INTRODUCTION

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In patients with asthma that is poorly controlled by low-dose inhaled corticosteroids, the addition to treatment of an inhaled long-acting bronchodilator has been shown to be more effective with regard to symptom control and objective assessment of pulmonary function than an increase in the dose of inhaled corticosteroid (1). It has also been shown that addition of an inhaled long-acting bronchodilator to inhaled steroid produces a further reduction in mild and severe exacerbations of asthma (4). These findings are reassuring from the viewpoint of safety, considering that the use of long-acting inhaled ₂-adrenoreceptor agonists in the treatment of asthma was initially undertaken with some concern, because of doubts expressed by Sears and colleagues about the possibility that regular use of short-acting inhaled ₂-agonist bronchodilators, especially fenoterol, may worsen asthma (5).

That a long acting ₂-agonist administered by inhalation has been shown to be more effective in the control of asthma symptoms and lung function than increasing the dose of inhaled corticosteroid (1, 2) raises the question of whether an oral, long-acting ₂-agonist would have a similar effect. Bambuterol is an oral terbutaline prodrug with a prolonged duration of bronchodilator action (6) that allows once-daily administration (7, 8), and has been reported to be of benefit in the treatment of patients with nocturnal symptoms (9). The study reported here was designed to compare the efficacy of once-daily oral bambuterol with twice-daily inhaled salmeterol in asthmatic patients with nocturnal symptoms insufficiently controlled with corticosteroid therapy.

	METHODS

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Study Design

The study was of a double-blind, double-dummy, randomized, multicenter, parallel group design, with a 2-wk run-in period during which patients took their usual medication, followed by a 6-wk active treatment period. Patients were randomized to take either inhaled salmeterol in a dose of 50 µg twice daily by pressurized metered dose inhaler (pMDI) (Serevent; Glaxo Wellcome, Middlesex, UK) plus placebo tablets, or bambuterol in tablet form in a dose of 10 mg (Bambec; Astra, Lund, Sweden) daily, in the evening, for 1 wk, and 20 mg daily in the evening for 5 wk, plus placebo delivered by pMDI. All other treatments remained constant throughout the study period. Twenty-three centers in the United Kingdom, Italy, and Norway took part in the study.

Subjects

Asthmatic patients were eligible for study if they were aged 18 yr or over; had been treated with corticosteroids at a constant daily dose for at least 4 wk with one of the following regimens: (1) inhaled corticosteroid 800 to 2,000 µg/d (beclomethasone dipropionate [BDP] or budesonide [through any device other than a Turbuhaler]), or (2) fluticasone propionate (FP) or budesonide (via Turbuhaler) at 400 to 2,000 µg/d, or (3) oral corticosteroid as prednisolone or equivalent at  20 mg/d; and were able to use a pMDI efficiently. Short-acting inhaled bronchodilators were allowed as rescue medication, but should not have been used within 6 h prior to lung function measurements. Other antiasthma treatments allowed, provided there had been no change in dose for 4 wk prior to and throughout the study, included sodium cromoglycate, nedocromil sodium, nasal corticosteroids, controlled release and rectal theophylline, and antihistamines. Oral or inhaled long-acting ₂-agonists other than the study medication were not allowed.

Inclusion Criteria

To be eligible for randomization into the active treatment limbs of the study, patients had to have had, during the run-in period: (1) at least one nocturnal awakening or early morning awakening caused by asthmatic symptoms and requiring rescue inhaled therapy, and (2) a  15% overnight decrease in peak expiratory flow (PEF) on 3 of the 7 d preceding the last entry on the diary card. The main exclusion criteria were use of parenteral depot corticosteroids within 3 months before the study, an exacerbation of asthma or respiratory infection requiring treatment within 4 wk of the study, and a dose of inhaled corticosteroid in excess of 2,000 µg/d.

Logistics

Patients were seen on four occasions: (1) at enrollment; (2) after 2 wk of the run-in period, when they were randomized into the active treatment groups if the entry criteria had been fulfilled; (3) after 3 wk of treatment; and (4) after 6 wk of treatment. At Visit 1, all patients were instructed about how to measure PEF and how to complete electronic diaries. A bronchodilator reversibility test was performed, with 1 mg of terbutaline sulfate administered by Turbuhaler. At the end of the run-in period, the diaries were checked for fulfillment of the randomization criteria. At this and all subsequent visits, pMDI technique was checked. Patients were withdrawn if they had an exacerbation of asthma (defined as deterioration of asthma requiring additional corticosteroid treatment) during the run-in period. During the treatment period, one exacerbation was allowed, providing the only treatment necessary for it was an increase in dose of inhaled corticosteroid for a period of 7 d or less. If the exacerbation required an increase in dose of inhaled corticosteroid for longer than 7 d, or an oral corticosteroid (or an increase in its dose), the patient was withdrawn from the study. Compliance was assessed at Visits 3 and 4 by counting remaining tablets. pMDI canisters were weighed before and after the study, and the number of doses of inhaled medication taken was calculated.

Throughout the study, patients used electronic diary cards (EDCs) (Apple Message Pad, Newton; Apple Computers, Inc., Cupertino, CA [10, 11]) at home, in the morning and evening, to record symptoms, bronchodilator use, and PEF (see the subsequent discussion). Morning values could be entered only between 3:00 A.M. and 3:00 P.M., and evening values between 3:00 P.M. and 3:00 A.M. (so that data could not be entered retrospectively), and the EDCs were programmed to calculate whether or not patients met the randomization criteria during the run-in period.

Measurements

Vitalograph peak flow meters were used to measure PEF (best of three readings) in the evening and in the morning. In the morning, patients recorded: (1) use of rescue medication within 6 h prior to PEF measurement (yes or no); (2) PEF not later than 10 min after waking; (3) nocturnal asthma symptoms on a scale of 0 to 3 (0 = no symptoms, 1 = mild [symptoms present but not troublesome], 2 = moderate [symptoms sufficient to interfere with daily activity], 3 = severe symptoms [incapacitating]); (4) number of puffs of rescue pMDI medication used after going to bed; and (5) number of nocturnal awakenings caused by asthma, including wakenings at times earlier than usual. If asthma symptoms caused an awakening during the night, PEF was measured immediately after the awakening and before rescue medication was taken, instead of in the morning. In the evening, patients recorded: (1) use of rescue medication within 6 h before PEF measurement; (2) PEF; (3) asthma symptoms during the day (same 0 to 3 scale as for nocturnal symptoms); (4) number of doses of rescue medication taken during the day; and (5) tremor during the day (0 to 3 on the same scale as for asthma symptoms). During the treatment period, patients were reminded by instructions in their EDCs to take study medication after measuring PEF, and compliance with this instruction was noted in the diary. For the analysis, PEF measurements made after patients took study medication were not included.

The study was conducted in accordance with guidelines for good clinical practice issued by the European Commission, in 1990, and with the Declaration of Helsinki of 1975, as revised in 1983. Appropriate ethics committee approval was obtained, and all patients gave written informed consent for their participation.

Efficacy and Safety Variables

The primary objective was efficacy. The primary efficacy variable was change in morning PEF as recorded in the EDCs. Secondary efficacy variables were change in evening PEF, overnight decrease in PEF, number of awakenings caused by asthma, percentage of nights in which an awakening occurred, nocturnal and daytime use of short-acting bronchodilator rescue pMDI medication, and nocturnal and daytime asthma scores. The secondary objective was to compare tolerance by asking patients a general question about adverse events at each visit and asking them to record any tremor in their daily diary.

Statistical Methods

The sample size for the study was calculated at 128 evaluable patients. This would give an 80% probability of detecting a true mean difference in PEF of 20 L/min between treatments when using a test at the 5% significance level and a standard deviation of the difference in PEF of 40 L/min. The analysis was conducted by incorporating patients for whom data for 15 treatment days or more were available (data from Days 1 to 14 were excluded). Efficacy and tremor variables were analyzed for change from baseline, defined as the mean of the last 7 d of the run-in period. For the treatment endpoints, means were calculated during Weeks 3 to 6. Variables were found to be not normally distributed, and comparisons of the change from baseline with different treatments were therefore made with the Mann-Whitney U test. Because the number of patients required was based on a parametric analysis for completeness, a t test was also conducted on the arithmetic mean for morning PEF.

	RESULTS

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Two hundred and sixty-five patients were enrolled in the study, of whom 135 were randomized to treatment and 118 completed the study. The reasons for the withdrawal of 130 patients before randomization were: failure to meet the inclusion criteria for 119 patients; asthma exacerbations for seven; an adverse event for two; lack of desire to continue for one; and erroneous cessation of inhaled corticosteroid therapy for one. After consideration of evaluability and eligibility, there were 126 patients considered valid for the analysis (60 given bambuterol, and 66 given salmeterol). The demographic data and baseline pulmonary function results for the patients included in the analysis are presented in Table 1, which shows that the treatment groups were well matched. Only one patient was receiving oral steroids.

Treatment Discontinuations

After randomization, 17 patients were withdrawn from the study, seven because of worsening of asthma (bambuterol: five patients; salmeterol: two patients), five because of adverse events (bambuterol: two patients; salmeterol: three patients), four because they were found to be ineligible after randomization, and one patient, taking salmeterol, who failed to attend at Visit 4.

Clinical Efficacy

There was no significant difference between the two groups with regard to morning PEF expressed as change from baseline with either the Mann-Whitney U test or t test analysis (Table 2, Figure 1).

View larger version (35K): [in this window] [in a new window]   Figure 1.   Morning PEF and change from baseline.

There were no significant differences between the two treatment groups with regard to any of the secondary efficacy variables (Table 3).

Tremor

The number of patients experiencing tremor after 14 d of treatment was similar in both treatment groups (bambuterol: 38; salmeterol: 40), but 33 patients in each group reported tremor in the run-in period. There was no statistically significant difference between the treatment groups in tremor scores.

Adverse Events

Six serious adverse events were reported during the study (three in the bambuterol group, consisting of one case of nausea and two of exacerbation of asthma), and three in the salmeterol group, consisting of one case of an allergic reaction to aspirin and two of exacerbation of asthma. It was considered by the appropriate investigators that none of these adverse events was related to the study drugs. Twelve patients had their study medication discontinued because of adverse events, none of which were classified as serious by the investigators. Seven of these patients were in the bambuterol group and five were in the salmeterol group. These adverse events included respiratory symptoms (five in the bambuterol and three in the salmeterol group), cardiovascular symptoms (one each in the bambuterol and salmeterol groups), and nonspecific symptoms (one each in the bambuterol and salmeterol groups). Nine patients had an exacerbation of respiratory symptoms (asthma or common cold) resulting in a change of steroid medication but remained in the study (four in the bambuterol and five in the salmeterol group). There was no significant difference between the two groups in terms of adverse events, respiratory problems, or number of dropouts.

Compliance

The two treatment groups were similar in their mean compliance with tablets and inhaler use (tablet use in both groups: 91%; inhaler use in the bambuterol group: 109%, and in the salmeterol group: 107%).

Cost

The cost of study and rescue medication was lower in all three countries in which the study was conducted during treatment with bambuterol as compared with salmeterol (mean cost of bambuterol: $0.71/d, and of salmeterol: $1.15/d).

	DISCUSSION

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It has been reported that patients whose asthma was not adequately controlled with low-dose BDP had better control of their symptoms and greater improvement in PEF when salmeterol was added to their treatment regimen than they did with increasing the dose of inhaled corticosteroid by 100% or more (1, 2). A large study of the effects of adding formoterol in a dose of 12 µg twice daily to budesonide in two different daily doses (100 and 400 µg, twice daily) concluded that the combination of formoterol with a low or a high dose of budesonide improves airway function and asthma control, and reduces the incidence of severe and mild exacerbations of asthma (4). Our finding of no difference between the clinical effects of oral bambuterol and inhaled salmeterol when given to patients with symptomatic asthma indicates that the route of administration does not influence the additive effect of long-acting ₂-agonist bronchodilator therapy in patients already being treated with inhaled corticosteroids. This confirms the results of two other studies, one of parallel (12) and one of crossover design (13), comparing bambuterol and salmeterol.

The patients we chose to investigate had to have nocturnal asthmatic symptoms to be eligible for entry into our study. Nocturnal symptoms are accepted as indicative of inadequately controlled asthma (14), and it is likely that the patients we studied had asthma at least as severe as those reported by Greening and associates (1) in their pivotal paper, which has influenced the majority of respiratory clinicians to favor the addition of a long-acting inhaled bronchodilator to unsuccessful inhaled corticosteroid treatment of asthma, rather than substantially increasing the dose of the inhaled corticosteroid. Their entry criteria were less rigorous than those used in our study, and it is therefore likely that the patients in our study had more troublesome symptoms at the time of entry. The baseline mean morning PEF values of 349 L/min (salmeterol and BDP) and 339 L/min (higher dose BDP) were higher in the report by Greening and associates (1) than the mean morning PEF values in our study (276 L/min for the bambuterol and 272 L/min for the salmeterol group). This could explain why salmeterol produced a greater improvement in PEF in our study than did salmeterol in its initial and longer term effects in the study by Greening and associates (1). However, it would have no influence on our finding that the bronchodilator efficacy of bambuterol and salmeterol was similar. The patients we studied did not have asthma severe enough to decrease the bronchodilator response to an inhaled aerosol.

The advantages of once-daily oral treatment for asthma compared with twice-daily inhaled therapy are numerous, provided the oral therapy is safe and free from adverse systemic effects, which is the case for the terbutaline prodrug bambuterol (15, 16). At least 50% of adults (17) and many more children (18) cannot use the conventional pMDI efficiently, and have to use alternative inhalation delivery systems. Spacer systems are bulky but of great value in the treatment of asthma, especially in children. Dry powder inhalers (DPIs) are much easier to use than pMDIs, but unfortunately these devices cannot be used by most children under the age of 5 yr, since they are unable to generate sufficient inspiratory flow to achieve adequate pulmonary deposition of medication (18). Virtually all patients can take oral therapy. Once-daily oral therapy is a simple regimen and is therefore likely to have a positive effect on compliance, which is known to be poor with pMDI therapy in asthma even in the clinical trial situation (19). Also, many patients prefer once-daily to twice-daily treatment (20). Inhaled long-acting ₂-agonists are expensive, and their use might not be possible in some communities on cost grounds alone. Oral bambuterol taken once-daily is considerably cheaper than twice-daily inhaled ₂-agonist treatment.

The study reported here was the first international, multicenter study in which we used electronic diaries. Patient acceptability was very high, with only one patient enrolling in the study and then deciding that she did not like the device. One distinct advantage of the electronic format over the paper format is that patients cannot retrospectively enter data. This could be a problem, and is difficult to detect with paper diaries. Also, EDCs are helpful in that they can be programmed to determine whether patients are suitable for a study if the inclusion criteria are based on diary variables.

The present comparison of once-daily treatment with bambuterol in a dose of 20 mg daily with inhaled salmeterol at 50 mg twice daily showed the two drugs to have no clinically significant difference in their effectiveness in patients with nocturnal symptoms of asthma despite treatment with inhaled corticosteroids. Both drugs were well tolerated, and in particular there was no difference between the two treatment groups in reported tremor. Once-daily oral bambuterol offers a convenient, safe, effective, and less expensive alternative to long-acting inhaled ₂-agonist bronchodilators for patients in whom troublesome nocturnal symptoms of asthma persist in the face of inhaled corticosteroids.