with therapeutically appropriate doses of oral slow-release THEO in symptomatic patients with COPD.

Section snippets

Patients

Patients were male or female outpatients aged ≥ 40 years, who were either current smokers or ex-smokers of > 10 pack-years had received a diagnosis of COPD, made according to the American Thoracic Society guidelines.^1,⁸ All patients gave written informed consent.

Inclusion criteria required that the patients' FEV₁ was < 70% of the predicted value and ≥ 0.75 L, with an FEV₁/vital capacity ratio of < 88% of that predicted in men and < 89% of that predicted in women.^1,^2,⁸ Daytime and/or nighttime

Patients

One thousand one hundred twenty-seven patients were screened, and 854 were randomized into this study (F12, 211 patients; F24, 214 patients; PL, 220 patients; and THEO, 209 patients) [Table 1]. A total of 232 patients were discontinued from the study prematurely, and 622 completed the 12-month treatment period. The lowest discontinuation rates were seen in the F12 and F24 groups, and the highest was seen in the THEO group (Table 1). The proportion of patients discontinuing the study in the

Discussion

The current first-line therapies for COPD patients are inhaled short-acting β₂-adrenoceptor agonists and ipratropium bromide, with THEO being the recommended add-on treatment for patients not adequately controlled by therapy with inhaled bronchodilators.^1,^2,^3,⁷ Slow-release preparations of THEO have a prolonged action and can be administered orally twice daily. For this reason, they are considered to be particularly indicated for those COPD patients who have nocturnal or early morning symptoms

Appendix

The following investigators, listed by country, also contributed randomized data to the Formoterol in Chronic Obstructive Pulmonary Disease (FICOPD) II Study.

Austria: K. Aigner, W. Domej, K. Puganigg, and K. Sertl.

Belgium: R. Deman.

Czech Republic: V. Vondra, J. Erban, O. Ostadal, Z. Merta, and J. Skrickova.

France: J.-L. Racineaux, J. Rochemaure, C. Wallaert, M. Aubier, J.F. Muir, X. Lebas, Piquet, Zuck, and J.-M. Vergnon.

Germany: H. Matthys, S. Scmidtmann, D. H. Worth, Wagner, and A. Forster.

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Theophylline is a popular drug for many respiratory diseases. However, certain toxic side effects may be developed and the narrow safety range raises the demand for sensitive methods to constantly monitor theophylline levels. This study presents an electrochemical approach towards theophylline detection based on the recognition by split RNA aptamers. Target induced construction of hand-in-hand RNA nanowire on the electrode surface could further absorb silver nanoparticles (Ag NPs) as electrochemical species. When theophylline is not present, RNA probes are stable and their conformations remain unchanged. In contrast, theophylline is able to trigger the hairpin opening of RNA probe and subsequent self-assembly of RNA nanowire, which could be captured by DNA tetrahedron on the electrode interface. After further decorating Ag NPs on the nanowire, silver stripping current is measured to reveal initial theophylline concentration. The developed sensing strategy shows excellent specificity and sensitivity with the limit of detection of 50 nM. Its practical utility is demonstrated by quantitative determination of theophylline levels in complex biological samples.
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A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD
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In total, 159 patients were randomized to treatment and 132 patients (52.2% male, mean age 62.8 years) were included in the intent-to-treat population. All doses of GFF MDI (except 1.2/9.6 μg) resulted in statistically significant improvements in FEV₁ AUC_0–12 versus monocomponents and open-label tiotropium. GFF MDI 18/9.6 μg consistently showing the greatest improvement over monocomponents and open-label tiotropium. Adverse events for each GFF MDI dose were similar versus GP MDI 18 μg, FF MDI 9.6 μg and open-label tiotropium.
These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI.
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: This study was sponsored by Novartis Pharma AG, Basel, Switzerland. According to their statement, 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 of other sorts from the sponsors (excluding the costs for conducting the study), do not have a proprietary or financial interests in the test product such as patent, trademark, copyright, or licensing agreements, and do not hold a significant equity interest in the sponsor of the study (ie, exceeding $50,000). Authors Thomson, Till, Kottakis, and Della Cioppa hold permanent positions with Novartis Pharmaceuticals.

^†: A complete list of the investigators is located in the ^Appendix

View full text

Chest

Clinical InvestigationsCOPDComparison of the Efficacy, Tolerability, and Safety of Formoterol Dry Powder and Oral, Slow-Release Theophylline in the Treatment of COPD

Study objective

Design

Setting

Patients

Intervention

Measurements and results

Conclusions

Section snippets

Patients

Patients

Discussion

Appendix

Chest

Chest

Respir Med

Clin Chest Med

J Allergy Clin Immunol

Respir Med

Chest

ATS statement: standards for the diagnosis and care of patients with chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Optimal assessment and management of chronic obstructive pulmonary disease (COPD)

Eur Respir J

BTS guidelines for the management of chronic obstructive pulmonary disease

Thorax

Long-acting β2-agonists in the management of stable chronic obstructive pulmonary disease

Drugs

Clinical Investigations
COPD
Comparison of the Efficacy, Tolerability, and Safety of Formoterol Dry Powder and Oral, Slow-Release Theophylline in the Treatment of COPD

Long-acting β₂-agonists in the management of stable chronic obstructive pulmonary disease