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Comparative Efficacy and Safety of Albuterol Sulfate Spiros Inhaler and Albuterol Metered-Dose Inhaler in Asthma
Comparative Efficacy and Safety of Albuterol Sulfate Spiros Inhaler and Albuterol Metered-Dose Inhaler in Asthma* Harold Nelson, MD; James P. Kemp, MD, FCCP; Stewart Bieler, BA; Leigh M. Vaughan, PharmD; and Malcolm R. Hill, PharmD†
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 mg/actuation of albuterol sulfate equivalent to 90 mg of albuterol base; the MDI group, who were given 90 mg/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. (CHEST 1999; 115:329 –335) Key words: aerosol; albuterol; asthma; bronchodilator; dry powder inhaler Abbreviations: ANCOVA 5 analysis of covariance; ANOVA 5 analysis of variance; AUCBL 5 area under the serial FEV1 curve and above baseline; CFC 5 chlorofluorocarbon; DPI 5 dry powder inhaler; FDA 5 Food and Drug Administration; LED 5 light-emitting diode; MDI 5 metered-dose inhaler; PEF 5 peak expiratory flow
drug delivery is the preferred method I nhalational of drug administration to the lung, and the 1,2
metered-dose inhaler (MDI) is currently the most *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. †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. Manuscript received February 17, 1998; revision accepted July 30, 1998. Correspondence to: Harold Nelson, MD, National Jewish Medical and Research Center, 1400 Jackson Street, B104, Denver, CO 80206
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 CHEST / 115 / 2 / FEBRUARY, 1999
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(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 breathactuated, 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 –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 swallowed or exhaled. With a breath-actuated DPI, the coordination of actuation and inhalation is automatic. In the present study, we compared the longterm 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. 330
Materials and Methods Spiros Inhalation System The Spiros Inhalation System is a small (4 3 10 3 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. The Spiros Inhalation System features an internal counting mechanism designed to deliver approximately 1,500 actuations (50 cassettes), under appropriate storage and use conditions. The system status switch checks the number of actuations remaining and the battery voltage each time the lid of the delivery system is opened approximately 90°. If the battery voltage is satisfactory, and if there are between 1 and 1,500 actuations left, a green light-emitting diode (LED) will light for 4 s (Fig 1). If more than 1,500 actuations have occurred, a red LED will blink for 4 s, but the inhaler will provide an additional 60 actuations beyond the 1,500 (approximately two cassettes) to allow the patient time to obtain a new Spiros Inhalation System DPI. After 1,560 actuations, the red LED will glow constantly for 4 s and the motor will not turn on. 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
Figure 1. The albuterol Spiros Inhalation System with cassette. Clinical Investigations
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 mg/actuation albuterol sulfate) and the MDI placebo (oleic acid and trichloromonofluoromethane); (2) the albuterol MDI (90 mg/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 administra-
tion 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 treatmentby-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 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 CHEST / 115 / 2 / FEBRUARY, 1999
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Table 1—Demographics and Pulmonary Function at Screening Spiros Group
MDI Group
Placebo Group
No. of patients 97 92 94 Gender Male 37 47 42 Female 60 45 52 Age, yr (SD) 34.2 (13.4) 34.6 (15.4) 32.4 (14.1) Stratification, % With anti-inflammatories 49 54 53 No anti-inflammatories 51 46 47 Mean FEV1, L (SD) 2.23 (0.60) 2.32 (0.59) 2.27 (0.62) Predicted, % (SD) 64 (11.4) 64 (10.3) 65 (10.6) Reversibility, % (SD)* 20.0 (7.4) 19.9 (8.0) 18.0 (6.7) PEF, L/min (SD)† Morning 342 (89) 332 (89) 338 (97) Evening 371 (95) 365 (92) 367 (106) Albuterol use, actuations/d† 4.3 4.4 5.1 *Increase in percent of predicted FEV1 (postdose predicted FEV1 2 predose predicted FEV1). †Calculated during run-in period.
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. Pulmonary Function The mean maximum percent change in the FEV1 from baseline (also called the maximum value) was at least 30% in the Spiros group, at least 29% in the MDI group, and no more than 12% in the placebo group at each of the four study visits. The Spiros and MDI groups were superior to the placebo group with respect to the mean maximum percent change in the FEV1 from the visit baseline at all visits (p 5 0.0001). The only time when the Spiros and MDI groups differed was at week 0, when the mean maximum value was significantly greater in the MDI group than in the Spiros group, respectively: 37.71 vs 31.29% (p 5 0.0255). With the repeated-measures analysis, there was a statistically significant overall visit effect (p 5 0.0396). This significant effect is attributable to the MDI group, in which the maximum percent change in the FEV1 at weeks 4, 8, and 12 was significantly lower than at week 0 (p # 0.0176). For the Spiros and placebo groups there were no significant changes in the maximum percent change in the FEV1 from week 0 through week 12, respectively: p $ 0.5830 and p $ 0.1733. For comparison, the baseline FEV1 values are presented in Table 2. 332
Table 2—Mean Baseline FEV1
Screening, N Mean (STD) Week 0, N Mean (STD) Week 4, N Mean (STD) Week 8, N Mean (STD) Week 12, N Mean (STD)
Spiros Group
MDI Group
Placebo Group
97 2.23 (0.60) 97 2.26 (0.64) 87 2.26 (0.65) 85 2.25 (0.67) 81 2.27 (0.74)
92 2.32 (0.59) 92 2.30 (0.61) 82 2.36 (0.73) 81 2.40 (0.73) 80 2.43 (0.77)
94 2.27 (0.62) 94 2.27 (0.62) 84 2.27 (0.76) 78 2.35 (0.75) 77 2.36 (0.81)
The AUCBL is presented in Table 3. The Spiros and MDI groups were superior to the placebo group with respect to the mean AUCBL at each visit (p 5 0.0001). The Spiros and MDI groups did not differ, except at week 0, when the mean AUCBL was significantly greater in the MDI group than in the Spiros group, respectively: 181.73 vs 141.50 L/min (p 5 0.0071). In order to interpret the effects of visit and treatment, an ANCOVA was performed using the AUCBL value at week 0 as the baseline covariate. The overall visit effect approached statistical significance (p 5 0.0993), but the mean values within each treatment group did not differ across the treatment weeks. In this model, the Spiros and MDI groups were superior to the placebo group with respect to the mean AUCBL (p 5 0.0001), with no difference between the Spiros and MDI groups (p 5 0.7193). The mean duration of clinically significant bronchodilation was at least 150 min in the Spiros group, 144 min in the MDI group, and no more than 30 min in the placebo group at any visit. The Spiros and MDI groups were superior to the placebo group with respect to the mean duration of effect at each visit (p 5 0.0001). The Spiros and MDI groups did not differ with respect to the mean duration of effect except at week 0, when the MDI group had a significantly longer mean duration of effect than the Spiros group, 192.0 vs 162.7 min, respectively (p 5 0.0086). With the repeated-measures analysis, the overall visit effect for duration approached significance (p 5 0.0812). For the MDI group, treatment week 0 was different from weeks 4, 8, and 12 (p # 0.0107), with the duration significantly lower at weeks 4, 8, and 12 than at week 0. For the Spiros and placebo groups, there was no significant change in the duration of effect from week 0 (p $ 0.6924) through week 12 (p $ 0.2105). 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 Clinical Investigations
Table 3—Mean AUCBL* for FEV1 Determined by Serial 6-h Pulmonary Function Testing (L/min) p Values†
Week 0 N Mean (SD) Range Week 4 N Mean (SD) Range Week 8 N Mean (SD) Range Week 12 N Mean (SD) Range
Spiros Group
MDI Group
Placebo Group
S vs P‡
V vs P
S vs V
96 141.50 (103.83) 0.25–564.94
92 181.73 (123.80) 0.70–519.08
94 44.33 (66.76) 0.00–391.80
0.0001
0.0001
0.0071
87 137.05 (99.14) 0.24–427.58
82 142.16 (92.57) 2.31–483.79
83 37.74 (58.31) 0.00–289.73
0.0001
0.0001
0.7029
85 136.96 (99.07) 0.29–440.40
81 137.44 (96.41) 0.16–404.14
78 37.01 (50.57) 0.00–226.61
0.0001
0.0001
0.4400
81 126.29 (106.16) 0.00–414.45
79 126.85 (86.59) 3.72–418.91
76 30.70 (56.57) 0.00–389.29
0.0001
0.0001
0.4353
Repeated Measures Test for Visit Effect: p 5 0.0993§ *The AUCBL was calculated using the trapezoidal rule without subtracting any area below baseline. AUCBL was calculated up to the first time point where the effect was equal to baseline. AUCBL was set to 0 if all postbaseline FEV1 values were less than baseline. †p Values from unadjusted pooled-variance t tests comparing least squared means. ‡S 5 Spiros group; M 5 MDI group; P 5 placebo group. §p Values based on repeated-measures ANCOVA controlling for treatment week 0, with treatment group and center treated as between-patient factors and visits (treatment weeks 4, 8, and 12) treated as within-patient factors.
weeks 4 and 8 for all treatment groups were similar to the curves observed at week 12.
respect to the asthma exacerbations, the daily use of rescue albuterol, or the asthma symptom scores.
Secondary Efficacy Variables
Safety
There were statistically significant differences in the mean changes from baseline with respect to morning and evening PEF values as seen in the Spiros, MDI, and placebo groups: 216 to 0, 23 to 6, and 213 to 24, respectively. Although the differences among the groups were statistically significant, they were small and were not considered to be clinically important. Among the treatment groups, there were no statistically significant differences with
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
Figure 2. The mean change from baseline for the FEV1 by treatment group for treatment week 0.
Figure 3. The mean change from baseline for the FEV1 by treatment group for treatment week 12. CHEST / 115 / 2 / FEBRUARY, 1999
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patients (3.1%) in the Spiros group (possible drugrelated 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 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 (6SD) FEV1 baseline values at screening and treatment week 0, respectively, for the Spiros group (2.23 6 0.60 and 2.26 6 0.64), the MDI group (2.32 6 0.59 and 2.30 6 0.61), and the placebo group (2.27 6 0.62 and 2.27 6 0.62) remained stable, the same baseline values at weeks 4, 8, and 12, respectively, for the Spiros group (2.26 6 0.65, 2.25 6 0.67, and 2.27 6 0.74), the MDI group (2.36 6 0.73, 2.40 6 0.73, and 2.43 6 0.77), and the placebo group (2.27 6 0.76, 2.35 6 0.75, and 2.36 6 0.81) reveal a rising baseline 334
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 b-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 bronchospasm. Along with providing a degree of safety and Clinical Investigations
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. Appendix Participants in the Albuterol Spiros Study Group were: Donald Aaronson, MD; James Baker, MD; Eugene Bleecker, MD; Thomas Casale, MD; Paul Chervinsky, MD; Arthur DeGraff, MD; Jordan Fink, MD; Jay Grossman, MD; Harold Kaiser, MD; James Kemp, MD; Phillip Korenblat, MD; Arthur Kotch, MD; Craig LaForce, MD; Dennis Ledford, MD; Harold Nelson, MD; Bruce Prenner, MD; Allen Segal, MD; Donald Tashkin, MD; Robert Townley, MD; and John Weiler, MD.
7 8 9
10 11 12 13 14 15 16 17
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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 mg/actuation of albuterol sulfate equivalent to 90 mg of albuterol base; the MDI group, who were given 90 mg/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. (CHEST 1999; 115:329 –335) Key words: aerosol; albuterol; asthma; bronchodilator; dry powder inhaler Abbreviations: ANCOVA 5 analysis of covariance; ANOVA 5 analysis of variance; AUCBL 5 area under the serial FEV1 curve and above baseline; CFC 5 chlorofluorocarbon; DPI 5 dry powder inhaler; FDA 5 Food and Drug Administration; LED 5 light-emitting diode; MDI 5 metered-dose inhaler; PEF 5 peak expiratory flow
drug delivery is the preferred method I nhalational of drug administration to the lung, and the 1,2
metered-dose inhaler (MDI) is currently the most *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. †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. Manuscript received February 17, 1998; revision accepted July 30, 1998. Correspondence to: Harold Nelson, MD, National Jewish Medical and Research Center, 1400 Jackson Street, B104, Denver, CO 80206
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 CHEST / 115 / 2 / FEBRUARY, 1999
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(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 breathactuated, 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 –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 swallowed or exhaled. With a breath-actuated DPI, the coordination of actuation and inhalation is automatic. In the present study, we compared the longterm 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. 330
Materials and Methods Spiros Inhalation System The Spiros Inhalation System is a small (4 3 10 3 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. The Spiros Inhalation System features an internal counting mechanism designed to deliver approximately 1,500 actuations (50 cassettes), under appropriate storage and use conditions. The system status switch checks the number of actuations remaining and the battery voltage each time the lid of the delivery system is opened approximately 90°. If the battery voltage is satisfactory, and if there are between 1 and 1,500 actuations left, a green light-emitting diode (LED) will light for 4 s (Fig 1). If more than 1,500 actuations have occurred, a red LED will blink for 4 s, but the inhaler will provide an additional 60 actuations beyond the 1,500 (approximately two cassettes) to allow the patient time to obtain a new Spiros Inhalation System DPI. After 1,560 actuations, the red LED will glow constantly for 4 s and the motor will not turn on. 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
Figure 1. The albuterol Spiros Inhalation System with cassette. Clinical Investigations
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 mg/actuation albuterol sulfate) and the MDI placebo (oleic acid and trichloromonofluoromethane); (2) the albuterol MDI (90 mg/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 administra-
tion 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 treatmentby-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 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 CHEST / 115 / 2 / FEBRUARY, 1999
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Table 1—Demographics and Pulmonary Function at Screening Spiros Group
MDI Group
Placebo Group
No. of patients 97 92 94 Gender Male 37 47 42 Female 60 45 52 Age, yr (SD) 34.2 (13.4) 34.6 (15.4) 32.4 (14.1) Stratification, % With anti-inflammatories 49 54 53 No anti-inflammatories 51 46 47 Mean FEV1, L (SD) 2.23 (0.60) 2.32 (0.59) 2.27 (0.62) Predicted, % (SD) 64 (11.4) 64 (10.3) 65 (10.6) Reversibility, % (SD)* 20.0 (7.4) 19.9 (8.0) 18.0 (6.7) PEF, L/min (SD)† Morning 342 (89) 332 (89) 338 (97) Evening 371 (95) 365 (92) 367 (106) Albuterol use, actuations/d† 4.3 4.4 5.1 *Increase in percent of predicted FEV1 (postdose predicted FEV1 2 predose predicted FEV1). †Calculated during run-in period.
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. Pulmonary Function The mean maximum percent change in the FEV1 from baseline (also called the maximum value) was at least 30% in the Spiros group, at least 29% in the MDI group, and no more than 12% in the placebo group at each of the four study visits. The Spiros and MDI groups were superior to the placebo group with respect to the mean maximum percent change in the FEV1 from the visit baseline at all visits (p 5 0.0001). The only time when the Spiros and MDI groups differed was at week 0, when the mean maximum value was significantly greater in the MDI group than in the Spiros group, respectively: 37.71 vs 31.29% (p 5 0.0255). With the repeated-measures analysis, there was a statistically significant overall visit effect (p 5 0.0396). This significant effect is attributable to the MDI group, in which the maximum percent change in the FEV1 at weeks 4, 8, and 12 was significantly lower than at week 0 (p # 0.0176). For the Spiros and placebo groups there were no significant changes in the maximum percent change in the FEV1 from week 0 through week 12, respectively: p $ 0.5830 and p $ 0.1733. For comparison, the baseline FEV1 values are presented in Table 2. 332
Table 2—Mean Baseline FEV1
Screening, N Mean (STD) Week 0, N Mean (STD) Week 4, N Mean (STD) Week 8, N Mean (STD) Week 12, N Mean (STD)
Spiros Group
MDI Group
Placebo Group
97 2.23 (0.60) 97 2.26 (0.64) 87 2.26 (0.65) 85 2.25 (0.67) 81 2.27 (0.74)
92 2.32 (0.59) 92 2.30 (0.61) 82 2.36 (0.73) 81 2.40 (0.73) 80 2.43 (0.77)
94 2.27 (0.62) 94 2.27 (0.62) 84 2.27 (0.76) 78 2.35 (0.75) 77 2.36 (0.81)
The AUCBL is presented in Table 3. The Spiros and MDI groups were superior to the placebo group with respect to the mean AUCBL at each visit (p 5 0.0001). The Spiros and MDI groups did not differ, except at week 0, when the mean AUCBL was significantly greater in the MDI group than in the Spiros group, respectively: 181.73 vs 141.50 L/min (p 5 0.0071). In order to interpret the effects of visit and treatment, an ANCOVA was performed using the AUCBL value at week 0 as the baseline covariate. The overall visit effect approached statistical significance (p 5 0.0993), but the mean values within each treatment group did not differ across the treatment weeks. In this model, the Spiros and MDI groups were superior to the placebo group with respect to the mean AUCBL (p 5 0.0001), with no difference between the Spiros and MDI groups (p 5 0.7193). The mean duration of clinically significant bronchodilation was at least 150 min in the Spiros group, 144 min in the MDI group, and no more than 30 min in the placebo group at any visit. The Spiros and MDI groups were superior to the placebo group with respect to the mean duration of effect at each visit (p 5 0.0001). The Spiros and MDI groups did not differ with respect to the mean duration of effect except at week 0, when the MDI group had a significantly longer mean duration of effect than the Spiros group, 192.0 vs 162.7 min, respectively (p 5 0.0086). With the repeated-measures analysis, the overall visit effect for duration approached significance (p 5 0.0812). For the MDI group, treatment week 0 was different from weeks 4, 8, and 12 (p # 0.0107), with the duration significantly lower at weeks 4, 8, and 12 than at week 0. For the Spiros and placebo groups, there was no significant change in the duration of effect from week 0 (p $ 0.6924) through week 12 (p $ 0.2105). 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 Clinical Investigations
Table 3—Mean AUCBL* for FEV1 Determined by Serial 6-h Pulmonary Function Testing (L/min) p Values†
Week 0 N Mean (SD) Range Week 4 N Mean (SD) Range Week 8 N Mean (SD) Range Week 12 N Mean (SD) Range
Spiros Group
MDI Group
Placebo Group
S vs P‡
V vs P
S vs V
96 141.50 (103.83) 0.25–564.94
92 181.73 (123.80) 0.70–519.08
94 44.33 (66.76) 0.00–391.80
0.0001
0.0001
0.0071
87 137.05 (99.14) 0.24–427.58
82 142.16 (92.57) 2.31–483.79
83 37.74 (58.31) 0.00–289.73
0.0001
0.0001
0.7029
85 136.96 (99.07) 0.29–440.40
81 137.44 (96.41) 0.16–404.14
78 37.01 (50.57) 0.00–226.61
0.0001
0.0001
0.4400
81 126.29 (106.16) 0.00–414.45
79 126.85 (86.59) 3.72–418.91
76 30.70 (56.57) 0.00–389.29
0.0001
0.0001
0.4353
Repeated Measures Test for Visit Effect: p 5 0.0993§ *The AUCBL was calculated using the trapezoidal rule without subtracting any area below baseline. AUCBL was calculated up to the first time point where the effect was equal to baseline. AUCBL was set to 0 if all postbaseline FEV1 values were less than baseline. †p Values from unadjusted pooled-variance t tests comparing least squared means. ‡S 5 Spiros group; M 5 MDI group; P 5 placebo group. §p Values based on repeated-measures ANCOVA controlling for treatment week 0, with treatment group and center treated as between-patient factors and visits (treatment weeks 4, 8, and 12) treated as within-patient factors.
weeks 4 and 8 for all treatment groups were similar to the curves observed at week 12.
respect to the asthma exacerbations, the daily use of rescue albuterol, or the asthma symptom scores.
Secondary Efficacy Variables
Safety
There were statistically significant differences in the mean changes from baseline with respect to morning and evening PEF values as seen in the Spiros, MDI, and placebo groups: 216 to 0, 23 to 6, and 213 to 24, respectively. Although the differences among the groups were statistically significant, they were small and were not considered to be clinically important. Among the treatment groups, there were no statistically significant differences with
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
Figure 2. The mean change from baseline for the FEV1 by treatment group for treatment week 0.
Figure 3. The mean change from baseline for the FEV1 by treatment group for treatment week 12. CHEST / 115 / 2 / FEBRUARY, 1999
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patients (3.1%) in the Spiros group (possible drugrelated 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 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 (6SD) FEV1 baseline values at screening and treatment week 0, respectively, for the Spiros group (2.23 6 0.60 and 2.26 6 0.64), the MDI group (2.32 6 0.59 and 2.30 6 0.61), and the placebo group (2.27 6 0.62 and 2.27 6 0.62) remained stable, the same baseline values at weeks 4, 8, and 12, respectively, for the Spiros group (2.26 6 0.65, 2.25 6 0.67, and 2.27 6 0.74), the MDI group (2.36 6 0.73, 2.40 6 0.73, and 2.43 6 0.77), and the placebo group (2.27 6 0.76, 2.35 6 0.75, and 2.36 6 0.81) reveal a rising baseline 334
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 b-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 bronchospasm. Along with providing a degree of safety and Clinical Investigations
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. Appendix Participants in the Albuterol Spiros Study Group were: Donald Aaronson, MD; James Baker, MD; Eugene Bleecker, MD; Thomas Casale, MD; Paul Chervinsky, MD; Arthur DeGraff, MD; Jordan Fink, MD; Jay Grossman, MD; Harold Kaiser, MD; James Kemp, MD; Phillip Korenblat, MD; Arthur Kotch, MD; Craig LaForce, MD; Dennis Ledford, MD; Harold Nelson, MD; Bruce Prenner, MD; Allen Segal, MD; Donald Tashkin, MD; Robert Townley, MD; and John Weiler, MD.
7 8 9
10 11 12 13 14 15 16 17
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