Mometasone or Tiotropium in Mild Asthma with a Low Sputum Eosinophil Level.

BACKGROUND: In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS: In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (<2% or ≥2%). The primary outcome was the response to mometasone as compared with placebo and to tiotropium as compared with placebo among patients with a low sputum eosinophil level who had a prespecified differential response to one of the trial agents. The response was determined according to a hierarchical composite outcome that incorporated treatment failure, asthma control days, and the forced expiratory volume in 1 second; a two-sided P value of less than 0.025 denoted statistical significance. A secondary outcome was a comparison of results in patients with a high sputum eosinophil level and those with a low level. RESULTS: A total of 73% of the patients had a low eosinophil level; of these patients, 59% had a differential response to a trial agent. However, there was no significant difference in the response to mometasone or tiotropium, as compared with placebo. Among the patients with a low eosinophil level who had a differential treatment response, 57% (95% confidence interval [CI], 48 to 66) had a better response to mometasone, and 43% (95% CI, 34 to 52) had a better response to placebo (P = 0.14). In contrast 60% (95% CI, 51 to 68) had a better response to tiotropium, whereas 40% (95% CI, 32 to 49) had a better response to placebo (P = 0.029). Among patients with a high eosinophil level, the response to mometasone was significantly better than the response to placebo (74% vs. 26%) but the response to tiotropium was not (57% vs. 43%). CONCLUSIONS: The majority of patients with mild, persistent asthma had a low sputum eosinophil level and had no significant difference in their response to either mometasone or tiotropium as compared with placebo. These data provide equipoise for a clinically directive trial to compare an inhaled glucocorticoid with other treatments in patients with a low eosinophil level. (Funded by the National Heart, Lung, and Blood Institute; SIENA ClinicalTrials.gov number, NCT02066298.).

Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma.

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.).

Albuterol/budesonide for the treatment of exercise-induced bronchoconstriction in patients with asthma: The TYREE study.

BACKGROUND: PT027 is a fixed-dose combination of albuterol (salbutamol) and budesonide in a single pressurized metered-dose inhaler. OBJECTIVE: To evaluate the efficacy and safety of albuterol/budesonide compared with placebo in patients with asthma and exercise-induced bronchoconstriction (EIB). METHODS: In this randomized, double-blind, 2-period, single-dose crossover study, adolescents and adults with asthma and EIB (defined by ≥20% decrease from pre-exercise challenge forced expiratory volume in 1 second [FEV1]) were randomized to albuterol/budesonide (180/160 µg) followed by placebo (n = 29) or the reverse sequence (n = 31). Subjects were stratified by background therapy (as-needed short-acting ß2-agonist alone or low-to-medium dose inhaled corticosteroid plus as-needed short-acting ß2-agonist). FEV1 was measured 5 minutes pre-dose, 30 minutes postdose (5 minutes pre-exercise challenge [baseline]), and 5, 10, 15, 30, and 60 minutes postexercise. The primary end point was maximum percentage fall from baseline in FEV1 up to 60 minutes postexercise challenge. RESULTS: Least squares mean maximum percentage fall in FEV1 up to 60 minutes postexercise challenge was 5.45% with albuterol/budesonide vs 18.97% with placebo (difference, -13.51% [95% confidence interval, -16.94% to -10.09%]; P < .001). More subjects were fully protected (maximum percentage fall in FEV1 post-exercise challenge < 10%) with albuterol/budesonide than with placebo (78.3% vs 28.3%; P < .001). The treatment effect was consistent irrespective of background inhaled corticosteroid therapy, and albuterol/budesonide was well tolerated. CONCLUSION: In adolescents and adults with asthma and EIB, a single dose of albuterol/budesonide 180/160 µg taken approximately 30 minutes before exercise was significantly more effective than placebo in preventing EIB. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04234464.

Albuterol multidose dry powder inhaler efficacy and safety versus placebo in children with asthma.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) that does not require coordination of actuation with inhalation has been developed. OBJECTIVE: To evaluate the efficacy and safety of albuterol MDPI versus placebo MDPI after chronic dosing in children with asthma. METHODS: This phase III, double-blind, parallel-group study included children with asthma (ages, 4-11 years) with forced expiratory volume in 1 second (FEV1) of 50-95% of predicted. After a 14-day run-in period wherein the patients continued their current asthma therapy and received single-blind placebo MDPI, they were randomized to albuterol MDPI 90 µg per inhalation, two inhalations four times daily (total daily dose, 720 µg), or placebo for 3 weeks. Pulmonary function was assessed on days 1 and 22. Efficacy and safety were evaluated by measuring the baseline-adjusted percent-predicted FEV1 (PPFEV1) area under the time curve over 6 hours (AUC0-6) after the dose and adverse events, respectively. RESULTS: The full analysis set included 184 patients. Patients treated with albuterol MDPI versus patients treated with placebo MDPI had significantly greater baseline-adjusted PPFEV1 AUC0-6 over 3 weeks (least squares mean difference, 25.0%•hour, which favored albuterol; p < 0.001). The benefit of albuterol (mean change in PPFEV1) was evident 5 minutes after dosing and lasted several hours; the maximal effect was noted 1 to 2 hours after dosing. Albuterol MDPI was well tolerated. CONCLUSIONS: In children with persistent asthma, albuterol MDPI improved pulmonary function significantly better than placebo MDPI over 3 weeks of treatment. Clinical efficacy was evident within 5 minutes of dosing and maintained for >2 hours. Four times daily administration was well tolerated.

A randomized study of BI 671800, a CRTH2 antagonist, as add-on therapy in poorly controlled asthma.

BACKGROUND: Asthma is characterized by a complex interaction of inflammatory mediators. The prostaglandin D2 receptor, chemoattractant receptor-homologous molecule on Th2 cells (CRTH2), plays a pivotal role in the pathogenesis of allergic airway inflammation. OBJECTIVE: To ealuate the efficacy, safety, and pharmacokinetics of BI 671800, a CRTH2 antagonist, when added to inhaled corticosteroid therapy in adult patients with symptomatic asthma. METHODS: In this phase IIa, 12-week, randomized, double-blind, three-period, four-treatment, incomplete block crossover trial, BI 671800 was administered either as a single 400-mg dose in the morning (A.M.) or evening (P.M.), or 200 mg twice daily (A.M. and P.M.) versus placebo, together with fluticasone propionate (44 µg, two inhalations twice daily). The primary end point was the change from baseline in trough forced expiratory volume in 1 second percentage predicted after 4 weeks. The secondary end point was the change in Asthma Control Questionnaire score from baseline. RESULTS: A total of 108 patients were randomized and treated. After 4 weeks, the adjusted mean (± SE) treatment differences for the primary end point versus placebo were 0.08 ± 0.62%, 0.28 ± 0.61%, and 0.67 ± 0.63% for BI 671800 at 200 mg twice daily, 400 mg A.M., and 400 mg P.M., respectively (not statistically significant). No statistically significant or clinically meaningful differences in the Asthma Control Questionnaire score were observed versus placebo. Each treatment was well tolerated. CONCLUSION: BI 671800 at a dose of 400 mg administered for 4 weeks with fluticasone propionate did not provide clinical improvement in patients with asthma; reasons for this are unclear, but it may be due to insufficient inhibition of the CRTH2 receptor at the doses used.

Randomized, placebo-controlled study of cetirizine and loratadine in children with seasonal allergic rhinitis.

BACKGROUND: Pharmacologic treatment is a mainstay of allergy therapy and many caregivers use over-the-counter antihistamines for the treatment of seasonal allergic rhinitis (SAR) symptoms in children. OBJECTIVE: To assess the efficacy and safety of cetirizine 10 mg syrup versus loratadine 10 mg syrup versus placebo syrup in a randomized double-blind study of children, ages 6-11 years, with SAR. METHODS: This randomized, double-blind, parallel-group, placebo-controlled study was conducted at 71 U.S. centers during the spring tree and grass pollen season. After a 1-week placebo run-in period, qualified subjects were randomized to once-daily cetirizine 10 mg (n = 231), loratadine 10 mg (n = 221), and placebo (n = 231) for 2 weeks. The primary efficacy end point was change from baseline in the subject's mean reflective total symptom severity complex (TSSC) score over 14 days. RESULTS: Children treated with cetirizine experienced significantly greater TSSC score reductions versus children treated with placebo over 14 days (least square mean change, -2.1 versus -1.6; p = 0.006). The differences in TSSC score improvement over 14 days between the cetirizine versus loratadine groups (-2.1 versus -1.8; p = 0.124) and between the loratadine versus placebo groups (-1.8 versus -1.6; p = 0.230) were not statistically significant. Predominant adverse events in the cetirizine, loratadine, and placebo groups were headache (3.5, 3.6, and 3.1%, respectively) and pharyngitis (3.5, 2.7, and 3.5%, respectively). Somnolence was reported in three subjects (1.3%) treated with cetirizine and in none of the other subjects. CONCLUSION: Cetirizine 10 mg was statistically significantly more efficacious than placebo in the treatment of SAR symptoms in children ages 6-11 years. Symptom improvement was not significantly different between the loratadine 10 mg and placebo groups.

Randomised, double-blind, placebo-controlled crossover study to investigate different dosing regimens of olodaterol delivered via Respimat® in patients with moderate to severe persistent asthma.

BACKGROUND: A Phase II, multicentre, randomised, double-blind, placebo-controlled, crossover trial comparing the 24-h forced expiratory volume in 1 s (FEV1) time profile after 3 weeks' treatment with once-daily (QD) or twice-daily (BID) olodaterol (at the same total daily dose) versus placebo delivered via Respimat® in patients with moderate to severe asthma. METHODS: Patients were randomised to different sequences of olodaterol with 2-week washout, either as a total daily dose of 5 µg (5 µg QD [AM] or 2.5 µg BID) or placebo, or 10 µg (10 µg QD [AM] or 5 µg BID) or placebo. Primary end point was FEV1 area under the curve from 0 to 24 h (AUC0-24) response (defined as change from study baseline FEV1) after 3 weeks. Key secondary end points were FEV1 AUC0-12 and AUC12-24 responses. RESULTS: Two hundred and six patients received treatment. All olodaterol treatments demonstrated statistically significant improvements in FEV1 AUC0-24 response at 3 weeks versus placebo (p < 0.0001); adjusted mean treatment difference versus placebo was 0.191 L for olodaterol 2.5 µg BID (95 % confidence interval [CI] 0.152, 0.229), 0.150 L for 5 µg QD (95 % CI 0.111, 0.189), 0.228 L for 5 µg BID (95 % CI 0.190, 0.266) and 0.209 L for 10 µg QD (95 % CI 0.170, 0.247). These results were supported by the key secondary end points. Olodaterol 5 µg QD provided numerically lower mean values for 24-h bronchodilation than olodaterol 2.5 µg BID (p = 0.0465), with no statistically significant difference between treatment with olodaterol 10 µg QD and 5 µg BID. No relevant differences in morning and evening peak expiratory flow or Asthma Control Questionnaire scores at 3 weeks were observed between different doses and regimens. Adverse events were generally mild to moderate and comparable between groups. CONCLUSIONS: All doses and dose frequencies provided adequate 24-h bronchodilation superior to placebo. Based on the results of this study, it would be reasonable to include both posologies of 5 µg olodaterol daily (5 µg QD or 2.5 µg BID, both delivered in two puffs per dose from the Respimat® inhaler) in subsequent studies. Further studies are necessary to confirm the optimum dosing regimen in asthma. No safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov NCT01311661.

Impact of exhaled nitric oxide measurements on treatment decisions in an asthma specialty clinic.

BACKGROUND: Asthma management in an outpatient setting is best accomplished by clinical evaluation coupled with spirometry and symptom evaluation, but these assessments do not provide information about airway inflammation. Exhaled nitric oxide (fraction of exhaled nitric oxide [FeNO]) measures T-helper cell type 2-mediated airway inflammation and may be a useful adjunct in asthma management. OBJECTIVE: To determine whether the use of FeNO in the specialist management of asthma results in more effective and cost-effective treatment decisions. METHODS: Fifty subjects 7 to 60 years old with established asthma participated in this observational study. Subjects were evaluated by clinical examination, spirometry, and symptom assessment using the Asthma Control Test, and clinicians estimated airway inflammation and made treatment decisions based on these assessments. Then, FeNO was measured, and changes in therapy based on FeNO levels were documented. The estimated cost impact of using FeNO was calculated presuming ongoing FeNO use in patient management. RESULTS: Without FeNO, the clinician's assessment of airway inflammation was incorrectly classified in 50% of subjects. FeNO results substantially altered treatment decisions in more than one third of subjects, notably medication augmentation in 10 (20%) and medication decreases in 8 (16%). Use of FeNO in addition to standard of care was estimated to save $629 per subject per year. CONCLUSION: Measurement of FeNO augments routine clinical assessment of asthma by measuring airway inflammation. Knowledge of FeNO affects medication treatment decisions to augment or decrease pharmacotherapy, which has important long-term asthma management implications, most notably the potential to lower the costs and morbidity associated with asthma exacerbation. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01729247.

Effect of cetirizine on symptom severity and quality of life in perennial allergic rhinitis.

The effect of cetirizine on quality of life (QOL) in subjects with perennial allergic rhinitis (PAR) has been previously evaluated using generic instruments. While generic QOL tools are used across various conditions, disease-specific instruments evaluate the impact of treatment on areas that are affected by that particular condition. This study evaluated the effect of cetirizine on symptom severity and health-related QOL, using a disease-specific instrument, in adults with PAR. This randomized, double-blind, placebo-controlled study was conducted at 15 U.S. centers outside the pollen allergy season. After a 1-week placebo run-in period, qualified subjects aged 18-65 years with PAR were randomized to once-daily cetirizine 10 mg (n = 158) or placebo (n = 163) for 4 weeks. Change from baseline in total symptom severity complex (TSSC) and overall Rhinitis Quality of Life Questionnaire (RQLQ) scores were primary efficacy end points. Cetirizine produced significantly greater improvements in mean TSSC for each treatment week (p < 0.05) and for the entire 4-week treatment period (p = 0.005) compared with placebo. After 4 weeks, cetirizine-treated subjects reported significantly greater overall improvement in RQLQ scores compared with placebo-treated subjects (p = 0.004). After 1 week, cetirizine produced significant improvements in the nasal symptoms, practical problems, and activities RQLQ domain scores compared with placebo (p < 0.05). After 4 weeks, cetirizine-treated subjects reported significant reductions in these RQLQ domain scores and in emotion domain scores compared with placebo-treated subjects (p < 0.05). Cetirizine 10 mg daily produced significant improvements in symptom severity and allergic rhinitis-related QOL compared with placebo in adults with PAR.

Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial.

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 ß-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.