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Comparison of Physician-, Biomarker-, and Symptom-Based Strategies For Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma
Comparison of Physician-, Biomarker-, and Symptom-Based Strategies For Adjustment of Inhaled Corticosteroid Therapy in Adults With Asthma
A
STHMA IS MANAGED BY CON-
1,2 low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-
sensus guidelines. Disease based adjustment of inhaled corticosteroids was not superior to physician assessment–
activity varies daily, season- based adjustment of inhaled corticosteroids in time to treatment failure.
ally, and episodically, presum-
Trial Registration clinicaltrials.gov Identifier: NCT00495157
ably related to airway inflammation.3 Ac-
JAMA. 2012;308(10):987-997 www.jama.com
cordingly, asthma management requires
periodic dose adjustments of controller Author Affiliations are listed at the end of this article.
For editorial comment see p 1036.
medications, particularly inhaled corti- Corresponding Author: William J. Calhoun, MD, Uni-
Author Video Interview available at versity of Texas Medical Branch, JSA 4.118, 301 Uni-
costeroids. Adjustments have been based versity Blvd, Galveston, TX 77555 (william.calhoun
www.jama.com. on (1) physician assessment of symp- @utmb.edu).
©2012 American Medical Association. All rights reserved. JAMA, September 12, 2012—Vol 308, No. 10 987
toms, activity limitation, rescue al- certain whether symptom-based adjust- randomized trial included 342 partici-
buterol use, lung function, and exacer- ment (SBA) of inhaled corticosteroids pants with mild to moderate persis-
bations at usual office or clinic visits,1 (2) might be a simple and effective strategy tent asthma; these individuals were re-
a biomarker of disease activity (eg, ex- for managing asthma therapy in a popu- cruited cooperatively with a concurrent
haled nitric oxide, sputum eosinophils, lation of patients with asthma com- Asthma Clinical Research Network
methacholine responsiveness),4-10 or (3) monly seen in primary care settings, and (ACRN) trial14 (FIGURE 1). The ACRN
the occurrence of symptoms on a day- to ascertain if biomarker-based adjust- data and safety monitoring board and
to-day basis.11-13 ment (BBA) was superior to physician as- clinical center institutional review
We hypothesized that adjustment of sessment–based adjustment (PABA). boards approved the protocol and con-
inhaled corticosteroids based on symp- sent form; all participants signed a writ-
toms or exhaled nitric oxide would be METHODS ten consent form. Race was self-
superior to adjustment based on physi- The Best Adjustment Strategy for reported as white, black, or other, and
cian assessment. Our purpose was to as- Asthma in the Long Term (BASALT) ethnicity as Latino or non-Latino, and
174 Excluded
59 Nonadherent
54 Withdrew consent
19 Ineligible
16 Lost to follow-up
9 Had asthma exacerbation
2 Had adverse events
1 Medication related
1 Not related to medication
or asthma
15 Other reasons
21 Excluded 79 Excluded
9 Withdrew consent
7 Nonadherent
2 Allocated in error
1 Lost to follow-up
2 Other reasons
114 Randomized by October 2009 115 Randomized by October 2009 113 Randomized by October 2009
to receive physician to receive biomarker-based to receive symptom-based
assessment–based adjustment adjustment adjustment
101 Completed trial by July 2010 b 92 Completed trial by July 2010 b 97 Completed trial by July 2010 b
114 Included in primary analysis 115 Included in primary analysis 113 Included in primary analysis
Patients were allocated to the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial based on achievement of forced expiratory volume in the first second
of expiration of greater than 70% during the run-in period and concomitant control of symptoms (score of 0 or 1 on each of 3 questions on the Asthma Evaluation Ques-
tionnaire; eSupplement at http://www.jama.com). Patients whose lung function was less than 70% of predicted or had quantitatively greater symptom burden were allo-
cated to the Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (TALC)
trial, which was a concurrently recruited Asthma Clinical Research Network trial.14
a Details for those screened but ineligible were not collected.
b Dropouts were included as censored observations.
988 JAMA, September 12, 2012—Vol 308, No. 10 ©2012 American Medical Association. All rights reserved.
recorded to assess representativeness in rolled in the BASALT trial. This time and nighttime symptom and res-
accordance with National Heart, Lung, approach yielded a population of par- cue -agonist diaries, Asthma Control
and Blood Institute guidelines. All par- ticipants with well or partially con- Questionnaire, Asthma Symptom Util-
ticipants had a physician diagnosis of trolled asthma, but excluded those with ity Index, and Asthma Quality-of-Life
asthma, and either reversible airflow poorly controlled asthma. During the Questionnaire were measured as in pre-
limitation (ⱖ12% improvement in prerandomization period, patients were vious ACRN trials11 as secondary out-
forced expiratory volume in the first given 3 inhalers coded as A, B, and C. comes. We analyzed the frequency of
second of expiration [FEV1] after 360 Inhaler A contained beclomethasone exacerbations (treatment failures re-
µg of albuterol), or airway hyperre- HFA (40 µg/puff) and inhalers B and C quiring systemic corticosteroids, an un-
sponsiveness (provocative concentra- contained placebo. An albuterol in- scheduled physician contact for asthma,
tion of methacholine [⬍8 mg/mL] caus- haler was provided for use as needed for or severe symptoms linked to lung func-
ing a 20% drop in FEV1). asthma symptoms. Participants were in- tion decline11), and quantified use of in-
We evaluated these approaches to dose structed to use 2 puffs twice daily from haled corticosteroids. The BASALT pro-
adjustment of inhaled corticosteroids in inhalers A and B, and to use 2 puffs from tocol at http://www.acrn.org/BASALT
a 3-group trial during 9 months in adults inhaler C each time they used 2 puffs of .html details the frequency and timing
with mild to moderate asthma that was albuterol for symptom relief. All me- of each outcome measure.
well controlled with low-dose inhaled tered dose inhalers were equipped with The BASALT trial was a parallel,
corticosteroids. The dose of inhaled cor- a Doser device (Meditrack Products) to 3-group trial with 2 primary compari-
ticosteroids was adjusted by (1) a strat- measure adherence during the trial. Pa- sons: PABA vs SBA and PABA vs BBA.
egy based on National Heart, Lung, and tients who demonstrated at least 75% ad- Based on proposed enrollment, we had
Blood Institute guidelines (PABA group), herence were randomized to 1 of 3 ad- 87% power to detect a 60% reduction in
(2) measurement of exhaled nitric ox- justment strategies: PABA, BBA, or SBA. treatment failure rate (30% vs 12%), as
ide (BBA group), or (3) occurrence of Beclomethasone HFA was provided at previously observed,5 for an overall ␣
symptoms prompting rescue use of al- a dosage of 2 puffs twice daily (40 µg/ level of .05 (.025 for each primary com-
buterol (SBA group). In the first 2 strat- puff) before randomization, correspond- parison), and a postrandomization drop-
egy groups, dose adjustments of in- ing to level 3 treatment. Hence, in- out rate of 15%. The comparison be-
haled corticosteroids were made at the haled corticosteroid therapy could be tween SBA and BBA was exploratory.
time of clinic visits (every 6 weeks); in intensified or deintensified during the To evaluate time to first treatment fail-
the third group, dose adjustment of in- trial. Following randomization, beclo- ure, Kaplan-Meier survival plots and log-
haled corticosteroids was performed by methasone HFA was contained only in rank tests were generated. A Cox propor-
matching inhaled steroid use on a puff- inhaler A for PABA participants, only in tionalhazardsregressionmodelcompared
per-puff basis with as-needed albuterol inhaler B for BBA participants, and only time to first treatment failure with adjust-
use. in inhaler C for SBA participants. There- ment for covariates of center and baseline
We selected these strategy groups be- after, inhaler A was adjusted by an in- FEV1. To accommodate multiple treat-
cause (1) PABA therapy represents stan- vestigator according to guidelines closely ment failures, a repeated-measures pro-
dard care in the United States, (2) BBA resembling the National Heart, Lung, portional hazards regression model was
in adults using exhaled nitric oxide may and Blood Institute National Asthma Ex- fit to time to treatment failure, with ad-
achieve good asthma control with re- pert Panel,1 and inhaler B was adjusted justment for center and baseline FEV1.
duced total use of inhaled corticoste- according to exhaled nitric oxide mea- Methods for secondary analyses are de-
roids, 5 and (3) SBA produces out- surements. Participants were in- scribed in the BASALT protocol.
comes equivalent to daily controller structed to use inhaler C only at the time All analyses followed intention-to-
therapy in patients with mild asthma.11,12 of albuterol use. Subsequent visits oc- treat principles and incorporated all avail-
We sought to determine if SBA would curred 2, 4, 6, 12, 18, 24, 30, and 36 able data. The statistical models and
be successful in patients with more se- weeks after randomization, at which analyses for the primary and secondary
vere asthma than in our previous study times outcomes were measured (the outcomes assumed missing data were
of patients with mild persistent asthma.11 BASALT Protocol appears at http://www missing at random. Because 2 primary
Patients were treated with 2 puffs .acrn.org/BASALT.html). comparisons were of interest, PABA vs
twice daily of beclomethasone HFA (40 Our primary outcome was time to first BBA and PABA vs SBA, comparisons
µg/puff) during the run-in period, and treatment failure, a clinically important were evaluated for statistical signifi-
if their asthma was acceptably con- worsening of asthma (BOX).11 Hospital- cance at the .025 level, as was the sec-
trolled (a score of 0 or 1 on each of 3 izations, urgent care visits, and other ondary comparison of BBA vs SBA, for
questions on the Asthma Evaluation adverse events were recorded at the time both primary and secondary outcomes.
Questionnaire [eSupplement at http: of scheduled clinic visits. Spirometry, Statistical tests were 2-sided and all sta-
//www.jama.com] and predicted bron- albuterol reversibility, methacholine re- tistical analyses were performed using
chodilator FEV1 ⬎70%), they were en- sponsiveness, sputum eosinophils, day- SAS version 9.3 (SAS Institute Inc).
©2012 American Medical Association. All rights reserved. JAMA, September 12, 2012—Vol 308, No. 10 989
©2012 American Medical Association. All rights reserved. JAMA, September 12, 2012—Vol 308, No. 10 991
80 Week 0 80 Week 2
Patients, %
40 40
20 20
0 0
1 2 3 4 5 1 2 3 4 5
Dose Level Dose Level
80 Week 4 80 Week 6
Patients, %
40 40
20 20
0 0
1 2 3 4 5 1 2 3 4 5
Dose Level Dose Level
80 Week 12 80 Week 18
Patients, %
40 40
20 20
0 0
1 2 3 4 5 1 2 3 4 5
Dose Level Dose Level
80 Week 24 80 Week 30
Patients, %
40 40
20 20
0 0
1 2 3 4 5 1 2 3 4 5
Dose Level Dose Level
No significant differences in dose distribution were observed between the biomarker-based adjustment (BBA) and the physician assessment–based adjustment (PABA)
strategies. Because there was no regularly scheduled dose in the symptom-based adjustment group, equivalent dose distributions cannot be reliably calculated for
participants randomized to this group. The corresponding dose and frequency for the dose levels appear in Table 2.
©2012 American Medical Association. All rights reserved. JAMA, September 12, 2012—Vol 308, No. 10 993
Figure 4. Mixed-Model Treatment Means of Pulmonary Function and Exhaled Nitric Oxide
35
90 30
25
85
20
80 15
PABA BBA SBA PABA BBA SBA 0 2 4 6 12 18 24 30 36
(n = 114) (n = 115) (n = 113) (n = 101) (n = 92) (n = 97) Treatment Period, wk
No. of patients
Treatment Week –4 Treatment Week 36 PABA 108 106 105 108 106 104 101 100 96
BBA 114 106 104 105 99 92 88 88 92
SBA 110 110 109 105 101 106 94 95 95
The data markers indicate geometric means and the error bars indicate 97.5% confidence intervals. FEV1 indicates forced expiratory volume in the first second of
expiration. No significant differences in prebronchodilator FEV1, postbronchodilator FEV1, or albuterol-induced reversibility were observed. The BBA group had very
little change in exhaled nitric oxide over the course of the trial because dosing of inhaled corticosteroids was adjusted to control exhaled nitric oxide. The SBA group
showed a small and statistically significant increase in exhaled nitric oxide over the course of the trial vs the BBA group (P=.007). Level of exhaled nitric oxide in the SBA
group did not differ significantly from the PABA group (P=.15).
methacholine responsiveness,9 which therapy reduces cumulative dose of in- the finding that quadrupling the dose
have had limited penetration into prac- haled corticosteroids. In BEST partici- of inhaled corticosteroids at the onset
tice. Of available biomarkers, exhaled pants whose asthma was comparable of symptoms reduced the risk of re-
nitric oxide is the easiest to imple- with BASALT, the dose of beclometha- quiring oral corticosteroids.19
ment, but adjustment based on ex- sone used was 250 µg/puff, which is 6 Our findings provide reassurance
haled nitric oxide was no more effec- times the dose used in BASALT. that SBA of inhaled corticosteroids dose
tive than the other strategies. O’Byrne et al13 showed that combi- may be appropriate in most patients
Symptom-based adjustment strate- nation formoterol and budesonide for with mild to moderate asthma. Pa-
gies are appealing because they are both maintenance and relief of symp- tients with asthma who poorly per-
simple to use and empower patients. toms resulted in better asthma control ceive their symptoms might be ex-
Whether these features might im- than scheduled treatment alone. The pected to have less favorable outcomes
prove adherence to therapy was not participants had more severe asthma, with SBA, but we could not directly as-
testable in this closely monitored trial. and received daily maintenance treat- sess this possibility. Moreover, pa-
Requiring all participants to use 2 in- ment with inhaled corticosteroids. For tients who are poorly adherent to pre-
halers (A and B) twice daily and a third US practitioners, it should be noted that scribed therapy would be expected to
(inhaler C) with symptoms could eas- use of a single combination inhaler for mimic our group of SBA participants,
ily have masked a benefit in quality of both maintenance and rescue treat- using their therapy only when symp-
life from the smaller burden of care with ment does not align with current US toms dictate. There may be ethnic dif-
the SBA approach. Food and Drug Administration policy. ferences in the associations of adjust-
Other studies have shown symptom- The innovation of BASALT is to couple ment strategies with study outcomes
driven treatment with inhaled cortico- the use of reliever and controller treat- because the small number of Hispanic
steroids performing as well as daily ments that are approved by the Food participants in our study did not have
treatments. In the Improving Asthma and Drug Administration for their re- as robust a response to SBA relative to
Control Trial (IMPACT), 11 partici- spective indications in a symptom- PABA (eFigure). This finding seems un-
pants with mild persistent asthma re- driven adjustment strategy. likely to have been a function of dif-
ceived daily inhaled corticosteroids, zaf- We observed a slight increase in ex- ferential access to care or medication,
irlukast, or placebo, plus 10 days of haled nitric oxide in the SBA group (14 but could reflect linguistic, socio-
high-dose inhaled corticosteroids trig- ppb vs 5 ppb in BBA; 10 ppb in PABA), cultural, 20,21 or ethnic-specific en-
gered by a symptom-based action plan. which is not surprising because the dose vironmental or pharmacogenetic
Asthma outcomes, including treat- of inhaled corticosteroids in the BBA differences that affect responses to
ment failure, did not differ by treat- group was adjusted by fraction of ex- triggers.22,23
ment. BASALT participants had signifi- haled nitric oxide. Similar small eleva- Several limitations of our study are
cantly more severe asthma than tions in exhaled nitric oxide have been worth noting. Our sample size was too
IMPACT participants.11 Despite treat- observed in patients with asthma con- small to determine the associations of
ment with daily beclomethasone dur- sidered too mild to warrant daily con- ethnicity and race with responsive-
ing the BASALT run-in period (con- trollers17 and in patients whose asthma ness to adjustment strategy for most
trasted with only as-needed albuterol is in clinical remission.18 outcomes. It is possible that some non-
in IMPACT), mean values for FEV1 Symptom-based adjustment of in- significant outcome differences could
(2.96 L [86%]) and AM peak expira- haled corticosteroids in patients with achieve significance with a larger
tory flow (447 L/m) were significantly mild to moderate asthma accom- sample size. However, the point esti-
lower at randomization in BASALT (vs plishes temporal personalization of con- mates on most of these outcomes fa-
IMPACT: 3.19 L [89%] for FEV1 and troller therapy and provides several ad- vored SBA over BBA or PABA, so the
AM peak expiratory flow of 465 L/m) vantages. Insofar as asthma triggers likelihood of us having missed an im-
(BASALT vs IMPACT: P = .049 for AM intensify airway inflammation (eg, al- portant detrimental association is
peak expiratory flow; P ⬍ .001 for lergens, viruses), the prompt increase small. Furthermore, findings in well-
FEV1). in anti-inflammatory medication could controlled clinical trials may not trans-
The Beclomethasone plus Salbuta- offset the inflammogenic stimulus. Our late directly to clinical practice.
mol Treatment (BEST)12 study showed observation that PABA participants had Power calculations were performed
that as-needed combination therapy significantly more exacerbations dur- based on the assumption of a certain
with beclomethasone and albuterol was ing autumn, a period of increased vi- treatment failure rate in our popula-
superior to as-needed albuterol alone, ral infections and allergen exposure, tion of interest, and a percentage re-
and comparable with twice daily be- while SBA participants did not, is con- duction that we deemed as clinically
clomethasone plus as-needed al- sistent with this concept. That early in- meaningful (60% treatment failure re-
buterol. BEST resembles BASALT in tervention may prevent worsening of duction from 30% in the PABA group
showing that as-needed combination asthma to exacerbation is suggested by to 12% in the BBA or SBA groups).
©2012 American Medical Association. All rights reserved. JAMA, September 12, 2012—Vol 308, No. 10 995
These estimates were based on pub- Drafting of the manuscript: Calhoun, Ameredes, support from GlaxoSmithKline, Merck, Amira, and Am-
King, Chinchilli, DiMango, Engle, Israel, Lemanske, gen. Dr Grant reported receiving funding from the
lished literature. If we had observed this Martin, Peters, Wasserman, Wechsler, Boushey. NHLBI for this study; serving on the US Food and Drug
size of reduction but without statistical Critical revision of the manuscript for important in- Administration’s (FDA’s) Allergenic Extracts Advisory
tellectual content: Calhoun, Ameredes, King, Icitovic, Committee; having grants pending with Baxter, Dyax,
significance, our study would have been Castro, Cherniak, Craig, Denlinger, DiMango, Fahy, and Pharming; lecture fees from Shire; payment for
underpowered. However, we observed Grant, Israel, Jarjour, Kazani, Kraft, Lazarus, Lemanske, manuscript preparation from Lev Pharma; and travel
reductions in treatment failure rates of Lugogo, Martin, Meyers, Moore, Pascual, Peters, expenses from American Academy of Allergy, Asthma
Ramsdell, Sorkness, Sutherland, Szefler, Wasserman, and Immunology (AAAAI), Shire, and the FDA’s Al-
9% (22% for PABA vs 20% for BBA) and Walter, Wechsler, Boushey. lergenic Extracts Advisory Committee. Dr Israel re-
32% (22% for PABA vs 15% for SBA), Statistical analysis: King, Icitovic, Chinchilli, Engle, ported consultancies with Abbott, Amgen, Astellas,
Kunselman, Lazarus, Meyers. Cowen, GlaxoSmithKline, Icagen, Infinity, AstraZen-
indicating that the treatment ap- Obtained funding: Calhoun, Ameredes, Castro, eca, Merck, newMentor, NKT, Novartis, Ono, PDL,
proaches were more similar in prevent- Chinchilli, Fahy, Israel, Kraft, Lemanske, Martin, Peters, Pumatrix, Regeneron, Schering, Sepracor, Teva Phar-
Sutherland, Wasserman, Boushey. maceuticals, and Agenzia; expert testimony for 6 law
ing treatment failure than anticipated. firms; having grants pending with Aerovance, Am-
Administrative, technical, or material support:
A very large study might be needed to Calhoun, Ameredes, Castro, Cherniak, Chinchilli, Craig, gen, Biota, Genetech, Icagen, Johnson & Johnson,
demonstrate statistical significance for DiMango, Fahy, Grant, Israel, Jarjour, Kazani, MedImmune, Novartis; speaking fees from Merck and
Kunselman, Moore, Peters, Ramsdell, Sorkness, Genentech; and royalties from UpToDate. Dr Jarjour
a difference in treatment failure rates of Sutherland, Wasserman, Walter, Wechsler, Boushey. reported receiving funding from the NHLBI for this
questionable clinical importance. Study supervision: Calhoun, Castro, Chinchilli, study; consultancies with AsthmaTx and Genentech;
Denlinger, DiMango, Israel, Lazarus, Lemanske, and having grants pending with Merck,
In summary, among adult partici- GlaxoSmithKline, and Genentech. Dr Kraft reported
Peters, Martin, Moore, Pascual, Ramsdell, Szefler,
pants with mild to moderate persis- Wasserman, Walter, Wechsler, Boushey. receiving funding from the NHLBI for this study; grant
tent asthma, neither the SBA nor the Conflict of Interest Disclosures: The authors have com- support from Merck, GE Healthcare, AsthmaTx, Novar-
pleted and submitted the ICMJE Form for Disclosure tis, N30, Genentech, and GlaxoSmithKline; board mem-
BBA strategy for inhaled corticoste- of Potential Conflicts of Interest. Drs Calhoun, Amer- bership for the American Thoracic Society; royalties
roid therapy was superior to the stan- edes, and Kazani reported receiving funding from the from Elsevier; and payment for continuing medical edu-
National Heart, Lung, and Blood Institute (NHLBI) for cation activities. Ms Kunselman reported receiving
dard PABA strategy for the outcome of funding from NHLBI for this study; having a pending
this study and reimbursement for study travel. Dr King
treatment failure. reported receiving funding from the NHLBI for this NIH grant; and stock in Merck. Dr Lemanske re-
study and having an NHLBI grant pending. Ms Ici- ported receiving funding from the NHLBI for this study,
tovic and Drs Lazarus and Walter reported receiving study travel, data review, manuscript review, and writ-
Author Affiliations: Department of Internal Medi-
funding from the NHLBI for this study. Dr Bleecker re- ing assistance; consultancies with Merck, Sepracor, SA
cine, University of Texas Medical Branch, Galveston
ported receiving funding from the NHLBI for this study, Boney, GlaxoSmithKline, AIR, Genentech, Double He-
(Drs Calhoun, Ameredes, and Grant); Department of
Public Health Sciences, Penn State University, State study-related travel, review activities, and writing or lix; having grants pending from the NHLBI and Phar-
College, Pennsylvania (Drs King, Chinchilli, and Craig reviewing this manuscript; consultancies with maxis; speaking fees from the Michigan Public Health
and Mss Icitovic, Engle, and Kunselman); School of Aerovance, AstraZeneca, Boehringer, Centocor, Institute, Allegheny General Hospital, American Acad-
Medicine, Wake Forest University, Winston-Salem, GlaxoSmithKline, Genentech, Merck, Novartis, Pfizer, emy of Pediatrics (AAP), West Allegheny Health Sys-
North Carolina (Drs Bleecker, Meyers, Moore, Pas- and Roche; lecture fees from Merck; and performing tem, AAP California chapter, Colorado Allergy Soci-
cual, and Peters); Department of Medicine, Washing- clinical trials at Wake Forest University supported by ety, Pennsylvania Allergy and Asthma Society, Harvard
ton University, St Louis, Missouri (Drs Castro and Wal- Boehringer, Centocor, GlaxoSmithKline, MedIm- Pilgrim Health, California Society of Allergy, New York
ter); National Jewish Health, Denver, Colorado (Drs mune, Genetech, Aerovance, Ception, AstraZeneca, City Allergy Society, World Allergy Organization, and
Cherniak, Martin, Sutherland, and Szefler); Severe Novartis, Amgen, Pfizer, Forest, and sanofi-aventis. American College of Chest Physicians; a pending pat-
Asthma Research Program, University of Wisconsin Dr Castro reported receiving funding from the NHLBI ent; and royalties from Elsevier and UpToDate. Dr Lu-
Hospital and Clinic, Madison (Drs Denlinger, Jarjour, for this study and study-related travel; consultancies gogo reported receiving funding from the NHLBI for
Lemanske, and Sorkness); Department of Medicine, with Schering, AsthmaTx, Genentech, IPS, Pulmo- this study and reimbursement for study travel; and hav-
Columbia University, New York, New York (Dr gen, and sanofi-aventis; grants pending from Ameri- ing a pending grant from the NIH. Dr Martin re-
DiMango); Department of Medicine, University of Cali- can Lung Association, AsthmaTx, Amgen, Ception, ported consultancies with Teva Pharmaceuticals,
fornia, San Francisco (Drs Fahy, Lazarus, and Boushey); enentech, MedImmune, Merck, Novartis, Merck, AstraZeneca, and Genentech/Novartis; hav-
Brigham and Women’s Hospital, Boston, Massachu- GlaxoSmithKline, and sanofi-aventis; lecture fees from ing grants pending with AsthmaNet, Genentech, and
setts (Drs Israel, Kazani, and Wechsler); Department Boehringer, Pfizer, Merck, GlaxoSmithKline, Genen- MedImmune; lecture fees from Teva Pharmaceuti-
of Medicine, Duke University, Durham, North Caro- tech, AsthmaTx; and royalties from Elsevier. Dr Chin- cals, Merck, and Genentech/Novartis; royalties from
lina (Drs Kraft and Lugogo); Department of Medi- chilli reported receiving funding from the NHLBI for UpToDate; and payment for educational presenta-
cine, University of California, San Diego (Drs Rams- this study; and consultancies with GlaxoSmithKline, tions from Teva Pharmaceuticals and Genentech. Dr
dell and Wasserman); and School of Medicine, Merck, AstraZeneca, and Novartis. Dr Craig reported Moore reported receiving funding from the NHLBI for
University of Colorado, Denver (Dr Szefler). consultancies with CSL Behring, Dyax, Viropharma, this study and study travel; and grants from Aero-
Author Contributions: Dr Calhoun had full access to and Shire; providing expert testimony in a legal case; vance, Amgen, AstraZeneca, Boehringer, Centacor,
all of the data in the study and takes responsibility for grants pending from Viropharma, CSL Behring, Shire, Ception, Forest, Genentech, GlaxoSmithKline, Med-
the integrity of the data and the accuracy of the data Dyax, Pharming, Forest, Genentech, Biota, Immune, Novartis, Pfizer, and sanofi-aventis. Dr Pas-
analysis. Drs Calhoun and Ameredes contributed GlaxoSmithKline, and Grifols; lecture fees from Viro- cual reported receiving funding from the NHLBI for
equally to the work. pharma, CSL Behring, Dyax, Merck, Novartis, Genen- this study; consultancies with United Therapeutics and
Study concept and design: Calhoun, Ameredes, King, tech, and Teva Pharmaceuticals; and educational de- Gilead; and having grants pending from United Thera-
Icitovic, Castro, Cherniak, Chinchilli, Craig, Denlinger, velopment funding from Vietnam Education peutics and Actelion. Dr Peters reported receiving fund-
DiMango, Fahy, Grant, Israel, Jarjour, Kazani, Kraft, Foundation. Dr Denlinger reported receiving funding ing from the NHLBI for this study, study travel, data
Kunselman, Lazarus, Lemanske, Martin, Meyers, Peters, from the NHLBI for this study; funding from the Ameri- review, manuscript review; consultancies with
Ramsdell, Sorkness, Sutherland, Szefler, Wasserman, can Thoracic Society; consultancy for Merck; having Aerocrine, AstraZeneca, Airsonnet, Delmedica,
Walter, Wechsler, Boushey. a grant pending with the National Institutes of Health GlaxoSmithKline, Merck, and Teva Pharmaceuticals;
Acquisition of data: Calhoun, Ameredes, Castro, (NIH); and holding a patent through the Wisconsin and lecture fees from Integrity and Merck. Dr Ramsdell
Chinchilli, Denlinger, DiMango, Fahy, Israel, Kazani, Alumni Research Foundation. Ms Engle reported re- reported receiving funding from NHLBI for this study;
Kunselman, Lazarus, Lemanske, Lugogo, Martin, ceiving funding from NHLBI for this study; and hav- and receiving a grant from Boehringer. Dr Suther-
Moore, Pascual, Peters, Ramsdell, Sorkness, Sutherland, ing a grant pending from the NIH. Dr Fahy reported land reported receiving funding from the NHLBI for
Wasserman, Walter, Wechsler, Boushey. receiving funding from the NHLBI for this study and this study and study travel; consultancies with For-
Analysis and interpretation of data: Calhoun, study travel; board membership for Cytokinetics; est, GlaxoSmithKline, Merck, Novartis, Day, and Ge-
Ameredes, King, Icitovic, Castro, Chinchilli, Denlinger, consultancies with Amira, Oxagen, Gilead, nentech; having grants pending from Boehringer,
DiMango, Engle, Fahy, Israel, Kraft, Lazarus, Lemanske, GlaxoSmithKline, Amgen, Portola, Five Prime Thera- Novartis, and the NIH; and fees for educational pre-
Martin, Meyers, Peters, Ramsdell, Szefler, Wasserman, peutics, and Merck; having grants pending with Ge- sentations from Genentech. Dr Szefler reported re-
Wechsler, Boushey. nentech, Boehringer, Aerovance; and receiving travel ceiving funding from the NHLBI for this study, study
996 JAMA, September 12, 2012—Vol 308, No. 10 ©2012 American Medical Association. All rights reserved.
travel, review, and writing; consultancies with Merck, U10 HL074225, U10 HL074227, U10 HL074231, and Paul Ferguson. San Francisco, California:
Genentech, Schering, Boehringer, Novartis, and U10 HL074204, U10 HL074212, U10 HL074073, Peggy Cadbury, RN, Jane Liu, MS, and Jean Schenk-
GlaxoSmithKline; having grants pending from U10 HL074206, U10 HL074208, and U10 kan. St Louis, Missouri: Pamela Kemp, RMA, Tina
GlaxoSmithKline, Ross, and Abbott; lecture fees from HL074218 that were awarded by the National Heart, Weber, RN, and Vanessa Curtis, RRT. Winston-
Merck; and fees for manuscript preparation from Ge- Lung, and Blood Institute. Teva Pharmaceuticals pro- Salem, North Carolina: Cheryl Wilmoth and Bob
nentech. Dr Wasserman reported receiving funding vided the study drug and matching placebo. Hmieleski.
from the NHLBI for this study and study travel; em- Role of the Sponsor: The National Heart, Lung, and Online-Only Material: eSupplement, 2 eTables, the
ployment by the AAAAI; and expert testimony for vari- Blood Institute had no role in the design and conduct eFigure, and the Author Video Interview are avail-
ous law firms. Dr Wechsler reported consultancies with of the study; in the collection, analysis, and interpre- able at http://www.jama.com.
and lecture fees from GlaxoSmithKline, Novartis, tation of the data; or in the preparation, review, or Additional Contributions: We gratefully acknowl-
Cephalon, Sepracor, Schering, NKT, AsthmaTx, Gen- approval of the manuscript. edge the diligent and responsible oversight of the data
zyme, MapPharma, Merck, Genentech, and Boeh- Data and Safety Monitoring Board: Andrea J. Apter, and safety monitoring board during the design, ex-
ringer. Dr Boushey reported receiving funding from MD, MSc, Serpil Erzurum, MD, Barbara Layman, Yancy ecution, and analysis of this trial; these individuals were
the NHLBI for this study; consultancies with Merck, Phillips, MD, MACP, Bruce M. Psaty, MD, PhD, and provided a small honorarium by the National Heart,
GlaxoSmithKline, Genentech, Kalblos, Pharmaxis, John- James Sheller, MD. Lung, and Blood Institute for their work. Aaron Deykin,
son & Johnson; having pending grants from Data Coordinating Center: Kelly Bixler, Lauren Le- MD, provided helpful advice on experimental design
GlaxoSmithKline, Genentech, and the Allergy, Asthma, shak, Jennifer Lucier, Aimee Merchlinski, Melanie Pay- and outcome measures during the design of the trial,
and Immunology Foundation of Northern California; ton, and Ronald Zimmerman. but was not compensated for his work. We thank the
lecture fees from Breath California; and royalties from Site Coordinators and Study Managers: Galveston, individuals who worked at the data coordinating cen-
McGraw-Hill. Drs Cherniack, DiMango, Meyers, and Texas: Lisa Sweeney, RN, CTC, Debra Altemus, RN, ter for their careful trial oversight and stewardship of
Sorkness reported no conflicts. and Alyson Clayborn, BS. Boston, Massachusetts: the research data; these persons were compensated
Funding/Support: This study was conducted with Muhammad Zahid, MD, MPH, Kathy Zheng, MPH, as employees of their respective institutions. The
the support of the Institute for Translational Sci- and Suzanne Vogt, MS. Denver, Colorado: Jennifer Asthma Clinical Research Network Steering Commit-
ences at the University of Texas Medical Branch, Brandorff, Mary Gill, Juno Pak, and Allen Stevens. tee expresses its profound thanks to the coordinators
supported in part by a Clinical and Translational Sci- Durham, North Carolina: Denise Beaver and and study managers at each site, whose
ence Award UL1TR000071 from the National Cen- Rhonda Webb. Madison, Wisconsin: Ann Sexton, diligence, meticulous effort, and unwavering com-
ter for Advancing Translational Sciences, National Tiffany Wirth, and Barb Miller. New York, New mitment made the conduct of this study possible; they
Institutes of Health. The study was also supported York: Erin Simpson and Surinder Narula. San Diego, were compensated for their work as employees of their
by the following National Institutes of Health grants California: Melissa Thrasher, Katie Kinninger, respective institutions.
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