Asthma Clinical Research Network (ACRN)
Asthma Clinical Research Network (ACRN)
This study will establish a network of interactive asthma clinical research groups to
 evaluate current therapies, new therapies, and management strategies for adult asthma.
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, which is triggered by a number of factors (e.g., allergens, drugs, chemicals,
 exercise, cold air, infections, and emotions), making asthma therapy difficult and sometimes
 complicated. Multiple drugs, including medications to treat and control symptoms
 (bronchodilator agents such as beta-adrenergic agonists, theophylline, and anticholinergics)
 and medications thought to control underlying airway inflammation (e.g., inhaled and systemic
 corticosteroids, cromolyn sodium, and nedocromil), are often required.

 Despite major advances in the understanding of the etiology and pathophysiology of asthma and
 the development of new therapeutic modalities, the prevalence, severity, and mortality from
 asthma in all age groups have increased over the past decade. 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 20 years. 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 (ACRN)
 program seeks to accomplish this through the development of a network of interactive asthma
 clinical groups that conduct clinical studies 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. It will also bring together
 and coordinate the necessary clinical expertise and administrative resources to conduct
 multiple therapeutic studies. 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 Institute (NHLBI) Advisory Council in May 1992.

 DESIGN NARRATIVE:

 The Beta-Agonist (Bags) study compared the safety and efficacy of regular plus "as needed"
 use of inhaled albuterol to the "as needed" use of inhaled albuterol in 255 patients with
 asthma of mild severity. A total of 230 patients completed the study. The study was
 randomized, double-blind, and placebo-controlled with parallel groups. Following a 6-week
 single-blind run-in period, patients were randomized in a double-blind manner and treated for
 16 weeks. There was a 4-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
 morning (AM) PEF, airway responsiveness, spirometric values, evening (PM) to AM PEF
 difference index, asthma symptoms, quality of life measures, use of rescue medications, and
 episodes of adverse asthma control. Recruitment began in December 1994. The study has
 completed and results have been published.

 The Colchicine in Moderate Asthma (CIMA) study examined if colchicine offered therapeutic
 benefit in the management of 71 patients with moderate asthma when corticosteroids were
 discontinued. The study was randomized, double-blind, and placebo-controlled with two
 parallel groups. A 2-week run-in with inhaled corticosteroid was followed by 2 weeks with
 inhaled corticosteroid and colchicine or placebo, and then by 6 weeks with no inhaled
 corticosteroid but with colchicine or placebo. There was a 6-week single-blind run-out.
 Outcome measures included treatment failure after cessation of inhaled corticosteroid, FEV1
 change, PM to AM PEF 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) study was a randomized, double-blind study to
 determine the utility of treating patients with moderately severe asthma with long-acting
 beta-agonists in place of inhaled corticosteroids (ICS). A total of 164 patients were
 randomized into one of the following three treatment arms (double-blind and double-dummy): 1)
 placebo; 2) inhaled corticosteroid triamcinolone alone; or 3) beta-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. To compare efficacy of therapy, the primary outcome
 variable was the change in AM PEF from the final week of the run-in period to the final week
 of the double-blind treatment period. To compare duration benefit, the primary outcome
 variable was again AM PEF, with a comparison of the change from the final week of the run-in
 period to the second and final weeks of the run-out period. Secondary endpoints included
 other markers of asthma severity (e.g., FEV1, symptom diaries, beta-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 were performed on a subset of patients. Enrollment began in
 February 1997 and ended in July 1998. Results have been published.

 The Salmeterol± Corticosteroids (SLIC) study examined the addition of a long acting
 beta-agonist, salmeterol, on a scheduled basis for patients with moderate asthma whose
 symptoms were sub-optimally 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 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. The
 enrollment of 175 patients ended in July 1998 and the last patient visits were completed in
 January 1999. Results have been published.

 The Dose of Inhaled Corticosteroids with Equisystemic Effects (DICE) study 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 that produced "equi-systemic" effects could be subsequently
 compared in future efficacy studies, including the efficacy study "Measuring Inhaled
 Corticosteroid Efficacy" (MICE). In DICE, a total of 156 (58% male and 31% minority) patients
 with mild to moderate asthma had a baseline visit and a placebo run-in period to practice
 taking scheduled doses (4 puffs twice a day) from a metered dose inhaler for 1 week. At the
 second visit, patients were randomized to placebo or to one of the following six steroid
 arms, including: 1) beclomethasone dipropionate metered dose inhaler (MDI); 2) budesonide dry
 powder; 3) flunisolide MDI; 4) fluticasone propionate MDI; 5) fluticasone propionate dry
 powder; or 6) triamcinolone acetonide MDI. The study addressed the following questions: 1)
 Were there dose-response relationships in the suppression of overnight plasma cortisol with
 the various inhaled corticosteroids and delivery systems?; 2) If the dose-response
 relationships existed, at which doses were comparable systemic effects evident as determined
 by suppression of overnight plasma cortisol?; and 3) 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. MICE used doses of inhaled corticosteroid for the full MICE
 protocol as derived from DICE, which induced minimal cortisol suppression (highest
 deliverable dose that caused less than 5% cortisol suppression), 20% to 30% cortisol
 suppression, and 40% to 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, multi-center study
 examining the effect of inhaled beclomethasone dipropionate (BDP) and fluticasone propionate
 (FP) both with an Opti-Chamber spacer device. The inhaled corticosteroids were administered
 to 30 patients in doses of increasing systemic effect to examine the corresponding effects on
 pulmonary function, bronchial hyper-responsiveness, asthma control, and resolution of airway
 inflammation in patients with persistent asthma. The intent was to compare the estimates of
 systemic effect for BDP and FP, derived from the DICE pilot study in which BDP and FP were
 administered in 1-week intervals, to that which occurred when BDP and FP doses were
 administered over 3- to 6-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) study was reviewed by the Protocol Review
 Committee in December 1998. Recruitment started in September 1999. BARGE was a 54-week
 randomized, double-blind, crossover study comparing the effects of regularly scheduled use of
 inhaled albuterol (2 puffs four times a day) to placebo. Two groups of 36 participants each
 included individuals who had mild to moderate asthma and who differed by their genotype at
 the codon for the 16th amino acid of the B2-adrenergic receptor. A total of 36 participants
 harbored the B16-Arg/Arg genotype and the other 36 harbored the B16-Gly/Gly genotype at the
 B2-adrenergic receptor. Qualified participants 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 PEF, spirometric values, AM/PM PEF 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. Participants 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).
 Asthma control was monitored by the above indicators during this time. At the end of the
 blinded treatment period, all participants were returned to single-blind regular use of a
 placebo inhaler (2 puffs 4 times a day) for an 8-week run-out period. Following cross-over to
 double-blinded treatment with albuterol or placebo, the 8-week run-out period also served as
 the run-in period for the second stage of the study. Asthma control was monitored by the same
 indicators as in the first stage. At the end of the second blinded treatment period, all
 participants were returned to single-blind regular use of a placebo inhaler (2 puffs 4 times
 a day) for an 8-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 and the end of Stage 1 run-in, and between
 the end of Stage 2 randomized treatment and the end of Stage 1 run-out. The study was
 completed and results have been published.

 The Improving Asthma Control Trial (IMPACT) was a double-blind, randomized, parallel group
 design clinical study to determine the best long-term strategy for treating adults with mild
 asthma who experienced symptoms more than occasionally. The study tested whether these
 patients should be taking anti-inflammatory medications on a daily basis and whether a newer
 class of medications provided the same benefit as older drugs. In the IMPACT study, 225
 adults with mild asthma, who had more than occasional symptoms, were enrolled in six clinical
 research centers. Following an initial evaluation, patients were randomized to receive either
 a twice daily inhaled corticosteroid, a twice daily anti-leukotriene, or a placebo. All
 patients received treatment for symptoms if, and when, they occured. The primary outcome was
 AM PEF. Other outcomes included FEV1 before and after bronchodilator treatment, the frequency
 of exacerbations, the degree of asthma control, the number of symptom-free days, and the
 quality of life. Recruitment ended in 2003. Study results were published in the April 14,
 2005 issue of the New England Journal of Medicine. In April 2001 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) study was a
 randomized, double-blind, cross-over study, which compared the effect of inhaled
 corticosteroid treatment delivered twice daily for 8 weeks in the following two groups of
 patients with persistent asthma: 1) smokers; and 2) 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 patients ages 18 to 35. The primary outcome was change in pre-bronchodilator FEV1 over the
 8-week treatment period in smokers compared with non-smokers. Secondary outcomes were AM and
 PM PEF, PC20 methacholine, and markers of inflammation in induced sputum. A secondary
 comparison examined the effect of 8 weeks of treatment with a leukotriene receptor antagonist
 in asthmatics who smoked to those who did not. An additional analysis compared the response
 to inhaled corticosteroid with the response to leukotriene receptor antagonist. The study was
 completed and results have been submitted to a journal for publication.

 The Salmeterol and Leukotriene Modifiers versus ICS Treatment (SLIMSIT) study initiated
 recruitment in September 2002. The goal was to randomize 180 participants. 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, participants 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, participants 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 participant over the duration of the study. The final visit of this run-in
 period served as the baseline of comparison for the study variables measured during the
 initial treatment phase. At the end of the initial run-in, participants with stable asthma
 symptoms were randomized to one of the following two treatment regimens for 14 weeks: 1)
 daily oral placebo, twice daily inhalation of salmeterol 50 mg by dry powder inhaler (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 MDI delivery device, while salmeterol was given by a DPI Diskusâ. A computer
 interface randomized participants into the two treatment groups, stratifying by clinical
 center and FEV1 at the randomization visit (less than 80% versus greater than 80% of
 predicted FEV1). During the first treatment period, participants 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,
 participants entered a second run-in period in which 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, participants 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. DSMB recommended termination of
 the study prior to target enrollment because sufficient data about the primary outcome had
 been obtained. SLIMSIT results were presented at the May 2005 American Thoracic Society
 Annual Meeting. The data are under analysis for subsequent publication.

 The Predicting Responses for Inhaled Corticosteroid Efficacy (PRICE) study was a follow-up
 study that looked for additional predictive biomarkers of response to inhaled
 corticosteroids. The study also evaluated whether short-term response to inhaled
 corticosteroids predicted asthma control and exacerbation rate, and whether it correlated
 with elastic recoil and upstream resistance. In this study, adults with a history of asthma
 underwent 6 weeks of ICS treatment, then were stratified by response and randomized in a
 double-blind fashion to continue ICS therapy or receive placebo for 16 weeks. ACRN
 investigators found that after 6 weeks of ICS therapy, patients with a good (15%) versus poor
 (less than 5%) increase in FEV1 experienced significantly better asthma control during
 continued ICS treatment. Interestingly, nitric oxide concentration in exhaled breath and
 airway sputum eosinophils, generally considered biomarkers of airway inflammation, were not
 significantly correlated with ICS treatment response. Explanation for this divergence in
 findings is unclear. PRICE results were presented at the May 2005 American Thoracic Society
 Annual Meeting

 In the Genetics of Asthma in Latino Americans (GALA) 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
 and underway.

 The Long Acting Beta Agonist Response by GEnotype (LARGE) study is the first protocol of ACRN
 II. It is a 60-week randomized, double-blind, cross-over study to compare the effects of
 long-acting beta-agonists in patients with asthma who are receiving inhaled corticosteroids
 and who express two distinct polymorphisms of the beta2-adrenergic receptor. The primary
 hypothesis is that those with the B16 Arg/Arg genotype will have worse asthma control, as
 defined by AM PEF rate, than those with the B16 Guj/Guj genotype. Recruitment started in
 December 2004 with a target of 80 randomized patients. See NCT00200967 for more information
 on this study.
Patients with asthma; specific eligibility criteria vary for each study.