Objective: As a secondary objective to a long-term study evaluating the bronchodilator effectiveness of Proventil HFA (albuterol), to assess the safety of Proventil HFA, Ventolin, and hydrofluoroalkane 134a (HFA-134a) placebo over 12 weeks of regular dosing.
Design: Randomized, double-blind, double-dummy_parallel group, placebo-controlled, multicenter trial of asthmatics requiring inhaled [Beta]-adrenergic bronchodilators for symptom control. Interventions: Treatment with Proventil HFA, Ventolin, or HFA-134a placebo, qid, for 12 weeks.
Measurements: Adverse events were reviewed at biweekly clinic visits. Between clinic visits, patients recorded morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of rescue [Beta]-adrenergic bronchodilator on diary cards daily. Investigators provided a global assessment of asthma control at weeks 0, 4, 8, and 12. Vital signs were recorded over 6 h after dosing with study drug at weeks 0, 4, 8, and 12. Standard laboratory tests, CBC count, serum chemistries, and urinalysis were obtained at study start and end.
Results: Adverse event reporting rates were similar for the three treatment groups. The morning PEF tended to be lower for the Proventil HFA and Ventolin groups than the HFA-134a placebo group, but the evening PEF tended to be higher for the active treatment groups. Daytime asthma symptom scores tended to be lower (better) with active treatment than placebo, but nighttime asthma sleep disturbance scores were similar for all three treatment groups. Use of Ventolin Rotacaps as rescue medication was significantly greater for the HFA-134a placebo group than the Proventil HFA and Ventolin groups. Diary card data did not change within groups over time. Investigator global assessments of asthma scores clustered between fair and good for all three treatment groups throughout the study. Changes in heart rate and BP were small after dosing with study drug and tended to be similar for the active treatments and HFA-134a placebo groups. No clinically meaningful changes in results of standard laboratory tests were found in any treatment group during this study.
Conclusions: Proventil HFA had a similar safety profile as Ventolin during regular use. A dosage of 16 puffs per day of propellant HFA-134a was well tolerated by asthmatics. Regular use of either Proventil HFA or Ventolin did not cause asthma control to deteriorate.
(CHEST 1998; 113-290-96)
Key words: albuterol; asthma; HFA-134a propellant
Abbreviations: ANCOVA=analysis of covariance; ANOVA-analysis of variance; CFC-chlorofluorocarbon; HFA-134a=hydrofluoroalkane 134a; MDI=metered-dose inhaler; PEF=peak expiratory flow
The Montreal Protocol represents international agreement that chlorofluorocarbon (CFC) production and use must be banned, because CFC release into the atmosphere leads to ozone depletion.[2,3] Consequently, CFC propellants in metered-dose inhalers (MDIs) must be replaced. Albuterol has been reformulated successfully in an MDI using the CFC-free propellant hydrofluoroalkane 134a (HFA-134a) (Proventil HFA; Schering Corporation; Kenilworth, NJ). Regulatory requirements for approval of this product included a 12-week study, featuring regular use of Proventil HFA, to allow a complete safety assessment of this new formulation. Incorporated into this study for comparison purposes were regular use of Ventolin (Glaxo Wellcome, Inc; Research Triangle Park, NC) and, as a placebo, propellant HFA-134a.
The design of this 12-week study, although based on a regulatory need to understand the relationship between adverse events and study drug use, raised an intriguing safety question. The Food and Drug Administration-approved labeling for albuterol MDI products indicates that they can be used regularly every 4 to 6 h. This labeling claim is based on the safety results from a relatively small study performed in the 1970s. Since then, regular use of [Beta]-adrenergic bronchodilators has been found to worsen bronchial hyperresponsiveness in asthmatics.[5,6] Retrospective, epidemiologic studies have also linked increased asthma mortality with more frequent use of [Beta]-adrenergic bronchodilators.[7-9] Both increased hyperresponsiveness and asthma mortality are postulated to be due to ongoing bronchial inflammation. Regular use of [Beta]-adrenergic bronchodilators may mask asthma symptoms, allow continued exposure to bronchial irritants, and actually promote bronchial inflammation.[10,11]
The results of this large prospective 12-week study provide reassuring data about the safety of Proventil HFA, used regularly per labeling claims. Proventil HFA had a safety profile similar to Ventolin and an incidence of adverse events lower than currently described. Propellant HFA-134A was well tolerated. Regular use of either Proventil HFA or Ventolin did not cause deterioration in asthma control over 12 weeks. In an accompanying report, results are provided showing that Proventil HFA provides bronchodilation comparable to Ventolin with regular use.
Materials and Methods
Patients 18 to 65 years of age with at least a 12-month history of asthma requiring inhaled P-adrenergic agonists for symptom control were eligible for enrollment. Asthma was considered stable if, over the month prior to study entry, there were no changes in asthma therapy and no asthma-related hospital visits. Patients had a baseline [FEV.sub.1] of 40 to 80% predicted, at least a 15% increase in [FEV.sub.1] within 30 min of inhaling 200 [Mu]g of Ventolin (administered as Ventolin Rotacaps with Rotahaler), and demonstrated satisfactory technique in the use of a placebo MDI. Women were nonpregnant, nonlactating, and using an acceptable method of contraception. Patients with significant concomitant disease, eg, cardiac arrhythmias, congestive heart failure, hypertension, nonreversible pulmonary disease, a recent (within 4 weeks) upper or lower respiratory tract infection. reported recent (within 4 weeks) use of oral corticosteroids, oral [Beta]-adrenergic bronchodilators, monoamine oxidase inhibitors, tricyclic antide-pressants or [Beta]-blockers, or a smoking history within 2 years of the screening visit were excluded. Prior to entry into the study, all patients provided written informed consent in accordance with participating institutional and US federal guidelines.
The details of the bronchodilator efficacy component of this randomized, parallel group, placebo-controlled, multicenter trial are provided in a companion report. Patients eligible for study entry after screening evaluation underwent a 7-day run-in period. during which they continued their usual asthma treatment regimens. At the end of this run-in period, patients were randomized to treatment math Proventil HFA, Ventolin, or HFA-134a placebo. Randomization was stratified so that half of the patients assigned to each study treatment were taking inhaled corticosteroids. A double-dummy technique was used to blind patients to the identity of their treatment (the MDIS for Proventil HFA and Ventolin were physically different in appearance) and to minimize the possible confounding effect of exposure to two different types of propellants. This was accomplished by preparing three separate placebos for this study. Propellant HFA-134a with ethanol and oleic acid was formulated in both a Proventil HFA MDI (white adapter, 25-[Mu]L valve) and a Ventolin MDI (blue adapter, 63-[Mu]L valve). Propellants CFC-11/12 with oleic acid were formulated in a Proventil HFA MDI (white adapter, 25-[Mu]L valve).
Dosing throughout the 12-week study was two puffs qid from a blue MDI and two puffs qid from a white MDI. Patients randomized to Proventil HFA treatment were given a blue MDI containing HFA-134a placebo and active drug in a white MDI. Patients in the Ventolin group had active drug in a blue MDI and CFC-11/12 placebo in a white MDI. The HFA-134a placebo group had both a blue and a white MDI containing propellant HFA-134a. Patients were allowed use of Ventolin Rotacaps as rescue medication.
All adverse events reported by the patients at biweekly visits were recorded. Relationship of the adverse event to study drug use and seriousness were assessed by the investigator. Asthma exacerbations, defined as a worsening of asthma symptoms requiring a change in asthma therapy, were recorded separately. Patients were supplied diary cards and instructed to record morning and evening peak expiratory flow (PEF), asthma symptom and nighttime asthma sleep disturbance scores, and use of Ventolin Rotacaps as rescue medication. PEF was measured by patients using a peak flowmeter (Mini-Wright; Clement Clarke; Columbus, Ohio) three times in the morning before using any medications and again in the evening. The highest of the three values was recorded. Asthma symptoms, specifically shortness of breath, chest tightness, wheezing, and cough, experienced during the day were individually assessed each evening by the patient using a five-point scale (0 being symptom not present ranging to 5 being symptom so severe that patient could not conduct normal daily activities). Nighttime sleep disturbance from asthma symptoms was assessed each morning by the patient using a four-point scale (0 being sleep not disturbed ranging to 4 being symptoms so severe that patient did not sleep at all). Each Ventolin Rotacap was considered a single use. The diary cards were collected and reviewed at biweekly clinic visits. At weeks 0, 4, 8, and 12, investigators provided a global assessment of overall asthma control based on a five-point scale (1 being very good ranging to 5 being very poor). Standard laboratory tests, CBC count, serum chemistries.. and urinalysis were performed by a central laboratory (Scicor; Indianapolis) at study start and end. Heart rate and BP were monitored over 6 h after dosing with study drug at weeks 0, 4, 8, and 12.
Adverse events were summarized by the World Health Organization's preferred terms as modified by 3M Pharmaceuticals and tabulated. The incidence of adverse events in each treatment group was compared using Fisher's Exact Test. Diary card data were averaged over 2-week periods (7 days for the run-in) and tested with an analysis of covariance (ANCOVA) model using pooled center, inhaled corticosteroid use (yes or no), treatment group, and interactions as factors in the model and the patient's mean run-in value as a covariate. The investigator global assessments and changes in vital signs were tested using an analysis of variance (ANOVA) model with the same factors as the ANCOVA model. laboratory, test results were categorized as normal vs high or low and transitions from normal to high or low were compared within treatment groups using a Wilcoxon signed rank test.
Post hoc analyses were performed to evaluate the influence of therapy duration on morning and evening PEF, asthma symptom and nighttime asthma sleep disturbance scores, Ventolin Rotacap use, and reporting of asthma exacerbations, adverse events, and study discontinuations with an ANOVA. Treatment, study week (0, 4, 8, and 12), and treatment-study week interactions were used as factors in the model.
Summary statistics, ANOVA, and ANCOVA were performed using software (SAS version 6.08; Cary, NC). All p values [is less than or equal to]0.05 were considered significant.
Five hundred sixty-five patients from 33 sites across the United States were randomized to receive Proventil HFA (193), Ventolin (186), or HFA-134a placebo (186) between June 1993 and April 1994. Demographic and baseline characteristics, concomitant medication use, asthma severity, and compliance with study drug use are described in an accompanying report. There were 29 patients who were discontinued from the study in both the Proventil HFA group (15%) and the Ventolin group (15.6%) and 43 (23.1%) from the HFA-134a placebo group (p=0.091). The most common reason for study discontinuation was asthma exacerbation: 19 (9.8%) from the Proventil HFA group, 17 (9.1%) from the Ventolin group, and 27 (14.5%) from the HFA-134a placebo group discontinued study participation for this reason (p [is greater than]0.10). Only 3 (1.6%), 4 (2.2%), and 8 (4.3%) discontinued from the Proventil HFA, Ventolin, and HFA-134a placebo groups, respectively, for adverse events. None of these adverse events were considered to be related to study drug.
There were 172 (89%) patients reporting adverse events in the Proventil HFA group, 160 (86%) in the Ventolin group, and 153 (82%) in the HFA-134a placebo group. The most frequently reported adverse events were headache (163 patients), acute asthma episode (133 patients), upper respiratory tract infection (111 patients), increased asthma symptoms (98 patients), and rhinitis (97 patients). Similar numbers of adverse events were attributed to use of study drug by the investigators in each treatment group; 71 (37%) with Proventil HFA, 68 (37%) with Ventolin, and 63 (34%) with HFA-134a placebo. There were five serious adverse events reported in the Proventil HFA group (increased asthma symptoms, allergic reaction to walnut sauce, pneumonia, motor vehicle accident, and lumbar laminectomy) and one each in the Ventolin (acute asthma episode with urticaria) and HFA-134a placebo groups (anaphylactic reaction to immunotherapy). Asthma exacerbations occurred in 26 (13%) of the Proventil HFA group, 23 (12%) of the Ventolin group, and 34 (18%) of the HFA-134a placebo group. No differences in the reporting rates of adverse events and asthma exacerbations between inhaled corticosteroid users and nonusers were found in any treatment group.
Individual adverse events occurring significantly more often in one treatment group than others are reported in Table 1. Reporting rates of adverse events that are typically associated with [Beta]-adrenergic bronchodilators but that were not reported significantly more often than placebo in this study follow: palpitations (2% with Proventil HFA and 2% with Ventolin); nausea (10% in Proventil HFA group and 9% in Ventolin group); increased BP (0% in both groups); and heartburn (0% in both groups). Shown in Table 2 are reporting rates for asthma exacerbations and study discontinuations over time by treatment group. These rates did not increase over the course of the study.
[TABULAR DATA 1 NOT REPRODUCIBLE IN ASCII]
Table 2 -- Reporting Rates of Asthma Exacerbations and Study Discontinuation Over Time by Treatment Group
Morning and Evening PEF
The morning PEF tended to be lower for the two active treatment groups than HFA-134a placebo throughout the study, but this difference was significant only over weeks 5 to 6 for the Proventil HFA group (p=0.03). Changes in morning PEF were not found within groups over time (Fig 1). The evening PEF tended to be higher for both active treatment groups than HFA-134a placebo throughout the study, with significant differences at weeks 1 to 2 and 5 to 6. Changes in evening PEF did not occur over time within groups (data not shown).
[FIGURE 1 ILLUSTRATION OMITTED]
Asthma Symptom Scores
Daytime wheezing scores tended to be lower (better) for the two active treatment groups throughout the study with significant differences (p [is less than]0.05) from HFA-134a placebo for Proventil HFA at weeks 1 to 2 and 3 to 4 and for Ventolin at weeks 1 to 2. Changes in daytime wheeze scores over time within groups were not found (Fig 2). Similar results were seen for daytime cough, chest tightness, and shortness of breath symptom scores (data not shown).
[FIGURE 2, ILLUSTRATION OMITTED]
Nighttime Asthma Sleep Disturbance Scores
Differences were not found between treatment groups for nighttime asthma sleep disturbance scores. Changes in these scores over time within treatment groups were not found (Fig 3).
[FIGURE 3, ILLUSTRATION OMITTED]
Use of Ventolin Rotacaps as Rescue Medication
The HFA-134a placebo group reported significantly p [is less than]0.001) more use of Ventolin Rotacaps as rescue bronchodilator medication throughout the study than either of the two active. treatment groups. The difference, however, tended to be small, because reported rescue use was only about one per day for the Proventil HFA and Ventolin groups and about two per day for the HFA-134a placebo group. Total daily use of [Beta]-adrenergic bronchodilators was much greater for the two active treatment groups taking into account their scheduled use of study drug. Reported use of Ventolin Rotacaps did not change within groups over time (Fig 4).
[FIGURE 4, ILLUSTRATION OMITTED]
Investigator Global Assessment of Asthma Scores
Scores for the two active treatment groups tended to be lower (better) than HFA-134a placebo throughout the study, with significant differences (p [is less than]0.01) from HFA-134a placebo for Proventil HFA at week 4 and Ventolin at week 4 and week 12. These scores, however, clustered between 2 and 3 (good and fair) for all treatment groups at each assessment point. Changes in these scores within groups over time did not occur (data not shown).
Heart Rate and BP
Mean changes in heart rate over 6 h after dosing with study drug at weeks 0, 4, 8, and 12 were very small, between -1.6 and 0.5 beats/min. When all test days were considered, there were only 12 (6%), 8 (4%), and 23 (12%) patients who had a [is greater than]20-beat/ min increase in heart rate at any time point over the 6 h after dosing with Proventil HFA, Ventolin, and HFA-134a placebo, respectively. Mean changes in systolic BP over 6 h after dosing with study drug at weeks 0, 4, 8, and 12 were also very small, between -2.0 and 0.9 mm Hg. Considering all test days, there were only 43 patients who had a [is grater than]20-mm Hg increase in systolic BP at any time point over the 6 h after dosing with Proventil HFA (15), Ventolin (13), and HFA-134a placebo (14), respectively. Similar results (13) were found for diastolic BP.
Standard Laboratory Tests
No clinically meaningful changes in CBC counts, serum chemistries, and urinalyses were found in any of the three treatment groups over the course of the study.
The results of this large prospective study demonstrate that Proventil HFA is a safe drug. The reporting rate of adverse events typically attributed to [Beta]-adrenergic bronchodilators was lower than previously described for albuterol MDI products. The CFC-free propellant HFA-134a was well tolerated. Regular use of either Proventil HFA or Ventolin for 12 weeks did not cause deterioration in asthma control.
Present available information describing the adverse event profile for albuterol products formulated in CFCs is based on a study of 147 patients performed in the 1970s.(4) The present study provides a considerably larger database for examining the adverse event profile of the tested drugs. Total adverse events and most individual adverse events were reported at similar rates in the Proventil HFA and Ventolin treatment groups. There were significant differences between reporting rates from the two active treatment groups, compared to HFA-134a placebo, for only a few individual adverse events. Significantly more adverse events were reported for inhalation taste sensation and nervousness in the Ventolin group than HFA-134a placebo and significantly more complaints about vomiting and allergic reactions (in this database, allergic reactions refer primarily to seasonal allergy, symptoms) came from the Proventil HFA group than HFA-134a placebo. No clear pattern emerges from these differences, suggesting a safety problem with either Proventil HFA or Ventolin. The patients receiving Proventil HFA did report significantly more episodes of "tachycardia" than either of the other two treatment groups. This may have reflected a coding peculiarity for this database. When reporting rates for "palpitations," other coding term used in this adverse event database with a similar connotation as "tachycardia," were combined with those for "tachycardia," significant differences among treatment groups were no longer found. No differences in either mean heart rate or numbers of patients with a [is greater than]20-beat/min increase in heart rate after dosing with study drug in the clinic were found between Proventil HFA and Ventolin. Reporting rates for adverse events typically associated with [Beta]-adrenergic bronchodilator use, eg, tremor, nervousness, palpitations, increased BP, and heartburn, were lower in this study than described in current labeling information.
Due to the double-dummy design of this study, patients randomized to HFA-134a placebo took 16 puffs of propellant HFA-134a as a placebo daily. Previous studies have shown that propellant HFA-134a is well tolerated in short-term dosing studies and with dosing for up to 1 month (data on file, 3M Pharmaceuticals). This study confirms that regular use of propellant HFA-134a alone for 12 weeks is also well tolerated. Multiple markers of asthma control were incorporated into the design of this study, eg, morning and evening PEF, asthma symptom and nighttime asthma sleep disturbance scores, and use of Ventolin Rotacaps as rescue bronchodilators. As changes in these parameters over time were not seen in the HFA-134a placebo group, it seems reasonable to assume that asthma control in this group did not deteriorate over the course of this study. Supporting this point are the relatively constant investigator global assessments of asthma scores for this group from week 0 to week 12. Predose [FEV.sub.1] obtained at weeks 0, 4, 8, and 12 increased by week 12 in the HFA-134a placebo group.
The HFA- 134a placebo group did report a significantly greater number of acute asthma symptoms occurring within 15 min of using their study drug at home than either of the two active treatment groups. There were no differences in the reporting rates for cough after study drug use among the three treatment groups and, of the 14 patients reporting this adverse event, only 3 had a 15% fall in [FEV.sub.1] within 15 min of taking HFA-134a placebo in the clinic. These observations suggest that this complaint does not represent an acute reaction to propellant HFA-134a. Another possible explanation is that asthma symptoms were present at the scheduled time of study drug use and patients did not obtain the expected benefit from their (unknowingly placebo) study drug.
Despite evidence that bronchodilator efficacy is reduced after 4 weeks of regular use of Proventil HFA and Ventolin, the stability, of multiple physiologic and subjective measures of asthma control throughout the course of this study is strong indication that asthma control did not deteriorate with the regular use of albuterol. These results agree with the findings of both Drazen et al and Chapman and colleagues. Unlike the results of others,[17-19] baseline pulmonary function in the two active treatment groups did not deteriorate. The morning PEF. obtained prior to the use of any asthma medication and considered it useful marker of asthma control on a daily basis, remained relatively constant in both the Proventil HFA and Ventolin treatment groups throughout the study. Similarly, [FEV.sub.1] values obtained prior to dosing with study drug and after washout of bronchodilators at weeks 0, 4, 8, and 12 did not change. Subjective measures of asthma control, ie, daytime asthma symptom and nighttime asthma sleep disturbance scores, recorded use of Ventolin Rotacaps as rescue medication, and investigator global assessment of asthma scores also did not change over the 12 weeks of this study. Furthermore, reporting rates for asthma exacerbations and study discontinuations did not vary over time during this study.
The relationship between regular use of [Beta]-adrenergic bronchodilators and asthma control is complex. The hypothesis that regular use of [Beta]-adrenergic bronchodilators might mask symptoms, allow continued exposure to bronchial irritants, and promote bronchial inflammation[10,11] is intriguing, but has not been supported by animal studies. Concomitant use of inhaled corticosteroids does not prevent the development of increased bronchial hyperresponsiveness with regular use of albuterol. It may be that the association between asthma deterioration and regular use of [Beta]-adrenergic bronchodilators is specific only for certain agents like fenoterol.[23-25] Albuterol is only a partial [Beta] receptor agonists. The less pronounced cardiac and metabolic effects with albuterol than with full [Beta]-receptor agonists like fenoterol may result in a smaller likelihood of albuterol negatively affecting overall asthma control.
Although asthma control did not deteriorate with regular use of Proventil HFA and Ventolin, there was no indication that it improved relative to placebo, despite greater overall use of [Beta]-adrenergic bronchodilators per day. This point reaffirms the clinical wisdom that using [Beta]-adrenergic bronchodilators on an as-needed basis provides effective control of asthma symptoms with less overall use of medication. Others have reached similar conclusions.
Concomitant use of inhaled corticosteroids did not affect asthma exacerbations within treatment groups. The use of inhaled corticosteroids was not controlled, because this study was intended to address the safety and efficacy of Proventil HFA in the context of the standard of care applied to asthmatics in the United States today. It is clear that asthma is an inflammatory disease and the role of inhaled corticosteroids in controlling bronchial inflammation and the overall course of asthma is clearly established.[28-30]
In summary, environmental concerns have led to a ban on the production and use of CFCs. In response to this ban, albuterol has been reformulated in the CFC-free propellant HFA-134a (Proventil HFA). This large prospective 12-week study demonstrates that Proventil HFA has a similar safety profile as Ventolin, a currently marketed albuterol product formulated in CFCs. The data also show that regular use of the propellant HFA-134a is well tolerated by asthmatics. Asthma control did not deteriorate over the course of this study with regular use of either Proventil HFA or Ventolin.
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