Efficacy of recombinant human C1 esterase inhibitor across anatomic locations in acute hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) may occur at or spread to multiple anatomic locations during an acute attack. Recombinant human C1 esterase inhibitor (rhC1-INH) is approved for treating acute HAE attacks. OBJECTIVE: To examine the time to the beginning of symptom relief with rhC1-INH by attack location. METHODS: Data for patients ≥12 years of age with an acute HAE attack who received rhC1-INH 50 IU/kg or placebo were pooled from two double-blind clinical trials with open-label extensions. The time to the beginning of symptom relief was defined as the first time point that the visual analog scale severity score at an attack location decreased by ≥20 mm versus baseline, with persistence. Data were reported as median time values (95% confidence interval [CI]). RESULTS: For abdominal attacks, the median time to the beginning of symptom relief was 60.0 minutes (95% CI, 47.0-62.0 minutes; n = 194 attacks) with rhC1-INH versus 240.0 minutes (95% CI, 45.0-720.0 minutes; n = 15 attacks) with placebo. The median time to the beginning of symptom relief for peripheral attacks was 105.0 minutes (95% CI, 90.0-120.0 minutes; n = 169 attacks) with rhC1-INH versus 303.0 minutes (95% CI, 180.0-720.0 minutes; n = 17 attacks) with placebo. For oro-facial-pharyngeal-laryngeal attacks or urogenital attacks, the median time to the beginning of symptom relief with rhC1-INH was 64.5 minutes (95% CI, 60.0-120.0 minutes; n = 36 attacks) and 119.0 minutes (95% CI, 40.0-270.0 minutes; n = 13 attacks), respectively, versus 306.0 minutes (95% CI, 30.0-495.0 minutes; n = 6 attacks) and 320.0 minutes (n = 1 attack) with placebo. CONCLUSION: In shortening the median time to the beginning of symptom relief of acute HAE attacks, rhC1-INH 50 IU/kg was efficacious, regardless of attack location.

Efficacy of recombinant human C1 esterase inhibitor for the treatment of severe hereditary angioedema attacks.

BACKGROUND: Severe attacks of hereditary angioedema (HAE) are debilitating and potentially life threatening, and can increase anxiety and the use of medical resources. OBJECTIVE: This post hoc assessment evaluated recombinant human C1 esterase inhibitor (rhC1-INH) used to treat acute severe HAE attacks. METHODS: In a double-blind, randomized-controlled trial (RCT), patients with an HAE attack (baseline visual analog scale score of ≥50 mm, with severe attacks defined as ≥75 mm) were randomly assigned to receive rhC1-INH (50 IU/kg for patients who weighed <84 kg; 4200 IU for patients who weighed ≥84 kg) or placebo. Also, in an open-label extension (OLE) study of rhC1-INH, oropharyngeal-laryngeal attacks were analyzed. Rescue therapy with rhC1-INH 50 IU/kg (≤4200 IU) was permitted after 4 hours or for life-threatening symptoms (in the RCT) or after 1 hour (in the OLE study). The primary end point measured the time to the beginning of symptom relief by using the Treatment Effects Questionnaire. RESULTS: Of 75 adults in the RCT, 43 had severe attacks and received either rhC1-INH (n = 24) or placebo (n = 19). The median (95% confidence interval) time to the onset of symptom relief totaled 90.0 minutes (95% confidence interval, 47.0-120.0 minutes) versus 334.0 minutes (95% confidence interval, 105.0 to not calculable minutes; hazard ratio, 2.5; p = 0.02), for rhC1-INH and placebo, respectively. Open-label rhC1-INH rescue therapy was administered to 1 of 24 in the rhC1-INH group (4.2%) and 10 of 19 in the placebo group (52.6%). During the OLE study, the median onset of symptom relief with rhC1-INH for eight oropharyngeal-laryngeal HAE attacks was 69.0 minutes (95% confidence interval, 59.0-91.0 minutes). CONCLUSION: In the current study, rhC1-INH was efficacious in resolving severe HAE attacks, including oropharyngeal-laryngeal attacks. The rhC1-INH rescue treatment rapidly improved symptoms for patients who received placebo and who experienced worsening or sustained symptoms.

Efficacy and safety of an intravenous C1-inhibitor concentrate for long-term prophylaxis in hereditary angioedema.

BACKGROUND: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis. OBJECTIVE: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP). METHODS: The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason. RESULTS: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port). CONCLUSION: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Recombinant Human C1-Esterase Inhibitor to Treat Acute Hereditary Angioedema Attacks in Adolescents.

BACKGROUND: Recombinant human C1-esterase inhibitor (rhC1-INH) is efficacious and well tolerated for managing hereditary angioedema (HAE) attacks in adults. However, there are insufficient data on its efficacy and safety in adolescents. OBJECTIVE: To evaluate the efficacy and safety profiles of rhC1-INH for acute HAE attacks in adolescents. METHODS: Adolescents (aged 12-18 y) with HAE enrolled in 2 randomized controlled trials and 2 open-label extension trials were included and received intravenous rhC1-INH for acute attacks. Times to the beginning of sustained symptom relief (visual analog scale change from baseline ≥20 mm) and minimal symptoms (visual analog scale score of <20 mm across locations) were assessed. Safety parameters included hypersensitivity reactions, anti-rhC1-INH antibodies, and host-related impurities. RESULTS: Sixteen adolescents (50 attacks, aged 14-18 y) received rhC1-INH. Attacks were managed with single-dose rhC1-INH 50 U/kg (46.0%) and single-dose rhC1-INH 2100 U (16%), and 32.0% were treated with additional doses after receiving an initial rhC1-INH 2100 U dose (total dose, 4200-6300 U). Most attacks (88.0%) occurred at a single location; 59.1% (26 of 44) were abdominal. Across the first 5 attacks, median times to the beginning of symptom relief ranged from 19.0 to 78.5 minutes; median times to minimal symptoms ranged from 120 to 190 minutes. Pharmacokinetics showed that rhC1-INH restored functional plasma C1-esterase inhibitor levels to the normal (>70%) range for almost all evaluable patients. No severe or drug-related adverse events or hypersensitivity reactions occurred. No treatment-emergent antibodies to rhC1-INH or host-related impurities were observed. CONCLUSIONS: rhC1-INH is efficacious and well tolerated among adolescents with HAE.

Oral immunotherapy for peanut allergy: multipractice experience with epinephrine-treated reactions.

BACKGROUND: Peanut allergy creates the risk of life-threatening anaphylaxis that can disrupt psychosocial development and family life. The avoidance management strategy often fails to prevent anaphylaxis and may contribute to social dysfunction. Peanut oral immunotherapy may address these problems, but there are safety concerns regarding implementation in clinical practice. OBJECTIVE: The purpose of this report is to communicate observations about the frequency of epinephrine-treated reactions during peanut oral immunotherapy in 5 different allergy/immunology practices. METHODS: Retrospective chart review of peanut oral immunotherapy performed in 5 clinical allergy practices. RESULTS: A total of 352 treated patients received 240,351 doses of peanut, peanut butter, or peanut flour, and experienced 95 reactions that were treated with epinephrine. Only 3 patients received 2 doses of epinephrine, and no patient required more intensive treatment. A total of 298 patients achieved the target maintenance dose for a success rate of 85%. CONCLUSION: Peanut oral immunotherapy carries a risk of systemic reactions. In the context of oral immunotherapy, those reactions were recognized and treated promptly. Peanut oral immunotherapy may be a suitable therapy for patients managed by qualified allergists/immunologists.

Budesonide inhalation suspension versus montelukast in children aged 2 to 4 years with mild persistent asthma.

BACKGROUND: Budesonide inhalation suspension (BIS) and montelukast provide acceptable asthma control, whereas overall measures favored BIS in children aged 2 to 8 years with mild persistent asthma. OBJECTIVE: We compared BIS and montelukast over a 1-year period in children aged 2 to 4 years with asthma. METHODS: Data were derived from a 52-week, open-label, randomized, active-controlled, multicenter study (NCT00641472). Children with mild asthma received either BIS 0.5 mg or montelukast 4 to 5 mg once daily. Patients were stepped up to twice-daily BIS or oral corticosteroids for mild or severe asthma worsening, respectively. Primary efficacy assessment was time to first additional asthma medication for exacerbation over 52 weeks. RESULTS: Two hundred two patients, age 2 to 4 years, received BIS (n = 105) or montelukast (n = 97). No difference was observed between the BIS and montelukast groups in median time to first additional asthma medication over 52 weeks (183 vs 86 days). Statistically significant differences were observed in favor of BIS over montelukast in the percentage of patients requiring oral steroids at 52 weeks (21.9% vs 37.1%; P = .022), the rate (number/patient/year) of additional courses of medication (1.35 vs 2.30; P = .003), the rate of additional oral steroid therapy (0.44 vs 0.88; P = .008), and caregivers' ability to manage the patient's symptoms (P = .026). Both treatments were well tolerated. CONCLUSION: BIS and montelukast provided acceptable asthma control in children aged 2 to 4 years with mild persistent asthma with no significant difference between treatments in the primary end point; however, several secondary outcomes showed statistically significant differences (and many had numerical differences) in favor of BIS over montelukast.

Nanofiltered C1 esterase inhibitor (human) for hereditary angioedema attacks in pregnant women.

Data are limited on hereditary angioedema (HAE) in pregnant women and the safety and efficacy of therapies for treatment and prevention of HAE attacks during pregnancy. Prospective studies are unlikely given the rarity of HAE and ethical considerations regarding enrollment of pregnant female subjects in clinical trials. A retrospective analysis of clinical trial and compassionate-use data was conducted to identify subjects who received nanofiltered C1 esterase inhibitor (C1 INH-nf; human) during pregnancy. This study evaluates the efficacy and safety of human C1 INH-nf for treatment and prevention of HAE attacks in pregnant women. Data from pregnant subjects enrolled in either open-label extensions of two randomized, double-blind, placebo-controlled trials of C1 INH-nf or in a compassionate-use program were retrospectively analyzed for efficacy (e.g., total attacks, attack frequency during prophylaxis, and monthly attack rates) and safety (e.g., pregnancy outcomes and adverse events). C1 INH-nf was administered as acute treatment, preprocedural prophylaxis, or routine prophylaxis. C1 INH-nf prophylaxis substantially reduced monthly attack rates. Of 16 subjects, 13 delivered 14 healthy neonates (1 set of twins). Two adverse fetal outcomes were reported; neither was considered by the principal investigator to be related to C1 INH-nf. One subject's pregnancy outcome was unknown. This analysis shows a favorable risk-benefit profile for C1 INH-nf for managing HAE during pregnancy. NCT Identifier: NCT00438815; NCT00462709.

Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study.

BACKGROUND: The efficacy of recombinant human C1 inhibitor (rhC1INH) for the treatment of patients with acute hereditary angioedema (HAE) attacks has been demonstrated in 2 randomized, double-blind, placebo-controlled studies. OBJECTIVE: To assess the safety and efficacy of rhC1INH for repeated treatment of acute attacks of HAE. METHODS: In this open-label extension study, patients with eligible HAE attacks were treated with an intravenous 50-U/kg dose of rhC1INH with an option for an additional dose of 50 U/kg based on clinical response. Time to beginning of relief was assessed by patients using a 100-mm visual analogue scale (VAS). Safety evaluation was based on the clinical laboratory results and adverse events. RESULTS: Sixty-two patients were treated for 168 attacks (range, 1-8 attacks per patient). A total of 90% of the attacks were treated with a single 50-U/kg dose of rhC1INH. Median times to beginning of symptom relief for the first 5 attacks were 37 to 67 minutes. More than 90% of attacks responded within 4 hours after treatment with rhC1INH. There was no requirement for increased dosing with successive treatments. Thirty-nine patients (63%) reported at least 1 treatment-emergent adverse event, with most events rated mild to moderate. Seven severe treatment-emergent adverse events were reported, and all were considered to be unrelated to treatment with rhC1INH. CONCLUSION: The results of this open-label extension support continued efficacy of rhC1INH after repeated treatments for subsequent HAE attacks. There was no increase in adverse event reporting after repeated exposure to rhC1INH.

Pathways activated during human asthma exacerbation as revealed by gene expression patterns in blood.

BACKGROUND: Asthma exacerbations remain a major unmet clinical need. The difficulty in obtaining airway tissue and bronchoalveolar lavage samples during exacerbations has greatly hampered study of naturally occurring exacerbations. This study was conducted to determine if mRNA profiling of peripheral blood mononuclear cells (PBMCs) could provide information on the systemic molecular pathways involved during asthma exacerbations. METHODOLOGY/PRINCIPAL FINDINGS: Over the course of one year, gene expression levels during stable asthma, exacerbation, and two weeks after an exacerbation were compared using oligonucleotide arrays. For each of 118 subjects who experienced at least one asthma exacerbation, the gene expression patterns in a sample of peripheral blood mononuclear cells collected during an exacerbation episode were compared to patterns observed in multiple samples from the same subject collected during quiescent asthma. Analysis of covariance identified genes whose levels of expression changed during exacerbations and returned to quiescent levels by two weeks. Heterogeneity among visits in expression profiles was examined using K-means clustering. Three distinct exacerbation-associated gene expression signatures were identified. One signature indicated that, even among patients without symptoms of respiratory infection, genes of innate immunity were activated. Antigen-independent T cell activation mediated by IL15 was also indicated by this signature. A second signature revealed strong evidence of lymphocyte activation through antigen receptors and subsequent downstream events of adaptive immunity. The number of genes identified in the third signature was too few to draw conclusions on the mechanisms driving those exacerbations. CONCLUSIONS/SIGNIFICANCE: This study has shown that analysis of PBMCs reveals systemic changes accompanying asthma exacerbation and has laid the foundation for future comparative studies using PBMCs.

Safety of daily albuterol in infants with a history of bronchospasm: a multi-center placebo controlled trial.

INTRODUCTION: Inhaled short-acting bronchodilators are recommended for the quick relief of bronchospasm symptoms in children including those less than five years of age. However, limited safety data is available in this young population. METHODS: Safety data were analyzed from a randomized, double-blind, parallel group, placebo-controlled multicenter, study evaluating albuterol HFA 90microg or 180microg versus placebo three times a day for 4 weeks using a valved holding chamber, Aerochamber Plus and facemask in children birth

Daclizumab improves asthma control in patients with moderate to severe persistent asthma: a randomized, controlled trial.

RATIONALE: Airway inflammation in asthma is associated with increased activated CD25(+) T cells, IL-2, and soluble IL-2 receptors (IL-2Rs). OBJECTIVES: A randomized, double-blinded, placebo-controlled study was used to evaluate the safety and efficacy of daclizumab, a humanized IgG1 monoclonal antibody against the IL-2R alpha chain (CD25) of activated lymphocytes, in adults with moderate to severe persistent asthma. METHODS: Patients with obstructive pulmonary functions, despite inhaled corticosteroids (ICS), were switched to equivalent dose inhaled triamcinolone acetate acetonide (TAA). Patients dependent on ICS were randomized (3:1) to daclizumab (intravenous loading dose, 2 mg/kg, then 1 mg/kg) or placebo every 2 weeks, added to stable-dose TAA through Week 12 (Treatment Period 1). Over Weeks 12-20 (Treatment Period 2), patients tapered TAA while on the study drug, and were followed for 16 weeks off the study drug. MEASUREMENTS AND MAIN RESULTS: Among 115 evaluable patients (88 daclizumab, 27 placebo), groups had similar age, disease duration, and length of ICS use. During Treatment Period 1, daclizumab improved FEV(1) (daclizumab, 4.4 +/- 1.80% vs. placebo, 1.5 +/- 2.39%; P = 0.05), and reduced daytime asthma symptoms (P = 0.018) and short-acting inhaled beta(2)-agonist use (P = 0.009). Daclizumab treatment prolonged time to exacerbation (P = 0.024). Adverse events were evenly distributed between groups, although there were more serious adverse events in the patients treated with daclizumab. CONCLUSIONS: Daclizumab improved pulmonary function and asthma control in patients with moderate to severe chronic asthma inadequately controlled on ICS. The mechanism of action likely involves inhibition of proinflammatory cytokine generation by IL-2R blockade in activated T cells. Clinical trial registered with www.clinicaltrials.gov (NCT00028288).

Asthma control in pediatric patients treated with once-daily or twice-daily nebulized budesonide inhalation suspension (Pulmicort Respules).

Composite end points may represent more meaningful assessments of asthma control compared with traditional discrete measures. The effects of budesonide inhalation suspension (BIS) on composite measures of asthma control have not been investigated. The purpose of this study was to assess changes from baseline in percentages of asthma control days (ACDs; days without asthma symptoms and rescue medication use; primary outcome), symptom-free days (SFDs), and rescue medication-free days (RFDs) with BIS treatment. We retrospectively analyzed separately data from three randomized, double-blind, placebo-controlled, 12-week studies (N = 1018) of BIS. Study I patients (4-8 years) were dependent on daily inhaled corticosteroids (ICS; n = 178). Study II patients (6 months to 8 years) were using one or more asthma medications (n = 481). Study III patients (6 months to 8 years) were using daily non-ICS asthma medication (n = 359). Patients treated with BIS showed substantial improvements from baseline in all composite variables (ACDs, 21-31% versus placebo [PBO], 10-18%; SFDs, 20-29% versus PBO, 11-18%; RFDs, 24-47% versus PBO, 12-28%). In study I, each BIS regimen statistically significantly improved all three asthma control measures versus PBO. In study II, BIS 0.5 mg twice daily (b.i.d.) improved ACDs, BIS 0.25 mg b.i.d. and 0.5 mg b.i.d. improved SFDs, and all BIS regimens improved RFDs statistically significantly. In study III, BIS 0.25 mg once daily (q.d.) improved all three measures, BIS 0.5 mg q.d. improved SFDs, and 1.0 mg q.d. improved RFDs statistically significantly. In conclusion, BIS improved composite measures of asthma control in children.

Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma.

BACKGROUND: Budesonide inhalation suspension and the leukotriene receptor antagonist montelukast have demonstrated efficacy in children with mild persistent asthma, but comparative long-term studies in young children are needed. OBJECTIVE: To compare the long-term efficacy and safety of budesonide inhalation suspension and montelukast. METHODS: After a run-in period, children 2 to 8 years old with mild asthma or recurrent wheezing were randomized to once-daily budesonide inhalation suspension 0.5 mg or once-daily oral montelukast 4 or 5 mg for 52 weeks. Subjects were stepped up to twice-daily budesonide inhalation suspension or oral corticosteroids for mild or severe asthma worsening, respectively. The primary outcome was time to first additional medication for asthma worsening at 52 weeks. Secondary variables included times to the first additional asthma medication measured at 12 and 26 weeks; times to the first asthma exacerbation (mild and severe) measured at 12, 26, and 52 weeks; exacerbation rates (mild and severe) over a period of 52 weeks; diary variables (eg, peak expiratory flow [PEF]); patient-reported outcomes; and Global Physician and Caregiver Assessments. RESULTS: No significant between-group differences were observed for time to first additional asthma medication at 52 weeks; however, time to first additional asthma medication was longer (unadjusted P = .050) at 12 weeks and exacerbation rates were lower over a period of 52 weeks (unadjusted P = .034) for budesonide versus montelukast. Time to first severe exacerbation (requiring oral corticosteroids) was similar in both groups, but the percentage of subjects requiring oral corticosteroids over a period of 52 weeks was lower with budesonide (25.5% vs 32.0%). Peak flow and Caregiver and Physician Global Assessments favored budesonide. CONCLUSION: Both treatments provided acceptable asthma control; however, overall measures favored budesonide inhalation suspension over montelukast. CLINICAL IMPLICATIONS: These findings are consistent with studies in older children demonstrating better outcomes with inhaled corticosteroids versus montelukast.

Efficacy and safety of inhaled fluticasone propionate chlorofluorocarbon in 2- to 4-year-old patients with asthma: results of a double-blind, placebo-controlled study.

BACKGROUND: Current asthma guidelines recommend inhaled glucocorticoids administered via pressurized metered-dose inhaler (MDI) with a holding chamber as the preferred therapy for young children with asthma. OBJECTIVE: To evaluate the efficacy and safety of fluticasone propionate chlorofluorocarbon MDI use in preschool-aged children with asthma. METHODS: Randomized, double-blind, placebo-controlled, parallel-group study of 332 children aged 24 to 47 months with asthma. Fluticasone propionate chlorofluorocarbon, 44 or 88 microg twice daily, or placebo (chlorofluorocarbon propellant alone) administered for 12 weeks via MDI with a valved holding chamber and an attached face mask. The primary efficacy measure was average change in 24-hour daily asthma symptom scores. Safety assessments included adverse events, 12-hour urinary cortisol excretion, and growth. RESULTS: Treatment failure (ie, asthma exacerbation) occurred in approximately half as many fluticasone propionate-treated patients (13%-14%) as placebo-treated patients (24%). Compared with placebo users, patients treated with fluticasone propionate, 88 microg twice daily, had a 13% greater improvement in the mean proportion of symptom- and albuterol-free days (P = .02); asthma symptom scores and albuterol use were also significantly reduced. Patients treated with fluticasone propionate, 44 microg twice daily, had greater improvements than placebo-treated patients; however, differences did not reach statistical significance. At end point, the growth velocities of fluticasone propionate-treated patients were within the range of those of placebo-treated patients. No clinically relevant changes in 12-hour overnight urinary cortisol excretion were observed. CONCLUSION: Compared with placebo use, fluticasone propionate, 88 microg administered twice daily, significantly reduced asthma exacerbations, asthma symptoms, and rescue albuterol use and was well tolerated, with no clinically relevant systemic effects, as measured by growth velocity or 12-hour urinary cortisol excretion levels.

Safety features of budesonide inhalation suspension in the long-term treatment of asthma in young children.

Early inhaled corticosteroid treatment improves symptom control and pulmonary function in children with asthma; however, long-term safety data are limited in infants and young children. This study assessed the long-term safety of budesonide inhalation suspension (BIS) in young children with persistent asthma. To continue to provide BIS to children who needed it-prior to US Food and Drug Administration approval-children 8 years of age or younger with mild, moderate, or severe persistent asthma who previously completed a 52-week open-label study of BIS were enrolled in an additional multicenter, open-label study that was to be concluded upon BIS approval. Patients already receiving BIS continued their current regimens. Patients younger than 4 years and those 4 years of age or older not receiving BIS at baseline started with total daily doses of 0.5 and 1.0 mg, respectively. BIS doses were adjusted throughout the study based on individual response. Adverse events and changes in laboratory parameters, vital signs, and physical examination findings were assessed. Of 198 enrolled patients, 152 (76.8%), 68 (34.3%), and 31 (15.7%) completed 1, 2, and 3 years of BIS treatment (mean daily dose 0.62+/-0.32 mg), respectively. One hundred sixty-six (83.8%) patients experienced an adverse event, of which 8.6% were considered by the investigator to be drug related. Adverse events were those typically occurring in a pediatric asthma population, with respiratory infection (49.0%) and sinusitis (25.3%) occurring at the greatest incidence. Only 2 patients withdrew due to adverse events. Mean changes in laboratory test results and physical examination findings were not clinically important throughout the study. Long-term BIS treatment is well tolerated in young children with persistent asthma, with a safety profile similar to that of short-term administration.

Effect of ciclesonide and fluticasone on hypothalamic-pituitary-adrenal axis function in adults with mild-to-moderate persistent asthma.

BACKGROUND: Despite their proven efficacy in the treatment and prevention of asthma exacerbations, current inhaled corticosteroids carry safety concerns, especially adrenal suppression. Ciclesonide (hydrofluoroalkane propellant) is a novel inhaled corticosteroid with few, if any, clinical adverse events. OBJECTIVE: To evaluate the potential effects of ciclesonide therapy on the dynamic cortisol response to sequential low- and high-dose cosyntropin stimulation in adults with mild-to-moderate persistent asthma. METHODS: This was a double-blind, randomized, placebo-controlled, 12-week study in adults with mild-to-moderate asthma. One hundred sixty-four patients were randomized and treated; 148 patients completed the study. Fluticasone propionate (chlorofluorocarbon propellant) was used as an active comparator. The doses administered were 320 microg of ciclesonide once daily, 320 microg of ciclesonide twice daily, and 440 microg of fluticasone propionate twice daily, all doses ex-actuator. RESULTS: For both ciclesonide groups, changes in mean low- and high-dose peak serum cortisol levels and in 24-hour urinary free cortisol levels corrected for creatinine were small vs baseline and comparable with placebo. For the fluticasone propionate group, significant reductions vs placebo in serum cortisol levels in response to high-dose cosyntropin stimulation and in 24-hour urinary free cortisol levels were observed. Oral candidiasis rates were 2.5% for 320-microg/d ciclesonide, 2.4% for 640-microg/d ciclesonide, and 22.0% for 880-microg/d fluticasone propionate. CONCLUSIONS: These findings confirm the safety of ciclesonide therapy, demonstrating that at doses up to 640 microg/d, the drug does not affect sensitive markers of adrenal function.

Variability of symptoms in mild persistent asthma: baseline data from the MIAMI study.

OBJECTIVE: To describe the variability of the asthma phenotype in patients with mild persistent asthma enrolled in the Mild Asthma Montelukast versus Inhaled Corticosteroid (MIAMI) study. METHODS: The variability of asthma rescue-free days, asthma symptoms, albuterol use, medical resource use, and exercise Limitations among patients with documented mild persistent asthma was compared between the month before study enrollment and the last 2 weeks of the run-in period. RESULTS: Patients eligible for randomization (n = 400), aged 15-85 years, exhibited symptoms (mean +/- SD) 3.6 +/- 1.3 days/week, beta-agonist use 3.5 +/- 1.3 days/week, and normal FEV1 (94.0 +/- 9.9% predicted) during the last 2 weeks of the run-in period. In the year before enrollment, medical intervention for asthma flares was common: 38.5% made office visits, 15.8% had oral corticosteroids, and 8.3% required emergency room or hospitalized care. In the month before enrollment, 11.8% experienced daily symptoms, and 28.3% had limitations of normal activity. Patients with daily symptoms in the month before study enrollment, compared with those having less-than-daily symptoms, experienced fewer rescue-free days (P = 0.024) and had more days per week with symptoms (P = 0.008) and requiring albuterol (P = 0.048) during the run-in; FEV1 was similar for both groups (93.1% vs. 94.2% predicted, respectively). CONCLUSION: Patients with mild persistent asthma reported a substantial disease burden in the year before enrollment. The asthma burden experienced by these patients both before and during the run-in period was of sufficient severity to support the recommendation that mild persistent asthma should be managed with daily controller therapy.