Albuterol multidose dry powder inhaler and albuterol hydrofluoroalkane versus placebo in children with persistent asthma.

BACKGROUND: Many children struggle with albuterol hydrofluoroalkane (HFA) inhalers. Albuterol multidose dry powder inhaler (MDPI) may simplify rescue bronchodilator use in children. OBJECTIVE: To demonstrate the comparability of albuterol MDPI and albuterol HFA in children with asthma. METHODS: This phase II, multicenter, double-blind, double-dummy, single-dose, five-period, crossover study randomized patients (ages 4-11 years) with persistent asthma and prestudy forced expiratory volume in 1 second (FEV1) of 60-90% of predicted to 1 of 10 treatment sequences that contained albuterol MDPI (90 and 180 µg), albuterol HFA (90 and 180 µg), and placebo MDPI and placebo HFA. Efficacy was evaluated by measuring the area under the baseline-adjusted percent-predicted FEV1-time curve over 6 hours (PPFEV1 AUC0-6) after dosing. Safety was evaluated by adverse events. RESULTS: The full analysis set included 61 patients. Albuterol MDPI and albuterol HFA significantly improved PPFEV1 AUC0-6 versus placebo (p ≤ 0.0107). Mean improvement (± standard error [SE]) in PPFEV1 AUC0-6 versus placebo with albuterol MDPI at 90 and 180 µg was similar (21.2 ± 4.87 [95% confidence interval {CI}, 11.60-30.81], and 22.6 ± 4.87 [95% CI, 13.00-32.20], %·hour, respectively). Mean improvement (± SE) with albuterol HFA 180 µg was significantly (p = 0.0226) greater versus albuterol HFA 90 µg (23.7 ± 4.85 [95% CI, 14.13-33.23], and 12.5 ± 4.85 [95% CI, 2.93-22.05], %·hour, respectively). All doses of albuterol were well tolerated. CONCLUSION: Albuterol MDPI 90 and 180 µg and albuterol HFA 180 µg provided similar and significant FEV1 improvements versus placebo; albuterol HFA 90 µg was significant versus placebo but seemed less effective based on absolute improvements in FEV1. ClinicalTrials.gov identifier: NCT01899144.

Safety and efficacy of pimecrolimus in atopic dermatitis: a 5-year randomized trial.

BACKGROUND AND OBJECTIVES: Atopic dermatitis (AD) primarily affects infants and young children. Although topical corticosteroids (TCSs) are often prescribed, noncorticosteroid treatments are needed because compliance with TCSs is poor due to concerns about their side effects. In this longest and largest intervention study ever conducted in infants with mild-to-moderate AD, pimecrolimus 1% cream (PIM) was compared with TCSs. METHODS: A total of 2418 infants were enrolled in this 5-year open-label study. Infants were randomized to PIM (n = 1205; with short-term TCSs for disease flares) or TCSs (n = 1213). The primary objective was to compare safety; the secondary objective was to document PIM's long-term efficacy. Treatment success was defined as an Investigator's Global Assessment score of 0 (clear) or 1 (almost clear). RESULTS: Both PIM and TCSs had a rapid onset of action with >50% of patients achieving treatment success by week 3. After 5 years, >85% and 95% of patients in each group achieved overall and facial treatment success, respectively. The PIM group required substantially fewer steroid days than the TCS group (7 vs 178). The profile and frequency of adverse events was similar in the 2 groups; in both groups, there was no evidence for impairment of humoral or cellular immunity. CONCLUSIONS: Long-term management of mild-to-moderate AD in infants with PIM or TCSs was safe without any effect on the immune system. PIM was steroid-sparing. The data suggest PIM had similar efficacy to TCS and support the use of PIM as a first-line treatment of mild-to-moderate AD in infants and children.

Safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate, a novel inhaled corticosteroid, in children aged 5-11 years with persistent asthma: A randomized trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate (FF) in children (5-11 years) with persistent asthma. Twenty-seven children received inhaled FF 100 µg or placebo via the ELLIPTA™ dry powder inhaler once daily for 14 days, with a ≥7 day washout period. Adverse events (AEs) were reported by eight (31%) and four (16%) subjects during FF 100 µg and placebo treatment, respectively. Headache was reported by three subjects during FF 100 µg treatment and by no subjects during placebo treatment, all other AEs were reported by only one subject on either treatment; there were no serious AEs. Following repeat dosing, the arithmetic mean (SD) FF Cmax was 26.71 pg/mL (9.16) at 31 minutes post-dose. Arithmetic mean (SD) FF AUC(0-t) was 121.44 pg h/mL (83.04). Arithmetic mean values for weighted mean (SD) serum cortisol (0-12 hours) on day 14 were 56.49 (16.51) and 67.57 (20.66) ng/mL for FF 100 µg and placebo, respectively. No clinically significant effect of FF on serum cortisol levels was observed. FF was well tolerated. Pharmacokinetic profiles were well defined and did not differ between age groups in the study population, and no clinically significant suppression of serum cortisol was observed.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting ß-Agonist, in Children Aged 5-11 Years with Persistent Asthma: A Randomized Trial.

This multi-center, randomized, double-blind, placebo-controlled, two-way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once-daily repeat doses of vilanterol 25 µg in children aged 5-11 years. Twenty-eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once-daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug-related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericia's correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well-tolerated and no long-acting ß2-agonist (LABA)-mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5-11 years.

A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age.

The trivalent inactivated influenza vaccine Fluarix™ is licensed in the US for adults and children from 3 years old. This randomized observer-blind study (NCT00764790) evaluated Fluarix™ at two doses; 0.25 ml (Flu-25) and 0.5 ml (Flu-50) in children aged 6-35 months. The primary objective was to demonstrate immunogenic non-inferiority vs. a control vaccine (Fluzone®; 0.25 ml). Children received Flu-25 (n = 1107), Flu-50 (n = 1106) or control vaccine (n = 1104) at Day 0 and for un-primed children, also on Day 28. Serum hemagglutination-inhibition titers were determined pre-vaccination and at Day 28 (primed) or Day 56 (un-primed). Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio, (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 10%). Reactogenicity/safety was monitored. The immune response to Flu-50 met all regulatory criteria. Indicated by adjusted GMT ratios [with 95% CI], the criteria for non-inferiority of Flu-50 vs. control vaccine were reached for the B/Florida strain (1.13 [1.01-1.25]) but not for the A/Brisbane/H1N1 (1.74 [1.54-1.98]) or A/Uruguay/H3N2 (1.72 [1.57-1.89]) strains. In children aged 18-35 months similar immune responses were observed for Flu-50 and the control vaccine. Flu-50 induced a higher response than Flu-25 for all strains. Temperature (≥ 37.5°C) was reported in 6.2%, 6.4%, and 6.6% of the Flu-25, Flu-50, and control group, respectively. Reactogenicity/safety endpoints were within the same range for all vaccines. In children aged 6-35 months, immune responses with Flu-50 fulfilled regulatory criteria but did not meet the pre-defined criteria for non-inferiority vs. control. This appeared to be due to differences in immunogenicity in children aged<18 months.

Efficacy and safety of triamcinolone acetonide aqueous nasal spray in children aged 2 to 5 years with perennial allergic rhinitis: a randomized, double-blind, placebo-controlled study with an open-label extension.

BACKGROUND: Intranasal corticosteroids (INSs) are the most effective treatment for allergic rhinitis (AR). However, available INS safety and efficacy data in children younger than 6 years are limited. OBJECTIVE: To report the first well-controlled study assessing the safety and efficacy of an INS in children aged 2 to 5 years with perennial AR. METHODS: In a 4-week, multicenter, double-blind, parallel-group study, patients were randomized to receive triamcinolone acetonide aqueous nasal spray (TAA AQ), 110 microg once daily, or placebo. A subset of children continued into a 6-month, open-label phase. Efficacy end points included total nasal symptom scores. Safety measures included reports of adverse events, morning serum cortisol levels before and after cosyntropin infusion, and growth as measured using office stadiometry. RESULTS: A total of 474 patients were randomized to receive TAA AQ (n = 236) or placebo (n = 238); 436 entered the open-label extension phase. Adjusted mean (SE) changes from baseline during the double-blind period in instantaneous and reflective total nasal symptom scores were -2.28 (0.16) and -2.31 (0.15), respectively, in the TAA AQ group (P = .09) vs -1.92 (0.16) and -1.87 (0.15) in the placebo group (P = .03). Adverse event rates were comparable between treatment groups. There was no significant change from baseline in serum cortisol levels after cosyntropin infusion at study end. The distribution of children by stature-for-age percentile remained stable during the study. CONCLUSIONS: Use of TAA AQ, 110 microg once daily, for up to 6 months offers a favorable efficacy to safety ratio in children aged 2 to 5 years with perennial AR.

Fluticasone propionate/salmeterol and exercise-induced asthma in children with persistent asthma.

RATIONALE: Exercise is a common trigger in children with persistent asthma and inhaled corticosteroids have been shown to effectively treat clinical manifestations of persistent asthma, including protection from decrements in lung function caused by exercise. The goal of this study was to evaluate the effectiveness of fluticasone propionate/salmeterol 100/50 mcg compared with fluticasone propionate 100 mcg for the prevention of airflow limitation triggered by standardized exercise challenge in pediatric and adolescent patients with persistent asthma. METHODS: Multicenter, randomized, double-blind, parallel group trial of 248 subjects with persistent asthma (age 4-17 years) randomized to receive fluticasone propionate/salmeterol (100/50 mcg twice daily) or fluticasone propionate alone (100 mcg twice daily) via Diskus for 4 weeks. Exercise challenge tests were performed during screening and approximately 8 hr after administration of the blinded study medication on Treatment Day 28. RESULTS: After 4 weeks of therapy both treatments provided protection following exercise challenge. The protection estimated by the maximal fall in FEV(1) was significantly better for fluticasone propionate/salmeterol (9.5 +/- 0.8% [mean +/- SE]) compared with fluticasone propionate alone (12.7 +/- 1.1%, P = 0.021). Statistically significant differences were not observed for asthma rescue-free days and asthma symptom-free days. CONCLUSION: Chronic dosing with fluticasone propionate/salmeterol in a single device provides superior protection compared with an inhaled corticosteroid alone in protecting against exercise-induced asthma in children with persistent asthma.

Efficacy and safety of fluticasone propionate hydrofluoroalkane inhalation aerosol in pre-school-age children with asthma: a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy and tolerability of fluticasone propionate (FP) hydrofluoroalkane (HFA) in children age 1 to < 4 years with asthma. STUDY DESIGN: Children were assigned (2:1) to receive FP HFA 88 mug (n = 239) or placebo HFA (n = 120) twice daily through a metered-dose inhaler with a valved holding chamber and attached facemask for 12 weeks. The primary efficacy measure was mean percent change from baseline to endpoint in 24-hour daily (composite of daytime and nighttime) asthma symptom scores. RESULTS: The FP-treated children had significantly greater (P < or = .05) reductions in 24-hour daily asthma symptom scores (-53.9% vs -44.1%) and nighttime symptom scores over the entire treatment period compared with the placebo group. Daytime asthma symptom scores and albuterol use were slightly more decreased with FP than with placebo; however, the differences were not statistically significant. Increases in the percentage of symptom-free days were comparable. The percentage of patients who experienced at least 1 adverse event was similar in the 2 groups. Baseline median urinary cortisol excretion values were comparable between the groups, and there was little change from baseline at endpoint. FP plasma concentrations demonstrated that systemic exposure was low. CONCLUSIONS: FP HFA 88 mug twice daily was effective and well tolerated in pre-school-age children with asthma.

Safety of budesonide inhalation suspension in infants aged six to twelve months with mild to moderate persistent asthma or recurrent wheeze.

OBJECTIVE: To compare the safety of budesonide inhalation suspension (BIS) with placebo in infants 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze. STUDY DESIGN: In this multicenter, randomized, double-blinded, parallel-group, placebo-controlled study, 141 patients received 0.5 mg BIS (n = 48), 1.0 mg BIS (n = 44), or placebo (n = 49) once daily for 12 weeks. The primary variable was adrenal function, based on cosyntropin-stimulated plasma cortisol levels. Spontaneous adverse events and clinical laboratory findings also were monitored. RESULTS: Overall, the types and frequencies of adverse events reported during the study were comparable across treatment groups. The response to cosyntropin stimulation was similar across treatment groups, with no significant difference between BIS treatment and placebo. CONCLUSIONS: The safety profile of BIS was similar to that of placebo, with no suppressive effect on adrenal function in patients 6 to 12 months of age with mild to moderate persistent asthma or recurrent wheeze.