Phenylephrine hydrochloride modified-release tablets for nasal congestion: a randomized, placebo-controlled trial in allergic rhinitis patients.

BACKGROUND: Over-the-counter phenylephrine hydrochloride (PEH) is used for relief of nasal congestion caused by allergic rhinitis; however, data to support its efficacy are lacking. The US Food and Drug Administration recommended clinical trials to evaluate the efficacy and safety of PEH in patients with this condition. OBJECTIVE: To evaluate the efficacy and safety of PEH 30-mg modified-release (MR) tablets in patients with nasal congestion caused by allergic rhinitis in a multicenter, randomized, double-blinded, placebo-controlled, 2-arm, parallel-group study. METHODS: Eligible adults at least 18 years old with documented hypersensitivity to fall pollen allergens were randomized to PEH-MR or placebo every 12 hours for 7 days from August 30 to October 12, 2011. The primary end point was mean change from baseline during the entire treatment period in daily reflective nasal congestion score. Secondary end points included changes in other symptom score assessments, time to maximal effect, duration of effect, and quality of life. Safety assessments included adverse events, serious adverse events, vital signs, physical examination, and electrocardiograms. RESULTS: Of 575 patients, 288 received PEH-MR and 287 received placebo. No significant beneficial difference was detected between PEH-MR and placebo for the primary end point (PEH-MR, mean -0.394, SD 0.4880; placebo, mean -0.412, SD 0.5383; P = .2655). Likewise, no significant differences were observed for most secondary end points or quality of life. Overall, 89 of 575 patients (15.5%), equally distributed between the PEH-MR and placebo groups, experienced at least 1 treatment-emergency adverse event. CONCLUSION: PEH-MR 30-mg tablets taken orally every 12 hours for 7 days is not more efficacious than placebo in relieving nasal congestion caused by allergic rhinitis. TRIAL REGISTRATION: clinicaltrials.gov, identifier NCT01413958, protocol CL2011-06.

Efficacy of daily intranasal fluticasone propionate on ocular symptoms associated with seasonal allergic rhinitis.

BACKGROUND: Allergic rhinitis (AR) is an inflammatory condition of the nasal mucosa characterized by symptoms of nasal discharge, itching, sneezing, and congestion. Ocular symptoms are commonly associated with AR and include itching or burning, tearing or watering, and redness. Intranasal corticosteroids are a mainstay of treatment, and their effect on nasal symptoms is well described. OBJECTIVE: To demonstrate that a 14-day course of 200 µg/d of nasal fluticasone propionate is superior to placebo in relieving ocular symptoms associated with AR. METHODS: This was a randomized, double-blind, parallel group, multicenter study comparing 200 µg/d of fluticasone propionate with placebo in patients with seasonal allergic rhinitis. The primary end point was mean change from baseline in patient-rated reflective total ocular symptom score (rTOSS). Key secondary end points included mean change from baseline in the morning and evening rTOSS, end-of-treatment assessment of response, and effect on activities of daily living. The primary analysis was performed using analysis of covariance with a linear fixed-effects model. RESULTS: Fluticasone was statistically significantly more efficacious in reducing the ocular symptoms of AR than placebo. The least squares mean difference in the change from baseline of rTOSS was -0.36 (P = .002). A statistically significant difference in mean change from baseline was observed in favor of fluticasone for morning and evening rTOSS. Significantly more patients taking fluticasone achieved an overall response compared with placebo. Fluticasone had a significantly greater effect on daily living activities and was well tolerated. CONCLUSION: This study supports the efficacy of fluticasone in treating ocular symptoms associated with AR. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01817790.

Effect of intranasal triamcinolone acetonide on basal hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis.

Intranasal corticosteroids are the most effective medication class for controlling allergic rhinitis (AR) symptoms. However, limited data are available on their effects on basal hypothalamic-pituitary-adrenal (HPA) axis function in children. This study was designed to determine the effect of 6-week triamcinolone acetonide aqueous (TAA-AQ) nasal spray treatment on HPA axis function by measuring 24-hour serum cortisol area under the curve (AUC(0-24h)) in children with AR aged 2-11 years. This phase 4, multicenter, double-blind, placebo-controlled, parallel-group study randomized children with AR to receive TAA-AQ (110 µg, 2-11 years old, or 220 µg, 6-11 years old) or placebo. At pre- and posttreatment domiciled visits, 24-hour serum cortisol and reflective total nasal symptom scores (rTNSSs) were assessed. Safety assessment included treatment-emergent adverse events (TEAEs) at each visit and trough levels of 24-hour serum cortisol. A total of 140 subjects (mean age, 7.2 years; males, 59%) were randomized; 66 from each group completed treatment. The ratio of TAA-AQ to placebo for change from baseline in serum cortisol AUC(0-24h) was 0.966 (95% confidence interval, 0.892-1.045). Reduction from baseline in mean rTNSS was significantly greater in the TAA-AQ than in the placebo group (difference: least square mean ± SE = -0.85 ± 0.24; p = 0.0007). The safety profile was similar (TEAEs, TAA-AQ, 27.5%; placebo, 25.4%), and so was the mean change in serum cortisol trough level (TAA-AQ, -0.4 µg/dL; placebo, -0.1 µg/dL; p = 0.1818 for treatment difference) from pre- to posttreatment. TAA-AQ was safe, well tolerated, and not associated with clinically meaningful suppression of serum cortisol AUC(0-24h) in children with AR. Clinical trial NCT01154153, www.clinicaltrials.gov.

Clinically relevant effect of a new intranasal therapy (MP29-02) in allergic rhinitis assessed by responder analysis.

BACKGROUND: It is unclear what constitutes a clinically meaningful response for allergic rhinitis (AR) outcomes. The objectives of these post hoc analyses were (1) to define a clinically meaningful response using novel efficacy analyses (including a responder analysis), and (2) to compare the efficacy of MP29-02 [a novel intranasal formulation of azelastine hydrochloride (AZE) and fluticasone propionate (FP)] with commercially available FP, AZE and placebo in seasonal AR (SAR) patients, using these novel analyses. METHODS: 610 moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Change from baseline in the reflective total nasal symptom score (rTNSS) over 14 days was the primary outcome. Post hoc endpoints included the sum of nasal and ocular symptoms (rT7SS), efficacy by disease severity and by predominant nasal symptom, and a set of responder analyses. RESULTS: MP29-02 most effectively reduced rT7SS (relative greater improvement: 52% to FP; 56% to AZE) and both nasal and ocular symptoms irrespective of severity. More MP29-02 patients achieved a ≥30, ≥50, ≥60, ≥75 and ≥90% rTNSS reduction, which occurred days faster than with either active comparator; MP29-02 alone was superior to placebo at the ≥60% (or higher) threshold. One in 2 MP29-02 patients achieved a ≥50% rTNSS reduction and 1 in 6 achieved complete/near-to-complete response. Only MP29-02 was consistently superior to placebo for all patients, whatever their predominant symptom. CONCLUSIONS: MP29-02 provided faster and more complete symptom control than first-line therapies. It was consistently superior irrespective of severity, response criteria or patient-type, and may be considered the drug of choice for moderate-to-severe AR. These measures define a new standard for assessing relevance in AR.

The mountain cedar model in clinical trials of seasonal allergic rhinoconjunctivitis.

BACKGROUND: Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar (Juniperus ashei) season as the predominate model. OBJECTIVE: To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. METHODS: The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. RESULTS: Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. CONCLUSION: Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis.

Efficacy of bepotastine besilate ophthalmic solution 1.5% for seasonal allergic conjunctivitis: a randomized, placebo-controlled, natural exposure, clinical trial.

Allergic conjunctivitis (AC) affects an estimated 20% of the population in the Western world, with a large fraction suffering due to seasonal or perennial allergen exposures. Bepotastine besilate ophthalmic solution (BBOS) 1.5%, a dual-acting histamine (H(1)) receptor antagonist and mast cell stabilizer, is indicated for itching associated with AC. This study was designed to evaluate the efficacy and safety of BBOS 1.5% for reducing ocular itching associated with AC in subjects enrolled in a natural exposure trial. Eligible subjects in a multicenter, double-masked, randomized, parallel-group, placebo-controlled, natural exposure clinical trial were randomly assigned to either BBOS 1.5% or placebo eyedrops on a 1:1 basis and instilled 1 drop of the test agent into both eyes twice daily for 2 weeks. The mean change from baseline in instantaneous and reflective ocular itching scores at the end of 2 weeks of treatment were evaluated based on subject-assessed severity of instantaneous and reflective itching. Subject-reported adverse events (AEs) were also recorded for safety. Treatment with BBOS 1.5% significantly reduced instantaneous and reflective ocular itching scores from baseline compared with placebo over the 2-week study period(p = 0.007 and p = 0.005, respectively). BBOS 1.5% was well tolerated, and AEs were generally transient and mild. This clinical study indicates BBOS 1.5% effectively and safely treated ocular itching in a natural exposure allergy study and is a useful treatment option for the management of ocular itching associated with AC. (ClinicalTrials.gov identifier number: NCT01174823.)

Once-daily treatment with beclomethasone dipropionate nasal aerosol does not affect hypothalamic-pituitary-adrenal axis function.

BACKGROUND: Intranasal corticosteroids are effective in controlling allergic rhinitis (AR) symptoms; however, chronic administration of corticosteroids may suppress hypothalamic-pituitary-adrenal (HPA)-axis function. OBJECTIVE: To evaluate the effects of 6 weeks of treatment with beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol on HPA-axis function in subjects with perennial AR (PAR). METHODS: In this randomized, double-blind, placebo- and active-controlled study, subjects aged 12 to 45 years were randomized to receive BDP nasal aerosol 320 µg/day (n = 50), placebo (n = 46), or placebo/prednisone (prednisone 10 mg/day for the last 7 days of the treatment period [n = 11]). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean (expressed as geometric mean ratio [GMR]) in the BDP and placebo group after 6 weeks of treatment. RESULTS: Geometric SC-weighted mean values were similar in the BDP and placebo groups at baseline (9.04 and 8.45 µg/dL, respectively) and after 6 weeks (8.18 and 8.01 µg/dL, respectively). After 6 weeks of treatment, BDP was noninferior to placebo with respect to the ratio from baseline in SC-weighted mean (GMR: 0.96 [95% CI: 0.87, 1.06]). In contrast, 7 days of prednisone treatment substantially reduced geometric SC-weighted mean values from baseline (approximate 3-fold reduction [from 7.33 to 2.31 µg/dL]) compared with placebo. BDP nasal aerosol was well tolerated, and the safety profile was similar to that of placebo. CONCLUSION: Treatment with BDP nasal aerosol, 320 µg once daily, was not associated with HPA-axis suppression in adolescent and adult subjects with PAR. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT01133626.

MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate) in the treatment of seasonal allergic rhinitis: a randomized, double-blind, placebo-controlled trial of efficacy and safety.

Many patients with allergic rhinitis (AR) have uncontrolled symptoms despite available treatment options. This study was designed to evaluate the efficacy and safety of MP29-02 (a novel intranasal formulation of fluticasone propionate [FP] and azelastine [AZ] hydrochloride), compared with monotherapy with FP, AZ, and placebo sprays for the treatment of seasonal allergic rhinitis (SAR). This 2-week randomized, double-blind, placebo-controlled trial was conducted in 779 patients with moderate-to-severe SAR. Treatments were administered 1 spray/nostril twice daily in the same vehicle and delivery device. Daily doses of AZ and FP were 548 and 200 micrograms, respectively. The primary efficacy variable was the 12-hour reflective total nasal symptom score (rTNSS), consisting of nasal congestion, sneezing, itchy nose, and runny nose. Secondary efficacy variables were (1) 12-hour reflective individual nasal symptom scores; (2) onset of action; (3) 12-hour reflective total ocular symptom score (rTOSS), including itchy eyes, watery eyes, and red eyes; and (4) the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) overall score. MP29-02 significantly reduced the mean rTNSS from baseline by -5.54 points compared with FP (-4.55; p = 0.038), AZ (-4.54; p = 0.032), and placebo (-3.03; p < 0.001), improving the rTNSS by 39% beyond the contribution of FP. All individual nasal symptoms contributed to the efficacy of MP29-02. Onset of action was within 30 minutes. MP29-02 significantly improved rTOSS compared with placebo, provided a clinically important improvement in the overall RQLQ score, and was well tolerated. In this study, MP29-02 provided more complete symptom relief than two widely used first-line AR treatments and was well tolerated.

A study of the efficacy and safety of ciclesonide hydrofluoroalkane nasal aerosol in patients with seasonal allergic rhinitis from mountain cedar pollen.

A nasal aerosol formulation of ciclesonide with a hydrofluoroalkane propellant (CIC-HFA) is currently in development for treatment of allergic rhinitis (AR). This study evaluated the efficacy and safety of once-daily administration of CIC-HFA 74 or 148 micrograms compared with placebo in patients with seasonal AR (SAR) from mountain cedar pollen. Patients ≥12 years of age with a ≥2-year history of SAR from mountain cedar pollen were randomized in a placebo-controlled, double-blind, parallel group, multicenter study to CIC-HFA 74 micrograms, CIC-HFA 148 micrograms, or placebo once daily in the morning for 2 weeks. Change from baseline in reflective total nasal symptom score (rTNSS), instantaneous TNSS (iTNSS), and reflective total ocular symptom score (rTOSS) in patients with baseline rTOSS ≥5.00 were evaluated. Adverse events (AEs) were monitored throughout the study. A statistically significant improvement in rTNSS (least squares [LS] mean change from baseline 1.04 and 1.02 respectively; p < 0.0001 versus placebo for both) and iTNSS (LS mean change from baseline 0.90 and 0.83 respectively; p < 0.001 vs placebo for both) was observed after treatment with CIC-HFA 74- or 148-microgram doses. Only the CIC-HFA 74-micrograms treatment group showed a statistically significant improvement in rTOSS (LS mean change from baseline 0.52; p = 0.0124) compared with placebo. The overall incidence of AEs was low and comparable between the treatment groups. In this study, statistically significant improvements in nasal symptoms of SAR were observed after treatment with CIC-HFA 74-microgram or CIC-HFA 148-microgram doses. Both active treatments were well tolerated. Clinical trial registry URL and registration number: www.clinicaltrials.gov/ct2/show/NCT01010971.

Efficacy and safety of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with seasonal allergic rhinitis.

An aerosol formulation may be preferred by some allergic rhinitis (AR) patients, to avoid the "wet feeling" and nasal runoff associated with aqueous nasal corticosteroid sprays. Beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol is a recently developed, nonaqueous, nonchlorofluorocarbon formulation of BDP for the treatment of AR. This study was designed to evaluate the efficacy, safety, and quality-of-life benefits of BDP nasal aerosol in subjects with seasonal AR (SAR). Eligible subjects (≥12 years of age) enrolled in this 2-week study were randomized to either BDP nasal aerosol at 320 µg/day (n = 169) or placebo (n = 171). Efficacy assessments included reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, reflective and instantaneous total ocular symptom scores (rTOSS and iTOSS, respectively), and physician-assessed total nasal symptom score (PNSS). Safety and tolerability were also assessed. Subjects receiving BDP nasal aerosol showed a significantly greater improvement from baseline in average A.M. and P.M. rTNSS versus placebo (treatment difference, -0.91; 95% confidence interval, -1.3, -0.5; p < 0.001) over 2 weeks of treatment. Greater improvements in rTNSS with BDP nasal aerosol compared with placebo were evident by day 2 and were maintained throughout the treatment period. Similarly, significant improvements were seen with BDP nasal aerosol in iTNSS (p < 0.001) and RQLQ score (p = 0.005) compared with placebo. Treatment with BDP nasal aerosol also resulted in greater improvements in rTOSS (p = 0.002), iTOSS (p = 0.003), and PNSS (p < 0.001) relative to placebo. BDP nasal aerosol was well tolerated and the overall safety profile was similar to placebo. Results from this clinical study indicated that BDP nasal aerosol provided significant AR symptom relief and was well tolerated in patients with SAR with an overall safety profile similar to placebo. Clinicaltrials.gov identifier: NCT01024608.

Comparison of intranasal azelastine to intranasal fluticasone propionate for symptom control in moderate-to-severe seasonal allergic rhinitis.

Intranasal corticosteroids are considered the most effective therapy for moderate-to-severe seasonal allergic rhinitis (SAR) and recommended first line in guidelines. It is uncertain whether intranasal antihistamines have comparable efficacy. This study was designed to compare the efficacy of azelastine (AZE; 137 µg/spray) and fluticasone propionate (FP; 50 µg/spray), both given as 1 spray/nostril bid (i.e., approved dosing regimen in the United States), in SAR via a post hoc analysis of data from a previously published direct-comparison study. Six hundred ten moderate-to-severe SAR patients (≥12 years old) were randomized into a double-blind, placebo-controlled, parallel-group trial. The primary efficacy variable was change from baseline in reflective total nasal symptom score (rTNSS (morning and evening), over 14 days. Reflective total ocular symptom score (rTOSS) was a key secondary variable. Reflective total of seven symptom scores (rT7SS [nasal plus ocular symptoms]) and time to ≥50% reduction from baseline in these key parameters were also analyzed. AZE and FP reduced rTNSS from baseline by a similar degree (-3.25 versus -3.84; p = 0.2014). Patients experienced comparable improvement in rTOSS (-2.62 versus -2.17; p = 0.2371) and rT7SS (-5.83 versus -6.05; p = 0.7820). FP was superior to AZE in alleviating rhinorrhea (-1.15 versus -0.87; p = 0.0433), but AZE showed comparable efficacy for all other nasal and ocular symptoms. There was no clinically or statistically significant difference between AZE (-1.17) and FP (-1.43) for reduction in the overall rhinitis quality of life questionnaire score (although FP, but not AZE, significantly differed from placebo). A similar proportion of patients in the AZE and FP groups achieved a 50% reduction in rTNSS. However, more AZE patients (53.0%) exhibited a 50% reduction in rTOSS by day 14 versus FP (39.6%), and ≤3 days faster (p = 0.028). Intranasal AZE (137 micrograms/spray) and intranasal FP (50 micrograms/spray), both 1 spray/nostril b.i.d., had comparable efficacy in symptom control in moderate-to-severe SAR.

An investigation of the pharmacokinetics, pharmacodynamics, safety, and tolerability of ciclesonide hydrofluoroalkane nasal aerosol in healthy subjects and subjects with perennial allergic rhinitis.

Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for treatment of allergic rhinitis. This Phase I study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of CIC-HFA in healthy subjects (N = 18) and subjects with perennial allergic rhinitis (PAR, N = 18) in a double-blind, placebo-controlled, 3-period crossover design following treatment with 282 µg or 148 µg CIC-HFA or placebo once-daily for 14 days. The concentrations of desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of CIC were measured by a validated high performance liquid chromatography with tandem mass spectrometry. Maximum serum concentration (C(max)), area under the serum concentration time curve (AUC), time to maximum serum concentration (t(max)) and elimination half life (t(1/2)) where feasible, were calculated. Serum cortisol (AUC(0-24h)) and adverse events (AE) were also evaluated. The overall systemic exposure of des-CIC was low. The mean C(max) for des-CIC on Day 14 was 35.84 ng/L and 25.98 ng/L for the CIC-HFA 282 µg and CIC-HFA 148 µg treatment groups respectively. Mean AUC((0, last)) for des-CIC on Day 14 was 213 ng·h/L and 112.3 ng·h/L for CIC-HFA 282 µg and 148 µg respectively. Mean serum cortisol (AUC(0-24h)) was similar for CIC-HFA 282 µg (178 µg·h/dL), CIC-HFA 148 µg (169 µg·h/dL), and placebo (174 µg·h/dL) on Day 14. The overall incidence of AEs was low and headache and epistaxis were the most common individual AEs reported. In this study, systemic exposure of des-CIC was low and similar in healthy subjects and subjects with PAR with no evidence of clinically relevant accumulation over the 14 day treatment period in either treatment group. Both doses of CIC-HFA were well tolerated without significant effect on cortisol levels.

The efficacy of intranasal antihistamines in the treatment of allergic rhinitis.

OBJECTIVES: To discuss the new use of intranasal antihistamines as first-line therapies, compare and contrast this class of medication with the traditionally available medications, and discuss the potential for intranasal antihistamines to provide relief superior to second-generation oral antihistamines. DATA SOURCES: Review articles and original research articles were retrieved from MEDLINE, OVID, PubMed (1950 to November 2009), personal files of articles, and bibliographies of located articles that addressed the topic of interest. STUDY SELECTION: Articles were selected for their relevance to intranasal antihistamines and their role in allergic rhinitis. Publications included reviews, treatment guidelines, and clinical studies (primarily randomized controlled trials) of both children and adults. RESULTS: This panel was charged with reviewing the place of intranasal antihistamines in the spectrum of treatment for allergic rhinitis. Intranasal antihistamines have been shown in numerous randomized, placebo-controlled trials to be more efficacious than the oral antihistamines. Although intranasal corticosteroids are considered by some to be superior to intranasal antihistamines, multiple studies have shown an equal effect of the 2 classes of medication. Both intranasal corticosteroids and intranasal antihistamines have been shown to reduce all symptoms of allergic rhinitis. In addition, some intranasal antihistamines have a more rapid onset of action than intranasal corticosteroids. CONCLUSIONS: The future of allergy treatment will likely involve a combination of both intranasal corticosteroids and intranasal antihistamines because of the benefits of local administration and their additive effect on efficacy.

Evaluation of the efficacy and safety of ciclesonide hydrofluoroalkane nasal aerosol, 80 or 160 µg once daily, for the treatment of seasonal allergic rhinitis.

BACKGROUND: A hypotonic aqueous nasal spray of ciclesonide is indicated for the treatment of allergic rhinitis (AR). A new nasal aerosol formulation of ciclesonide containing a hydrofluoroalkane propellant delivered via a metered-dose inhaler (CIC-HFA) is currently in clinical development as a potential treatment for AR. OBJECTIVES: To study the efficacy and safety of once-daily administration of CIC-HFA 80 or 160 µg compared with placebo in subjects 12 years and older with seasonal AR (SAR). METHODS: Subjects 12 years and older with a ≥ 2-year history of SAR were randomized in a placebo-controlled, double-blind, parallel-group, multicenter study to receive CIC-HFA 80 or 160 µg or placebo once daily in the morning for 2 weeks. Changes from baseline in reflective total nasal symptom scores (rTNSSs), instantaneous TNSSs (iTNSSs), and reflective total ocular symptom scores (rTOSSs) in subjects with a baseline rTOSS of ≥ 5.00 were evaluated. Treatment-emergent adverse events were monitored throughout the study. RESULTS: Seven hundred seven subjects were randomized. From baseline, CIC-HFA 80 or 160 µg demonstrated 15.1% and 16.0% reductions in rTNSSs (P < .0001, 3.7% for placebo), 14.3% and 15.4% reductions in iTNSSs (P < .0001, 3.9% for placebo), and 15.7% and 15.0% reductions in rTOSSs (P < .001, 6.8% for placebo). The overall incidence of treatment-emergent adverse events was low and comparable between the CIC-HFA and placebo groups. CONCLUSIONS: In this study, once-daily treatment with CIC-HFA 80 or 160 µg demonstrated statistically significant improvements in nasal and ocular symptoms of SAR. Both doses of active treatment were well tolerated.

Safety and tolerability of levocetirizine dihydrochloride in infants and children with allergic rhinitis or chronic urticaria.

Allergic rhinitis (AR) and chronic idiopathic urticaria (CIU) are common causes of substantial illness and disability in preschool children. Antihistamines are commonly used to treat preschool children with these conditions, but their use is based mostly on extrapolated efficacy from adult populations; it is thus important to characterize the safety of antihistamines in the pediatric population. This study was designed to assess the safety of levocetirizine dihydrochloride oral liquid drops in infants and children with AR or CIU. Two multicenter, double-blind, randomized, parallel-group studies randomized infants aged 6-11 months (study 1, n = 69) and children aged 1-5 years (study 2, n = 173) to levocetirizine, 1.25 mg (q.d. or b.i.d., respectively), or placebo for 2 weeks, using a 2:1 ratio. Safety evaluations included treatment-emergent adverse events (TEAEs), vital signs, electrocardiographic (ECG) assessments, and laboratory tests. The overall incidence of TEAEs was similar between levocetirizine and placebo in both studies. Most TEAEs were mild or moderate in intensity. TEAEs prompted discontinuation of therapy in three patients receiving levocetirizine in study 1. No clinically relevant changes from baseline in vital signs or laboratory parameters were apparent in either study; changes from baseline in these evaluations were similar between groups. No significant changes were observed in ECG parameters, including corrected QT interval. Levocetirizine, 1.25 and 2.5 mg/day, was well tolerated in infants aged 6-11 months and in children aged 1-5 years, respectively, with AR or CIU.

Effects of olopatadine hydrochloride nasal spray 0.6% in the treatment of seasonal allergic rhinitis: a phase III, multicenter, randomized, double-blind, active- and placebo-controlled study in adolescents and adults.

BACKGROUND: Seasonal allergic rhinitis (SAR) is an allergen-induced inflammatory reaction that occurs during periods of high pollen count. Current treatments for SAR include allergen avoidance, systemic antihistamines, and steroidal and nonsteroidal intranasal sprays. Olopatadine is a selective antihistamine and an inhibitor of proinflammatory mediators from human mast cells. An intranasal formulation of olopatadine has been developed for the treatment of SAR. OBJECTIVE: The aim of this study was to compare the efficacy and tolerability of olopatadine hydrochloride nasal spray 0.6% (OLO) relative to azelastine hydrochloride nasal spray 0.1% (AZE) and an inactive vehicle in the treatment of SAR. METHODS: This Phase III, multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study was conducted at 21 centers across the United States. Eligible patients were aged > or =12 years and had a history of SAR and verified allergy to a prevalent local allergen. After a run-in period during which inactive vehicle was administered, patients were randomly assigned to OLO, AZE (active control), or inactive vehicle (identical to OLO; placebo control), 2 sprays in each nostril BID for 16 days. The timing of enrollment was correlated with the start of the allergy season at each site. Symptoms were recorded twice daily in an electronic diary. Efficacy assessments included changes in mean daily reflective total nasal symptom scores (TNSS). Tolerability was evaluated based on adverse events (AEs) and nasal, physical, and cardiovascular parameters. RESULTS: A total of 544 patients were randomized. The mean age was 36 years (range, 12-77 years); men and boys represented 32.2% of the population; and the patients were predominantly white (75.4%). The mean reductions from baseline in reflective TNSS were 26.8%, 29.9%, and 18.4% with OLO, AZE, and inactive vehicle, respectively (P = 0.003 OLO vs inactive vehicle; 95% CI, -2.5% to 8.7% OLO vs AZE [non-inferiority]). The most commonly reported treatment-related AE in the OLO and AZE groups was bitter taste (12.2% [22/180] and 19.7% [37/188], respectively). The prevalence and intensity of bitter taste were significantly lower with OLO than with AZE (P = 0.05 and P = 0.005, respectively). In the group that received inactive vehicle, the prevalence of bitter taste was 1.7% (3/176). The prevalences of other treatment-related AEs, including epistaxis and nasal discomfort, were < or =3.7% in each group and did not differ significantly between groups. CONCLUSIONS: In this small study in patients aged > or =12 years with SAR, the percentage reduction from baseline in TNSS was significantly greater with OLO (2 sprays in each nostril BID) compared with vehicle and not significantly different from that with AZE. OLO and AZE were similarly well tolerated, with the exception of prevalence and intensity of bitter taste, which were significantly lower with OLO.

HPA axis safety of fluticasone furoate nasal spray once daily in children with perennial allergic rhinitis.

The effects of intranasal corticosteroids (INSs) on the hypothalamic-pituitary-adrenal (HPA) axis should be assessed for any to be marketed INS. The objective of this study was to assess the effects of fluticasone furoate nasal spray (FFNS) on cortisol production (as a measure of HPA axis function) following 6 wk of treatment with FFNS 110 microg once daily (QD) compared with placebo in pediatric patients with perennial allergic rhinitis (PAR). In this double-blind, parallel-group study, patients (n = 112) aged 2-11 yr with a 1-yr history of PAR (6 months for patients aged 2-3 yr) were randomized in a 1:1 ratio to either placebo or FFNS. Serum cortisol (SC) concentrations and urinary cortisol (UC) excretion were measured over a 24-h period at the randomization (baseline) and final treatment (week 6) visits for HPA axis evaluation in a domiciled environment (overnight in the clinic). Plasma samples were collected for FFNS at several time points over the 24 h after the final dose for pharmacokinetic analyses. FFNS was non-inferior to placebo with respect to change from baseline (expressed as a ratio) in 24-h SC weighted mean. The lower limit of the two-sided 95% confidence interval (CI) for the treatment ratio was greater than the pre-specified non-inferiority margin of 0.8 (treatment ratio = 0.97, 95% CI 0.88-1.07). UC excretion over 24 h at baseline and end of treatment was similar between treatment groups; no patients had 24-h excretion levels below normal range after 6 wk of treatment. Plasma concentrations of FFNS were generally non-quantifiable (<10 pg/ml). Results of the current study indicate that FFNS 110 microg QD has no significant effect on HPA axis function in 2- to 11-yr-old pediatric patients with PAR.

Safety and efficacy of olopatadine hydrochloride nasal spray 0.6% in pediatric subjects with allergic rhinitis.

Olopatadine (OLO) nasal spray 0.6% is indicated for treatment of seasonal allergic rhinitis (SAR) in subjects > or = 12 years of age. This study was designed to present the results of two studies that evaluated the efficacy, safety, and pharmacokinetics (PK) of OLO in children with allergic rhinitis (AR). These were multicenter, double-blind, randomized, parallel-group studies in subjects 6 to <12 years of age (study 1) and 2 to <6 years of age (study 2) with SAR (study 1) or AR (study 2). In study 1, nasal and ocular symptoms were scored for efficacy, and study 2 included PK analyses. In both studies, subjects were evaluated based on physical/nasal examinations and adverse events (AEs). Overall, 1188 subjects (study 1) and 132 subjects (study 2) were randomized, respectively. OLO (1 or 2 sprays/nostril, b.i.d.) was superior to vehicle in the percent decrease in reflective total nasal symptom scores (p < or = 0.0120). OLO 1 spray/nostril b.i.d. was also superior to vehicle in the percent decreases in reflective total ocular symptom scores (p < or = 0.0084), change from baseline in Pediatric Rhinoconjunctivitis Quality-of-Life Questionnaire scores (p < or = 0.0377), Caregiver Treatment Satisfaction Questionnaire scores (p < or = 0.0450), and proportions of subjects reporting improvements in Subject Global Assessments (p = 0.0035). The most frequently reported treatment-related events in the OLO group were bad/bitter taste and epistaxis. In subjects 6 to <12 years of age, OLO was superior to vehicle in the treatment of SAR. In subjects 2 to <12 years of age, OLO had an overall low rate of AEs and low systemic exposure.

Ciclesonide and beclomethasone dipropionate coadministration: effect on cortisol in perennial allergic rhinitis.

Coexisting asthma and allergic rhinitis (AR) are often treated with both intranasal and inhaled corticosteroids. This study investigated whether intranasal ciclesonide 200 microg once daily has an additional effect on cortisol suppression when coadministered with inhaled hydrofluoroalkane-beclomethasone dipropionate (HFA-BDP). Adult patients (n = 150) with perennial AR received HFA-BDP 320 microg twice daily and placebo once daily during a run-in period. Patients were then randomized to ciclesonide or placebo and HFA-BDP (43 days). A single 2-mg dose of dexamethasone was administered on the last treatment day. Plasma cortisol decreased by 67.8 microg x h/dL (p < 0.001) during the run-in period. When ciclesonide was added, the change in mean plasma cortisol was similar for ciclesonide and placebo (8.5 microg x h/dL and 1.0 microg x h/dL, respectively). Dexamethasone decreased mean plasma cortisol (p < 0.001), demonstrating that further cortisol suppression was possible. This study suggests that intranasal ciclesonide can be used with an inhaled corticosteroid without increased cortisol suppression.

Intranasal corticosteroids in the treatment of allergic rhinitis.

Intranasal corticosteroids (INCSs) have been established as the first-line treatment of moderate to severe allergic rhinitis (AR). Compared with other monotherapies, INCSs are most effective at controlling underlying allergic inflammation and providing symptom relief. Although currently available INCSs show comparable efficacy in controlling nasal symptoms of AR, onset and duration of action are thought to be somewhat variable among the INCSs. The low frequency of side effects suggests that, at recommended doses, INCSs are safe for the treatment of AR. However, concerns remain regarding the long-term systemic side effects associated with INCS therapy. Recent clinical studies have indicated that ciclesonide provides effective relief from nasal symptoms of AR and may have a rapid onset of action. Moreover, the results of two clinical trials, including a 52-week study, have suggested that intranasal ciclesonide does not cause cortisol suppression. Furthermore, intranasal ciclesonide does not have an additive effect on the hypothalamic-pituitary-adrenal-axis function when administered in combination with inhaled corticosteroids (ICSs), indicating that intranasal ciclesonide can be used in combination with an ICS in patients with asthma and comorbid AR. Therefore, intranasal ciclesonide appears to provide an additional treatment option for patients with AR.