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* From Allergy and Asthma Associates of Santa Clara Valley Research Center (Dr. Wolfe), San Jose, CA; North Carolina Clinical Research (Dr. LaForce), Raleigh, NC; Allergy, Asthma, Bronchitis and Immunology Associates (Dr. Friedman), Fountain Valley, CA; Health Research Institute (Dr. Sokol), Newport Beach, CA; Novartis Horsham Research Centre (Ms. Till and Dr. Della Cioppa), Horsham, UK; and Novartis Pharmaceuticals (Dr. van As), East Hanover, NJ.
Correspondence to: James Wolfe, MD, Allergy and Asthma Associates of Santa Clara Valley Research Center, 4050 Moorpark Ave, San Jose, CA 95117; e-mail: aaascv{at}asthmaresearch.com
Abstract
Study objectives: The primary objective was to determine whether high-dose formoterol, 24 µg bid, was associated with more asthma exacerbations compared with lower formoterol doses in patients with stable persistent asthma. Serious asthma exacerbations (life threatening or requiring hospitalization) were the primary end point. Secondary end points included significant exacerbations requiring systemic corticosteroids, all exacerbations, and changes in FEV1.
Design: In a multicenter, placebo-controlled, parallel-group study, patients were randomized to 16 weeks of treatment with formoterol, 24 µg bid; formoterol, 12 µg bid, with up to two additional 12-µg doses daily on demand for worsening symptoms (12 µg bid plus on demand); formoterol, 12 µg bid; or placebo. The formoterol 12-µg-bid plus on-demand regimen was administered open label, while the other three regimens were double blind.
Setting: Outpatient clinics.
Patients: A total of 2,085 patients aged 
12 years with stable, persistent asthma were enrolled and treated; 65% (n = 1,347) received regular concomitant antiinflammatory therapy during the study.
Measurements and results: Nine patients had respiratory-related serious adverse events (SAEs) requiring hospitalization: two patients (0.4%) in the 24-µg-bid group; one patient (0.2%) in the 12-µg-bid plus on-demand group; five patients (0.9%) in the 12-µg-bid group; and one patient (0.2%) in the placebo group. All of these events were asthma related, except for two SAEs in the 12-µg-bid group that were later considered not to be asthma related by independent reviewers who were not associated with the conduct of the study. The proportions of patients with significant asthma exacerbations (requiring systemic corticosteroids) were similar in the 24-µg-bid group (6.3%, 33 of 527 patients), 12-µg-bid group (5.9%, 31 of 527 patients) and placebo group (8.8%, 45 of 514 patients) and lower in the 12-µg-bid plus on-demand group (4.4%, 23 of 517 patients; p = 0.0057 vs placebo). All treatments were well tolerated. All formoterol treatment regimens had a significant effect on FEV1 measured 2 h after dose during the study (p < 0.0001 vs placebo); and on predose trough FEV1 measured at all visits after baseline (p < 0.002 vs placebo).
Conclusions: Treatment with formoterol, 24 µg bid, was not associated with an increase in serious asthma exacerbations compared with the lower formoterol doses or placebo.
Key Words: adverse events • Aerolizer • asthma • bronchodilation • exacerbations • formoterol • high dose
The use of inhaled corticosteroids (ICS) is recommended as a rational approach for the management of underlying airway inflammation that results in the many manifestations of asthma. This approach is often supplemented with short-acting, inhaled, ß2-agonist bronchodilators, which provide symptomatic relief. The introduction of long-acting ß2-agonists (LABAs; formoterol and salmeterol) has resulted in improved outcomes when they are used concurrently with ICS, compared with use of either monotherapy alone. Both LABAs are classified as controller medications for use in patients with persistent asthma and are usually recommended for use in conjunction with ICS.12
Formoterol and salmeterol have a similar duration of bronchodilation of at least 12 h, but formoterol has a fast onset of action of < 3 min, whereas salmeterol can take up to approximately 20 min to produce clinically relevant bronchodilation.345678 Formoterol has been available for > 10 years, originally as a pressurized metered-dose inhaler and subsequently as a dry powder inhaler (DPI), and has been shown to be well tolerated and effective in long-term studies.910 Formoterol was approved in Europe and worldwide in the mid-1990s; subsequently, a single-dose DPI (Foradil Aerolizer; Novartis Pharmaceuticals; East Hanover, NJ) was approved in 2001 by the US Food and Drug Administration (FDA) for use as maintenance treatment of asthma and COPD at a dose and schedule of 12 µg (one capsule) inhaled bid. Treatment with formoterol DPI has been shown to be effective and well tolerated in children and adults with asthma in studies up to 1 year in duration.1112131415
The safety of LABAs has been the focus of much recent discussion after a placebo-controlled study in approximately 26,000 patients revealed a small but significant increase in asthma-related deaths among patients receiving salmeterol.16 In the case of formoterol, concerns were raised about a possible link between the use of higher doses of this agent (24 µg bid via single-dose DPI) and an increase in serious asthma exacerbations, based on findings from two 12-week studies and a 1-year study.11121317 Using the frequency of the serious asthma exacerbations in these three studies, the present study in more than 2000 asthma patients was designed and powered to answer the latter question. We therefore evaluated the safety and efficacy of the 24-µg-bid dose (approved in most countries, but not in the United States) taken for 16 weeks in adolescents and adults with stable persistent asthma compared with the 12-µg-bid regimen (approved in the United States) and an open-label arm that allowed use of formoterol, 12 µg bid, with up to two additional 12-µg doses taken as needed (12 µg bid plus on demand) and placebo. The primary end point was the percentage of patients with serious asthma exacerbations.
Materials and Methods
Study Design
This was a 2,085-patient, multicenter, randomized, parallel-group, double-blind, placebo-controlled study with a 2-week run-in and a 16-week treatment period during which patients visited the clinic at 4-week intervals. At baseline, patients were evaluated for medical history, vital signs, physical examination, history of asthma treatment and asthma exacerbations, bronchodilator reversibility testing, and ECG. Blood and urine samples were collected for laboratory testing. At each visit, vital signs and physical examination were repeated and information was gathered on medication use, adverse events (AEs), and emergency department (ED) visits. FEV1 was measured at each visit before the administration of study drug or placebo, and 2 h after dose. Patients completed a questionnaire on their satisfaction with their asthma management prior to and at the end of the treatment period.
Inclusion/Exclusion Criteria
Male and female patients aged 12 years with persistent asthma were enrolled at 194 outpatient asthma clinics across the United States. Among the inclusion criteria were appropriate treatment for asthma according to management guidelines2; FEV1 40% of predicted normal following washout from inhaled bronchodilator treatment; and FEV1 reversibility 12% after inhalation of up to four puffs of albuterol (360 µg) at screening or documented within the past year.
Exclusion criteria included pregnancy, nursing, or child-bearing potential and absence of reliable contraception; clinically significant cardiovascular disease; malignancy; history of insulin-dependent diabetes mellitus; upper respiratory tract infection 1 month before and during the run-in period; a recent or > 10 pack-year smoking history; ED or hospital treatment for an acute asthma attack 1 month before or during the run-in; and any significant medical condition or laboratory profile that might compromise patient safety or adherence. Also excluded were any patients receiving parenteral, oral, or nebulized ß2-agonists in the 2 weeks before or during the run-in period; systemic corticosteroids, nedocromil, or ketotifen in the 1 month before run-in; astemizole or desensitization therapy initiated in the 3 months before run-in; antihistamines that could affect the QTc interval; nonpotassium-sparing diuretics; ß-blockers; quinidine-like agents; and tricyclic antidepressants, fluoxetine, or monoamine oxidase inhibitors. Fixed-combination LABAs and ICS were discontinued, and the same dose of the same ICS was prescribed as monotherapy, with stable treatment for at least 1 month before randomization.
Informed consent was obtained from all patients prior to any study procedures. The study was performed in accordance with the Helsinki Declaration of 1964 (amended 1975, 1983, 1989, 1996) and approved by the review boards of the participating centers.
Study Treatment
Eligible patients were randomized to one of four treatment groups: (1) formoterol, 24 µg bid, double blind; (2) open-label formoterol, 12 µg bid, with up to 2 additional 12-µg daily doses of formoterol as needed for worsening symptoms (12 µg bid plus on demand); (3) formoterol, 12 µg bid, double blind; or (4) placebo, double blind. Study medications were administered by inhalation from a single-dose DPI bid between 6 AM and 9 AM (morning dose) and 6 PM and 9 PM (evening dose). The extra (up to two daily) doses of formoterol in the 12-µg-bid plus on-demand study arm were also administered from the single-dose DPI. The capsules containing formoterol and placebo were identical in appearance. The planned duration of study treatment was 16 weeks.
Concomitant Medication
Patients in the three double-blind treatment groups were allowed rescue medication (albuterol pressurized metered-dose inhaler, 90 µg per actuation; up to eight puffs per day) for worsening symptoms. Patients in the formoterol 12-µg-bid plus on-demand group were allowed up to four puffs per day of albuterol as rescue medication, after receiving the two additional 12-µg daily doses of formoterol on demand. At each postrandomization visit, investigators recorded the number of rescue formoterol capsules inhaled since the last visit. The total formoterol intake was not to exceed 48 µg/d.
Antiinflammatory therapy with inhaled (and intranasal) corticosteroids, leukotriene antagonists, and inhaled cromolyn was recommended but not mandatory. The antiinflammatory regimen was kept stable for at least 3 weeks before randomization. Initiation of recommended antiinflammatory treatment described above was allowed at any time during the course of the study if deemed necessary by the investigator. Sustained-release theophylline was permitted with individual minor dose adjustments as necessary. Systemic corticosteroids or anticholinergic agents were allowed only to treat an intercurrent asthma exacerbation.
Study End Points
Serious Asthma Exacerbations:
This was the primary outcome variable of this study, and was the percentage of patients with defined (prior to unblinding the treatment codes) preferred terms in the Medical Dictionary of Regulatory Activities, as one or more of the following asthma-related AEs: chest discomfort, asthma, cough, wheezing, dyspnea, dyspnea exacerbated, status asthmaticus, respiratory distress, bronchospasm, acute respiratory failure, and hypoxia. In this context, "serious" signifies that the AE is fatal or life threatening, or requires or prolongs hospitalization.
Significant Asthma Exacerbations:
This was defined as asthma-related AEs (using preferred terms as above) that required oral or parenteral corticosteroid use but did not necessarily qualify to be defined as serious.
Combined Serious Asthma Exacerbations, Asthma-Related Discontinuations, and ED Visits for Asthma:
In order to increase the chance of detecting any safety signal, this variable combined the proportions of patients experiencing a serious asthma exacerbation or discontinuing the study prematurely due to an asthma-related AE, or having an asthma-related ED visit during the study.
All Asthma-Related AEs:
This variable included all asthma-related AEs (regardless of severity).
All AEs newly occurring or worsening in severity during treatment were assessed, and vital signs were monitored. It was planned to follow up all patients in this study for 16 weeks, including those who were discontinued prematurely for any reason.
Efficacy was a secondary objective of the study and was evaluated at clinic visits based on predose and 2-h postdose FEV1. Patients were asked to avoid taking rescue albuterol for the 8-h period prior to a visit and not to take rescue formoterol after the dose of the previous evening unless absolutely necessary, in order to avoid affecting FEV1 measurements at that visit. However, any such use of rescue medication was recorded in order to evaluate any differences between groups that could influence the FEV1 data by rescue treatment intervention.
The questionnaire assessing the patient’s satisfaction with their asthma management at the start and end of the treatment period assigned a value from 1 (lowest level) to 5 (highest level of satisfaction) in response to the question, "How do you rate your current asthma treatment and the way it helps you control your asthma?"
Statistical Analysis
The safety and intent-to-treat (ITT) populations comprised all randomized patients who received at least one dose of study medication. Additional subpopulations were defined based on regular use of antiinflammatory medication.
The number of patients having a serious asthma exacerbation, a significant exacerbation, any asthma-related AE, and premature discontinuations due to asthma were compared between treatment groups using Fisher’s exact test. The end points involving serious asthma exacerbations and premature discontinuations due to asthma were prospectively determined in the protocol; however, the corresponding inferential analyses were determined post hoc. In the original analysis plan, it was decided not to conduct inferential analyses on these end points because of the small number of qualifying events. Likewise, all the subgroup analyses based on antiinflammatory use were determined post hoc.
Additionally, the number of patients experiencing a serious asthma exacerbation or a premature discontinuation due to asthma or an ED visit due to asthma (combined end point) was analyzed in the same way. As these three qualifying features are not mutually exclusive, each event with multiple qualifying features was counted only once in the combined end point. This end point was defined and analyzed post hoc. No imputation of events was made for patients discontinuing early for any of these safety variables.
Predose and postdose FEV1 measurements were analyzed using an analysis of covariance model controlling for treatment, baseline FEV1, gender, and center. All FEV1 values were included regardless of rescue medication usage. Vital signs were analyzed using analysis of covariance similar to that used for FEV1. The patient satisfaction questionnaire was analyzed using the van Elteren test stratified by center. All treatment comparisons were made at the 5% significance level (two sided).
The trial was designed to detect a difference in the percentage of patients having a serious asthma exacerbation between the 24-µg-bid group and the 12-µg-bid group during the 16-week treatment period. Using a two-sided test, approximately 500 patients per group were required to give 80% power to detect a rate of serious asthma exacerbations of 4.5% in the formoterol 24-µg-bid group vs 1.5% in the formoterol 12-µg-bid group as being statistically significant at the 5% level. This trial design, including the assumed rates for serious exacerbations, was prospectively agreed on with the Pulmonary-Allergy Division of the FDA in response to a review of Foradil safety.
Results
Patients
A total of 2,085 patients were treated. Demographic and baseline characteristics of the ITT population were similar across the treatment groups (Table 1
), and asthma severity was comparable. Most patients demonstrated a stable history of asthma in the previous year: 20.4% (426 of 2,085 patients) had nonscheduled physician visits, 16.7% (349 of 2,085 patients) had exacerbations that were treated by oral corticosteroids, and 6.7% (140 of 2,085 patients) had ED visits for asthma. Hospitalizations were rare in the year before enrollment (1.5%; 32 of 2,085 patients).
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Safety Results
Serious Asthma Exacerbations:
Nine patients (< 1% in each treatment group) had serious respiratory-related adverse events, all needing hospitalization (Table 3
). Figure 1
shows the estimated differences between groups in the percentage of patients with these events. There were no statistically significant differences between the treatment groups (p > 0.21).
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Significant Asthma Exacerbations Requiring Systemic Corticosteroids:
The percentage of patients with significant asthma exacerbations, ie, requiring a course of oral or parenteral corticosteroid, were 6.3% (33 of 527 patients) in the formoterol 24-µg-bid group, 4.4% (23 of 517 patients) in the formoterol 12-µg-bid plus on-demand treatment group, 5.9% (31 of 527 patients) in the formoterol 12-µg-bid group, and 8.8% (45 of 514 patients) in the placebo group (Table 4
). The only statistically significant treatment contrast occurred between the formoterol 12-µg-bid plus on-demand group and placebo group (p = 0.0057). Among patients receiving regular antiinflammatory therapy (Table 4), the formoterol treatment groups had fewer patients with significant exacerbations (5 to 7%) compared with placebo (11%); this difference was statistically significant for the formoterol 12-µg-bid plus on-demand group compared with placebo (p = 0.0059). In patients without regular antiinflammatory therapy (Table 4), proportions of patients with significant exacerbations were similar in all the treatment groups (p > 0.46).
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All Asthma-Related AEs:
The proportion of patients with any asthma-related AEs was similar in the formoterol 24-µg-bid and 12-µg-bid groups and not significantly different from placebo (p > 0.38). Significantly fewer patients had asthma-related AEs in the formoterol 12-µg-bid plus on-demand group than in the placebo group (p = 0.0094) [Table 5
].
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The proportions of patients with asthma-related AEs leading to premature discontinuation were not statistically significantly different between any groups (p > 0.25) [Table 5]. When examining the asthma-related discontinuations in patients receiving antiinflammatory treatment, there were no significant differences between any groups (p > 0.14). Similar data, but with smaller differences, were obtained for patients not receiving antiinflammatory treatment (p > 0.42) [Table 5].
Other AEs
Overall AE rates are shown in Table 6
. Most were mild or moderate in severity. Overall, 9% of patients had AEs that were suspected as being related to study drug: 15% in the 24-µg-bid treatment group, and 6%, 8%, and 6% for formoterol 12-µg-bid plus on-demand group, formoterol 12-µg-bid group, and placebo, respectively. The higher rate in the 24-µg-bid group was primarily related to higher rates of tremor, "feeling jittery," and insomnia, which are typical for the ß2-agonist class.19 These were also the primary cause for the increased dropout rate among those patients who discontinued treatment because of an AE in the 24-µg-bid group (overall rate, 7.0% [37 of 527 patients], compared with 3.9% [20 of 517 patients] in the 12-µg-bid plus on-demand group, 3.8% [20 of 527 patients] in the 12-µg-bid group, and 4.1% [21 of 514 patients] in the placebo group). In the formoterol 24-µg-bid group, no case of tremor and only one report of insomnia were classified as severe.
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The frequency of serious AEs (SAEs) was low and similar across the treatment groups (1 to 2%). Two patients had SAEs that were suspected to be related to study medication. One patient in the 12-µg-bid group (the same patient mentioned previously) had a myocardial infarction and respiratory distress. One patient in the placebo group required hospitalization for an asthma exacerbation. In both cases, study medication was discontinued. There were no deaths during the study.
Vital Signs
There were no clinically meaningful differences between treatment groups in pulse rate and BP.
Patient Satisfaction Questionnaire
The scores showed that more patients in the active treatment groups believed their asthma control was improved during the study compared with placebo. At baseline, the number of patients recording scores of 4 or 5 (the two highest levels of satisfaction) was 57% (24 µg bid), 56% (12 µg bid plus on demand), 60% (12 µg bid), and 53% (placebo). At the final visit, this had increased to 73 to 76% for the formoterol groups and had remained similar for the placebo group (54%). Results were statistically significantly in favor of formoterol (all three groups; p < 0.0001) compared with placebo. The formoterol 12-µg-bid plus on-demand group (76%) and formoterol 12-µg-bid group (73%) were significantly different (p < 0.01).
Efficacy
All three formoterol treatment groups achieved statistically significant (p < 0.0001) and clinically relevant estimated treatment differences of 270 to 320 mL compared with placebo in FEV1 measured 2 h after dose after the first dose and after 16 weeks of treatment (Fig 2
). A significant treatment difference of 240 mL between formoterol treatment regimens and placebo was maintained at all study visits (p < 0.0001). Comparisons between the formoterol treatment groups (not shown in Fig 2) showed that there was a 50-mL statistically significant difference between the formoterol 24-µg-bid and 12-µg-bid groups (p = 0.0065) in favor of the higher dose for FEV1 measured after the first dose, but not at the end of 16 weeks of treatment.
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0.0012), with a consistent estimated treatment difference of approximately 100 mL. There were no clinically relevant or statistically significant differences between the three formoterol groups at any time point. During the 8-h period prior to the study visit at week 16 (when patients were asked to refrain from using rescue medication), rescue albuterol was used by 12.0% (55 of 458 patients) in the formoterol 24-µg-bid group, 9.7% (44 of 453 patients) in the formoterol 12-µg-bid plus on-demand group, 10.1% (46 of 457 patients) in the 12-µg-bid group, and 15.5% (68 of 438 patients) in the placebo group, which represents a decline in all groups of one to two percentage points from week 4. In the formoterol 12-µg-bid plus on-demand group, 62% (289 of 446 patients) used rescue formoterol at least once during the first 4 weeks of treatment, declining to 48.6% (209 of 430 patients) in the final 4 weeks.
Discussion
This study was carried out as a postapproval safety commitment to the FDA. The concern that prompted the study is summarized in an article by Mann and colleagues17 published in 2003. Mann and colleagues17 reviewed the three pivotal trials submitted to the FDA to support the approval of Foradil Aerolizer (Novartis Pharmaceuticals) in the United States, published individually elsewhere.111213 Each of these trials showed a somewhat higher incidence of asthma-related SAEs in patients treated with formoterol 24 µg bid compared with those receiving formoterol 12 µg bid and placebo. Only one of the studies12 also showed a small imbalance for the formoterol 12-µg-bid dose vs placebo. Mann and colleagues17 concluded that regular treatment with high-dose formoterol (24 µg bid) may be associated with more frequent serious asthma exacerbations compared with the lower dose of 12 µg that was approved in the United States. The primary objective of the present study was to test the hypothesis of a dose-related increase in serious asthma exacerbations. Data from other large studies conducted with formoterol Aerolizer did not reflect a higher incidence of asthma-related SAEs in patients treated with formoterol 24 µg bid compared with those receiving formoterol 12 µg bid and placebo.20
Another large safety study that raised a related concern, although more specific to mortality, is the Salmeterol Multicenter Asthma Research Trial (SMART), in which the long-acting ß2-agonist salmeterol was compared to placebo. This study, involving > 26,000 patients, was prematurely halted after interim findings suggested patients treated with salmeterol were at higher risk of asthma-related deaths and "near-death" experiences (intubation and mechanical ventilation) compared with those receiving placebo. The SMART study is published in this issue.16
No deaths occurred in the present study. There were very few serious asthma-related exacerbations, far fewer than expected in the planning of the sample size based on previous data. Additionally, the results do not confirm the previous observation of a dose-dependent increase in serious asthma exacerbations. The primary end point of the study, serious asthma exacerbations, was no different from placebo in all three formoterol treatment arms, and the overall incidence was < 1%.
An accepted and clinically meaningful category of asthma exacerbations is represented by those patients requiring a course of systemic corticosteroids (referred to as a significant asthma exacerbation in the present study). There were fewer significant asthma exacerbations in the formoterol groups than in the placebo group, although statistical significance was only reached in the contrast between the open-label formoterol 12-µg-bid plus on-demand group and placebo (Table 4).
By combining serious asthma exacerbations and/or premature discontinuations due to asthma and/or ED visits due to asthma as a post-hoc analysis, a larger number of events becomes available for analysis and makes the chance of detecting a safety signal more meaningful. This analysis showed a very similar rate across the three formoterol dose levels and placebo. While this study was not designed to compare patients receiving antiinflammatory medications or not, for the combined end point we observed a slightly higher frequency of events in patients not receiving concomitant antiinflammatory medications than in those receiving them. Therefore, in keeping with currently accepted guidelines, it is recommended that LABAs be used in conjunction with an appropriate antiinflammatory agent.
The present study was designed with safety as the primary outcome, while efficacy (FEV1) was a secondary outcome. As expected, relative to placebo, each of the three formoterol treatment regimens had a significant effect on lung function measured before the morning dose of study treatment and measured 2 h after dose. The measurements of patient satisfaction with their asthma management favored the active treatment groups and were consistent with the improvements in FEV1, indicating that formoterol use was associated with improved asthma control. This improved control is also reflected in the lower frequency of asthma-related events in the formoterol treatment groups compared with placebo (Tables 4, 5). This difference reached statistical significance in the open-label formoterol 12-µg-bid plus on-demand group as compared with placebo. This suggests that, with the exception of serious asthma exacerbations, the less serious events can be better controlled with the on-demand use of formoterol together with regular use than with albuterol on demand. This was the only open-label treatment arm of the study, and these results should be interpreted with caution.
Although the frequency of serious asthma AEs was smaller than anticipated, this study does not suggest an increased rate of clinically serious exacerbations in formoterol-treated patients, either dose related or overall. This conclusion is further supported by the fact that there was no difference in the frequency of significant asthma exacerbations requiring oral steroids or an increase in frequency of all asthma-related events combined compared with placebo.
Appendix
The principal investigators and site locations were as follows: Dr. Francisco Candal, Northshore Research, Slidell, LA; Dr. Stephen Kreitzer, Tampa Medical Research Associates, Tampa, FL; Dr. Sherwin Gillman, Division of Allergy, Asthma & Immunology, Orange, CA; Dr. Catherine Van Kerckhove, Catherine Kolehmainen, Littleton, CO; Dr. Lawrence J. Sindel, Pulmonary Associates, P.C., Mobile, AL; Dr. Ken Cohen, New West Physicians Clinical Research, Golden, CO; Dr. Robert Nathan, Asthma and Allergy Associates, PC, Colorado Springs, CO; Dr. Kenneth Kim, West Coast Clinical Trials, Long Beach, CA; Dr. Paul Qaqundah, Pediatric Care Medical Group, Huntington Beach, CA; Dr. Stephen Tilles, A.S.T.H.M.A., Inc., Seattle, WA; Dr. Anthony DeMeo, Diablo Clinical Research, Inc., Walnut Creek, CA; Dr. Tonny Tanus, Lotus Medical Center of Allergy Asthma, Bakersfield, CA; Dr. Jacob Pinnas, Arizona Clinical Studies, Tucson, AZ; Dr. Amy Silverthorn, Arizona Pulmonary Specialists, Phoenix, AZ; Dr. Robert Kearl, Arizona Pulmonary Specialists, Phoenix, AZ; Dr. Henry Gong, USC Rancho Los Amigos Medical Center, Downey, CA; Dr. Cash Beechler, Arizona Pulmonary Specialists, LTD, Scottsdale, AZ; Dr. Leonard Caputo, The Asthma and Allergy Institute, Mobile, AL; Dr. Andrew Davidson, Allergy & Asthma Consultants, LLP, Charleston, SC; Dr. Marc Gottlieb, Diagnostic and Medical Clinic, PA, Mobile, AL; Dr. Pragnesh Patel, Allergy and Asthma Specialists, Altamonte Springs, FL; Dr. Andrew Martin, Asthma & Allergy Clinical Research Center, New Brunswick, NJ; Dr. Bernard Levine, Pulmonary Associates, PA, Phoenix, AZ; Dr. Michael Manning, Allergy and Immunology Association, Scottsdale, AZ; Dr. Nancy Ostrom, Asthma & Allergy Medical Group & Research Center, San Diego, CA; Dr. Sammy Campbell, VA Hospital, Pulmonary/1–111A, Tucson, AZ; Dr. Maurice Archuleta, Rocky Mountain Clinical Research, Golden, CO; Dr. Linda Ford; The Asthma and Allergy Center, PC, Papillion, NE; Dr. Thomas Kaelin, Low Country Lung and Critical Care, PA, Charleston, SC; Dr. Albert Finn, Radiant Research, Charleston-North Charleston, SC; Dr. Graham Scott, Charleston Pulmonary Associates, Charleston, SC; Dr. J. Allen Meadows; Drud Research and Analysis Corporation, Montgomery, AL; Dr. Jim Christensen, Nevada Access to Research & Education Society, Las Vegas, NV; Dr. Andrew Grant, UTMB, Galveston, TX; Dr. Warren Pleskow, Radiant Research, San Diego North, Encinitas, CA; Dr. John Lafata, Progressive Clinical Research, Vista, CA; Dr. David Laman, Consolidated Clinical Trials, Inc., Pittsburgh, PA; Dr. William Calhoun, UPMC, Pittsburgh, PA; Dr. Karl Sitz, Little Rock Allergy & Asthma Clinic, PA, Little Rock, AR; Dr. Manuel Lopez, Tulane University Health Sciences Center, New Orleans, LA; Dr. Maria Franco, Miami Children’s Hospital, Miami, FL; Dr. F. Charles Hiller, University of Arkansas for Medical Sciences, Little Rock, AR; Dr. Louis Kalish, Rx Research, Woodstock, GA; Dr. Dean Atkinson, Oklahoma Allergy & Asthma Clinic, Oklahoma City, OK; Dr. Kevin Kelly, Medical College of Wisconsin Asthma & Allergy Center, Milwaukee, WI; Dr. Edward Lisberg, Asthma & Allergy Center of Chicago, River Forest, IL; Dr. Mercedes Samson; B.P. Center Clinical Trials, Inc., Buena Park, CA; Dr. M. Ross Thomas, Midwest Allergy & Asthma Clinic Omaha, NE, Dr. James Baker; Allergy Associates Medical Center, Portland, OR; Dr. Keith Klatt, Radiant Research, Portland, OR; Dr. Richard Gower, Rockwood Clinic, PS, Spokane, WA; Dr. Paul Scheinberg, Atlanta Pulmonary Group, Atlanta, GA; Dr. David Graft, Park Nicollet Institute, Asthma & Allergy Research Center, Minneapolis, MN; Dr. James Cury, Shands Jacksonville Medical Center, Jacksonville, FL; Dr. Alan Aven, Arlington Heights, IL; Dr. Michael Rowe, Michigan Asthma & Allergy Center, Novi, MI; Dr. Peter Schochet, Presbyterian Hospital of Plano, Plano, TX; Dr. Jeffrey Leflein, Respiratory Medicine Research Institute, Ypsilanti, MI; Dr. Gregory Gottschlich, New Horizons Clinical Research, Cincinnati, OH; Dr. Jeff Craig, Sterling Research Group, LTD, Cincinnati, OH; Dr. Phillip Korenblat, The Clinical Research Center, LLc, St. Louis, MO; Dr. J. Allen Cooper, Birmingham VA Medical Center, Birmingham, AL; Dr. Robert Settipine, Allergy and Asthma Center, Providence, RI; Dr. Scott Yates, North Texas Medical Research, The Colony, TX; Dr. Brian Carlin, Consolidated Clinical Trials, Inc., Pittsburgh, PA; Dr. John Yarbrough, Allergy & Asthma Clinic of Northeast Georgia, Gainesville, GA; Dr. Robin Levy, Family Allergy and Asthma Center, Atlanta, GA; Dr. Randy S. Stoloff, Empire State Asthma & Allergy Treatment & Research Center, Plattsburgh, NY; Dr. Arthur DeGraff, Physician’s Research Center, Inc., Hartford, CT; Dr. Hugh Windom, Asthma & Allergy Research Center, Sarasota, FL; Dr. Carolyn Comer, Alabama Allergy & Asthma Center, Birmingham, AL; Dr. Jonathan Bernstein, Berstein Clinical Research Center, Cincinnati, OH; Dr. Paul Chervinsky, New England Research Center, North Dartmouth, MA; Dr. Suzanne Weakley, Clinical Trials, North Houston, Houston, TX; Dr. Lyndon Mansfield, El Paso Institute for Medical R&D, El Paso, TX; Dr. Jacques Caldwell, Radiant Research, Daytona Beach, FL; Dr. Michael Lawrence, Center for Clinical Research, Taunton, MA; Dr. Juan Sotomayer, Allergy and Asthma Diagnostic Office, Liverpool, NY; Dr. John J. Condemi, Allergy, Asthma & Immunology of Rochester Research Center, Rochester, NY; Dr. Howard Knapp, Deaconess Research Division, Billings, MT; Dr. David Valacer, New York Presbyterian-Cornell Weil, New York, NY; Dr. Janet Despot, Cardinal Respiratory, PC, Springfield, IL; Dr. Harmon Davis, IMG Clinical Research Center, LLC, Cheyenne, WY; Dr. A.M. Aminian, Allergy Institute Fresno, CA; Dr. Christopher Smith, Asthma and Allergy Associates, Ithaca, NY; Dr. Wilfred Beaucher, Certified Research Consultants, Chelmsford, MA; Dr. Azmi Farag, Mountain View Clinical Research, Denver, CO; Dr. Judith Kirstein, Jordan Valley Family Clinic, West Jordan, UT; Dr. Pardeep Rihal, Christus St. Catherines, Katy, TX; Dr. Thomas Ellis, Medical Specialty Clinic, Jackson, TN; Dr. Anthony Rooklin, Allergy Research Associates, Upland, PA; Dr. Alexander Shepherd, University of Texas Health Science Center at San Antonio, San Antonio, TX; Dr. Kim Jones, Louisianna State University Health Sciences Center, Shreveport, LA; Dr. Narinder Arora, Charlottsville Medical Research, Charlottsville, VA; Dr. Leslie Couch, University of Texas Health Center at Tyler, Tyler, TX; Dr. Jeffrey Wald, Kansas City Allergy and Asthma Associates, Overland Park, KS; Dr. Curtis Mello, JM Clinical Trials, Inc., Swansea, MA; Dr. Bruce Pfuetze, Multi-Specialty Clinical Research, College Park Family Care Center, Overland Park, KS; Dr. Matthew Beacom, Dr. Thomas A. McKnight, Fremont, NE; Dr. Harold Kaiser; Clinical Research Institute, Minneapolis, MN; Dr. John Cohn, Asthma Allergy & Pulmonary Associates, PC, Philadelphia, PA; Dr. Dennis Doherty, University of Kentucky Medical Center, Lexington, KY; Dr. Timothy Craig, Penn State Hershey Medical Center, Hershey, PA; Dr. Christopher Vanderneck, Meridian Clinical Research, Omaha, NE; Dr. Rebecca Gruchella, Utah Southwestern Medical School, Dallas, TX; Dr. Alan Reichman, Reichman & Associates, Sugarland, TX; Dr. Milan Slijvich; Allergy Clinic of Garland PA, Garland, TX; Dr. Michael Ruff, Pharmaceutical Research & Consulting, Inc, Dallas, TX; Dr. Mary Strek, University of Chicago, Chicago, IL; Dr. Peter Constantini, Atlantic Research Associates, Margate, NJ; Dr. Kathy Lampl, Asthma and Allergy Associates, Rockville, MD; Dr. Michael Spandorfer; Pulmonary & Critical Care Medicine, Charleston, SC; Dr. Robert Townley, Creighton University Center for Allergy, Asthma & Immunology, Omaha, NE; Dr. Rohit Patel, Pinnacle Research Group, LLC, Anniston, AL; Dr. Douglas Schumacher, Radiant Research Columbus, OH; Dr. Lawrence Gelber, Commonwealth Clinical Research Specialists, Richmond, VA; Dr. Donald Brandon, California Research Foundation, San Diego, CA; Dr. Robert Lapidus, Rocky Mountain Center for Clinical Research, Wheat Ridge, CO; Dr. David Schneider, Rx R&D, Metairie, LA; Dr. Bruce Prenner, Allergy Associates Medical Group, San Diego, CA; Dr. Steven Radwany, Akron Internists Research Foundation, Akron, OH; Dr. Robert Webb, Allergy and Asthma Research Associates, Kirkland, WA; Dr. Naomi Fieman, Mountain View Clinical Research, Denver, CO; Dr. Carlos deLaGarza, Unifour Medical Research, Hickory, NC; Dr. Meenashki Patel, Valley Medical Center, Centerville, OH; Dr. Edward Kent, Timber Lane Allergy and Asthma Research LLC, South Burlington, VT; Dr. Raul Laguarda, Charles River Medical Associates, Natick, MA; Dr. Eliot Dunsky, Philadelphia, PA; Dr. Irwin Spirn, Delaware Valley Clinical Research, Cherry Hill, NJ; Dr. Eugene Fletcher, University of Louisville, Louisville, KY; Dr. Imran Khawaja, Robin Ashford, Huntington, WV; Dr. Don McNeil; Optimed Research, LLC, Columbus, OH; Dr. Jonathan Matz, Atlantic Asthma and Allergy Center, Baltimore, MD; Dr. William Rees, PI-Coor Clinical Research, Burke, VA; Dr. Sooji Lee-Rugh, Millenium Clinical Research, LLC, Arlington, VA; Dr. Marcus Zervos, William Beaumont Hospital Royal Oak, MI; Dr. Patricia Buchanan, River Road Medical Group, Willamette Valley Clinical Studies, Eugene, OR; Dr. Tracy Green, Family Health Center, Sparks, NV; Dr. Jonathan Ilowite, Winthrop University Hospital Pulmonary Associates, Mineola, NY; Dr. John Behm, Northern Area Family Medicine, Pittsburgh, PA; Dr. Ronald H. Saff, Allergy & Asthma Diagnostic Treatment Center, Tallahassee, FL; Dr. David Brown, Mountain Allergy & Asthma, Asheville, NC; Dr. Jean-Claude Labissiere, Essex Medical Associates, Orange, NJ; Dr. Arnold Funkes, Alta Clinical Research, LLC, Tucson, AZ; Dr. William Massey, Pulmonary Associates of the Southeast, PC, Birmingham, AL; Dr. Frederick Kahn, Montana Health Research, Billings, MT; Dr. Alan Heller, San Jose Clinical Research, San Jose, CA; Dr. Richard Castaldo, Private Practice, Tonowanda, NY; Dr. Russell Leftwich, Nashville Asthma & Allergy, Nashville, TN; Dr. Selwyn Spangenthal, Charlotte Lung and Health, Charlotte, NC; Dr. Angelo Sparagna, Atlantic Research Associates, Margate, NJ; Dr. Jeffrey Glassheim, Fresno, CA; Dr. Michael Brown, Crescent Clinical Research, Inc., Pensacola, FL; Dr. Lauro Roberto, Children’s Hospital Central California, Madera, CA; Dr. David Gross; Ntouch Research, Washington, DC; Dr. Richard White, University of California Davis, General Medicine Investigative Clinic, Sacramento, CA; Dr. George Bensch, Bensch Clinical Research Associates; Stockton, CA; Dr. Richard Weiss, Medical Research Unlimited, Hialeah, FL; Dr. Matthew Hegewald, Bend Memorial Clinic, Bend, OR; Dr. Andres Redondo, CliniTrials, Miami, FL; Dr. David Hugh Frazer, Drug Research and Analysis Corporation, Montgomery, AL; Dr. Joel Porter; IHC Health Center, Layton, UT; Dr. Thomas M. Hyers, CAR.E. Clinical Research, St. Louis, MO; Dr. Jatin J. Kadakia, Access Clinical Trials, Inc., Clarksville, TN; Dr. Jon K. Van Valkenburg, Medford Medical Clinic, Medford, OR; Dr. Alan Nolasco, MediClinic, Houston, TX; Dr. Shull Lemire, Northwest Physicians Research Network, Inc., Missoula, MT; Dr. Ricardo Tan, California Allergy & Asthma Medical Group, Palmdale, CA; Dr. James McFeely, Berkeley Pulmonary Medical Group, Berkeley, CA; Dr. David G. Hill, Waterbury Pulmonary Associates, Waterbury, CT; Dr. Richard Mangi, Allergy, Arthritis and Infectious Disease Associates, Hamden, CT; Dr. Bobby Lanier; North Texas Institute for Clinical Trials; Fort Worth, TX; Dr. David Bouda, Heartland Clinical Research, Inc., Omaha, NE; Dr. John. Murray, ASAP Research, Nashville, TN; Dr. Bharat Latthe, North Belt East Medical Clinic, PA, Houston, TX; Dr. Reynold Karr, Physicians Pharmaceutical Study Services, Everett, WA; Dr. Constantine Saadeh, Amarillo Center for Clinical Research, Ltd.; Amarillo, TX; Dr. Kevin Schaffer, Allergy & Asthma Clinical Research Center, LLC, Lawrenceville, GA; Dr. Jonathan Corren, Allergy Research Foundation, Los Angeles, CA; Dr. Susheela Bala, Allergy & Asthma Clinic, San Bernardino, CA; Dr. Gregory Lux, St John’s Medical Research, Springfield, MO; Dr. Stephen Pollard, Family Asthma & Allergy Research Institute, Louisville, KY; Dr. Kajori Thusu, Universal Biopharma Research Inc., Dinuba, CA; Dr. Ashok Patel, Academy Allergy, Asthma & Immunology, Pueblo, CO; Dr. Alan Bakst, Medical Specialists of Palm Beaches, Inc., Boynton Beach, FL; Dr. David Cardona, Universal Biopharma Research Inc., Fresno, CA; Dr. Shams Iqbal, Asthma & Allergy Group, Riverside, CA; Dr. Jimmie Tarro, Allergy Asthma & Dermatology Research Center, LLC, Lake Oswego, OR; Dr. Eugene Bleecker, Cloverdale Research Facility, Winston Salem, NC; Dr. John Oppenheimer, Pulmonary & Allergy Associates, Springfield, NJ; Dr. John F. Pinto, Clinical Research Center of Nevada, Las Vegas, NV; Dr. June Hawkins, Asthma Allergy Center, Tigard, OR; Dr. Jan Westerman, Private Practice, Jasper, AL; Dr. A. Lynne Brannen, University Medical Associates, LLP, Augusta, GA; Dr. James Good, South Denver Pulmonary Associates, PC, Englewood, CO; Dr. Stephen H. Kimura, MED3000 Clinical Solutions Inc., Pensacola, FL; Dr. Pinkus Goldberg; Clinical Research Center of Indiana, Indianapolis, IN; Dr. Robert Gao, Advanced Practice Clinical Research, Las Vegas, NV; Dr. Vicente Chavarria, Lovelace Scientific Resources; Miami, FL; Dr. Rachakonda Prabhu, Redrock Research Center, Las Vegas, NV; Dr. Terence T. Hart, Muscle Shoals, AL; Dr. Robert Webb, Yakima Chest Clinic PC, Yakima, WA; Dr. Dennis K. Ledford, University of South Florida Asthma, Allergy, Immunology, Tampa, FL; Dr. Jay K. Udani, Pacific West Research Corporation, Northridge, CA; Dr. Gary A. Cohen, Allergy and Asthma Prevention and Treatment Center, San Diego, CA; Dr. Allen Segal, Allergy Associates Research, Dallas, TX; Dr. Phillip Korenblat; The Clinical Research Center, LLC, St. Louis, MO; Dr. Aftab Naz, Madera Family Medical Group, Madera, CA; Dr. Elizabeth Gallup, Radiant Research, Overland Park, KS; Dr. Leon Greos, Colorado Allergy & Asthma Centers, PC, Englewood, CO; Dr. David Pearlman, Colorado Allergy and Asthma Centers, P.C., Denver, CO; Dr. Thomas Littlejohn, Piedmont Medical Research Associates, Winston Salem, NC; Dr. Edward Peters; Radiant Research, Austin, TX; Dr. Steven Weinstein, Allergy and Asthma Specialists Medical Group and Research Center, Huntington Beach, CA; Dr. Edward LeDoux, Pulmonary Consultants, PLLC, Tacoma, WA; Dr. Edward Kent, Timber Lane Allergy & Asthma, South Burlington, VT; Dr. Grant Olson, Colorado Allergy & Asthma Centers, PC, Lakewood, CO; Dr. Nathan Schultz, Allergy & Asthma Medical Group, Walnut Creek, CA; Dr. Stephen C. Ulrich, Pharmacotherapy Research Associates, Inc., Zanesville, OH; Dr. Andrew Pedinoff, Princeton Center for Clinical Research, Princeton, NJ; Dr. Harold Nelson, National Jewish Medical and Research Center, Denver, CO; Dr. Robert Berkowitz, Rx Research, Woodstock, GA; Dr. Jonathan Bernstein, Bernstein Clinical Research Center, LLC, Cincinnati, OH; Dr. Anjuli Nayak and Dr. Nicholas Nayak, Sneeze, Wheeze & Itch Associates, LLC, Normal, IL; Dr. Linda Ford, The Asthma and Allergy Center, Papillion, NE; Dr. David Levin, VAMC, Oklahoma City, OK; and Dr. Michael Blumberg, VA Adult & Pediatric Allergy & Asthma, Richmond, VA.
Acknowledgements
We extend special thanks to the investigators and staff at the study sites. We thank Jackie Thirlwell for statistical input and Sarah Filcek for her help in preparing the manuscript. Thanks are also due to Chad Orevillo, Barbara Ziehmer, and Stephan Stenglein of Novartis Clinical Research.
Footnotes
Abbreviations: AE = adverse event; CI = confidence interval; DPI = dry powder inhaler; ED = emergency department; FDA = Food and Drug Administration; ICS = inhaled corticosteroids; ITT = intent to treat; LABA = long-acting ß2-agonist; SAE = serious adverse event
Ms. Till has a declared conflict of financial interest in that she is an employee of Novartis and owns Novartis shares.
Dr. Della Cioppa has a declared conflict of financial interest in that he is an employee of Novartis and owns Novartis shares.
Dr. van As has a declared conflict of financial interest in that he was an employee of Novartis and owns Novartis shares.
This study was supported by Novartis Pharmaceuticals.
Received for publication March 18, 2005. Accepted for publication November 3, 2005.
References
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