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Context: No consensus exists for adjusting inhaled corticosteroid therapy in patients with asthma. Approaches include adjustment at outpatient visits guided by physician assessment of asthma control (symptoms, rescue therapy, pulmonary function), based on exhaled nitric oxide, or on a day-to-day basis guided by symptoms.Objective: To determine if adjustment of inhaled corticosteroid therapy based on exhaled nitric oxide or day-to-day symptoms is superior to guideline-informed, physician assessment-based adjustment in preventing treatment failure in adults with mild to moderate asthma.Design, Setting, and Participants: A randomized, parallel, 3-group, placebo-controlled, multiply-blinded trial of 342 adults with mild to moderate asthma controlled by low-dose inhaled corticosteroid therapy (n = 114 assigned to physician assessment-based adjustment [101 completed], n = 115 to biomarker-based [exhaled nitric oxide] adjustment [92 completed], and n = 113 to symptom-based adjustment [97 completed]), the Best Adjustment Strategy for Asthma in the Long Term (BASALT) trial was conducted by the Asthma Clinical Research Network at 10 academic medical centers in the United States for 9 months between June 2007 and July 2010.Interventions: For physician assessment-based adjustment and biomarker-based (exhaled nitric oxide) adjustment, the dose of inhaled corticosteroids was adjusted every 6 weeks; for symptom-based adjustment, inhaled corticosteroids were taken with each albuterol rescue use.Main Outcome Measure: The primary outcome was time to treatment failure.Results: There were no significant differences in time to treatment failure. The 9-month Kaplan-Meier failure rates were 22% (97.5% CI, 14%-33%; 24 events) for physician assessment-based adjustment, 20% (97.5% CI, 13%-30%; 21 events) for biomarker-based adjustment, and 15% (97.5% CI, 9%-25%; 16 events) for symptom-based adjustment. The hazard ratio for physician assessment-based adjustment vs biomarker-based adjustment was 1.2 (97.5% CI, 0.6-2.3). The hazard ratio for physician assessment-based adjustment vs symptom-based adjustment was 1.6 (97.5% CI, 0.8-3.3).Conclusion: Among adults with mild to moderate persistent asthma controlled with low-dose inhaled corticosteroid therapy, the use of either biomarker-based or symptom-based adjustment of inhaled corticosteroids was not superior to physician assessment-based adjustment of inhaled corticosteroids in time to treatment failure.Trial Registration: clinicaltrials.gov Identifier: NCT00495157. [ABSTRACT FROM AUTHOR]

Background: Some studies suggest that patients with asthma who are homozygous for arginine at the 16th amino acid position of the beta2-adrenergic receptor (B16 Arg/Arg) benefit less from treatment with longacting beta2 agonists and inhaled corticosteroids than do those homozygous for glycine (B16 Gly/Gly). We investigated whether there is a genotype-specific response to treatment with a longacting beta2 agonist in combination with inhaled corticosteroid.Methods: In this multicentre, randomised, double-blind, placebo-controlled trial, adult patients with moderate asthma were enrolled in pairs matched for forced expiratory volume in 1 s and ethnic origin, according to whether they had the B16 Arg/Arg (n=42) or B16 Gly/Gly (n=45) genotype. Individuals in a matched pair were randomly assigned by computer-generated randomisation sequence to receive inhaled longacting beta2 agonist (salmeterol 50 microg twice a day) or placebo given in a double-blind, crossover design for two 18-week periods. Open-label inhaled corticosteroid (hydrofluoroalkane beclometasone 240 microg twice a day) was given to all participants during the treatment periods. The primary endpoint was morning peak expiratory flow (PEF). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00200967.Findings: After 18 weeks of treatment, mean morning PEF in Arg/Arg participants was 21.4 L/min (95% CI 11.8-31.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). In Gly/Gly participants, morning PEF was 21.5 L/min (11.0-32.1) higher when participants were assigned to receive salmeterol than when assigned to receive placebo (p<0.0001). The improvement in PEF did not differ between genotypes (difference [Arg/Arg-Gly/Gly] -0.1, -14.4 to 14.2; p=0.99). In Gly/Gly participants, methacholine PC20 (20% reduction in forced expiratory volume in 1 s; a prespecified secondary outcome) was 2.4 times higher when participants were assigned to salmeterol than when assigned to placebo (p<0.0001). Responsiveness to methacholine did not differ between salmeterol and placebo in Arg/Arg participants (p=0.87). The 2.5 times higher genotype-specific difference in responsiveness to methacholine was significant (1.32 doubling dose difference between genotypes, 0.43-2.21, p=0.0038). Seven Arg/Arg participants (placebo, n=5; salmeterol, n=2) and six Gly/Gly participants (placebo, n=3; salmeterol, n=3) had an asthma exacerbation. Five serious adverse events were reported, one each during the pre-match and run-in phases on open-label inhaled corticosteroid, two during double-blind treatment with salmeterol/inhaled corticosteroid, and one during double-blind treatment with placebo/inhaled corticosteroid. None of the serious events was asthma-related or related to study drugs or procedures.Interpretation: In asthma patients with B16 Arg/Arg and B16 Gly/Gly genotypes, combination treatment with salmeterol and inhaled corticosteroid improved airway function when compared with inhaled corticosteroid therapy alone. These findings suggest that patients should continue to be treated with longacting beta2 agonists plus moderate-dose inhaled corticosteroids irrespective of B16 genotype. Further investigation is needed to establish the importance of the genotype-specific difference in responsiveness to methacholine.Funding: National Institutes of Health. [ABSTRACT FROM AUTHOR]

Rationale: Long-acting beta-agonists (LABAs) and inhaled corticosteroids administered together appear to be complementary in terms of effects on asthma control. The elements of asthma control achieved by LABAs (improved lung function) and leukotriene receptor antagonists (LTRAs; protection against exacerbations) may be complementary as well.Objective: We sought to determine whether the combination of the LTRA montelukast and the LABA salmeterol could provide an effective therapeutic strategy for asthma.Methods and Measurements: In a randomized, placebo-controlled, crossover study of 192 subjects with moderate asthma, we compared the clinical efficacy of regular treatment over 14 weeks with the combination of montelukast and salmeterol to that with the combination of beclomethasone and salmeterol in moderate asthma. The primary efficacy outcome was time to treatment failure.Main Results: Three months after the randomization of the last subject, the Data and Safety Monitoring Board determined that the primary research question had been answered and terminated the trial. The combination of montelukast and salmeterol was inferior to the combination of beclomethasone and salmeterol as judged by protection against asthma treatment failures (p = 0.0008), lung function (26 L/min difference in a.m. peak expiratory flow rate, p = 0.011), asthma control score (0.22 difference in Asthma Control Questionnaire score, p = 0.038), and markers of inflammation and airway reactivity.Conclusions: Patients with moderate asthma similar to those we studied should not substitute the combination of an LTRA and an LABA for the combination of inhaled corticosteroid and an LABA. [ABSTRACT FROM AUTHOR]

Background: Pharmacogenetic studies in asthma cohorts, primarily made up of White people of European descent, have identified loci associated with response to inhaled beta agonists and corticosteroids (ICSs). Differences exist in how individuals from different ancestral backgrounds respond to long-acting beta agonist (LABA) and ICSs. Therefore, we sought to understand the pharmacogenetic mechanisms regulating therapeutic responsiveness in individuals of African descent., Methods: We did ancestry-based pharmacogenetic studies of children (aged 5-11 years) and adolescents and adults (aged 12-69 years) from the Best African Response to Drug (BARD) trials, in which participants with asthma uncontrolled with low-dose ICS (fluticasone propionate 50 μg in children, 100 μg in adolescents and adults) received different step-up combination therapies. The hierarchal composite outcome of pairwise superior responsiveness in BARD was based on asthma exacerbations, a 31-day difference in annualised asthma-control days, or a 5% difference in percentage predicted FEV 1 . We did whole-genome admixture mapping of 15 159 ancestral segments within 312 independent regions, stratified by the two age groups. The two co-primary outcome comparisons were the step up from low-dose ICS to the quintuple dose of ICS (5 × ICS: 250 μg twice daily in children and 500 μg twice daily in adolescents and adults) versus double dose (2-2·5 × ICS: 100 μg twice daily in children, 250 μg twice daily in adolescents and adults), and 5 × ICS versus 100 μg fluticasone plus a LABA (salmeterol 50 μg twice daily). We used a genome-wide significance threshold of p<1·6 × 10 -4 , and tested for replication using independent cohorts of individuals of African descent with asthma., Findings: We included 249 unrelated children and 267 unrelated adolescents and adults in the BARD pharmacogenetic analysis. In children, we identified a significant admixture mapping peak for superior responsiveness to 5 × ICS versus 100 μg fluticasone plus salmeterol on chromosome 12 (odds ratio [OR local African ] 3·95, 95% CI 2·02-7·72, p=6·1 × 10 -5 ) fine mapped to a locus adjacent to RNFT2 and NOS1 (rs73399224, OR allele dose 0·17, 95% CI 0·07-0·42, p=8·4 × 10 -5 ). In adolescents and adults, we identified a peak for superior responsiveness to 5 × ICS versus 2·5 × ICS on chromosome 22 (OR local African 3·35, 1·98-5·67, p=6·8 × 10 -6 ) containing a locus adjacent to TPST2 (rs5752429, OR allele dose 0·21, 0·09-0·52, p=5·7 × 10 -4 ). We replicated rs5752429 and nominally replicated rs73399224 in independent African American cohorts., Interpretation: BARD is the first genome-wide pharmacogenetic study of LABA and ICS response in clinical trials of individuals of African descent to detect and replicate genome-wide significant loci. Admixture mapping of the composite BARD trial outcome enabled the identification of novel pharmacogenetic variation accounting for differential therapeutic responses in people of African descent with asthma., Funding: National Institutes of Health, National Heart, Lung, and Blood Institute., Competing Interests: Declaration of interests VEO reports consulting fees from Sanofi and fees for serving on independent data monitoring committees for Sanofi and Regeneron Pharmaceuticals. SJS reports receiving consulting fees, paid to his institution, from AstraZeneca, GlaxoSmithKline, Moderna, Propeller Health, Regeneron, and Sanofi, as well as a research grant from Propeller Health. ERB reports receiving consulting fees and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, consulting fees from AstraZeneca, MedImmune, GlaxoSmithKline, Novartis, and Sanofi–Regeneron, and participating in trials as an employee of Wake Forest School of Medicine and the University of Arizona for AstraZeneca, MedImmune, Boehringer Ingelheim, Cephalon–Teva Pharmaceuticals, Genentech, GlaxoSmithKline, Johnson & Johnson (Janssen), Novartis, and Sanofi–Regeneron. VMC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. WP reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DM reports receiving grant support and donated drugs from GlaxoSmithKline, Genentech, Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, fees for serving on a data and safety monitoring board from Novartis, and donated drugs from Merck. FDM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support from Johnson & Johnson, and consulting fees from Copeval and Commence. EH-L reports a fellowship from the Spanish Ministry of Science, Innovation, and Universities. MP-Y reports grants from the Spanish Ministry of Economy, Industry, and Competitiveness, the State Research Agency and the European Regional Development Funds from the European Union (MICIU/AEI/FEDER, UE), and grant support from GlaxoSmithKline, Spain. SJK reports receiving donated drugs from Merck–Organon, Genentech, GlaxoSmithKline, and Regeneron and owning stock in Merck. LBB reports receiving consulting fees and lecture fees from Aerocrine, GlaxoSmithKline, Genentech–Novartis, and AstraZeneca, advisory board fees and donated drugs from Merck, fees for serving on a data safety monitoring board from DBV Technologies, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals and Boehringer Ingelheim, honoraria from WebMD–Medscape, advisory board fees and lecture fees from Sanofi–Regeneron, advisory board fees and consulting fees from Vectura, and advisory board fees from Circassia. MDC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and consulting fees from Genentech and Novartis. JCC reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. MC reports receiving grant support, lecture fees, and donated drugs from Boehringer Ingelheim, donated drugs from Merck, consulting fees, lecture fees, and donated drugs from Teva Pharmaceuticals, consulting fees and lecture fees from Boston Scientific and Genentech, consulting fees from Nuvaira, Aviragen, 4D Pharma, VIDA Diagnostics, Mallinckrodt Pharmaceuticals, Theravance, Therabron, and Vectura, grant support, consulting fees, and lecture fees from Sanofi-Aventis, grant support and lecture fees from AstraZeneca and GlaxoSmithKline, grant support from Chiesi and Novartis, and lecture fees from Regeneron Pharmaceuticals. LCD reports receiving grant support and consulting fees from AstraZeneca, and consulting fees from Sanofi–Regeneron. FH reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. DJJ reports grant support from GlaxoSmithKline, consulting fees from Novartis, Sanofi, Regeneron, Vifor Pharma, and AstraZeneca, and fees for serving on a data and safety monitoring board from Pfizer. NJ reports receiving honorarium for consulting from GlaxoSmithKline pharmaceuticals and Pulmocide. MK reports receiving grant support from Chiesi and Sanofi. JAK reports personal fees for independent data monitoring committee participation from Sanofi and research funding from the American Lung Association—Airway Clinical Research Centers Network. SCL reports grant funding from the American Lung Association—Airway Clinical Research Centers Network. RFL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, and lecture fees from Thermo Fisher Scientific. JJL reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. NL reports receiving grant support, advisory board fees, and donated drugs from GlaxoSmithKline, grant support, consulting fees, and advisory board fees from AstraZeneca, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, grant support from Genentech, grant support and advisory board fees from Sanofi–Regeneron, and donated drugs from Merck and Boehringer Ingelheim. WCM reports receiving grant support and donated drugs from Boehringer Ingelheim, donated drugs from Merck and Teva Pharmaceuticals, grant support and advisory board fees from AstraZeneca, GlaxoSmithKline, and Sanofi–Regeneron, and grant support from Novartis, Cumberland Pharmaceuticals, and Gossamer Bio. SPP reports receiving advisory board fees from AstraZeneca, GlaxoSmithKline, Mylan, Teva Pharmaceuticals, Sanofi–Regeneron, and Theravance, fees for serving as clinical trial adjudicator from Quintiles, fees for serving on a data and safety monitoring board from Genentech, fees for serving as chair of a data and safety monitoring board from Novartis, and honoraria from PRIME. JAP reports receiving donated drugs from Boehringer Ingelheim, Merck, Teva Pharmaceuticals, and GlaxoSmithKline. LJS reports receiving donated drugs from Boehringer Ingelheim and Teva Pharmaceuticals, and fees for serving on a data and safety monitoring board and donated drugs from Merck. JS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, advisory board fees from PulmOne Advanced Medical Devices, advisory board fees, honoraria, and travel support from Regeneron–Sanofi–Genzyme, holding patents #6 090 618, #6 114 311, #6 284 743, #6 291 211, #6 297 221, #6 331 527, and #7 169 764 on a smooth-muscle gene promoter (SM22 alpha), holding pending patent PCT/US2014/032186 on a method for determining respiratory physiological parameters, holding pending patent 62/872,980 on remodilins for airway remodelling and organ fibrosis, and holding pending patent 62/828,122 on remodilins to prevent or treat cancer metastasis, glaucoma, and hypoxia. CAS reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. SW reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals, grant support and consulting fees from AstraZeneca and Sanofi, and consulting fees from Pieris Pharmaceuticals. DAM reports receiving donated drugs from Boehringer Ingelheim, Merck, and Teva Pharmaceuticals. EI reports receiving grant support and consulting fees from AstraZeneca, Novartis, and Genentech, consulting fees from Regeneron Pharmaceuticals, Bird Rock Bio, Nuvelution Pharmaceuticals, Vitaeris, Sanofi Genzyme, Entrinsic Health Solutions, Pneuma Respiratory, 4D Pharma, Sienna Biopharmaceuticals, and Equillium, grant support, consulting fees, and donated drugs from Merck, Teva Pharmaceutical Industries, and GlaxoSmithKline, serving as a consultant for Vorso, receiving grant support and donated drugs from Vifor Pharma, Boehringer Ingelheim, and Teva Pharmaceuticals, grant support from Sanofi and AstraZeneca, and donated drugs from Circassia. MEW reports receiving grant support and consulting fees from AstraZeneca, Novartis, Sanofi, and GlaxoSmithKline, consulting fees from Regeneron Pharmaceuticals, Mylan, Genentech, Restorbio, Equillium, Boston Scientific, Genzyme, Gala Therapeutics, and Pulmatrix, fees for serving on a data and safety monitoring board from Sentien Biotechnologies, grant support, consulting fees, advisory board fees, and donated drugs from Teva Pharmaceuticals, consulting fees and donated drugs from Boehringer Ingelheim and Merck. MD, GAH, EJA CC, CE, AMF, DH, AM, ETN, SPS, MAS, SRW, EGB, and KB declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Morbidity from asthma is disproportionately higher among black patients than among white patients, and black patients constitute the minority of participants in trials informing treatment. Data indicate that patients with inadequately controlled asthma benefit more from addition of a long-acting beta-agonist (LABA) than from increased glucocorticoids; however, these data may not be informative for treatment in black patients., Methods: We conducted two prospective, randomized, double-blind trials: one involving children and the other involving adolescents and adults. In both trials, the patients had at least one grandparent who identified as black and had asthma that was inadequately controlled with low-dose inhaled glucocorticoids. We compared combinations of therapy, which included the addition of a LABA (salmeterol) to an inhaled glucocorticoid (fluticasone propionate), a step-up to double to quintuple the dose of fluticasone, or both. The treatments were compared with the use of a composite measure that evaluated asthma exacerbations, asthma-control days, and lung function; data were stratified according to genotypic African ancestry., Results: When quintupling the dose of fluticasone (to 250 μg twice a day) was compared with adding salmeterol (50 μg twice a day) and doubling the fluticasone (to 100 μg twice a day), a superior response occurred in 46% of the children with quintupling the fluticasone and in 46% of the children with doubling the fluticasone and adding salmeterol (P = 0.99). In contrast, more adolescents and adults had a superior response to added salmeterol than to an increase in fluticasone (salmeterol-low-dose fluticasone vs. medium-dose fluticasone, 49% vs. 28% [P = 0.003]; salmeterol-medium-dose fluticasone vs. high-dose fluticasone, 49% vs. 31% [P = 0.02]). Neither the degree of African ancestry nor baseline biomarkers predicted a superior response to specific treatments. The increased dose of inhaled glucocorticoids was associated with a decrease in the ratio of urinary cortisol to creatinine in children younger than 8 years of age., Conclusions: In contrast to black adolescents and adults, almost half the black children with poorly controlled asthma had a superior response to an increase in the dose of an inhaled glucocorticoid and almost half had a superior response to the addition of a LABA. (Funded by the National Heart, Lung, and Blood Institute; BARD ClinicalTrials.gov number, NCT01967173.)., (Copyright © 2019 Massachusetts Medical Society.)

Importance: In asthma and other diseases, vitamin D insufficiency is associated with adverse outcomes. It is not known if supplementing inhaled corticosteroids with oral vitamin D3 improves outcomes in patients with asthma and vitamin D insufficiency., Objective: To evaluate if vitamin D supplementation would improve the clinical efficacy of inhaled corticosteroids in patients with symptomatic asthma and lower vitamin D levels., Design, Setting, and Participants: The VIDA (Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma) randomized, double-blind, parallel, placebo-controlled trial studying adult patients with symptomatic asthma and a serum 25-hydroxyvitamin D level of less than 30 ng/mL was conducted across 9 academic US medical centers in the National Heart, Lung, and Blood Institute's AsthmaNet network, with enrollment starting in April 2011 and follow-up complete by January 2014. After a run-in period that included treatment with an inhaled corticosteroid, 408 patients were randomized., Interventions: Oral vitamin D3 (100,000 IU once, then 4000 IU/d for 28 weeks; n = 201) or placebo (n = 207) was added to inhaled ciclesonide (320 µg/d). If asthma control was achieved after 12 weeks, ciclesonide was tapered to 160 µg/d for 8 weeks, then to 80 µg/d for 8 weeks if asthma control was maintained., Main Outcomes and Measures: The primary outcome was time to first asthma treatment failure (a composite outcome of decline in lung function and increases in use of β-agonists, systemic corticosteroids, and health care)., Results: Treatment with vitamin D3 did not alter the rate of first treatment failure during 28 weeks (28% [95% CI, 21%-34%] with vitamin D3 vs 29% [95% CI, 23%-35%] with placebo; adjusted hazard ratio, 0.9 [95% CI, 0.6-1.3]). Of 14 prespecified secondary outcomes, 9 were analyzed, including asthma exacerbation; of those 9, the only statistically significant outcome was a small difference in the overall dose of ciclesonide required to maintain asthma control (111.3 µg/d [95% CI, 102.2-120.4 µg/d] in the vitamin D3 group vs 126.2 µg/d [95% CI, 117.2-135.3 µg/d] in the placebo group; difference of 14.9 µg/d [95% CI, 2.1-27.7 µg/d])., Conclusions and Relevance: Vitamin D3 did not reduce the rate of first treatment failure or exacerbation in adults with persistent asthma and vitamin D insufficiency. These findings do not support a strategy of therapeutic vitamin D3 supplementation in patients with symptomatic asthma., Trial Registration: clinicaltrials.gov Identifier: NCT01248065.

Study Objective: Obstructive sleep apnea is prevalent among people with asthma, but underlying mechanisms remain unknown. Inhaled corticosteroids may contribute. We tested the effects of orally inhaled fluticasone propionate (FP) on upper airway (UAW) during sleep and wakefulness., Study Design: 16-week single-arm study., Participants: 18 (14 females, mean [ ± SD] age 26 ± 6 years) corticosteroid-naïve subjects with mild asthma (FEV1 89 ± 8% predicted)., Interventions: High dose (1,760 mcg/day) inhaled FP., Measurements: (1) UAW collapsibility (passive critical closing pressure [Pcrit]); (2) tongue strength (maximum isometric pressure-Pmax, in KPa) and endurance-time (in seconds) able to maintain 50% Pmax across 3 trials (Ttot)-at anterior and posterior locations; (3) fat fraction and volume around UAW, measured by magnetic resonance imaging in three subjects., Results: Pcrit overall improved (became more negative) (mean ± SE) (-8.2 ± 1.1 vs. -12.2 ± 2.2 cm H2O, p = 0.04); the response was dependent upon baseline characteristics, with older, male gender, and worse asthma control predicting Pcrit deterioration (less negative). Overall, Pmax increased (anterior p = 0.02; posterior p = 0.002), but Ttot generally subsided (anterior p = 0.0007; posterior p = 0.06), unrelated to Pcrit response. In subjects studied with MRI, fat fraction and volume increased by 20.6% and 15.4%, respectively, without Pcrit changes, while asthma control appeared improved., Conclusions: In this study of young, predominantly female, otherwise healthy subjects with well-controlled asthma and stiff upper airways, 16-week high dose FP treatment elicited Pcrit changes which may be dependent upon baseline characteristics, and determined by synchronous and reciprocally counteracting local and lower airway effects. The long-term implications of these changes on sleep disordered breathing severity remain to be determined.

Clinical asthma studies across different age groups (ie, cross-age studies) can potentially offer insight into the similarities, differences, and relationships between childhood and adult asthma. The National Institutes of Health's Asthma Research Network (AsthmaNet) is unique and innovative in that it has merged pediatric and adult asthma research into a single clinical research network. This combination enhances scientific exchange between pediatric and adult asthma investigators and encourages the application of cross-age studies that involve participants from multiple age groups who are generally not studied together. The experience from AsthmaNet in the development of cross-age protocols highlights some of the issues in the evaluation of cross-age research in asthma. The aim of this review is to summarize these challenges, including the selection of parallel cross-age clinical interventions, identification of appropriate controls, measurement of meaningful clinical outcomes, and various ethical and logistic issues., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Tiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described., Objective: We sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response., Methods: Data from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs)., Results: Although approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not., Conclusion: Although these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy., (Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: Long-acting beta-agonist (LABA) therapy improves symptoms in patients whose asthma is poorly controlled by an inhaled glucocorticoid alone. Alternative treatments for adults with uncontrolled asthma are needed., Methods: In a three-way, double-blind, triple-dummy crossover trial involving 210 patients with asthma, we evaluated the addition of tiotropium bromide (a long-acting anticholinergic agent approved for the treatment of chronic obstructive pulmonary disease but not asthma) to an inhaled glucocorticoid, as compared with a doubling of the dose of the inhaled glucocorticoid (primary superiority comparison) or the addition of the LABA salmeterol (secondary noninferiority comparison)., Results: The use of tiotropium resulted in a superior primary outcome, as compared with a doubling of the dose of an inhaled glucocorticoid, as assessed by measuring the morning peak expiratory flow (PEF), with a mean difference of 25.8 liters per minute (P<0.001) and superiority in most secondary outcomes, including evening PEF, with a difference of 35.3 liters per minute (P<0.001); the proportion of asthma-control days, with a difference of 0.079 (P=0.01); the forced expiratory volume in 1 second (FEV1) before bronchodilation, with a difference of 0.10 liters (P=0.004); and daily symptom scores, with a difference of -0.11 points (P<0.001). The addition of tiotropium was also noninferior to the addition of salmeterol for all assessed outcomes and increased the prebronchodilator FEV1 more than did salmeterol, with a difference of 0.11 liters (P=0.003)., Conclusions: When added to an inhaled glucocorticoid, tiotropium improved symptoms and lung function in patients with inadequately controlled asthma. Its effects appeared to be equivalent to those with the addition of salmeterol. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00565266.).

The asthmatic response to the common cold is highly variable, and early characteristics that predict worsening of asthma control following a cold have not been identified. In this prospective multicentric cohort study of 413 adult subjects with asthma, the mini-Asthma Control Questionnaire (mini-ACQ) was used to quantify changes in asthma control and the Wisconsin Upper Respiratory Symptom Survey-21 (WURSS-21) to measure cold severity. Univariate and multivariable models were used to examine demographic, physiological, serological and cold-related characteristics for their relationship to changes in asthma control following a cold. Clinically significant worsening of asthma control was observed following a cold (mean+/-SD increase in mini-ACQ score of 0.69+/-0.93). Univariate analysis demonstrated that season, centre location, cold duration and cold severity measurements were all associated with a change in asthma control. Multivariable analysis of the covariates available within the first 2 days of cold onset revealed that the day 2 and cumulative sum of day 1 and 2 WURSS-21 scores were significant predictors of the subsequent changes in asthma control. In asthmatic subjects, cold severity within the first 2 days can be used to predict subsequent changes in asthma control. This information may help clinicians prevent deterioration in asthma control following a cold.

We hypothesized that using calcium channel blockers (CCBs) that dilate microvasculature during percutaneous coronary intervention (PCI) would result in lower postprocedural creatine phosphokinase (CPK). PCI can be complicated by elevated CPK that has been associated with impaired microvascular perfusion. Nitroglycerin (NTG), the conventional PCI vasodilator, dilates epicardial arteries but does not affect the microvasculature. We hypothesized that using CCBs that dilate the microvasculature would result in lower postprocedural CPK values. Patients (n = 816) without evidence of acute myonecrosis undergoing PCI were divided into two groups based on whether they received intracoronary NTG or CCB during PCI. Postprocedural CPK values were compared using a repeated-measures ANOVA and a random coefficient model. By repeated-measures analysis, the NTG group had CPK values of 88%, 83%, and 89% of the CCB group's CPK values at < 8, 8-14, and > 14 hr after PCI (P = 0.0080, 0.0002, and 0.0244), respectively. In a random coefficient model, the NTG group had CPK values 84%, 84%, and 89% of the CCB group's mean CPK values at 6, 12, and 18 hr after PCI (P = 0.0003, 0.0006, and 0.0403), respectively. Peak CPK values occurred earlier with CCB, although the maximal CPK was similar in both groups. Intracoronary CCB use is associated with an accelerated release of CPK after PCI compared with NTG. This is consistent with more efficient relief of microvascular obstruction with CCB. It suggests that myonecrosis may originate with vascular trauma at the time of PCI and its enzymatic expression is modifiable with different vasodilators., ((c) 2005 Wiley-Liss, Inc.)

The operative treatment of elderly patients with inflammatory bowel disease (IBD) has often been avoided in favor of medical management because of a perceived increase in surgical risk. This study sought to define the following in the elderly IBD patient population: (1) the risk of surgical management and (2) those factors affecting risk. Thirty patients with IBD, aged 60 years or more, who were surgically managed by a single surgeon over a 10-year period, were retrospectively matched to 75 patients with IBD who were less than 60 years of age; patients were matched according to sex, date of surgery, and type of surgery performed. Regression analysis using generalized estimating equation methodology to account for the matched clusters of patients was performed to evaluate the effect of age group on the complication rate, operating room time, and length of hospital stay. Presence of comorbid conditions, surgical indications, prior surgery for IBD, and the use of immunosuppressive medications were studied in multivariate models, adjusting for age group. By means of univariate analysis, the odds of complications in elderly IBD patients were shown to be statistically higher than the odds seen in younger patients (47% vs. 20%, P = 0.01). Also observed in the elderly group were a longer length of hospital stay (11.5 days vs. 7.1 days, P = 0.001) and longer operating room time (249 minutes vs. 212 minutes, P = 0.02). Multivariate analysis revealed that the effect of age remained statistically significant, even when adjusted for potential confounding variables such as comorbidity, medications, date of diagnosis of IBD, and indications for surgery. The complication outcome was significantly associated with the surgical indication, with obstruction, fistula, and bleeding having increased odds of complications as compared with other indications (odds ratio = 1.7 vs. 4.2 vs. 7.2, respectively, P = 0.02). The length of hospital stay similarly was significantly associated with the surgical indication (fistula, 10.5 days vs. bleeding, 9.8 days vs. obstruction, 7.4 days vs. other, 9.3 days; P = 0.04) and a history of prior surgery. A significant interaction for length of hospital stay was present between age group and prior surgery status (with prior surgery: old, 18 days vs. young, 6.4 days, P = 0.0001; without prior surgery: old, 9.5 days vs. young 7.3 days, P = 0.10). Elderly patients with IBD have an increased rate of postoperative complications along with an increased length of hospital stay and increased operating room time. This effect of age persists when adjusted for comorbidity and immunosuppressive therapy. Complications are most dependent on surgical indications, with obstruction being the least and bleeding the worst predictive factors. The longest hospital stay is associated with patients who require surgery for fistulous disease and patients who have undergone previous surgery. The fact that the higher complication rate seen in older patients with IBD is associated with disease-defined surgical indications suggests that IBD in elderly patients may be more aggressive than what is observed in younger individuals.

The goal of this study was to establish a reliable method to evaluate systemic bioavailability and to determine equisystemic effects (microgram dose producing equal systemic cortisol suppression) of inhaled corticosteroids (ICS). Steroid naive asthma subjects (n = 156) were enrolled at six centers. A 1-week doubling dose design was used for each of six ICS and matched placebos for a total of four doses. Systemic effect was evaluated by hourly plasma cortisol concentrations (8 P.M. to 8 A.M.), 12- and 24-hour urine cortisol concentrations, and a morning blood osteocalcin. The area under the concentration-time curve for hourly cortisol concentrations was the best outcome variable to assess systemic effect. For the six ICS and matching placebos (beclomethasone-chlorofluorocarbon [CFC], budesonide dry powder inhaler [DPI], fluticasone DPI, fluticasone-CFC metered dose inhaler [MDI], flunisolide-CFC, and triamcinolone-CFC), only the placebo group and fluticasone DPI did not demonstrate a significant dose-response effect. Thus microgram comparison of all ICS could only be performed at a 10% cortisol suppression: flunisolide-CFC - 936; triamcinolone-CFC - 787; beclomethasone-CFC - 548; fluticasone DPI - 445; budesonide DPI - 268; fluticasone-CFC MDI - 111. This study represents the first step in evaluation of ICS efficacy based on equisystemic (cortisol suppression) effects of a given ICS, rather than doses judged arbitrarily to be comparable on a microgram basis.

Randomization is a required component for the success of most controlled clinical trials. To ensure that the benefits of randomization are realized, well defined and carefully planned procedures must be put in place prior to the start of a trial. This paper presents a detailed account of the registration and randomization procedures implemented for the first four clinical trials of the Asthma Clinical Research Network.

Because there is reason to believe that genetic variants could account for different treatment responses in subjects with asthma, it is important to collect blood for genetic-analysis purposes when conducting clinical trials in asthma. This article describes issues related to maintaining subject confidentiality, tracking and shipping blood samples, quality control procedures at the laboratory performing the genotyping, and necessary data verification checks when implementing the genetic-analysis database for the Asthma Clinical Research Network.

Well-designed data management processes are essential in ensuring the quality of data collected in multicenter clinical trials. This paper describes the data management processes and systems that were developed by the data coordinating center of the Asthma Clinical Research Network. A combination of manual and electronic processes has been designed to process clinical trial data from the point of collection to statistical analysis. A distributed database management system consisting of modular applications for separate data processing activities was developed to enter, track, verify, validate, and edit collected data. In addition, processes for monitoring and reporting data quality are discussed.

The objective of the present study was to determine the role of sex steroids in the development of self-perceived competence during adolescence. The Harter Self-Perception Scale was administered to 56 adolescents with delayed puberty who were receiving depo-testosterone (males) or conjugated estrogens (females) administered in 3-month blocks alternating with placebo. Treatment was given at three dose levels approximating early, middle, and late pubertal replacement levels. Hormone treatments had a significant positive effect for both males and females in one subscale domain--perceived job competence. Significant positive hormone effects were also obtained for perceptions of romantic appeal and close friendship in females and perception of athletic abilities in males. It can be inferred from the results of this study that the hormonal changes associated with sexual maturation have targeted influences on specific domains of self-perceived competence and that there are clear gender differences.

We studied 49 boys and girls with delayed physical sexual maturation during treatment with sex steroids. We found significant agreements, but also some disagreements between physicians' and subjects' Tanner sexual maturity ratings. We found neither effects of treatment with sex steroids nor gender differences, comparing ratings between physicians and patients.

The purpose of this study was to investigate the effects of administration of sex steroids on self-reported sexual responses and behaviors in hypogonadal adolescents. We used a randomized, double blind, placebo-controlled, cross-over, clinical trial as the experimental design. The subjects were 39 boys and 16 girls with delayed puberty. We treated girls with oral conjugated estrogen and boys with testosterone enanthate in 3 dose levels intended to simulate early, middle, and late pubertal levels. We administered a modification of the Udry sexual behavior questionnaire after each 3-month placebo and treatment period to detect the effect of sex steroids on self-reported sexual behaviors and responses. We employed a strict intent to treat statistical analytical model. The data showed significant effects of the administration of testosterone to boys causing increases in nocturnal emission and touching behaviors at the mid- and high doses. No other treatment effects on sexual behaviors or responses were seen in boys. For girls, there was a significant increase in necking caused by the administration of estrogen only at the late pubertal dose. No other treatment effects on sexual behaviors or responses were seen in girls. We noted some gender differences for thinking about sex, sexual "turn-on," and the nature of sexual behavior. The administration of physiological doses of sex steroids to boys or girls with delayed puberty have few effects on sexual behaviors and responses.

Although peak expiratory flow (PEF) measurements are recommended for monitoring and assessing treatment of asthmatic patients, and widely employed to assess outcome in clinical trials and epidemiologic studies, information about performance of peak flow meters (PFM) under field conditions is lacking. We describe a simple testing system consisting of a testing chamber, a spirometer, and a calibration syringe to evaluate the relative accuracy or median relative bias (MRB), precision, or inter-quartile range (IQR) of the mini-Wright PFM. The relative accuracy ranged from -4.4 to 13.2% (mean, 4.1%) and the precision from 0.06 to 11.5% (mean, 1.2%). Durability of this PFM was assessed during a 26-wk clinical trial in 255 asthmatic subjects at five centers. Seventy-one PFM (19.9%) were identified as having failed to meet acceptance criteria, predominantly because of loss of relative accuracy, by the clinics at follow-up visits (n = 36), and by the Data Coordinating Center on retrospective review of quality control measurements submitted by the clinics (n = 35). This study indicates that a simple device can be used to evaluate the relative accuracy and precision of a given PFM and to ensure the quality of PEF measurements during a clinical trial. To the extent that one can extrapolate these data to other devices, our findings indicate that the failure rate of PFM over time can be high, indicating that quality control of a PFM over time is absolutely essential in clinical trials as well as in routine clinical care.

A randomized, double-blinded, placebo-controlled cross-over clinical trial was used to determine the role of sex steroids on the development of aggressive behaviors in 35 boys and 14 girls. Depo-testosterone (to boys) or conjugated estrogens (to girls) was administered in 3-month blocks alternating with placebo at three dose levels approximating early, middle and late pubertal amounts. The Olweus Multifaceted Aggression Inventory was administered after each placebo and treatment period to ascertain the effect of sex steroids on self-reported aggressive behaviors. We employed a strict intent-to-treat analytical model. The data demonstrated significant hormone effects on physical aggressive behaviors and aggressive impulses, but not in verbal aggressive behaviors nor aggressive inhibitions in both boys and girls. These results are the first to causally relate the administration of physiological doses of sex steroids to changes in aggressive behaviors in adolescents.

Objective: To characterize the patient population referred for radiation therapy for tonsillar cancer and to assess the effectiveness of use of only radiation therapy in this population., Design: We retrospectively reviewed the medical records of 21 patients referred to the Mayo Clinic in Rochester, Minnesota, from 1970 through 1988 for radiation therapy for squamous cell carcinoma of the tonsillar region., Material and Methods: The median age of the 21 study patients was 65 years (range, 45 to 92), and the male:female ratio was 12:9. In all patients, follow-up continued until death or for 2.25 to 16.25 years. Of the 21 patients, 17 had tumors that were either surgically unresectable or medically inoperable, and 20 had clinical stage III or IV disease. The median total dose of irradiation was 55 Gy., Results: Local control of the tonsillar cancer was as follows: T2, four of five patients; T3, seven of seven; and T4, five of nine. Thus, the local control rate was 76%. No associations were discovered among local control, total dose of radiation therapy, dose per fraction, overall duration of treatment, age, sex, or reason for referral for radiation therapy. Control of metastatic cervical adenopathy was as follows: clinical stage N1, seven of seven patients; N2, six of seven; and N3, one of one. (Six study patients had no nodal involvement.) The estimated 5-year cause-specific survival and overall survival rates were 77% and 31%, respectively., Conclusion: This study substantiates the effectiveness of radiation therapy in patients with squamous cell carcinoma of the tonsil.

Background: The authors determined the patterns of treatment failure in patients treated with surgery alone or surgery combined with postoperative radiation therapy for squamous cell carcinoma of the tonsil., Methods: Seventy-two patients underwent surgery alone (56) or surgery and postoperative adjuvant radiation therapy (16). All patients were followed up until death (40 patients) or for a minimum of 3.5 years. For patients treated with surgery alone, clinic notes, operative notes, and pathology reports and slides were reviewed to identify clinical or pathologic predictors of recurrence above the clavicles, cause-specific survival, and overall survival. For patients undergoing postoperative adjuvant radiation therapy, demographic, treatment, and pathologic variables were analyzed to identify factors associated with control of disease above the clavicles, disease-free survival, and overall survival., Results: The main pattern of treatment failure was above the clavicles. It occurred in 39% of patients treated with surgery alone and was significantly related (P = 0.002) to the overall clinical TNM stage. Disease recurrence above the clavicles occurred in 31% of patients undergoing surgery and postoperative adjuvant radiation therapy, despite their more advanced neck disease. Five-year overall survival for patients with clinical Stage III and IV disease who were treated with surgery and post-operative adjuvant radiation therapy was 100% and 78%, respectively. Five-year overall survival for patients treated with surgery alone who had clinical Stage III, IVA, or IVB disease was 56%, 43%, and 50%, respectively., Conclusion: We recommend postoperative adjuvant radiation therapy for patients with clinical Stage III or IV squamous cell carcinoma of the tonsil who have undergone complete surgical resection because this appears to improve control of disease above the clavicles and overall survival.

Background: The authors previously reported that 30 minutes of oral cryotherapy inhibits 5-fluorouracil (5-FU)-induced stomatitis. The current trial was designed to determine whether a longer duration of cryotherapy would provide additional protection., Methods: This trial involved patients who were receiving their first course of a 5-FU plus leucovorin chemotherapy regimen, for which stomatitis is a major dose-limiting toxicity. These patients were randomized to receive either 30 or 60 minutes of oral cryotherapy given at around the same time as the 5-FU therapy., Results: A total of 178 evaluable patients were studied. Both cryotherapy groups had similar degrees of mucositis., Conclusion: The authors continue to recommend the use of 30 minutes of oral cryotherapy for patients receiving bolus intensive courses of 5-FU-based chemotherapy.

Between January 1971 and December 1986, 55 patients with squamous cell carcinoma of the tongue base underwent complete surgical resection with curative intent. No preoperative or postoperative adjuvant therapy was administered. The study group consisted of 41 men and 14 women (median age 61 years). All patients were followed until death (39 patients) or for a median of 9.4 years. Local control at 5 years was 74%. No predictors of local recurrence were discovered. Control in the dissected neck at 5 years was 68%. Control of cancer above the clavicles at 5 years was 48%. Distant metastases developed in 14% of the patients by 5 years. Cause-specific survival at 5 years was 65%. A Cox multivariate regression analysis revealed that pathologic N stage was the only significant independent predictor of recurrence in the dissected neck, recurrence above the clavicles, and cause-specific survival. The 5-year overall survival was 55%. Surgical mortality was 4%.

Between January 1975 and December 1985, 45 patients with carcinoma in situ or invasive squamous cell carcinoma of the glottic larynx received radiation therapy at the Mayo Clinic. Local control in the entire group of 45 patients was 84% (in 6 of 6 with carcinoma in situ and in 32 of 39 with invasive cancers). Three of seven patients (43%) with local recurrences underwent successful larynx-preserving surgical procedures; thus, the rate of laryngeal preservation was 91%. In our study of several treatment factors, including the duration of treatment, type of treatment (continuous course versus split course), photon energy (60Co versus 4-MV photons versus 6-MV photons), total dose, and dose per fraction, we found that only total dose of 6,300 cGy or more was associated with significantly improved local control (in 35 of 38 patients [92%]). Two patients (4%) died of uncontrolled delayed nodal metastases, one of which was preceded by a local recurrence. Severe laryngeal edema developed in two patients, associated with recurrent glottic carcinoma in one of them. No larynx was lost because of complications. In our current treatment recommendations, patients receive a total dose of 6,300 cGy in 28 fractions of 225 cGy each, administered in a continuous course with use of 6-MV photons.