Clinical Trial: Asthma Clinical Research Network (ACRN)


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Sponsored by:	National Heart, Lung, and Blood Institute (NHLBI)
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)

Condition	Treatment or Intervention	Phase
Asthma Lung Diseases	Drug: albuterol Drug: colchicine Drug: adrenal cortex hormones Drug: adrenergic-beta agonists	Phase III

Study Type: Interventional
Study Design: Treatment, Randomized, Double-Blind, Placebo Control, Parallel Assignment

BACKGROUND: Asthma is an increasingly serious cause of morbidity and mortality in the United States. There are approximately 12 million asthmatics and the disease affects both sexes and impacts all racial and ethnic groups. It is now recognized that asthma is a complex disease of varied etiology triggered by a number of factors such as allergens, drugs, chemicals, exercise, cold air, infections, and emotions, making asthma therapy difficult and sometimes complicated. Multiple drugs are often required, including medications to treat and control symptoms (bronchodilator agents such as beta-adrenergic agonists, theophylline, and anticholinergics), as well as drugs thought to control underlying airway inflammation (inhaled and systemic corticosteroids, cromolyn sodium, and nedocromil).

Despite major advances in understanding the etiology and pathophysiology of asthma and the development of new therapeutic modalities, the prevalence, severity, and mortality from asthma have increased over the past decade in all age groups. Mortality rates are disproportionately high in urban and rural minority populations. Hospitalizations for asthma have doubled in adults and increased five-fold for children over the past twenty years, and asthma continues to place a heavy burden on patients and their families, the health care system, and society as a whole. Therefore, new approaches are needed to help alleviate this growing problem.

A particularly important need at this juncture is a mechanism for the rapid evaluation of new and existing therapeutic approaches for asthma and for the dissemination of laboratory and clinical findings to the health care community. The Asthma Clinical Research Network program seeks to accomplish this through the development of a network of interactive asthma clinical groups that conduct clinical trials employing common protocols in a coordinated and multidisciplinary setting. This will ensure ready access to an adequate number of well characterized patients from diverse populations and age groups, and will bring together and coordinate the necessary clinical expertise and administrative resources to conduct multiple therapeutic trials. Centralized protocols will promote high quality design, decrease the variability in supportive modalities, and reduce the redundant utilization of resources required for rapidly conducting multiple independent clinical studies. The separate data coordinating center supports protocol and questionnaire development, sample size calculations, complete data analysis, and overall study coordination.

The initiative was developed by the Pulmonary Diseases Advisory Committee working group, approved by the full committee at the February 1992 meeting, and given concept clearance by the National Heart, Lung, and Blood Advisory Council in May 1992.

DESIGN NARRATIVE: The Beta-Agonist Protocol (Bags) compared the safety and efficacy of regular plus "as needed" use of inhaled albuterol versus the "as needed" use of inhaled albuterol in 255 patients with asthma of mild severity. A total of 230 patients completed the trial. The trial was randomized, double-blind, and placebo-controlled, with parallel groups. Following a six week single-blind run-in period, patients were randomized in a double-blind manner and treated for sixteen weeks. There was a four week withdrawal or run-out period. Changes in lung function and asthma symptoms were assessed to determine whether regular or as-needed beta-agonist use was more beneficial in the treatment of mild asthma. Specific outcome measures included A.M. peak flow, airway responsiveness, spirometric values, P.M.-A.M. peak flow difference index, asthma symptoms, quality of life measures, use of rescue medications, and episodes of adverse asthma control. Recruitment began in December, 1994. The trial has ended and results have been published.

The Colchicine in Moderate Asthma (CIMA) Protocol examined if colchicine offered therapeutic benefit in the managment of 71 patients with moderate asthma when corticosteroids were discontinued. The trial was randomized, double-blind, and placebo-controlled with two parallel groups. After a two week run-in with inhaled corticosteroid, there were two weeks with inhaled corticosteroid and colchicine or placebo and six weeks with no inhaled corticosteroid but with colchicine or placebo. There was a six week single-blind run-out. Outcome measures included treatment failure after cessation of inhaled corticosteroid, FEV1 change, P.M.-A.M. peak flow difference index, airway responsiveness, asthma symptoms, quality of life measures, use of rescue medications, and episodes of adverse asthma control. The protocol was approved in April, 1994. Recruitment ran from February, 1996 through August, 1996. Results have been published.

The Salmeterol or Corticosteroids (SOCS) was a randomized double blind study to determine the utility of treating patients with asthma of moderate severity with long-acting B-agonists in place of inhaled corticosteroids (ICS). A total of 164 patients were randomized into one of three treatment arms (double-blind, double-dummy): placebo, the inhaled corticosteroid triamcinolone alone, or the B-agonist salmeterol alone. Treatment continued for 16 weeks, followed by a 6-week run-out period in which all patients were placed on placebo. The purpose of the run-out period was to evaluate the effects of treatment cessation on asthma control. For comparing efficacy of therapy, the primary outcome variable was the change in AM peak expiratory flow (PEF) from the final week of the run-in period to the final week of the double-blind treatment period. For comparing the duration of benefit, the primary outcome variable again was AM PEF, with a comparison of the change from the final week of the run-in period to the second week and the final week of the run-out period. Secondary endpoints included other markers of asthma severity (FEV1, symptom diaries, B-agonist rescue, quality-of-life scores, methacholine responsiveness, and asthma exacerbations). To evaluate markers of inflammation, sputum induction was performed on all patients and bronchoalveolar lavage and bronchial biopsy on a subset of patients. Enrollment began in February, 1997 and ended in July, 1998. Results have been published.

Salmeterol+/- Corticosteroids (SLIC) protocol examined the addition of the long acting beta-agonist, salmeterol, on a scheduled basis to patients with moderate asthma whose symptoms were suboptimally controlled by using an inhaled beta-agonist on an "as needed" basis and an inhaled corticosteroid on a scheduled basis. The study determined if the addition of the long acting beta-agonist, salmeterol, on a scheduled basis permitted a reduction in dose, and/or elimination of, inhaled corticosteroids over time without a concomitant increase in asthmatic symptoms or a decrease in the bronchoprotective effect to aerosolized methacholine. Recruitment of randomized patients with moderate asthma began in January, 1997. Additional patients were randomized at the Harlem Center, a center added to the network in December, 1995. Enrollment of 175 patients ended in July, 1998 and last subject visits were completed in January, 1999. Results have been published.

The Dose of Inhaled Corticosteroids with Equisystemic Effects (DICE) protocol estimated dose-response curves with respect to adrenal suppression for six distinct inhaled corticosteroids. The inhaled steroids and delivery systems were characterized in terms of systemic effects so that doses which produced "equi-systemic" effects could be subsequently compared in future efficacy trials including the efficacy trial "Measuring Inhaled Corticosteroid Efficacy" (MICE). In DICE, a total of 156 ( 58%male, 31% minority) patients with mild to moderate asthma had a baseline visit and a placebo run-in period for subjects to practice taking scheduled doses (4 puffs twice a day) from a metered dose inhaler for one week. At visit 2, patients were randomized to placebo or to one of the six steroid arms including beclomethasone dipropionate metered dose inhaler (MDI), budesonide dry powder, flunisolide MDI, fluticasone propionate MDI, fluticasone propionate dry powder, triamcinolone acetonide MDI. The study addressed the following questions. Were there dose-response relationships in the suppression of overnight plasma cortisol with the various inhaled corticosteroids and delivery systems? If the dose-response relationships existed, at which doses were comparable systemic effects evident as determined by suppression of overnight plasma cortisol? If dose-response relationships existed, which dose produced a 10, 20, 30 or 40% suppression of adrenal steroid secretion (cortisol) for each inhaled steroid and delivery system? DICE was initiated in September, 1998 and completed in November, 1999. Results have been published.

The Measuring Inhaled Corticosteroid Efficacy (MICE) pilot study was approved by the Protocol Review Committee in August 1998. The MICE used doses of inhaled corticosteroid for the full MICE protocol as derived from DICE which induced minimal (highest deliverable dose that caused less than 5% cortisol suppression) cortisol suppression, 20-30% cortisol suppression, and 40-60% cortisol suppression. The intent was to determine if different inhaled corticosteroids which had equisystemic effects had differential salutary therapeutic effects in chronic asthma or if therapeutic efficacy paralleled systemic effects. MICE was a 24-week, randomized, open-label, prospective multicenter trial examining the effect of inhaled beclomethasone dipropionate (BDP) and fluticasone propionate (FP) both with Opti-Chamber spacer device. The inhaled corticsteroids were administered to 30 patients in doses of increasing systemic effect to examine the corresponding effects on pulmonary function, bronchial hyperresponsiveness, asthma control, and resolution of airways inflammation in subjects with persistent asthma. The intent was to confirm the estimates of systemic effect for BDP and FP, derived from the DICE pilot trial, where they were administered in one week intervals to that which occured when BDP and FP doses were administered over three - six week intervals with incremental doses. MICE also explored which efficacy/systemic relationships, if any, suggested that there may be a difference between the two prototype inhaled corticosteroids, BDP and FP. Recruitment was completed in the Spring of 2000. Results have been published.

The Beta Agonist Response by Genotype (BARGE) protocol was reviewed by the Protocol Review Committee in December 1998. Recruitment started in September, 1999. BARGE was a 54-week randomized, double-blind, crossover trial comparing the effects of regularly scheduled use of inhaled albuterol (2 puffs four times a day) to placebo, in two groups of 36 patients each, with mild to moderate asthma who differed by their genotype at the codon for the 16th amino acid of the B2-adrenergic receptor. A total of 36 patients harbored the B16-Arg/Arg genotype and the other 36 harbored the B16-Gly/Gly genotype at the B2-adrenergic receptor. Qualified patients entered a 6-week single-blind run-in period during which they were treated with an inhaled placebo, 2 puffs 4 times a day, and given inhaled ipratropium bromide for use as a rescue medication. Asthma control was characterized by AM peak flow, spirometric values, AM/PM peak flow variability index, asthma symptoms, quality of life, use of rescue medications, and occurrence of events of adverse asthma control. Baseline data were obtained on airway responsiveness, the protective effect of albuterol against methacholine-induced bronchoconstriction, the maximum bronchodilator effect of albuterol, and exhaled nitric oxide. Subjects were then randomized to a 16-week double-blind treatment phase in which they received either inhaled albuterol or placebo, two puffs 4 times a day. During this time, asthma control was monitored by the above indicators. At the end of the blinded treatment period, all subjects were returned to single-blind regular use of a placebo inhaler, 2 puffs 4 times a day, for an eight-week run-out period. The eight-week run-out period also served as the run-in period for the second stage of the study, following crossover to double-blinded treatment with albuterol or placebo. During this stage, asthma control was monitored by the same indicators as in the first stage. At the end of the second blinded treatment period, all subjects were returned to single-blind regular use of a placebo inhaler, 2 puffs 4 times a day, for an eight-week run-out period. During the entire study, participants used inhaled ipratropium bromide as rescue medication to avoid the confounding effects of B2-adrenergic stimulation on the outcome variables to be monitored. In the event that an episode of adverse asthma control responded incompletely to ipratropium, albuterol was used as a superseding rescue medication. Comparisons of asthma control within each genotypic group during periods of randomized treatment were assessed as the difference in the change in outcome variables between the end of Stage 1 randomized treatment versus end of Stage 1 run-in and between end of Stage 2 randomized treatment versus the end of Stage 1 run-out. The trial has ended and the manuscript is in preparation.

Improving Asthma Control Trial (IMPACT) is a double-blind, randomized, parallel group design clinical trial to determine the best long-term strategy for treating adults with mild asthma who experience symptoms more than occasionally. The trial will test whether these patients should be taking anti-inflammatory medications on a daily basis and whether a newer class of medications provides the same benefit as older drugs. In the IMPACT study, 234 adults with mild asthma who have more than occasional symptoms will be enrolled in six clinical research centers. Following an initial evaluation, patients will be randomized to receive either a twice daily inhaled corticosteroid, a twice daily anti-leukotriene, or a placebo. All patients will receive treatment for symptoms if and when they occur. The results should demonstrate whether medication is required on a daily basis by these patients, and if so, whether inhaled corticosteroids and leukotriene modifiers are equally effective. Recruitment ended in 2003. The trial is expected to be completed in 2003. In April 2001 the NHLBI initiated an ancillary study to IMPACT entitled "Modification of Allergic Immunologic Response by Leukotriene Antagonists" under R01HL67684. The ancillary study has its own site in this database.

The Smoking Modulates Outcomes of Glucocorticoid Therapy in Asthma (SMOG) trial was a randomized, double-blind, crossover trial which compared the effect of inhaled corticosteroid treatment delivered twice daily for eight weeks in two groups of subjects with persistent asthma: one group was comprised of smokers; the other group was comprised of non-smokers. Smokers and non-smokers were matched into pairs according to gender and FEV1 status prior to the run-in period. Each member of the matched pair was randomized together to the same crossover sequence. There were 96 subjects ages 18 to 35. The primary outcome was change in pre-bronchodilator FEV1 over the eight week treatment period in smokers compared with non-smokers. Secondary outcomes were morning and evening PEF, PC20 methacholine, and markers of inflammation in induced sputum. A secondary comparison examined the effect of eight weeks of treatment with a leukotriene receptor antagonist in asthmatics who smoked versus asthmatics who did not smoke. An additional analysis compared the response to inhaled corticosteroid with the response to leukotriene receptor antagonist.

The Salmeterol and Leukotriene Modifiers versus ICS Treatment (SLIMSIT) initiated recruitment in September, 2002. The goal was to randomize 180 subjects. SLiMSIT was a 36 week, double-blind, placebo-controlled, cross-over study with time to treatment failure as the primary endpoint. Prior to each double-blind treatment phase, subjects underwent a 4-week run-in period with combined inhaled beclomethasone HFA and the leukotriene receptor antagonist (LTRA) montelukast. This was followed by 14 weeks of double-blind treatment. During the initial 4-week run-in period, subjects who met National Asthma Education Program criteria for moderate persistent asthma received a controller regimen to obtain baseline information on symptoms, beta-agonist use, and PEF for use in defining treatment failure for each subject over the duration of the study. The final visit of this run-in period served as the baseline for comparison for the study variables measured during the initial treatment phase. At the end of the initial run-in, subjects with stable asthma symptoms were randomized to one of two treatment regimens used for 14 weeks: 1) daily oral placebo, twice daily inhalation of salmeterol 50 mg by DPI, and twice daily inhalation of beclomethasone HFA 80 mg by MDI; or 2) once daily oral montelukast 10 mg, twice daily inhalation of salmeterol 50 mg by DPI, and twice daily inhalation of placebo. Active beclomethasone HFA and the beclomethasone HFA placebo were given via a metered dose inhaler delivery device, while salmeterol was given by a dry powder inhaler (DPI) Diskusâ. A computer interface randomized subjects into the two treatment groups, stratifying by clinical center and FEV1 at the randomization visit (<80% versus ³80% of predicted FEV1). During the first treatment period, subjects made three visits to the clinic over 14 weeks. These visits included re-assessment of the study variables and careful monitoring for increasing asthma symptoms and potential treatment failure. Subsequently, subjects entered a second run-in period where they received single-blind treatment with inhaled beclomethasone HFA and oral montelukast as in the first run-in period. At the end of the second run-in period, subjects crossed over to the alternate treatment regimen for the second 14-week treatment phase, which included three visits to the clinic. These visits again included re-assessment of the study variables and careful monitoring for increasing asthma symptoms and potential treatment failure. The DSMB recommended termination of the study prior to target enrollment because sufficient data about the primary outcome had been obtained. The data are under analysis for subsequent publication.

Predicting Responses for Inhaled Corticosteroid Efficacy (PRICE) is a follow-up study which looks for additional predictive biomarkers of response to inhaled corticosteroids as well as evaluates whether short term response to inhaled corticosteroids predicts asthma control, exacerbation rate and correlates with elastic recoil and upstream resistance. The study will allow better understanding of asthma groups and establish a basis for inhaled corticosteroid treatment in persistent asthma patients. Recruitment started in June 2003 with an expected 80 subjects.

Genetics of Asthma in Latino Americans (GALA). In this study, two ACRN centers compared asthma-related clinical characteristics of 684 Mexican and Puerto Rican asthmatics recruited from San Francisco, New York City, Puerto Rico, and Mexico City. Results of the published study indicate that asthmatic Puerto Ricans had reduced lung function, greater morbidity, and longer asthma duration than asthmatic Mexicans.

The ACRN was renewed in September 2003 through July 2008. New protocols are under development. The Long Acting Beta Agonist Response by GEnotype (LARGE) is the first protocol of ACRN II. It is a 60 week randomized, double-blind, crossover trial to compare the effects of long acting beta agonists in patients with asthma receiving inhaled corticosteroids who express two distinct polymorphisms of the beta2-adrenergic receptor. The protocol is still under development.

Male and female patients with asthma.

Homer Boushey, University of California, San Francisco
William Calhoun, University of Pittsburgh at Pittsburgh
Mario Castro, Washington University School of Medicine
Vernon Chinchilli, Pennsylvania State University Medical Center
Vernon Chinchilli, Pennsylvania State Univ Hershey Medical Center
Elliot Israel, Brigham and Women's Hospital
Robert Lemanske, University of Wisconsin at Madison
Richard Martin, National Jewish Medical & Research Center
Stephen Peters, Wake Forest University
Stephen Wasserman, University of California at San Diego

King TS, Chinchilli VM and the Asthma Clinical Research Network:. Robust estimators of the concordance correlation coefficient. Joint Statistical Meetings, Page 50, August 2001.