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Comparative Efficacy and Safety of Albuterol Sulfate Spiros Inhaler and Albuterol Metered-Dose Inhaler in Asthma^*

^* From the National Jewish Medical and Research Center (Dr. Nelson), Denver, CO; the Allergy and Asthma Medical Group and Research Center (Dr. Kemp), San Diego, CA; and Dura Pharmaceuticals, Inc. (Mr. Bieler, and Drs. Vaughan and Hill), San Diego, CA.

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Study objective: To compare the long-term efficacy and safety of albuterol administration using a Spiros Inhalation System (Dura Pharmaceuticals; San Diego, CA) dry powder inhaler (DPI) and albuterol (Ventolin; Glaxo Wellcome; Research Triangle Park, NC) administration using a metered-dose inhaler (MDI) in patients with asthma.

Materials and methods: This was a phase III, 12-week, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, multicenter study of 283 adolescent and adult patients with mild to moderate asthma. The patients were randomized into one of three treatment groups: the Spiros group, who were given 108 µg/actuation of albuterol sulfate equivalent to 90 µg of albuterol base; the MDI group, who were given 90 µg/actuation of albuterol; and the placebo group.

Results: Over the length of the study, the Spiros and MDI groups were comparable in all FEV₁ parameters. Both active treatment groups were superior to the placebo group for each FEV₁ parameter at all visits. With the exception of differences at treatment week 0 for the maximum percent change in the FEV₁, the duration of effect, and the area under the curve at baseline, there were no statistically significant differences between the Spiros and MDI groups for any FEV₁ parameters. Using a repeated-measures analysis, the FEV₁ parameters at week 0 for the Spiros group were not statistically significantly different from the parameters at weeks 4, 8, and 12. The same analysis effect at week 0 for the MDI group was greater for maximum percent change in the FEV₁ from baseline (weeks 4, 8, and 12) and duration of effect. Adverse events and changes in clinical laboratory values, vital signs, ECG results, and physical examinations were reported with similar incidence in each of the three treatment groups.

Conclusion: Both active treatments were superior to the placebo treatment. The Spiros DPI was well tolerated and was as effective as the albuterol MDI in treating patients with moderate asthma.

Key Words: aerosol • albuterol • asthma • bronchodilator • dry powder inhaler

	Introduction

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Inhalational drug delivery is the preferred method of drug administration to the lung,^{1 ,2} and the metered-dose inhaler (MDI) is currently the most prescribed type of delivery system.^{1 ,3 ,4} The MDI owes its popularity to its high degree of patient acceptance, its perceived simplicity of use, its portability, and its multiple-dose capacity.⁵ However, most currently marketed MDIs use chlorofluorocarbon (CFC) propellants. At an international conference in 1987, the Montreal Protocol was established to phase out ozone-depleting substances such as CFCs by January 1, 1996.⁶ More than 150 nations are parties to the Montreal Protocol.⁷ Successive 1-year temporary medical exemptions were granted to MDIs by the US Food and Drug Administration (FDA) for the period 1996 to 1998. Consequently, alternative systems of aerosolized drug delivery have been developed, including dry powder inhalers (DPIs) and MDIs that use environmentally safe hydroxy-fluoro-alkane propellants.^{5 ,8} The FDA has issued an advance notice of proposed rulemaking to phase out CFC-propelled MDIs once acceptable alternatives are available.⁹

In addition to the phaseout of CFCs, other factors make the development of alternatives important. Patients often have difficulties using MDIs.¹⁰ In order to operate MDIs efficiently, the patient is required to coordinate his/her inspiratory effort with the actuation of the canister, a procedure that can be difficult to manage for the elderly, some adults, and very young children.^{1 ,11} This problem has been addressed by the use of spacers and breath-actuated MDIs.¹² Another problem is that patients often have difficulty determining when it is time to replace their MDI.¹³

The Spiros Inhalation System (Dura Pharmaceuticals; San Diego) has been developed to allow convenient inhalation of powdered drug aerosols into the lung. The Spiros Inhalation System consists of a dry powder blend of micronized albuterol sulfate and lactose monohydrate delivered by a breath-actuated, effort-assisted inhaler that creates an aerosol plume for inspiration by the patient.

The main design objective of the Spiros Inhalation System was to create an inhalation system that functions relatively independently of the patient's inspiratory flow rate. This approach has several beneficial outcomes. First, the inhaler can be used by patients with low inspiratory flow rates, such as adolescents, the elderly, or patients experiencing respiratory distress. Currently marketed DPIs deliver different drug amounts to the lung depending on the inspiratory flow rate.^{14 ,15 ,16} Second, as discussed above, MDIs require a significant amount of patient coordination in order to be used correctly. MDIs are manually actuated and deliver the drug at a high velocity; therefore, the moment at which the actuation occurs in the respiratory cycle is crucial. If actuation does not occur near the beginning of inspiration, the majority of the dose may be deposited in the throat and swal-lowed or exhaled. With a breath-actuated DPI, the coordination of actuation and inhalation is automatic.

In the present study, we compared the long-term efficacy and safety of two methods for delivering inhaled bronchodilators: albuterol sulfate delivered using a Spiros DPI; and albuterol (Ventolin; Glaxo Wellcome; Triangle Park, NC) delivered using an MDI. A Spiros lactose placebo and an MDI-propellant placebo were used as controls.

	Materials and Methods

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
Spiros Inhalation System
The Spiros Inhalation System is a small (4 x 10 x 6-cm) inhaler that is breath actuated to minimize the need for patient coordination. It contains a removable circular multiple-dose cassette containing 30 wells. Each well is filled with a premetered drug/lactose powder blend (Fig 1 ). A dose is loaded into the aerosolization chamber by opening the lid approximately 135° and then closing it. This action advances the cassette, allowing one dose to fall into the aerosolization chamber. In this chamber, the rapid spinning of an inspiration-actuated, battery-powered, twin-blade impeller generates an aerosol cloud. This concentration is drawn by the inspiratory airstream through radially arranged holes into the mouthpiece, where it mixes with air from bilateral ducts to allow a slow, full breath of the aerosol to the lung.

View larger version (37K): [in this window] [in a new window] [Download PPT slide]   Figure 1. The albuterol Spiros Inhalation System with cassette.

Study Population
The patients were nonsmokers and at least 12 years old with mild to moderate asthma, as defined in accordance with American Thoracic Society criteria,¹⁷ and which had been documented for a minimum of 1 year prior to entering the study. All of the patients had stable asthma and were otherwise healthy as judged by their medical history, a physical examination, a 12-lead ECG, and clinical laboratory tests. The asthma was considered to be clinically stable if there had been no changes in current asthma therapy, and no admissions to the hospital or visits to the emergency department for treatment of asthma within 4 weeks prior to the study.

Study Design
This was a randomized, double-dummy, double-blind, placebo-controlled, three-way parallel-group study conducted at 20 clinical centers throughout the United States. All patients gave written informed consent, and the study protocol was approved by a central institutional review board or by the institutional review board at each study center. This 12-week study approximated the study design and procedures used in two previous 12-week inhaled bronchodilator studies.^{18 ,19}

After signing informed consent documents, the eligible patients were required to meet the following entry criteria: an FEV₁ between 40 and 80% of predicted normal values following the washout of asthma medications as required by the protocol; and an FEV₁ reversibility of at least 12% of the percent predicted within 30 min following two inhalations from an albuterol MDI. The predicted FEV₁ was obtained by using the normal prediction equations of Polgar and Promadhat²⁰ for the 12- to 17-year-old patients, or Crapo et al²¹ for the patients who were 18 years old. The patients received training in MDI and Spiros Inhalation System techniques using supplied placebo inhalers.

Once the screening procedures were completed, the patients entered a run-in period of 7 to 14 days immediately preceding treatment week 0. After being issued a peak flowmeter, each patient was instructed on its correct use and how to record the peak expiratory flow (PEF) measurements on the diary card. Also recorded on the diary card were daytime and nighttime asthma symptoms and the need for rescue albuterol. During the run-in period, the patients were allowed only inhaled albuterol MDIs as needed, except for patients who were previously on anti-inflammatory agents, which were continued throughout the study.

At the end of the run-in period, the patients meeting the entry criteria were randomly assigned to receive one of the following treatment combinations, administered as two actuations qid from each inhaler for 12 weeks in a double-blinded manner: (1) the Spiros Inhalation System DPI (108 µg/actuation albuterol sulfate) and the MDI placebo (oleic acid and trichloromonofluoromethane); (2) the albuterol MDI (90 µg/actuation albuterol) and the Spiros Inhalation System placebo (lactose powder); or (3) the Spiros Inhalation System placebo and the MDI placebo.

During the first 4 weeks of the study, clinical visits were scheduled every 2 weeks, and then every 4 weeks for the final 8 weeks of the study. At the randomization visit to the clinic at week 0, the patients were questioned about any asthma exacerbations that had occurred during the run-in period. The patients were excluded from the study if oral steroids had been administered. On the morning of the first day of treatment at week 0, and at weeks 4, 8, and 12, baseline spirometry was performed at 30 and 10 min prior to dosing. A 12-lead ECG was recorded, and vital signs were obtained prior to the administrations of the study medications. The patients were instructed to take two actuations each, consecutively, from the study medications used in the Spiros Inhalation System and the study medications used for the MDI, with each actuation separated by a 60-s interval. Pulmonary function testing was performed at 15, 30, 45, 60, 90, 120, 180, 240, 300, and 360 min postdose. Vital signs were obtained immediately before spirometry, a 12-lead ECG was recorded at 60 min postdose, and a blood sample for analysis of serum potassium was obtained at 75 min postdose. The midday dose of the study drug was not taken until the completion of all of the procedures.

At weeks 0, 4, 8, and 12, the primary efficacy measures were based on spirometry over a 6-h period following the administration of the study medications. These measures included the following parameters based on the FEV₁ response: maximum value (the maximum percent change from baseline in the FEV₁); the area under the curve and above baseline (AUCBL) for serial FEV₁ values; and the duration of effect. Secondary efficacy measures included the following: the use of rescue albuterol; the number of episodes of asthma exacerbation; the PEF values; and the daily and nocturnal asthma symptom scores derived from the diary cards. Safety measures were assessed through physical examinations, adverse events noted on diary cards prior to and following study participation, vital signs, laboratory tests for serum potassium, and 12-lead ECGs monitoring cardiac output corrected for heart rate during the 6-h clinical spirometry visits.

Statistical Analysis
The primary outcome measure was the FEV₁ response based on the change from baseline. This includes the peak percent increase, the area under the curve, and the duration of bronchodilator response derived from the 6-h clinical spirometry visits at weeks 0, 4, 8, and 12. Clinically significant bronchodilation was defined as a 15% increase in the FEV₁ over baseline (the average of the FEV₁ performed at 10 and 30 min prior to the administration of the study medication).

The primary efficacy variables during the 6-h clinical spirometry visits at weeks 0, 4, 8, and 12 were analyzed using three different statistical methods:

1. An analysis of variance (ANOVA) performed by treatment week with treatment group, center, and treatment-by-center interactions as factors in the model to interpret any differences among the three groups at each treatment week.

2. A repeated-measures ANOVA with treatment group and center as between-patients factors and treatment weeks (treatment week 0, 4, 8, and 12) treated as within-patient factors to determine whether there was a difference within each treatment group across treatment weeks.

3. A repeated-measures analysis of covariance (ANCOVA) using treatment week 0 as the baseline covariate, and treatment group and center as between-patients factors, and treatment weeks as within-patients factors were utilized if the treatment-by-visit interactions in the repeated-measures ANOVA were significant. These analyses were used to determine whether there was any difference within each treatment group across treatment weeks controlling for the outcome variable at treatment week 0.

With the expectation that there would be no differences among the three treatment groups, statistical analyses were performed on the following secondary efficacy variables: the use of rescue bronchodilator medication, the PEF values, the exacerbations of asthma (defined as the need for additional asthma medication beyond rescue albuterol and a maintenance anti-inflammatory dose if applicable), and the asthma symptom scores.

	Results

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
A total of 283 patients were enrolled in the study. The patients in each treatment group were comparable at baseline with respect to patient demographics and pulmonary function (Table 1 ). Of the 43 patients who did not complete the study, 15 of 97 (15%) were in the Spiros group, 11 of 92 (12%) were in the MDI group, and 17 of 94 (18%) were in the placebo group. The most commonly cited reason for discontinuation was asthma exacerbation requiring a change in asthma medication; this was recorded by 6 of 97 patients (6%) in the Spiros group, 4 of 92 patients (4%) in the MDI group, and 7 of 94 patients (7%) in the placebo group. Seven patients were discontinued because of adverse events: three patients in the Spiros group, one in the MDI group, and three in the placebo group.

The mean changes in the serial FEV₁ from baseline at weeks 0 and 12 for all treatment groups are shown in Figures 2 and 3 . The curves observed at weeks 4 and 8 for all treatment groups were similar to the curves observed at week 12.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 2. The mean change from baseline for the FEV1 by treatment group for treatment week 0.

Safety
At least one adverse event was reported by 63 of 97 patients (64.9%) in the Spiros group, 56 of 92 patients (60.9%) in the MDI group, and 59 of 94 patients (62.8%) in the placebo group. The adverse events reported were generally what would be expected in a population of healthy asthmatic patients over a 12-week period. Adverse events resulting in withdrawal from the study were reported in 3 of 97 patients (3.1%) in the Spiros group (possible drug-related events were severe itchy skin, headaches, and insomnia in 1 patient and severe chills, wheezing, and vomiting in another patient), in 1 of 92 patients (1.1%) in the MDI group (possible drug-related chest pain in 1 patient), and in 3 of 94 patients (3.2%) in the placebo group (probable drug-related increase of asthma symptoms in 1 patient). One patient in each treatment group had at least one serious adverse event: one Spiros group patient had abdominal pain; one MDI group patient had neck pain secondary to an automobile accident; and one placebo group patient had an acute asthma attack. All of the serious adverse events were determined to be unrelated or not likely to be related to the study medication.

The changes in clinical laboratory values, vital signs, ECG results, and physical examinations were similar among the three treatment groups, with no notable trends observed in the safety variables.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 
The results from this study clearly demonstrate that albuterol delivered by the Spiros Inhalation System inhaler provides a comparable clinical effect and does not produce any untoward safety concerns when compared to albuterol delivered by MDI in patients with mild to moderate asthma.

When compared to the Spiros Inhalation System inhaler, the MDI elicited a greater response at week 0 for the maximum percent change in FEV₁, the duration of effect, and the AUCBL. Furthermore, the MDI group responses for these same parameters, but not those of the Spiros group, decreased to varying degrees over the 12 weeks, as elucidated by the repeated measures of analysis. Although some of these parameter decreases for the MDI group were statistically significant, they are not likely to be clinically important. There are several possible explanations for the change over time with the response to the MDI. One possibility is the variability in baseline pulmonary function that was observed among the study days in this treatment group (Table 2 ). Although the mean (±SD) FEV₁ baseline values at screening and treatment week 0, respectively, for the Spiros group (2.23 ± 0.60 and 2.26 ± 0.64), the MDI group (2.32 ± 0.59 and 2.30 ± 0.61), and the placebo group (2.27 ± 0.62 and 2.27 ± 0.62) remained stable, the same baseline values at weeks 4, 8, and 12, respectively, for the Spiros group (2.26 ± 0.65, 2.25 ± 0.67, and 2.27 ± 0.74), the MDI group (2.36 ± 0.73, 2.40 ± 0.73, and 2.43 ± 0.77), and the placebo group (2.27 ± 0.76, 2.35 ± 0.75, and 2.36 ± 0.81) reveal a rising baseline increase of 5.6% for the MDI group and 4.0% for the placebo group, compared to 0.4% for the Spiros group.

As the baseline FEV₁ drifts up over time, the parameters calculated on the change from baseline in the MDI group (such as the maximum percent change in the FEV₁, the duration of effect, and the AUCBL) may appear as if they are decreasing over time; but this is likely an artifact of the increased baseline that was observed in this group (Table 2 ). There is some upward drift in the baseline values for the placebo group as well, and there is some decrease in the values for the parameters calculated on change from baseline in this group (Table 2 ); however, these values were generally not statistically significant over time. Conversely, the baseline FEV₁ values in the Spiros group, as shown above, appear to be steady over time. It is unlikely that changes in the baseline FEV₁ in the MDI group are clinically important or are related to the pharmacodynamics of albuterol in this patient population.

An alternative consideration for a diminution of response over time in an inhaled ß-agonist study using bronchodilation is the development of subsensitivity or tolerance. In a previous study by Repsher and colleagues,²² albuterol delivered using an MDI was associated with decreased bronchodilation when utilized on a regular basis (two inhalations qid) over a 12-week study period. This decreased bronchodilation was characterized by a significant decrease in the duration of action and a nonsignificant decrease in the maximum change from baseline in the FEV₁. Over the 12 weeks of the study, there was no significant change in the baseline FEV₁. In the study by D'Alonzo and colleagues,¹⁹ with two albuterol actuations qid there was a gradual decrease of 24% in the mean AUCBL from weeks 0 to 12 that was not statistically significant. The values for the baseline FEV₁ were not reported. In the current study, the AUCBL response in the Spiros group did not change significantly over the 12-week study period, with only an 11% decrease from week 0 to week 12; however, there was a 43% decrease shown by the MDI group, and a 31% decrease shown by the placebo group.

The incidence pattern of the reported adverse events in this study is consistent with the pattern expected in a generally healthy asthmatic population over a period of time. Adverse events generally were reported with a similar frequency in all three treatment groups.

In summary, once approved by the FDA for marketing, the Spiros Inhalation System inhaler will be an important addition to the range of products available for the prevention and relief of broncho-spasm. Along with providing a degree of safety and efficacy comparable to that of the MDI, the Spiros Inhalation System inhaler, like breath-actuated MDIs and other DPIs, eliminates the necessity of coordinating canister actuation and inspiratory breath. The Spiros Inhalation System inhaler is also propellant free, and it offers its user the convenience of being able to see when the cassette and inhaler need to be replaced. However, unlike most other DPIs,¹² the Spiros Inhalation System is designed to deliver a respirable dose that is relatively independent of the patient's inspiratory flow rate. These features may represent particular advantages for adolescents, the elderly, and patients in respiratory distress.

View larger version (14K): [in this window] [in a new window] [Download PPT slide]   Figure 3. The mean change from baseline for the FEV1 by treatment group for treatment week 12.

	Appendix 1

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

	Footnotes

 
A complete list of contributing investigators from the Albuterol Spiros Study Group is located in the ^Appendix. Supported by a grant from Dura Pharmaceuticals, Inc, San Diego, CA.

Correspondence to: Harold Nelson, MD, National Jewish Medical and Research Center, 1400 Jackson Street, B104, Denver, CO 80206

Abbreviations: ANCOVA = analysis of covariance; ANOVA = analysis of variance; AUCBL = area under the serial FEV₁ curve and above baseline; CFC = chlorofluorocarbon; DPI = dry powder inhaler; FDA = Food and Drug Administration; LED = light-emitting diode; MDI = metered-dose inhaler; PEF = peak expiratory flow

Received for publication February 17, 1998. Accepted for publication July 30, 1998.

	References

TOP Abstract Introduction Materials and Methods Results Discussion Appendix 1 References

 

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This Article Abstract Full Text (PDF) Free Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Add to My Personal Article Archive Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Nelson, H. Articles by Hill, M. R. Search for Related Content PubMed PubMed Citation Articles by Nelson, H. Articles by Hill, M. R.