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Background The role of roflumilast as a potential asthma treatment is not yet fully understood. A series of placebo-controlled trials were undertaken in order to investigate the safety and efficacy of roflumilast in asthma. Aim To evaluate the efficacy of roflumilast in nine randomized proof-of-concept, placebo-controlled monotherapy and combination therapy phase II and III clinical studies performed between 1997 and 2005. Methods The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 24 weeks. Data were analyzed from 4873 patients, 12–70 years of age, of whom 2668 received roflumilast. At randomization patients had a forced expiratory flow (FEV 1 ) of 45–90%. Roflumilast was investigated at doses of 125, 250 and 500 μg versus placebo. In two studies, 500 μg roflumilast was added on top of standard therapy with inhaled corticosteroids (ICS), 250 μg fluticasone propionate, or 400 μg beclomethasone dipropionate (BDP). Improvement in FEV 1 from baseline was the primary endpoint in seven studies. Key secondary endpoints included asthma symptom scores and time to first severe exacerbation. Results Roflumilast consistently improved FEV 1 across the nine studies compared with placebo, reaching statistical significance in three studies. When given in addition to ICS, roflumilast provided additional improvements in FEV 1 which was statistically significant for 500 μg roflumilast/400 μg BDP versus placebo/400 μg BDP. Conclusion Together these studies show that roflumilast has potential as an effective anti-inflammatory therapy for the treatment of asthma. Additional beneficial effects are observed when given in combination with ICS, which warrant further investigation. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177 , NCT00076076 , NCT00163527 .

Background The safety profile of roflumilast, a phosphodiesterase 4 inhibitor, has been extensively researched in patients with chronic obstructive pulmonary disease (COPD). Adverse events (AEs) including headache, diarrhoea and weight loss have been reported. Much less is known about the safety of roflumilast treatment in patients with bronchial asthma. Aim To evaluate the safety and tolerability of roflumilast using safety data from one open-label and ten pooled placebo-controlled phase II and III clinical studies completed between 1997 and 2005. Subjects and methods The studies were conducted at sites in Europe, North and South America, Africa, Australasia and Asia and study length varied from 4 to 40 weeks. Data for 5169 patients between 12 and 70 years of age, of whom 2851 received roflumilast at doses of 125, 250 and 500 μg, were analyzed. At randomization patients had a forced expiratory flow of 45–100%. Results Headache was the most frequent AE with an incidence rate of 50 and 29.2 per 100 patient-years in the 500 μg roflumilast and placebo groups, respectively. Gastrointestinal AEs were common. Nausea and diarrhoea occurred in 28.7 and 28.3 per 100 patient-years in the 500 μg roflumilast and placebo groups, respectively. The extent of weight loss in roflumilast-treated patients was small. AEs reported in 465 patients in the 4-week open-label follow-up study reflected those of the pooled studies. Conclusions The severity and incidence of AEs reported from this pooled safety analysis confirm that roflumilast is generally well tolerated by patients with asthma. This reflects the general safety profile reported previously in patients with COPD. All studies were funded by Takeda. Trial registration numbers available on ClinicalTrials.gov: NCT00073177 , NCT00076076 , NCT00163527 .

Inhaled corticosteroids (ICS) are recommended as the standard treatment for children with persistent asthma. However, compliance with ICS therapy can be difficult, especially with complicated dosin...

In this randomized, double-blind, placebo-controlled trial, 397 patients with moderate to severe asthma, previously treated with bronchodilators alone, received fluticasone propionate 88, 220, or 440 microg twice daily, or placebo via metered dose inhaler (MDI) for 12 weeks. Mean change from baseline to endpoint in pre-dose percent predicted forced expiratory volume in one second (FEV1) was greater (p < 0.001) in each fluticasone propionate group (9.0%, 88 microg bid; 9.8%, 220 microg bid; 11.2%, 440 microg bid) versus placebo (3.4%). Morning and evening peak expiratory flow (PEF), asthma symptoms, and supplemental albuterol use also improved in all fluticasone propionate groups versus placebo. The incidence of adverse events and 24-hour urine cortisol excretion rates were similar between active treatments and placebo.

Montelukast, a potent leukotriene receptor antagonist, is an effective therapy for symptoms of seasonal allergic rhinitis, a disease governed by patients' individual sensitivity and exposure to relevant allergens.To evaluate the relationship of montelukast treatment effect vs pollen exposure in studies conducted during 3 consecutive fall allergy seasons.A combined analysis of these multicenter, randomized, double-blind, parallel-group studies was performed; 1 of the 3 studies is presented for the first time in this article. After a placebo run-in period, 1,862 symptomatic patients were randomly assigned to receive either a 10-mg montelukast tablet (n = 929) or placebo (n = 933) once daily for 2 weeks. Pollen exposure was summarized by mean daily weed pollen count. The interaction between treatment effect and pollen exposure was evaluated on the primary efficacy endpoint and daytime nasal symptom score, as rated by patients; also evaluated was the influence of the timing of the 2-week treatment period relative to the peak of the weed pollen season.Montelukast significantly improved daytime nasal symptoms score and individual scores of congestion, rhinorrhea, itching, and sneezing compared with placebo. There was a significant interaction (P.043) between treatment effect and weed pollen exposure; a larger treatment effect was noted in patients exposed to higher pollen counts. An interaction between treatment effect and timing of treatment in relation to peak pollen season was suggested.Montelukast significantly improved daytime nasal symptoms score in patients with seasonal allergic rhinitis, and the effect was greater in patients exposed to higher pollen levels.

Treatment with omalizumab, an anti-IgE antibody, improves symptoms and quality of life in patients with seasonal allergic rhinitis but has not previously been investigated in patients with perennial symptoms.To investigate the efficacy, safety, and tolerability of omalizumab in the treatment of perennial allergic rhinitis (PAR).Two hundred eighty-nine patients (aged 12 to 70 years) with moderate-to-severe symptomatic PAR were randomized to 16 weeks' double-blind subcutaneous treatment with either placebo (n = 145) or omalizumab (at least 0.016 mg/kg/IgE [IU/mL] per 4 weeks; n = 144). The primary efficacy variable was the mean daily nasal severity score, as determined from patient daily diary cards. Secondary efficacy variables included use of rescue antihistamine, rhinoconjunctivitis-specific quality of life (RQoL), and patients' evaluation of treatment efficacy. Safety and tolerability were evaluated from adverse event reports and laboratory safety parameters.Throughout 16 weeks of treatment, the mean daily nasal severity score was significantly lower in omalizumab-treated patients than with placebo (P0.001). The improvement in symptoms when taking omalizumab was paralleled by a reduction in use of rescue antihistamine (Por = 0.005 overall) and improved RQoL relative to placebo. Patients' evaluation of treatment efficacy significantly favored omalizumab over placebo (P = 0.001). Omalizumab therapy was well tolerated. There were no safety concerns.Omalizumab was safe and well tolerated in the treatment of patients with PAR, providing effective control of symptoms and improved RQoL while simultaneously minimizing reliance on rescue antihistamines.

The primary objective of this study was to determine whether montelukast, an oral leukotriene receptor antagonist, provides additional clinical benefit to the effect of inhaled corticosteroids. A total of 642 patients with chronic asthma (FEV(1) 50 to 85% of predicted value and at least a predefined level of asthma symptoms) incompletely controlled with inhaled beclomethasone, 200 microg twice daily using a spacer device, during the 4-wk run-in period were randomly allocated, in a double-blind, double-dummy manner to one of four treatment groups: (1) montelukast 10 mg plus continuing inhaled beclomethasone; (2) placebo tablet plus continuing inhaled beclomethasone; (3) montelukast 10 mg and inhaled placebo (after blind beclomethasone removal); and (4) placebo tablet and inhaled placebo (after blind beclomethasone removal). The primary endpoints were FEV(1) and daytime asthma symptoms score. Montelukast provided significant (p < 0.05) clinical benefit in addition to inhaled beclomethasone by improving FEV(1), daytime asthma symptom scores, and nocturnal awakenings. Blind removal of beclomethasone in the presence of placebo tablets caused worsening of asthma control, demonstrating that patients received clinical benefit from inhaled corticosteroids. Blind removal of beclomethasone in the presence of montelukast resulted in less asthma control but not to the level of the placebo group. All treatments were well tolerated; clinical and laboratory adverse experiences were generally similar to placebo treatment in this study. In conclusion, montelukast provided additional asthma control to patients benefitting from, but incompletely controlled on, inhaled beclomethasone.

Background Triamcinolone acetonide (TAA) inhalation aerosol (Azmacort Inhalation Aerosol), a well-established corticosteroid treatment for bronchial asthma, utilizes the chlorofluorocarbon (CFC) propellant P-12, which will be phased out because of environmental concerns. Two TAA aerosol formulations have been developed using a non-chlorofluorocarbon propellant, HFA-134a (Azmacort HFA Inhalation Aerosol delivering TAA 75 μg/puff or 225 μg/puff). Objective This study compared the efficacy and safety of the new 225 μg/puff formulation (TAA-HFA 225) to the marketed TAA inhalation aerosol (TAA-CFC) and to placebo in adult patients with moderate-to-severe persistent asthma. Methods After a 5-day to 21-day baseline period during which all patients received TAA-CFC 150 μg/day, 538 patients were randomized to one of the following treatment schedules: TAA-HFA 450, 900, or 1800 μg/day; TAA-CFC 450 or 900 μg/day; or placebo for 12 weeks. Results All active treatment groups showed statistically significant improvement compared with placebo in pulmonary function (FEV1, FEF25-75%, morning and evening PEF), use of rescue albuterol, and asthma symptom scores. Improvements in all variables occurred within 1 week of treatment. Conclusions The TAA-HFA 225 exhibited similar safety and efficacy profiles to the two equivalent doses of TAA-CFC studied. Our findings indicate that TAA-HFA is a safe and effective replacement for the currently marketed CFC-containing product. The higher strength 225 μg/puff formulation provides effective control of asthma with fewer inhalations.

A new formulation of mometasone furoate (MF) for administration by dry powder inhaler (DPI) was evaluated for the treatment of asthma. A 12-week, double-blind, placebo-controlled dose-ranging study compared the efficacy and safety of three doses of MF DPI (100, 200 and 400 mcg b.i.d) with beclomethasone dipropionate (BDP) 168 mcg b.i.d. administered by metered dose inhaler in 365 adult or adolescent patients being treated with inhaled glucocorticoids. The mean change from baseline to endpoint (last treatment visit) for forced expiratory volume in 1 sec (FEV1) was the primary efficacy variable. Secondary efficacy variables included other objective measures of pulmonary function [forced vital capacity (FVC), forced expiratory flow 25–75% (FEV25–75%.) and peak expiratory flow rate (PEFR)] as well as subjective measures of therapeutic response (patients' daily evaluation of asthma symptoms and physicians' evaluation). At endpoint, all four active treatments were significantly more effective than placebo (P

Background: Although inhaled corticosteroids are widely used for the treatment of inflammation in asthma, prospective, long-term, placebo-controlled trials characterizing their systemic safety with chronic use are lacking. Objective: This study was designed to prospectively evaluate the long-term safety of inhaled fluticasone propionate therapy. Methods: Fluticasone propionate powder, 500 μg, or placebo was administered twice daily by means of the Diskhaler for 104 weeks to 64 adults with mild persistent asthma in a randomized, double-blind, parallel-group study. Primary safety variables were measured at baseline and every 6 months thereafter. Although evaluation of efficacy was not an objective of this study, pulmonary function testing was performed at monthly intervals. Results: Two years of treatment with fluticasone propionate had no significant effects on the skeletal system. No clinically significant changes were observed in ophthalmic parameters (glaucoma and posterior subcapsular cataracts). Mean change from baseline in lumbar spine (L 1 to L 4 ) bone density at week 104 was not significantly different between fluticasone propionate (–0.006 ± 0.008 g/cm 2 ) and placebo (–0.007 ± 0.010 g/cm 2 ). Markers of bone formation (serum osteocalcin) and resorption (urinary N-telopeptide) did not differ significantly between treatment groups. The effects of fluticasone propionate treatment on the hypothalamic-pituitary-adrenal axis were minimal, with no alterations in morning plasma cortisol concentrations and minor but statistically significant decreases in poststimulation mean peak plasma cortisol concentrations ( P = .021) and 8-hour plasma cortisol area under the curve values ( P = .020) at week 104. Drug-related adverse events were primarily topical effects of inhaled corticosteroids. Pulmonary function improved significantly during 2 years of fluticasone propionate treatment. Conclusion: Fluticasone propionate powder, 500 μg twice daily for up to 2 years, was efficacious and well tolerated, with no clinically relevant effects on the hypothalamic-pituitary-adrenal axis, bone density, or ophthalmic parameters in adults with mild asthma. (J Allergy Clin Immunol 1999;103:1062-8.)

Background Perennial rhinitis is a common condition that affects up to 10% to 20% of the population. Multiple agents are frequently administered since no single agent provides complete relief. Studies assessing the benefit/risk of combined therapy are important especially for newly approved agents such as ipratropium bromide nasal spray 0.03%, a topical anticholinergic agent, approved specifically for the treatment of rhinorrhea in allergic and non-allergic perennial rhinitis. Objective To compare the efficacy and safety of the combined use of ipratropium bromide nasal spray 0.03% (42 μg per nostril tid) and beclomethasone dipropionate nasal spray (84 μg per nostril bid) against that of either active agent alone for the treatment of rhinorrhea. Design Multicenter, 6-week, double-blind, randomized active- and placebo-controlled, parallel trial. Setting Allergist and general practitioner clinical practices. Patients Five hundred thirty-three patients with perennial rhinitis (279 allergic and 274 non-allergic), 8 to 75 years of age, who had at least a mild degree of severity of rhinorrhea for a minimum of 2 hours per day during the 1 week screening period as well as congestion or sneezing also of at least mild severity. Intervention Either (1) ipratropium bromide nasal spray 0.03% (42 μg per nostril tid) plus beclomethasone dipropionate nasal spray (84 μg per nostril bid), (2) ipratropium bromide nasal spray 0.03% (42 μg per nostril tid) alone, (3) beclomethasone dipropionate nasal spray (84 μg per nostril bid) alone, or (4) vehicle [matching placebo nasal spray for the ipratropium bromide (2 sprays per nostril tid)] or beclomethasone dipropionate (2 sprays per nostril bid). Main Outcome Measure Severity and duration of rhinorrhea, and patient and physician global assessment of control of rhinorrhea. Results Ipratropium bromide nasal spray plus beclomethasone nasal spray was more effective than either active agent alone or vehicle in reducing the average severity and duration of rhinorrhea during 4 weeks of treatment. The advantage of ipratropium bromide plus beclomethasone nasal spray was evident by the first day of combined treatment and continued throughout the 2-week treatment period. Ipratropium bromide nasal spray had a faster onset of action during the first week of treatment and reduced the duration of rhinorrhea more than beclomethasone. Beclomethasone nasal spray was more effective in reducing the severity of congestion and sneezing than ipratropium. In patients who had not responded well to a nasal steroid prior to participation in the study based on a questionnaire administered at screening, ipratropium bromide was as effective in the steroid non-responders as steroid responders, whereas beclomethasone was more effective in steroid responders. Combined active therapy was well tolerated with no increase in adverse events over that seen previously with ipratropium bromide or beclomethasone nasal spray alone. Conclusions The combined use of ipratropium bromide nasal spray with beclomethasone dipropionate nasal spray is more effective than either active agent for the treatment of rhinorrhea, and does not result in a potentiation of adverse drug reactions. Ipratropium bromide nasal spray 0.03% alone should be considered in patients for whom rhinorrhea is the primary symptom, and its use in combination with a nasal steroid should be considered in patients where rhinorrhea is one of the predominant symptoms, or in patients with rhinorrhea not fully responsive to other therapy.

Study objectives This study investigates the long-term cardiovascular safety of salmeterol powder vs placebo in adolescent and adult patients with mild persistent asthma. Design Multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Setting Eighteen US clinical centers. Patients Three hundred fifty-two patients (≥ 12 years) with mild persistent asthma (duration ≥ 6 months) requiring pharmacotherapy; with FEV 1 of 70 to 90% of predicted and without abnormal ECG/continuous ambulatory ECG (Holter). Interventions Randomized to twice-daily salmeterol powder (50 μg) or placebo via breath-actuated device for 52 weeks. Backup albuterol was available to control asthma symptoms. Measurements and results Cardiovascular safety was regularly assessed by 12-lead ECG with a 15-s lead II rhythm strip, 24-h continuous ambulatory ECG (Holter) monitoring, serial vital sign measurements, and review of adverse cardiovascular events. No deaths occurred during the study. No clinically significant between-group differences were observed in pulse rate, ECG QTc interval, median number of ventricular or supraventricular ectopic events, incidence of ventricular ectopic couplets and runs, or incidence of > 100 ventricular or supraventricular ectopic events in 24 h. No clinically significant between-group differences were observed in arterial BP or incidence of adverse cardiovascular events. Salmeterol was well tolerated throughout the 52-week study period, with a cardiovascular safety profile similar to that of placebo. Conclusions Long-term, twice-daily pharmacotherapy with salmeterol powder is safe and is not associated with unfavorable clinically significant changes in cardiac function or increases in cardiovascular adverse effects.

The current stepwise approach to pharmacotherapy in the treatment of asthma includes the initiation of an inhaled corticosteroid with the addition of a long-acting inhaled bronchodilator if low dose inhaled corticosteroid fails to control asthma symptoms.To determine whether initiation of salmeterol and fluticasone propionate treatment together improves asthma control greater than initiation of monotherapy with the individual agents alone with no additional safety risk in patients with asthma who had not previously been treated with inhaled corticosteroids.A total of 136 male and female patients at least 12 years of age with asthma [forced expiratory volume in 1 second (FEV) between 50% and 80% of predicted] were randomized to twice daily salmeterol 42 microg, fluticasone propionate 88 microg, fluticasone propionate 220 microg, salmeterol 42 microg plus fluticasone propionate 88 microg, salmeterol 42 microg plus fluticasone propionate 220 microg, or placebo for 4 weeks.Patients treated with salmeterol combined with fluticasone propionate had improvements over baseline in FEV at endpoint that were at least twice as great (0.6 to 0.7 L) as improvements in patients treated with salmeterol (0.3 L) or fluticasone propionate alone (0.3 L) (P.05). Patient-rated data (peak expiratory flow, asthma symptom scores, percent of days with no asthma symptoms) confirmed greater (P.05) mean change from baseline improvements after combined treatment compared with fluticasone propionate alone. No clinically significant differences were noted between treatment groups in any safety measurement.Initiation of maintenance therapy with salmeterol and fluticasone propionate in patients with asthma treated with short-acting beta2-agonists alone provides greater improvements in pulmonary function and symptom control than initiation of maintenance therapy with fluticasone propionate alone.

Objective The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control. The present study was undertaken to test this hypothesis. Design A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy (inhaled β-agonist and CFC-BDP [≤ 400 μg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12 days, was followed to establish the patients were steroid responsive and to provide an“ in-study” baseline of “optimal” asthma control. Patients A total of 347 patients were then randomized to HFA-BDP 400 μg/d, CFC-BDP 800 μg/d, or HFA-placebo for 12 weeks. Results Morning peak expiratory flow ( am PEF) measurements showed that HFA-BDP 400 μg/d achieved equivalent control of asthma to CFC-BDP 800 μg/d at all time intervals after oral steroid treatment. All other efficacy variables supported the am PEF results and both active treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported. Conclusions These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily dose.

The objective of this study was to determine whether the therapeutic benefits of inhaled fluticasone propionate are mediated through topical or systemic effects. Two hundred seventy-four patients with asthma receiving beclomethasone dipropionate or triamcinolone acetonide during a 2-wk, single-blind, run-in period were randomized to inhaled fluticasone propionate powder 100 or 500 micrograms twice daily, oral fluticasone propionate 20 mg once daily, or placebo during a 6-wk treatment period. Patients receiving inhaled fluticasone propionate had a significantly greater probability of remaining in the study over time compared with patients receiving oral fluticasone propionate or placebo (p = 0.001). FEV1 and PEF rates at end point were significantly higher with inhaled fluticasone propionate treatment regimens than with oral fluticasone propionate (with the exception of PEF rates for inhaled fluticasone propionate 100 micrograms) or placebo treatments (p < or = 0.004). Systemic exposure to fluticasone propionate as assessed by trough plasma concentrations and/or 12-hr plasma concentration area under the curve analyses (AUC12) was higher with the oral fluticasone propionate than with the two inhaled fluticasone propionate treatment groups. The results of this study suggest that the therapeutic benefits of inhaled fluticasone propionate are mediated through topical effects in the lungs and not through systemic effects.

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 micrograms and 42 micrograms administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral beta-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vital signs, electrocardiogram (ECG), and 24-hr ECG (Holter) monitoring. Both the 21-micrograms and 42-micrograms doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV1) (p < or = 0.02) and PEFR (p < or = 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-micrograms dosage producing consistently higher serial FEV1 and PEFR than did the 21-micrograms dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p < or = 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECGs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 micrograms or 42 micrograms twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 micrograms twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 micrograms.

A new double-strength (84 micrograms/spray) formulation of beclomethasone dipropionate (BDP-ds) as an aqueous suspension has been introduced to control symptoms of allergic rhinitis with once-daily intranasal dosing. This paper reviews the results of three clinical reports which show that BDP-ds given once a day is more effective than placebo and as effective as regular-strength beclomethasone dipropionate given twice daily in reducing the nasal symptoms of seasonal allergic rhinitis. Symptom improvement was seen within 2 days of treatment initiation and was maintained for the subsequent 4 weeks. BDP-ds was found to be as safe and well tolerated as placebo. Adverse effects, which were generally mild, included headache, nasal burning/irritation, epistaxis, coughing, and pharyngitis. BDP-ds is safe for children as young as 6 years of age, and its once-daily dosing schedule may improve patient compliance.

This study examined the effect of fluticasone propionate aerosol on oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated with placebo or fluticasone propionate aerosol (750 or 1000mgr;g twice daily) for 16 weeks. The dosage of oral prednisone was adjusted weekly according to predetermined criteria. Fluticasone propionate 750 and 1000mgr;g twice daily resulted in 69% and 88% of patients (low and high doses, respectively) not using any prednisone compared to 3% of placebo-treated patients by the end of the study. In the fluticasone propionate groups, forced expiratory volume in 1 s (FEV(1)) and peak expiratory flow rates and the number of nighttime awakenings improved at the last evaluable visit. In addition, the number of nighttime awakenings and symptomatic albuterol use declined relative to placebo values (p0.05). Fluticasone propionate aerosol was well tolerated. Fluticasone propionate aerosol (750 or 1000mgr;g twice daily) effectively and safely allowed most asthmatics who were dependent on oral corticosteriods to reduce or eliminate oral prednisone use while improving pulmonary function.

Background: Recent emphasis on the control of airway inflammation in asthma highlights the need for safe and effective antiinflammatory agents. Fluticasone propionate is one of the most potent antiinflammatory corticosteroids developed to date. Objective: This study assessed the safety and efficacy of fluticasone propionate aerosol in the treatment of mild to moderate asthma. Methods: Fluticasone propionate aerosol (25, 100, or 500 μg twice daily) or placebo was given for as long as 8 weeks to adults with mild to moderate asthma in a randomized, double-blind, parallel-group study. Patients were removed from the study if they showed predefined signs of worsening asthma. Results: Sixty-three percent of placebo-treated patients and 23%, 13%, and 4% of patients treated with fluticasone propionate 25, 100, and 500 μg twice daily, respectively, were removed from the study. Mean forced expiratory volume in 1 second, forced vital capacity, and forced expiratory flow at midexpiratory phase at weekly visits throughout the study demonstrated that fluticasone propionate was more efficacious than placebo in maintaining asthma control. Measurements of peak expiratory flow and symptom scores significantly improved and nighttime awakenings and albuterol use to treat symptoms significantly declined in fluticasone propionate-treated groups relative to the placebo-treated group. Differences among fluticasone propionate groups for these variables were not statistically significant. Incidence and severity of adverse events were similar across groups. Fluticasone propionate did not affect morning or stimulated plasma cortisol concentrations, although slight, transient reductions in urinary free cortisol and urinary 17-hydroxy steroids occurred in the group receiving 500 μg fluticasone propionate twice daily. Conclusion: These data indicate that fluticasone propionate provides safe and effective treatment for mild to moderate asthma.

Azelastine is a novel antiallergy medication currently under investigation for the treatment of allergic rhinitis and asthma. Pharmacologic studies in laboratory animals and in vitro model systems indicate that azelastine exerts multiple actions including modulation of airways smooth muscle response, interference with inflammatory processes, and inhibition of allergic reactions. In a previous controlled clinical trial, azelastine nasal solution (ASTELIN N.S.™) demonstrated effectiveness in controlling symptoms of seasonal allergic rhinitis (SAR). The objective of this 2-week double-blind, parallel-group study was to further assess the effectiveness of azelastine nasal solution in improving allergic rhinitis symptoms. Two hundred forty-seven patients (≥12 years) with symptomatic SAR who satisfied a minimum symptoms score during a 1-week, single-blind, baseline evaluation period were randomized to receive azelastine 2 sprays per nostril bid, azelastine 2 sprays per nostril qd, chlorpheniramine 12 mg bid, or placebo using a double-dummy technique to insure blinding. The primary efficacy variables were changes in Major Symptom Complex (nose blows, sneezes, runny nose/sniffles, itch nose, and watery eyes) and Total Symptom Complex (Major plus itchy eyes/ears/throat/palate, cough, and postnasal drip) severity scores. Patients treated with azelastine nasal solution qd and bid had mean percent improvements in the Total and Major Symptom Complex severity scores that were clinically significant (≥50% improvement over placebo) after both weeks, at endpoint, and overall. The improvements for the azelastine bid group were statistically significant (P≤.05) at all evaluation points. Adverse experiences occurred infrequently, and none was considered serious or potentially limiting to the clinical utility of the nasal solution. The favorable safety profile of azelastine nasal solution together with its rapid onset and prolonged duration of action in relieving rhinitis symptoms and advantages over currently marketed topical treatments make it a good choice for treatment of SAR. The results of this trial demonstrate that azelastine nasal solution provides an alternative to oral medication in the treatment of SAR.

Patient-reported outcomes (PROs) are important for evaluating asthma therapy.To evaluate PROs in adults with moderate to severe persistent asthma receiving budesonide and formoterol administered via 1 pressurized metered-dose inhaler (pMDI).This 12-week, double-blind, double-dummy, placebo-controlled, multicenter study randomized 596 patients 12 years or older to budesonide/formoterol pMDI 160/4.5 microg x 2 inhalations (320/9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg) + formoterol dry powder inhaler (DPI) 4.5 microg x 2 inhalations (9 microg); budesonide pMDI 160 microg x 2 inhalations (320 microg); formoterol DPI 4.5 microg x 2 inhalations (9 microg); or placebo, each twice daily, after 2 weeks of budesonide pMDI 80 microg x 2 inhalations (160 microg) twice daily. PROs were assessed in 553 patients 18 years or older using the standardized Asthma Quality of Life Questionnaire (AQLQ[S]), Medical Outcomes Survey (MOS) Sleep Scale, Patient Satisfaction With Asthma Medication (PSAM) questionnaire, diary data, and global assessments.Patients receiving budesonide/formoterol reported significantly greater improvements from baseline on the AQLQ(S) and asthma control variables (based on symptoms and rescue medication use; all P.001) vs placebo. Clinically important improvements (increase ofor = 0.5 points) from baseline to end of treatment in AQLQ(S) overall scores were achieved by 43.6% of patients receiving budesonide/formoterol vs 22.6% of patients receiving placebo (P = .001). The MOS Sleep Scale scores generally showed no differences among treatment groups. Patients receiving budesonide/formoterol had significantly greater PSAM questionnaire scores and better outcomes on physician-patient global assessments at end of treatment vs placebo (all Por = .001).Significantly greater improvements in health-related quality of life and asthma control and greater treatment satisfaction were observed with budesonide/formoterol pMDI vs placebo.

Background Ciclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be safe and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration. However, the long-term safety and efficacy of ciclesonide are unknown. Objective To demonstrate the long-term safety of intranasal ciclesonide, 200 μg once daily, in patients with PAR. Methods Patients (≥12 years old) with a 2-year or longer history of PAR were randomized in a double-blind fashion to receive ciclesonide, 200 μg, or placebo once daily in the morning for up to 52 weeks. Spontaneous and elicited adverse events were monitored throughout the study. Ear, nose, and throat examinations were performed to evaluate local tolerability. Additionally, 24-hour urinary free cortisol level, morning plasma cortisol level, intraocular pressure, and lens opacification were monitored to evaluate the systemic safety of intranasal ciclesonide. Ciclesonide efficacy was determined by measuring 24-hour reflective total nasal symptom scores. Results No clinically relevant differences were observed between the ciclesonide and placebo groups in adverse events, ear, nose, and throat examinations, or 24-hour urinary free or morning plasma cortisol levels. Similarly, no clinically relevant differences were found between treatment groups in intraocular pressure, visual acuity, or lens opacification. With regard to efficacy, ciclesonide achieved a significantly greater reduction in 24-hour reflective total nasal symptom score compared with placebo over more than 52 weeks ( P Conclusion In this study, intranasal ciclesonide, 200 μg once daily, was safe and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.

Although antihistamines are highly effective in alleviating many symptoms associated with seasonal allergic rhinitis (SAR), relief from nasal congestion is variable. The efficacy of desloratadine, an effective antihistamine, in combination with pseudoephedrine, a potent nasal decongestant, was evaluated to determine whether combination therapy was more effective than individual component therapy in reducing nasal congestion, as well as other SAR symptoms. This multicenter, randomized, double-blind, three-arm study included 650 patients with SAR. For 2 weeks, patients were administered a combination tablet of desloratadine plus pseudoephedrine (desloratadine/pseudoephedrine, 2.5/120 mg) twice per day (b.i.d.), desloratadine (5 mg) once per day, or pseudoephedrine (120 mg) b.i.d. Patients assessed the severity of their SAR symptoms twice daily on symptom diary cards. The primary variable-change from baseline in the reflective A.M./P.M. total symptom score, excluding nasal congestion-was significantly superior (-6.7) compared with desloratadine (-5.4) or pseudoephedrine (-5.3) alone (por = 0.001 versus either group). Secondary efficacy variables including total symptom scores (plus congestion), total nasal symptom scores, and total nonnasal symptom scores were significantly reduced after desloratadine/pseudoephedrine therapy compared with the individual components. The most frequently reported adverse events were insomnia, headache, and dry mouth. Desloratadine/pseudoephedrine, 2.5/120 mg b.i.d., therapy was more effective in reducing total symptom scores of SAR, including nasal congestion, than were the individual components. These results support the use of this combination therapy over desloratadine or pseudoephedrine alone.

Experimental studies have shown that doxofylline is endowed with a remarkable bronchodilator activity with less extra-respiratory effects than theophylline. This trial was designed to compare the efficacy and safety of doxofylline, theophylline, and placebo in patients with chronic reversible bronchial asthma.Three hundred forty-six patients were randomly assigned to a 12-week oral treatment with either doxofylline 400 mg t.i.d. (high dose), doxofylline 200 mg t.i.d. (low dose), theophylline 250 mg t.i.d. (active control) or placebo. Pulmonary function tests (PFTs) were performed biweekly. Patients kept records of peak flow meter (PFM) measurements, asthma attack rate and beta-2-agonist use (albuterol).Changes in FEV1 2 hours after the administration of treatments versus baseline exhibited statistically significant differences between doxofylline 400 mg t.i.d. and placebo and between theophylline and placebo. Similar differences were monitored on the other variables (FVC, PFER, FEF(25-75%). Asthma attack rate and use of albuterol decreased remarkably with doxofylline 400 mg t.i.d. and theophylline. There were few statistically significant differences between doxofylline 200 mg t.i.d. and placebo. Significantly more patients had to interrupt treatment because of adverse events under theophylline than under doxofylline 400 mg t.i.d. (p=0.001). With doxofylline 400 mg t.i.d., the number of patients treated to spare one drop-out due to theophylline was 5.This study provides evidence that doxofylline 400 mg t.i.d. is an effective treatment for relieving airway obstruction and displays a better safety profile with respect to theophylline 250 mg t.i.d. with a favorable risk-to-benefit ratio.

Background The efficacy and safety of the aerosol metered-dose inhaler (MDI) formulation of salmeterol for asthma symptoms have been established. Recently, salmeterol has been introduced as a micronized powder formulation administered via a breath-activated multidose powder inhaler (Diskus). Objective A multicenter, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study involving 498 adolescents and adults with mild-to-moderate asthma was conducted to compare the efficacy and safety of salmeterol powder 50 μg twice daily via Diskus, salmeterol aerosol 42 μg twice daily via MDI, and placebo. Methods Patients were randomized to one of the three treatment groups for 12 weeks. Efficacy was assessed by serial measurements of forced expiratory volume in one second (FEV 1 ) over 12 hours, daily peak expiratory flow (PEF), self-rated asthma symptom scores, nighttime awakenings, and supplemental albuterol use. Safety of each treatment was evaluated by monitoring vital signs, electrocardiograms, Holter monitoring, and occurrence of adverse events. Results As compared with placebo, both salmeterol powder and aerosol produced significant improvement in FEV 1 and PEF and decreased nighttime awakenings and supplemental albuterol use. There were no significant differences in the efficacy of the two salmeterol formulations. The magnitude of improvement in pulmonary function was undiminished over the 12-week study. Both formulations of salmeterol were well tolerated, with safety profiles not significantly different from placebo. Conclusion Results of this study indicate that salmeterol, administered either as a powder 50 μg twice daily via Diskus or as an aerosol 42 μg twice daily via MDI, produces clinically significant and comparable improvement in pulmonary function and is well tolerated in patients with mild-to-moderate persistent asthma.

Objective. Intranasal beclomethasone dipropionate (BDP) has generally been considered to have no systemic activity at recommended doses, but the potential for long-term effects on growth has not previously been evaluated. This study was undertaken to assess the effects of 1 year of treatment with intranasal BDP on growth in children. Study Design. In this double-blind, randomized, parallel-group study, 100 prepubertal children 6 to 9 years old with perennial allergic rhinitis were treated with aqueous BDP 168 μg twice daily (n = 51) or placebo (n = 49) for 1 year. Subjects' baseline heights were required to be between the 5th and 95th percentile, and skeletal age as determined by left wrist radiograph was required to be within 2 years of chronological age. Washout periods for medications known to affect growth, including other forms of corticosteroids, were established, and these medications were prohibited during the study. However, short courses of oral prednisolone lasting no more than 7 days, and short courses of dermatologic corticosteroids lasting no more than 10 days, were allowed. Height was measured with a stadiometer after 1, 2, 4, 6, 8, 10, and 12 months of treatment. The hypothalamic-pituitary-adrenocortical axis was assessed by measurements of 8 am basal cortisol concentrations and response to .25 mg cosyntropin stimulation. The primary safety parameter was the rate of change in standing height. Statistical analyses were based on all randomized subjects who received at least 1 dose of medication (intent-to-treat principle). The rate of change in standing height was analyzed for all subjects who entered the study and for those completing the full 12 months of treatment (n= 80). The rate of change in standing height over the 1-year study was calculated as the slope of a linear regression line fitted to each subject's height measurements over time. Because there was a statistically significant between-group difference in standing height at baseline, an analysis of covariance was performed for all analyses of standing height data. Results. Of the 100 subjects enrolled, 90 completed the study. The 2 treatment groups were generally comparable at baseline; however, at baseline, mean age and mean height were significantly greater in the BDP treatment group that the in placebo treatment group. In both analyses, overall growth rate was significantly slower in BDP-treated subjects than placebo-treated subjects. The mean change in standing height after 1 year was 5.0 cm in the BDP-treated subjects compared with 5.9 cm in the placebo-treated subjects. The difference in growth rates was evident as early as the 1-month treatment visit, suggesting that the effect on growth occurred initially. The growth-suppressive effect of BDP remained consistent across all age and gender subgroups, and among subjects with and without a previous history of corticosteroid use. Use of additional exogenous corticosteroids during the study was similar in both groups and did not affect the results. Because there was a baseline imbalance in height, a supplemental analysis of the differences in prestudy growth rates was performed. This analysis found no baseline imbalance in prestudy growth rates. To determine whether the difference in growth rates during the study could be attributed to preexisting growth rates, a z score analysis was performed. The heights of both groups were normalized at baseline and at the end of the study using the US National Center for Health Statistics data for mean and standard deviations of height. This analysis confirmed that the difference in growth rates between the 2 groups was primarily attributable to the treatment rather than to any preexisting difference in growth. Additional analyses confirmed that the results were not influenced by outlier values. No significant between-group difference were found in the hypothalamic-pituitary-adrenocortical axis assessments. No unusual adverse events were observed. No evidence of other systemic effects of BDP was found, including analysis for fluid and electrolyte imbalances; alterations in protein, lipid, or carbohydrate metabolism; alterations in formed elements in blood; and alterations in differential white blood cell counts, including eosinophils. Conclusions. Additional study is warranted to define the clinical relevance of these findings. This study suggests, however, that intranasal BDP may slow growth rate in children without suppressing basal 6 am cortisol concentrations or the response to cosyntropin stimulation, which are commonly used clinically to test for adrenal suppression. The effect on final height is unknown. Alterative explantations for the finding of drug-induced growth suppression, including the possibility that the results were affected by either differences in height and age at baseline between the 2 groups or by outlier values, were discounted upon additional analysis. The results of this study were considered by the Food and Drug Administration in the development of recently proposed new class labeling for all inhaled and intranasal corticosteroids, which states that these agents may cause a reduction in growth velocity in pediatric patients (see reference 21). However, both the Food and Drug Administration and several professional bodies in the United States concur that, depending on disease severity, the benefits of intranasal corticosteroid therapy may outweigh the risks (see reference 22). Because the effect, if any, on final height in not known, the height of children receiving long-term therapy should be monitored periodically during treatment, and should be plotted on a growth or growth-velocity chart to monitor for growth suppression. To minimize the risks of systemic corticosteroid exposure, including growth suppresson, dose-reduction strategies should be considered. For patients who concomitantly receive exogenous corticosteroids via other routes for other conditions, such as inhaled corticosteroids for asthma, clinicians should consider the total corticosteroid exposure and titrate each patient to the lowest effective dose. Clinicians should also consider each medication's potential for systemic effects when selecting among the various available corticosteroids. beclomethasone dipropionate, intranasal corticosteroids, growth, allergic rhinitis, pediatric.

Montelukast, an oral leukotriene-receptor antagonist, has demonstrated efficacy and tolerability for the treatment of chronic asthma in adults. A once-daily 10 mg dose (film-coated tablet) was selected as the optimal adult dose based on dose-ranging studies. Asthma is a similar disease and is treated with the same medications in children and adults. These observations suggested that a dose of montelukast in children providing overall drug exposure (i.e., montelukast plasma concentrations) similar to that of the 10 mg film-coated tablet dose in adults would be efficacious, well tolerated, and obviate the need for separate dose-ranging studies in children. Therefore, the dose of montelukast for 6- to 14-year-old children was selected by identifying the chewable tablet dose of montelukast yielding a single-dose area under the plasma concentration-time curve (AUC) comparable to that achieved with the adult 10 mg film-coated tablet dose. Based on this approach, which included dose normalization of data from several pediatric pharmacokinetic studies, a 5 mg chewable tablet dose of montelukast was selected for use in clinical efficacy studies in 6- to 14-year-old children with asthma.

Dose-response relationships with inhaled corticosteroids in the treatment of asthma have been difficult to establish. A multicenter, double-blind, parallel-group study was conducted to evaluate the clinical efficacy and safety of low doses of inhaled fluticasone propionate (FP) in patients with mild to moderate asthma. Methacholine challenge testing was conducted in addition to measurement of traditional efficacy variables. After a single-blind screening period, 138 patientsor = 12 years of age were randomly assigned to receive placebo, FP 50 microg, or FP 100 microg, twice daily for 8 weeks. The results of methacholine challenge testing averaged over all visits favored FP 200 microg/day over placebo and FP 100 microg/day (p0.05); there were no significant differences between placebo and FP 100 microg/day. Mean changes from baseline to endpoint favored each dose of FP over placebo based on forced expiratory volume in 1 sec (FEV1), patient-measured peak expiratory flow (PEF), total symptom scores, and rescue bronchodilator use (p0.05); there were no differences in these parameters between the two doses of FP. The addition of methacholine challenge testing allowed definition of a dose-response relationship that was not apparent with traditional efficacy variables.

Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent.The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma.In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test.The mean baseline FEV1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo (p0.001). The mean changes in morning peak expiratory flow were 12, 22, 27, and 30 L/min in the 200, 400, 800, and 1600 microg budesonide total daily dose groups, respectively, and -27 L/min for the placebo group. A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1. Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo. There were no clinically significant differences in treatment-related adverse experiences among groups.Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses. It was well tolerated and significantly more effective than placebo.

Topical nasal corticosteroids are rapidly gaining acceptance as first-line therapy for seasonal allergic rhinitis, but there is a desire for effective corticosteroids with an improved safety profile over existing products.A multicenter, double-blind dose ranging study was conducted to compare the activity and tolerance of four doses of mometasone furoate nasal spray (tradename Nasonex) and placebo in adult patients with seasonal allergic rhinitis.Four hundred eighty patients with seasonal allergic rhinitis were enrolled and randomized to receive mometasone furoate nasal spray 50 micrograms (n = 96), 100 micrograms (n = 95), 200 micrograms (n = 98) or 800 micrograms (n = 95), or placebo vehicle (n = 95) once daily for 28 days.All of the doses of mometasone furoate nasal spray showed activity in reducing the severity of rhinitis. The 200-microgram dose reduced total nasal symptom scores and total symptom scores throughout the study (P.05 versus placebo vehicle). The 50-microgram dose and the 100-microgram dose showed less consistent activity at early timepoints (days 3 and 7), while the 800 microgram dose did not provide significant additional benefits over the 200-microgram dose. All dose levels were well toleratedThe results of this trial indicate that 200 micrograms once daily is the optimum dose of mometasone furoate nasal spray for the treatment of seasonal allergic rhinitis.

Objective: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid. Methods: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 μg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 μg) bid; group 2, 4 inhalations (1000 μg) qd in the morning; group 3, 4 inhalations (1000 μg) qd in the evening; or group 4, 2 inhalations (500 μg) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV 1 , and methacholine PC 20 . In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization. Results: Outcome measures in the four groups were not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 μg daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 μg qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC 20 or 24-hour urinary cortisol levels in any group. Conclusions: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 μg) bid, switching to 4 inhalations (1000 μg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 μg) qd in the morning, however, leads to a deterioration in asthma control. (J Allergy Clin Immunol 1997;99:278-85.)

BACKGROUND: The use of intranasally administered corticosteroid sprays is an established treatment option for seasonal allergic rhinitis. METHODS: In this double-blind, placebo-controlled, multicenter study, 438 patients with moderate to severe symptoms of seasonal allergic rhinitis were treated for 4 weeks with double-strength beclomethasone dipropionate (BDP) aqueous nasal spray (84 μg/spray: BDP-ds), once daily; regular-strength BDP (42 μg/spray: BDP-rs), twice daily; high-strength BDP (336 μg/spray: BDP-hs), once daily; or placebo. BDP-hs was included as a safety comparison group. All treatments were given as two sprays per nostril. RESULTS: Physician-rated nasal symptom scores were significantly improved in all three active treatment groups compared with those of the placebo group within the initial 3 days of treatment. Improvement was maintained throughout the 4-week treatment period. BDP-ds and BDP-rs were equivalent at all time points. The BDP-ds, BDP-rs, and BDP-hs groups had greater numbers of patients with a good or excellent therapeutic response at end point than the placebo group. All treatments were well-tolerated, and no unexpected adverse events were reported. No effects on laboratory evaluations or vital signs were evident for any treatment group. CONCLUSIONS: The results of this study show that BDP-ds given once a day and BDP-rs given twice a day in the same total daily dose are comparably safe and effective in the treatment of patients with seasonal allergic rhinitis. (J ALLERGY CLIN IMMUNOL 1996;98:302-8.)

Rationale Daclizumab (Zenapax®), a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25, Tac), is approved for prevention of renal allograft rejection and is under evaluation for treatment of patients with asthma and autoimmune diseases. Daclizumab inhibits Th1 and Th2 cytokine secretion and acts synergistically with dexamethasone in vitro (JACI, 2002, 109(1): S27). In this phase II trial, we studied the safety and efficacy of daclizumab in patients with moderate to severe chronic asthma. Methods Non-smoking asthmatics age 18-70 with baseline FEV1 50-80% predicted despite use of ≥1200 μg daily inhaled triamcinolone (TAA) or equivalent were enrolled in a randomized, multi-center, double-blind, placebo-controlled, parallel trial. Patients with demonstrated requirement for inhaled corticosteroids during run-in were randomized (3:1 active: placebo) to daclizumab (loading dose of 2 mg/kg i.v. followed by 1 mg/kg i.v. every 2 weeks) or placebo added to stable dose TAA. Starting at week 12, patients underwent 25% reduction of TAA every two weeks while continuing study drug. The primary efficacy endpoint was the change in FEV1 from baseline at week 12. Results Baseline characteristics of the 116 randomized patients included: (mean ± SD) age 42.6 ± 12.5 years, disease duration 22.9 ± 13.5 years, FEV1 (% predicted) pre-bronchodilator 68.8 ± 8.7 and post-bronchodilator 80.3 ± 10.8. Eight patients have reported serious adverse events, of which 3 patients had events assessed as related to (blinded) study drug. Conclusions Preliminary safety and efficacy will be assessed following completion of study follow up visits. Unblinded analysis will be presented.

This study examined the ability of fluticasone propionate aerosol to reduce oral prednisone requirements in patients with severe asthma. Ninety-six patients dependent on oral prednisone were treated for 16 wk with placebo or fluticasone propionate aerosol (750 or 1,000 micrograms twice daily). Their dosage of oral prednisone was adjusted weekly according to predetermined criteria. A total of 69% and 88% of patients treated with fluticasone propionate 750 and 1,000 micrograms twice daily, respectively, compared with 3% of placebo-treated patients used no prednisone by the end of the study. In the fluticasone propionate groups, FEV1 and peak expiratory flow rates at the last evaluable visit/date improved and the number of night awakenings and symptomatic albuterol use declined relative to placebo values (p < 0.05). Patient-rated asthma symptoms improved in the groups receiving fluticasone propionate but not in the placebo group (p < 0.005). Fluticasone propionate aerosol was well-tolerated, and it improved some dimensions of health-related quality of life measured using a standard patient survey. Fluticasone propionate aerosol (750 or 1,000 micrograms twice daily) effectively and safely allowed most asthmatics dependent on oral corticosteroids to reduce or eliminate oral prednisone use while improving pulmonary function and quality of life.

The aim of this double-blind, multicenter trial was to determine the duration of bronchodilating activity of a single 4-mg dose of azelastine in chronic asthmatics. Eligible patients had an FEV1 of 40-79% of predicted value with demonstrated reversibility of airway obstruction. A single dose of azelastine 4 mg resulted in rapid onset of bronchodilating activity with a 12-hr duration of action as demonstrated by a clinically and statistically significant mean percent improvement in FEV1, from hours 2–12. As an overall measure of improvement in FEV1, the area under the curve was statistically significantly greater for azelastine than for placebo. Mean improvements in symptom severity in the azelastine group exceeded those for placebo at all observations points. No serious adverse experiences were associated with azelastine.

An effective, long-acting bronchodilator could benefit patients with asthma who have symptoms not controlled by antiinflammatory drugs. We compared a new long-acting, inhaled beta 2-adrenoceptor agonist, salmeterol, with a short-acting beta 2-agonist, albuterol, in the treatment of mild-to-moderate asthma.We randomly assigned 234 patients (150 male and 84 female patients 12 to 73 years old) to one of three treatment groups: one group received 42 micrograms of salmeterol twice daily, one received 180 micrograms of albuterol four times daily, and one received placebo. Treatment was assigned in a double-blind fashion, and all patients could use supplemental inhaled albuterol as needed during the 12-week treatment period.Measurements of the forced expiratory volume in one second, performed hourly for 12 consecutive hours, showed that a single dose of salmeterol produced a greater mean area under the curve than two doses of albuterol taken 6 hours apart (6.3 vs. 4.9 liter.hr, P0.05). The difference was significant on day 1 and at week 4 of the study, but not at week 8 or 12. Salmeterol was also more effective than albuterol or placebo (with albuterol taken as needed) in increasing the morning peak expiratory flow rate: salmeterol induced a mean increase of 24 liters per minute over the pretreatment values, as compared with a decrease of 6 liters per minute with albuterol (P0.001) and an increase of 1 liter per minute with placebo (P = 0.002). The mean overall symptom score was improved most by salmeterol treatment (P0.05), with the number of days with symptoms and of nights with awakenings decreasing by 22 percent and 52 percent, respectively; there were no differences in results between albuterol treatment and placebo administration. We found no evidence of tolerance to the bronchodilating effects of salmeterol, and adverse reactions to all the treatments were infrequent and mild.For the management of mild-to-moderate asthma, salmeterol given twice daily is superior to albuterol given either four times daily or as needed.

16 Improvements in Health-Related Quality of Life With Once-Daily (Evening) or Twice-Daily Dosing of Mometasone Furoate Dry Powder Inhaler (MF-DPI) in Children With Asthma M. Noonan1, M. E. Ruff2, P. Chervinsky3, W. Berger4; 1Allergy Associates Research, Portland, OR, 2Pharmaceutical Research & Consulting, Dallas, TX, 3New England Clinical Studies, North Dartmouth, MA, 4Southern California Research, Mission Viejo, CA. RATIONALE: To evaluate the effects of mometasone furoate dry powder inhaler (MF-DPI) 100 mcg administered once daily in the evening (QD PM) on health-related quality of life (HQOL) in children with asthma previously maintained on inhaled corticosteroids (ICS). METHODS: A randomized, placebo-controlled, 12-week study in children (4 11 years of age) with asthma evaluated (as secondary efficacy variables) the HQOL effects of MF-DPI 100 mcg QD PM, MF-DPI 100 mcg BID, and placebo. The HQOL data were collected using the Child Health Questionnaire Parent Form (CHQ-PF28) and an asthma-specific module (ASM). The primary HQOL variables were changes from baseline in the physical summary score (PSS) of CHQ-PF28, and in the disability domain of the ASM. Data for the HQOL domains were analyzed for Week 8, Week 12 and endpoint using ANOVA. RESULTS: Of 296 randomized subjects, 292 (99%) completed both HQOL questionnaires at baseline and endpoint. Mean HQOL scores were similar among treatment groups at baseline, and suggested impaired function and well-being compared with the general population. At endpoint, the mean PSS improved significantly with MF-DPI 100 mcg QD PM vs placebo (3.4 and -2.1, respectively; p = 0.002). The mean ASM-disability score also improved significantly with MF-DPI 100 mcg QDPM vs placebo (9.2 and 0.3, respectively; p

Objectives To determine the clinical effect of oral montelukast sodium, a leukotriene receptor antagonist, in asthmatic patients aged 15 years or more. Design Randomized, multicenter, double-blind, placebo-controlled, parallel-group study. A 2-week, single-blind, placebo run-in period was followed by a 12-week, double-blind treatment period (montelukast sodium, 10 mg, or matching placebo, once daily at bedtime) and a 3-week, double-blind, washout period. Setting/Patients Fifty clinical centers randomly allocated 681 patients with chronic, stable asthma to receive placebo or montelukast after demonstrating a forced expiratory volume in 1 second 50% to 85% of the predicted value, at least a 15% improvement in forced expiratory volume in 1 second (absolute value) after inhaled β-agonist administration, a minimal predefined level of daytime asthma symptoms, and inhaled β-agonist use. Twenty-three percent of the patients used concomitant inhaled corticosteroids. Primary End Points Forced expiratory volume in 1 second and daytime asthma symptoms. Results Montelukast improved airway obstruction (forced expiratory volume in 1 second, morning and evening peak expiratory flow rate) and patient-reported end points (daytime asthma symptoms, "as-needed" β-agonist use, nocturnal awakenings) ( P P P Conclusions Montelukast, compared with placebo, significantly improved asthma control during a 12-week treatment period. Montelukast was generally well tolerated, with an adverse event profile comparable with that of placebo.

Anticholinergic aerosols provide effective bronchodilation in some patients with obstructive lung disease. Glycopyrrolate is a quaternary ammonium anticholinergic compound that is poorly absorbed from mucus membranes, thus reducing anticholinergic side effects. In 20 adult patients with asthma, we evaluated bronchodilation to a single administration of metered-dose glycopyrrolate aerosol (GA) to ascertain its onset and duration of action along with evaluation of safety. In this randomized, double-blind, placebo-controlled, single-dose, crossover trial, bronchodilation was evaluated on five separate occasions to either placebo or a GA dose of 80, 240, 480, or 960 micrograms. Baseline spirometry for each patient on each visit was similar (mean FEV1 +/- SD of 62.2 +/- 13.6% predicted). After aerosol dosing, spirometry was measured at 30 minutes and then at hourly intervals up to 12 hours. Compared to placebo, metered-dose aerosols of 240, 480 and 960 micrograms elicited significantly greater bronchodilation at each test time. Furthermore, significant bronchodilation was noted within 30 minutes of dosing and was sustained for at least 12 hours. Bronchodilation with the 480 and 960 micrograms dose was equal, and both were greater than 240 micrograms. A subset of four asthma patients with baseline FEV1 values less than 50% predicted did not have a bronchodilating response with GA. No notable side effects occurred. Thus, a single aerosol dose of GA provides clinically significant, safe 12-hour bronchodilation in patients with asthma without severe airway obstruction (i.e., FEV1 greater than 50% predicted).

Triamcinolone acetonide aerosol (TAA) and a placebo aerosol were compared in a six-week, double-blind multicenter study. Ninety-six steroid-independent asthmatic patients were randomized into two parallel groups. Each patient was evaluated weekly. After four weeks of treatment, those patients treated with TAA showed highly significant (P 1 , FVC, and FEF25-75%) and in asthmatic symptoms, whereas no significant improvement was observed in those patients who received placebo aerosol. In the TAA-treated patients, 78 percent were rated with an excellent or good response, compared with 24 percent in the placebo patients. During the subsequent one-week washout period, mean pulmonary function test values of the TAA-treated group were significantly reduced (P

This article reviews the use of ipratropium bromide concomitantly with other bronchodilators, with a focus on its use in patients with asthma. Patients with asthma generally have demonstrated a greater response to the combination of ipratropium and other anti-asthma drugs than to either drug alone. No increase in side effects has been observed when ipratropium has been used in combination with other bronchodilating drugs. Overall, the combination of ipratropium with other agents appears to offer promise in therapy for asthma; further investigation of combinations in larger patient populations is warranted.

In a double-blind, multicenter study, we compared the effects of SCH 434 (Claritin-D; Schering Corp., Kenilworth, N.J.), a new sustained-release, combination antihistamine/decongestant medication, with the effects of its individual components and placebo in 435 patients with seasonal allergic rhinitis. SCH 434 contains 5 mg of loratadine, a nonsedating antihistamine, and 120 mg of pseudoephedrine as the decongestant component. Administered twice daily in this study, SCH 434 effected a 50% decrease in total symptom scores at day 4 and was significantly (p less than or equal to 0.03) more effective than the components alone or the placebo. Loratadine or pseudoephedrine alone, with 43% and 33% decline in symptom scores, respectively, also was more effective than placebo (p less than 0.05). As expected, pseudoephedrine alone was more effective than loratadine (p less than 0.01) in relieving nasal stuffiness; SCH 434 was more effective (p less than or equal to 0.01) than placebo and loratadine in relieving nasal stuffiness. All treatments were safe and well tolerated, although insomnia and dry mouth were noted in a significant number of patients who received either SCH 434 or pseudoephedrine. No serious side effects were noted. The incidence of sedation did not differ significantly among the four treatment groups. We conclude that SCH 434 is a safe and effective treatment for symptoms of seasonal allergic rhinitis. The combination drug (SCH 434) was better than its components for some, but not all, symptoms.