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From Pulmonary Consultants (Dr. Taylor), Tacoma, WA; Danbury Hospital (Dr. Kotch), Danbury, CT; VA Medical Center (Dr. Rice), Minneapolis, MN; and Boehringer Ingelheim Pharmaceuticals, Inc. (Drs. Ghafouri, Kurland, Witek, and Ms. Fagan), Ridgefield, CT.
The study investigators are listed in the Appendix.
Correspondence to: Mo Ghafouri, PhD, Senior Associate Director, Clinical Research, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Rd, PO Box 368, Ridgefield, CT 06877-0368; e-mail: mghafour{at}rdg.boehringer-ingelheim.com
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Abstract |
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Design: This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. The primary efficacy parameter was acute bronchodilator response. The primary end points were peak change in FEV1 from baseline and area under the response-time curve.
Setting: Thirty-one clinical centers in the United States participated in this project.
Patients: A total of 507 patients with moderate-to-severe COPD were randomized, and 444 patients completed the trial.
Interventions: Twelve weeks of treatment four times daily with one of the following: ipratropium bromide HFA, 42 µg; ipratropium bromide HFA, 84 µg; HFA placebo; ipratropium bromide inhalation aerosol, 42 µg; or CFC placebo.
Measurements and results: Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV1 from baseline of at least 15%. Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV1, area under the time-response curve from 0 to 6 h, and peak response. FVC results were similar to those seen with FEV1. There were no significant differences in adverse events, laboratory findings, or ECG findings among the treatment groups.
Conclusions: Ipratropium bromide HFA, 42 µg, provided bronchodilation comparable to the marketed ipratropium bromide CFC, 42 µg, over 12 weeks of regular use.
Key Words: chlorofluorocarbon • COPD • hydrofluoroalkane-134a • ipratropium bromide
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Introduction |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Hydrofluoroalkane (HFA)-134a (1,1,1,2-tetrafluoroethane) has been shown4 5 6 7 8 9 to be a suitable replacement for CFCs in MDIs. HFA-134a has environmental advantages over CFCs because it does not contain chlorine and is therefore considered to have no ozone-depleting potential.10 Preclinical evaluations11 have demonstrated the acceptability of this propellant in terms of pharmacology, toxicology, and safety. Ipratropium bromide inhalation aerosol (Atrovent; Boehringer Ingelheim; Ridgefield, CT) has been established as a first-line medication for maintenance treatment of bronchospasm in patients with COPD.12 This drug has been reformulated successfully with the new HFA-134a propellant system. The present study was designed to compare the efficacy and safety of the new Atrovent HFA-134a formulation and the currently marketed Atrovent inhalation aerosol in COPD patients.
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Materials and Methods |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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65% predicted normal
and FEV1 70% of the FVC.13 An acute bronchodilator test in response to short-acting ß2 agonist was not performed as a selection criterion in this study. Patient selection followed standard COPD selection criteria14 designed to exclude patients with asthma. Specifically, patients with a history of asthma, allergic rhinitis, atopy, or those who had a total eosinophil count > 600/µL were excluded. Also excluded were patients who required > 10 mg of oral prednisone daily within 6 weeks before entry into the study. Before admission to the trial, each patient had his/her medical history taken and underwent laboratory testing, physical examination, and 12-lead ECG recording; these tests were repeated at the completion of the study.
Five hundred seven patients were selected and randomized into the trial. Visits to the clinic were scheduled once every 2 weeks throughout the treatment period. During these visits, adverse events, use of concomitant medications, and other evaluations were recorded.
While continued use of stable doses of theophylline was allowed during the study (28% of patients were receiving theophylline), regular use of inhaled bronchodilators other than the study drug was not allowed. Temporary increases or additions of theophylline and corticosteroids during exacerbations were permitted but limited to two periods of 5 days and 7 days, respectively, during the 85-day trial. The use of cromolyn sodium, oral ß-agonists, and ß-blockers was not allowed. Patients were allowed to receive inhaled albuterol for control of symptoms as necessary during the study period.
The study was double blind. A blinding device (blinding jacket) was used to blind all study medications. Therefore, there were no visual differences in the treatment groups. However, the taste of the HFA and CFC formulations were different, HFA formulation contains alcohol and citric acid while CFC formulation does not. Since we had included the placebo of both formulations in this study, patients could not distinguish between the taste of active and placebo treatments of each formulation.
Patient compliance was monitored by patient diary cards. Patients completed a daily worksheet indicating each dose of investigational drug and rescue medication (albuterol) taken. After reviewing this worksheet with the patient, the investigator recorded on the case report forms the patient’s usual daily dosing regimen and the number of puffs of albuterol that the patient took during the 2-week period preceding that visit.
Treatments
Following a 2-week baseline period to establish clinical
stability, patients were randomly assigned by order of entry to receive
one of the following treatments: ipratropium bromide HFA, 42 µg
(125 patients); ipratropium bromide HFA, 84 µg (127 patients); HFA
placebo (62 patients); ipratropium bromide CFC, 42 µg (127 patients);
or CFC placebo (66 patients) [Table 1
]. Patient stability was defined based on the patient’s respiratory
medication (ie, no changes) and the absence of respiratory
infections in the preceding 6 weeks. Patients with any viral infection
or febrile illness including upper respiratory tract infections during
the 6-week period preceding the visit were excluded from participation
in the study.
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Observations
Pulmonary function testing, including measurements of
FEV1 and FVC, was conducted four times, on
treatment days 1, 29, 57, and 85, to assess the consistency of response
during the 12-week study period. Testing was done immediately before
drug administration, at 15, 30, 60, 90, and 120 min after drug
administration, and hourly thereafter, for a total of 8 h.
Theophylline treatment was withheld for at least 24 h, and
treatment with ß-adrenergic bronchodilators and the study drug was
withheld for at least 12 h prior to pulmonary function testing.
The study drug was administered between 7 AM and 10
AM, after baseline spirometry had been performed. All
pulmonary function tests were conducted in triplicate, and the
spirometric results with the greatest sum of FEV1
and FVC were recorded and used for analysis. Spirometers met American
Thoracic Society standards.15
BP and pulse rates were
measured on each test day, just prior to each pulmonary function test
for a period of 8 h. Severity of COPD symptoms (wheezing,
shortness of breath, coughing, and tightness of chest) was reported at
the end of the 2-week baseline period and every 2 weeks thereafter.
Investigators rated the severity of symptoms using a 4-point scale:
none (0), mild (1), moderate (2), and severe (3). This assessment was
based on the patient’s condition since the previous visit. This
evaluation was made before the start of pulmonary function testing. A
global evaluation of each patient’s overall condition was made by the
investigator at each visit and was expressed as a numerical value from
1 (poor) to 8 (excellent). This global evaluation was based on the
physician’s assessment of the overall condition of the patient’s
disease, need for concomitant medication, number and severity of
exacerbations, severity of cough, ability to exercise, and amount of
wheezing, etc.
Statistical Evaluation
Acute bronchodilator response was measured by
changes from baseline in the spirometric variables
FEV1 and FVC. The primary end points were peak
change from baseline and average area under the response-time curve
from 0 to 6 h (AUC0–6), as calculated by
the trapezoidal rule.16
FEV1
responses were also used to derive the onset of end point and duration
of therapeutic response (defined as 15% increase from test-day
baseline) and time to peak response. Response was considered terminated
when patients no longer demonstrated improvement in
FEV1 > 15% from the baseline at two
consecutive time points. Duration of action was defined as the interval
between onset and termination of therapeutic response. The FVC response
was similarly evaluated in terms of AUC0–6 and
peak response.
Analysis of covariance with test-day baseline as the covariate was used to evaluate acute bronchodilator response. Other terms used in the model were treatment, center, and treatment-by-center interaction. The efficacy analysis was performed using intent-to-treat data set. End point analyses (last observation carried forward) were performed to account for withdrawals after day 1.
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Results |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Median durations of action, defined as 15% increases from test-day baseline values, are summarized in Table 5 . Median duration of action on the 4 test days ranged from 2.3 to 3.1 h for ipratropium bromide CFC, 42 µg; 2.0 to 2.8 h for ipratropium bromide HFA, 42 µg; and 1.6 to 4.1 h for ipratropium bromide HFA, 84 µg. Pairwise comparisons of ipratropium bromide CFC, 42 µg, vs ipratropium bromide HFA, 42 µg, and ipratropium bromide HFA, 84 µg, showed that differences between the groups were not statistically significant.
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Other Efficacy Variables
Adjusted mean physician’s global evaluation scores were between
4.8 to 5.4 for all treatment groups, which represent a rating of
"fair to good." The COPD symptom scores (wheezing, shortness of
breath, coughing, and tightness of chest) did not change over time and
did not differ among the placebo and active treatment groups. In
general, they were of mild severity. During any 2-week treatment
period, there was no difference in the percentage of patients who
reported using their study drug more often than four times daily
(range, 0 to 2% of patients).
On average, patients were using albuterol for rescue medication approximately two to three times per day. Patients in the placebo groups reported slightly higher use of albuterol. There was no difference in the use of albuterol in the active treatment groups.
Safety
Adverse events included any new or worsened condition without
respect to any possible relationship to study medication. In general,
the incidence of adverse events was similar across all treatment
groups. The most frequently occurring adverse events were COPD
exacerbations and upper respiratory tract infections. Adverse events
that were possibly drug related were reported in 6 patients (4.8%)
receiving ipratropium bromide HFA, 42 µg; 10 patients (7.9%)
receiving ipratropium bromide HFA, 84 µg; 8 patients (12.9%)
receiving HFA placebo; 17 patients (13.4%) receiving ipratropium
bromide CFC, 42 µg; and six patients (9.1%) receiving CFC placebo.
The most common adverse event that was judged possibly related to
therapy was headache, which was reported in up to 3.1% of patients in
different treatment groups. Six patients (1.2%) died during the study
period: one patient (1.6%) in the group receiving HFA placebo (cause
of death, pulmonary carcinoma); four patients (3.2%) in the group
receiving ipratropium bromide HFA, 42 µg (cause of death, COPD
exacerbation in two patients, pulmonary carcinoma in one patient, and
pancreatitis in one patient); and one patient (0.8%) in the group
receiving ipratropium bromide HFA, 84 µg (cause of death, pulmonary
carcinoma). None of the six deaths were reported to be related to the
study drug.
The most common adverse event leading to patient discontinuation was COPD exacerbation. This event was reported in two patients (1.6%) in the group receiving ipratropium bromide HFA, 42 µg; four patients (3.1%) in the group receiving ipratropium bromide HFA, 84 µg; two patients (3.2%) in the group receiving HFA placebo; seven patients (5.5%) in the group receiving ipratropium bromide CFC, 42 µg; and four patients (6.1%) in the group receiving CFC placebo. All adverse events occurring in > 3% of the patients are shown in Table 6 .
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Discussion |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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The formulation of ipratropium bromide using the alternative propellant HFA was an important first step as the general safety and tolerability of the propellant itself has been established.4 Nevertheless, the drug-device combination using this new formulation in clinical trials was needed to ensure, at a minimum, comparable safety and efficacy to the innovator CFC product. Such clinical testing is prudent, as the changes to the ultimate product involve an array of pharmaceutical considerations, ranging from suitable additives, suitable sealing elastomers, optimization of the actuator, and development or optimization of the manufacturing technique for mass production.17 As in vivo studies have indicated that the fine-particle dose of ipratropium bromide-containing HFA propellant is comparable to that of the CFC product, the clinical program had a reasonable basis for demonstrating comparability.
In this study, both formulations of ipratropium bromide provided superior bronchodilation compared to their respective placebo treatments, as would be expected. Importantly, the spirometric efficacy of the currently marketed 42-µg CFC aerosol was comparable to the HFA product, thus supporting a dose-for-dose switch between the two formulations. Such dose-for-dose comparability is consistent with other bronchodilators, including albuterol7 8 9 and the combination formulation of ipratropium bromide/fenoterol,18 as well as for the mediator-modifying compound cromolyn.19 This is in contrast to the formulation of beclomethasone for asthma, where significant reduction of particle size from the HFA formulation resulted in marketing of a reduced dose for comparable effects.20
In the current study, there was no significant difference observed between 42 µg and 84 µg of HFA ipratropium bromide, which is consistent with previous single-dose trials21 that found these two doses on the plateau of the dose-response curve. While there was a difference noted between 84-µg HFA and 42-µg CFC that was limited to the first test day, analysis of the 4 test days reveals an atypically small 42-µg CFC response on this initial test day. The difference in the first test day may have been a simple chance finding.
There was a small but statistically significant difference between placebo and active CFC formulation with regard to the use of albuterol as rescue medication. Placebo patients, on average, used slightly more albuterol during the study period. A possible explanation for a lack of a larger difference between active and placebo groups is that patients were not specifically instructed to try to decrease the use of rescue medication. Therefore, they continued to use albuterol as it was used prior to participation in the study.
The incidence of side effects that are common to the anticholinergic class was low and similar among different treatment groups. For example, dry mouth (4.8% and 2.4%) and taste perversion (0% and 0.8%) were in reported groups receiving ipratropium bromide HFA, 42 µg, and ipratropium bromide CFC, 42 µg, respectively.
In summary, the results of this study show that ipratropium bromide HFA, 42 µg, can provide both similar clinical benefit as the currently marketed ipratropium bromide CFC, 42 µg, formulation, and a comparable tolerability profile. This supports a smooth transition for patients with COPD when prescribed the new formulation of ipratropium bromide.
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Appendix 1 |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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Footnotes |
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This study was supported by a grant from Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT.
Dr. Ghafouri, Dr. Witek, and Ms. Fagan are employed by Boehringer Ingelheim Pharmaceuticals, Inc. Dr. Kurland is a former employee of Boehringer Ingelheim Pharmaceuticals, Inc.
Received for publication May 24, 2000. Accepted for publication May 1, 2001.
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References |
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TOPAbstractIntroductionMaterials and MethodsResultsDiscussionAppendix 1References |
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