Once versus twice daily formoterol via Novolizer® for patients with moderate to severe COPD—A double-blind, randomised, controlled trial

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Abstract

Study objectives

To evaluate in patients with moderate to severe COPD whether a single morning dose of 24 μg formoterol from the Novolizer® is not inferior to two divided doses of 12 μg formoterol inhaled in the morning and in the evening.

Design

Randomised, double blind, active-controlled, parallel-group, multi-centre study with a 2-week run-in period and a 12-week treatment phase.

Setting

Forty-seven outpatient centres in Germany, including private practices.

Participants

N=321 symptomatic patients with moderate to severe COPD aged 40–70 years with an FEV1 of 30–80% predicted and the requirement of 3–12 actuations of salbutamol per day on ⩾5 days during the run-in period.

Treatment

Eligible patients were randomised to inhale formoterol either (a) as a single 24 μg dose in the morning (OD) or (b) in two divided 12 μg doses in the morning and in the evening (b.i.d.).

Measurements and results

The mean age was 60.3 (SD 7.3) years, and mean baseline pre-dose FEV1 was 1.5 l (0.5 l) or 50% (12%) of predicted, respectively. After 12 weeks of treatment, pre-dose FEV1 improved in both groups (mean: OD, +104 ml, b.i.d., +135 ml, mean difference between groups: 31 ml). The 95% CI exceeded the pre-determined margin of 100 ml by 2 ml, so that the statistical hypothesis of non-inferiority of once daily dosing was not confirmed. No statistically significant differences were seen for improvements in PEF, MEF75, MEF50, and MEF25. COPD symptoms, percentage of symptom-free days and quality of life (SGRQ) improved in both groups to a similar degree. There were no relevant differences in the incidence of adverse events.

Conclusions

Based on a comparable efficacy and tolerability, the dosing schedule with formoterol via Novolizer® as once daily in the morning seems to be an alternative compared to twice daily treatment. The primary endpoint suggests the equivalence of both treatment schedules from a clinical perspective.

This regimen can be considered as an alternative therapeutic approach for a subgroup of COPD patients and may help to improve patient compliance.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, which is not fully reversible, usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Drug treatment aims at controlling symptoms and improving exercise tolerance and health status of the patients. Bronchodilators are essential for symptom control, and drugs such as inhaled beta-agonists, anticholinergics or methylxanthines are recommended by national and international guidelines.

Long-acting beta agonists (LABA) are indicated for patients with moderate or severe COPD (6). The LABA formoterol was proved to be superior to placebo [1], and its efficacy is at least comparable to that of salmeterol, theophylline and ipratropium bromide [1], [2], [3], [4].

In many patients with COPD, symptoms are particularly frequent and disturbing in the morning, whereas nocturnal symptoms are uncommon, so that bronchodilators should preferably be inhaled early during the day. In a recent study, patients with asthma inhaled formoterol once daily via the Novolizer®, a refillable, multiple dose dry powder inhaler. The inhalation in the morning provided a bronchodilatory effect for more than 12 h [5]. Considering the experience in asthmatic patients, we hypothesised that formoterol inhaled once per day in the morning could be sufficient for symptom control in patients with moderate to severe COPD.

Since COPD is a disease with a complex therapeutic regimen, suboptimal compliance is frequent among patients. In a recent study, 63% of ambulatory patients were identified as non-adherent [6], and an earlier paper had reported that 60% of patients with moderate to severe COPD were poorly adherent with inhaled corticosteroids [7]. Notably, better adherence of COPD patients was associated with a lower number of hospital visits in the latter investigation. Non-adherence is generally more likely if treatment regimens are lengthier and more complicated [8]. Simpler, once-daily therapies are thought to improve compliance [9], as well as medication regimens that fit well into the patient's daily routine [10]. The once-daily inhalation used in the present study was expected to facilitate better treatment adherence.

The current trial in patients with moderate to severe COPD intended to evaluate if a daily dose of 24 μg formoterol via Novolizer® was of equal efficacy whether inhaled as a single dose in the morning or administered in two divided doses in the morning and in the evening. The primary end-point was the change in pre-dose FEV1 from baseline to the value after 12 weeks of treatment.

Section snippets

Study design

We designed a randomised, double blind, active-controlled, parallel-group, multi-centre study with a 2-week run-in period and a 12-week treatment phase. The study was performed in 47 outpatient centres in Germany. Five study visits (at weeks −2, 0, 4, 8, and 12) were planned, each of which was scheduled in the morning, preferably between 8:00 and 10:00 a.m., prior to the morning dose of study medication.

Eligibility criteria

Male or female patients aged 40–70 years with moderate to severe COPD (Stage II or III

Results

A total of 364 patients were screened for the study, and 321 participants were randomised to treatment between January and November 2004 (Table 1). The most frequent reasons for not being randomised were inclusion/exclusion criteria not met in 20 cases (46.5%), withdrawal of consent (14%), and other reasons (14.0%). About 302 patients completed the study. The most frequent reason for withdrawal was loss to follow-up. The ITT group consisted of 155 randomized patients in Group 1 (24 μg formoterol

Discussion

Most COPD patients experience more symptoms in the morning than in the evening. For example, dyspnoea on exertion is a major complaint which is important mainly during the daytime waking hours. When designing the present trial we hypothesised that inhaling a single dose of 24 μg formoterol in the morning would provide sufficient bronchodilatation and symptom control and would not be inferior to two daily inhalations of 12 μg formoterol. To our knowledge, a study into this question has never been

Acknowledgements

The authors are indebted to the study of physicians of the FoNoCo1 trial for recruiting patients into the study: Prof. Dr. T. Welte, Hannover; Dr. A. Piecyk, Magdeburg; Dr. R. Bamberg, Potsdam; Dr. D. Bauer, St. Ingbert; Dr. E. Baumann, München; Dr. E. Beck, Rüdersdorf; Dr. H.-C. Blum, Dortmund; Dr. U. Botzen, Solingen; Dr. J. Eberhardt, Mettmann; Dr. J. Eller, Berlin; Dr. W. Feußner, Kassel; Dr. H. Fickinger-Woerner, Saarbrücken; Dr. H.W. Fischer, Verden; Dr. H.G. Flack, Hagen; Dr. K.-H.

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