Efficacy and safety of GSP301 nasal spray in children aged 6 to 11 years with seasonal allergic rhinitis.

BACKGROUND: GSP301 nasal spray is a fixed-dose combination of the antihistamine olopatadine hydrochloride and the corticosteroid mometasone furoate. OBJECTIVE: To evaluate the efficacy, safety, and tolerability of GSP301 in pediatric patients (aged ≥6 to <12 years) with seasonal allergic rhinitis (SAR). METHODS: This double-blind, randomized, parallel-group study randomized 446 eligible patients 1:1 (GSP301 [olopatadine hydrochloride 665 µg and mometasone furoate 25 µg] or placebo) as 1 spray/each nostril twice daily for 14 days. The primary end point was change from baseline in average morning and evening subject-reported 12-hour reflective Total Nasal Symptom Score (rTNSS) over a 14-day treatment period analyzed using mixed-effect model repeated measures. Additional assessments included instantaneous Total Nasal Symptom Score, Pediatric Rhinoconjunctivitis Quality of Life Questionnaire, reflective Total Ocular Symptoms Score, instantaneous Total Ocular Symptoms Score, individual symptoms, Physician-assessed Nasal Symptom Score, and adverse events. RESULTS: GSP301 showed clinically meaningful and statistically significant improvement in rTNSS vs placebo (-0.6; 95% confidence interval, -0.9 to -0.2; P = .001). Statistically significant improvements favoring GSP301 were shown for all individual rTNSS symptoms, instantaneous Total Nasal Symptom Score, and most of its individual symptoms, Physician-assessed Nasal Symptom Score (P = .01), and Pediatric Rhinoconjunctivitis Quality of Life Questionnaire (P < .001). For ocular symptoms, numerical improvements favoring GSP301 were observed, with statistical significance achieved only for reflective "tearing/watering eyes" (P = .04). Treatment-emergent adverse events occurred in 12.0% and 10.4% of patients in the GSP301 and placebo groups, respectively. One subject (0.5%) (placebo group) experienced a serious adverse event (suspected viral meningitis) that was not related to the study treatment and was resolved. CONCLUSION: GSP301 was well tolerated and efficacious for treating SAR symptoms in pediatric patients and showed a favorable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03463031.

AR101 Oral Immunotherapy for Peanut Allergy.

BACKGROUND: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions. METHODS: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms. RESULTS: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older. CONCLUSIONS: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).

Device mechanics and evaluation of inspiratory flow rate required of the beclomethasone dipropionate breath-actuated inhaler.

Background: Approximately 80% of patients with asthma and chronic obstructive pulmonary disease incorrectly use a metered-dose inhaler and, therefore, fail to obtain full benefit from their inhaler medication. Beclomethasone dipropionate (BDP) hydrofluoroalkane, an inhalation aerosol administered via a breath-actuated inhaler (BAI) has been designed to improve ease of use over press-and-breathe metered-dose inhalers by eliminating the need for hand-breath coordination. Objective: To present the mechanics of the BAI device, assess the minimum reliable inspiratory flow rate required to trigger an actuation, and evaluate if intended users can safely and effectively use the BDP BAI according to the instructions for use (IFU). Methods: Six random batches (three batches each of 40 µg and 80 µg) of 10 inhalers were evaluated for the minimum inspiratory flow rate required for actuation trigger. Each inhaler was tested for actuation at five flow rates: 12, 14, 16, 18, and 20 L/min. Simulated-use testing was conducted with 91 participants from six representative user groups in the United States to assess the use of a placebo-filled production-equivalent BDP BAI according to the IFU. Results: Across the 40-µg batches, 83% of the devices actuated at 16 L/min and 100% actuated at 18 and 20 L/min. For the 80-µg batches, 67% and 100% actuated at 18 L/min and 20 L/min, respectively. All the participants demonstrated successful use of the BDP BAI during the study session. Isolated safety-critical errors with the potential for no-dose delivery were recorded for 15 participants but were considered unrelated to the design of the IFU. Conclusion: The BDP BAI consistently triggered actuation at an airflow rate of 20 L/min and was successfully used based on guidance from the IFU only. This device provides an alternative for patients who find it difficult to use metered-dose inhaler devices correctly.

Olopatadine-mometasone combination nasal spray: Evaluation of efficacy and safety in patients with seasonal allergic rhinitis.

Background: GSP301 is an investigational fixed-dose combination nasal spray that contains the antihistamine, olopatadine hydrochloride (HCl), and the corticosteroid, mometasone furoate. Objective: To evaluate the efficacy and safety of GSP301 in patients with seasonal allergic rhinitis (SAR). Methods: In this double-blind, randomized, parallel-group study, patients (≥12 years of age) with SAR were equally randomized to intranasal GSP301 (olopatadine 665 µg and mometasone 25 µg), olopatadine HCl (665 µg), mometasone furoate (25 µg), or placebo for 14 days of twice-daily treatment. The primary end point was the mean change from baseline in the average A.M. and P.M. 12-hour reflective Total Nasal Symptom Score (rTNSS) analyzed by using mixed-effect model repeated measures (p < 0.05 indicates statistical significance). Additional assessments included instantaneous TNSS (iTNSS), individual nasal symptoms, reflective Total Ocular Symptom Score (rTOSS) and instantaneous Total Ocular Symptom Score (iTOSS), onset of action, Physician-assessed Nasal Symptom Score (PNSS), quality of life, and adverse events (AE). Results: A total of 1180 patients were randomized. Over 14 days of treatment, GSP301 significantly improved average A.M. and P.M. rTNSS versus placebo (least squares mean difference -0.98 [95% confidence interval, -1.38 to -0.57]; p < 0.001) and versus olopatadine (p = 0.003), and approached statistical significance versus mometasone (p = 0.059). GSP301 also significantly improved average A.M. and P.M. iTNSS versus placebo and both monotherapies (p < 0.05, all). Further, GSP301 significantly improved individual nasal symptoms, overall ocular symptoms (rTOSS and iTOSS), and overall quality of life versus placebo (p < 0.01, all). Onset of action for GSP301 was observed within 15 minutes and was maintained at all subsequent time points assessed. Results for the PNSS also were significant for GSP301 versus placebo (p < 0.001). The percentages of patients with treatment-emergent AEs treated with GSP301, olopatadine, mometasone, and placebo were 12.9, 12.5, 7.1, and 9.4%, respectively. Conclusion: GSP301 was efficacious and well tolerated for the treatment of SAR symptoms compared with placebo, with a rapid onset of action of 15 minutes in patients ≥12 years of age.Clinical trial NCT02631551, www.clinicaltrials.gov.

Evaluation of beclomethasone dipropionate (80 and 160 micrograms/day) delivered via a breath-actuated inhaler for persistent asthma.

BACKGROUND: Breath-actuated inhalers (BAI) may simplify the delivery of inhaled medications compared with other devices. OBJECTIVE: To evaluate the efficacy and safety of beclomethasone dipropionate BAI versus matching placebo in adolescent and adult patients with persistent asthma. METHODS: This phase III, 12-week, double-blind study enrolled patients with asthma aged ≥12 years who were previously treated with a stable dose of inhaled corticosteroid or noncorticosteroid therapy. After a run-in period of 14 to 21 days, patients were randomly assigned in a 1:1:1 ratio to beclomethasone dipropionate BAI 80 or 160 micrograms/day (40 or 80 micrograms twice daily) or placebo BAI. The primary end point was the standardized baseline-adjusted trough morning forced expiratory volume in 1 second (FEV1) area under the effect curve from time 0 to 12 weeks (AUEC[0-12 weeks]). Secondary end points included peak expiratory flow, rescue medication use, asthma symptoms, and the time to withdrawal due to meeting predefined criteria for worsening asthma. Additional end points evaluated quality of life, instructions for use, and safety. RESULTS: The full analysis and the safety sets included 270 and 273 patients, respectively. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had significant improvements in FEV1 AUEC(0-12 weeks) versus placebo (p ≤ 0.001). Improvements in secondary end points were also apparent in patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day compared with placebo. Patients who received beclomethasone dipropionate BAI 80 or 160 micrograms/day had greater increases in Asthma Quality of Life Questionnaire scores versus placebo patients at week 12. Of 98 patients who participated in the instructions-for-use substudy, 87 (88.8%) used the inhaler successfully on their first attempt. Treatment was generally safe and well tolerated. CONCLUSION: Beclomethasone dipropionate BAI 80 and 160 micrograms/day were effective and well-accepted treatments in patients with asthma, with safety comparable to beclomethasone dipropionate delivered via a metered-dose inhaler.Clinical trial NCT02040779, www.clinicaltrials.gov.

No hypothalamic-pituitary-adrenal function effect with beclomethasone dipropionate nasal aerosol, based on 24-hour serum cortisol in pediatric allergic rhinitis.

BACKGROUND: Intranasal corticosteroids are the mainstay of allergic rhinitis (AR) treatment. Their potential to suppress the hypothalamic-pituitary-adrenal axis should be evaluated, especially after long-term daily use in children. OBJECTIVE: To evaluate the effects of treatment with non-aqueous beclomethasone dipropionate (BDP) nasal aerosol on hypothalamic-pituitary-adrenal axis function in children with perennial AR. METHODS: In this double-blinded, placebo-controlled, parallel-group study, patients (6-11 years old) with perennial AR were randomized (2:1) to BDP nasal aerosol at 80 µg/day (n = 67) or placebo (n = 32). The primary end point was change from baseline in 24-hour serum cortisol (SC) weighted mean for BDP nasal aerosol and placebo after 6 weeks of treatment, which was analyzed in the per-protocol population. RESULTS: The per-protocol population included 97 patients (BDP nasal aerosol, n = 66; placebo, n = 31). Baseline geometric mean SC weighted mean values were similar in the 80-µg/day BDP nasal aerosol and placebo groups (5.97 and 6.47 µg/dL, respectively). After 6 weeks' treatment, geometric mean values were 6.19 and 7.13 µg/dL, respectively, with no decrease from baseline in either group. Geometric mean SC ratio of BDP nasal aerosol at 80 µg/day to placebo was 0.91 (95% confidence interval 0.81-1.03), indicating predefined noninferiority. SC concentration-time profiles were similar for the placebo and 80-µg/day BDP nasal aerosol groups at baseline and week 6. BDP nasal aerosol at 80 µg/day was generally well tolerated. CONCLUSION: In pediatric patients with perennial AR, 24-hour SC profiles were comparable for BDP nasal aerosol and placebo, indicating that once-daily BDP nasal aerosol treatment did not significantly affect hypothalamic-pituitary-adrenal axis function. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01697956.

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.

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.

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.

Continuous and Daily Oral Immunotherapy for Peanut Allergy: Results from a 2-Year Open-Label Follow-On Study.

BACKGROUND: The randomized, controlled PALISADE trial demonstrated the benefit of daily oral immunotherapy with Peanut (Arachis Hypogaea) allergen powder-dnfp (PTAH, formerly AR101) in peanut-allergic children and adolescents. OBJECTIVE: ARC004, the open-label follow-on study to PALISADE, used 5 dosing cohorts to explore PTAH treatment beyond 1 year and alternative dosing regimens in peanut-allergic individuals. METHODS: Active arm (PTAH-continuing) PALISADE participants who tolerated 300-mg peanut protein at the exit double-blind placebo-controlled food challenge and placebo arm (PTAH-naive) participants could enter ARC004. PTAH-continuing participants were assigned to receive daily (cohorts 1 and 3A) or non-daily (cohorts 2, 3B, and 3C) dosing regimens; PTAH-naive participants were built up to 300 mg/d PTAH, followed by maintenance dosing. At study completion, participants underwent an exit double-blind placebo-controlled food challenge with doses up to 2000 mg peanut protein. Data were assessed using descriptive statistics. RESULTS: Overall, 358 (87.5%) eligible participants (4-17 years) entered ARC004 (PTAH-continuing, n = 256; PTAH-naive, n = 102). Among PTAH-continuing participants, exposure-adjusted adverse event rates were 12.94 to 17.54/participant-year and 25.95 to 42.49/participant-year in daily and non-daily dosing cohorts, respectively; most participants (83%) experienced mild or moderate adverse events. Daily dosing cohorts appeared to have higher desensitization rates than non-daily dosing cohorts. Of all PTAH-continuing cohorts, cohort 3A had the longest daily dosing duration and the highest desensitization rates. Changes in immune markers with PTAH continuation demonstrated ongoing immunomodulation. Outcomes in PTAH-naive participants mirrored those of the PALISADE active arm. CONCLUSIONS: Continued daily PTAH treatment beyond 1 year showed sustained safety and efficacy. Ongoing immunomodulation was observed during the second year of treatment.

Early bronchodilatory effects of budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and albuterol pMDI: 2 randomized controlled trials in adults with persistent asthma previously treated with inhaled corticosteroids.

Two identically designed, randomized, multicenter, single-dose, crossover studies were conducted in patients aged > or = 18 years with mild to moderate asthma previously treated with inhaled corticosteroids. After 2 weeks on twice-daily budesonide pressurized metered-dose inhaler (pMDI) 160 microg, patients received a randomized sequence of budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), fluticasone/salmeterol dry powder inhaler (DPI) 250/50 microg x 1 inhalation, albuterol pMDI 90 microg x 2 inhalations (180 microg), and placebo pMDI (3-to 14-day washout periods). Improvements in forced expiratory volume in 1 second (FEV(1)) at 3 minutes were significantly (p < 0.001) greater after treatment with budesonide/formoterol pMDI compared with fluticasone/salmeterol DPI and similar to that of albuterol pMDI. In addition, significantly (p < 0.001) more patients treated with budesonide/formoterol pMDI achieved a 15% improvement in FEV(1) within 15 minutes compared with patients treated with fluticasone/salmeterol DPI and placebo. Thus, the early bronchodilatory effects of budesonide/formoterol pMDI were greater than with fluticasone/salmeterol DPI.

Efficacy and safety of inhaled zanamivir in the prevention of influenza in community-dwelling, high-risk adult and adolescent subjects: a 28-day, multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Influenza can cause significant morbidity and mortality in subjects at high risk for complications, including the elderly (age >or=65 years) and those with chronic respiratory, cardiovascular, or metabolic conditions. Effective prophylaxis can significantly reduce the disease burden in this population. Previous studies conducted primarily in non-high-risk subjects have reported the efficacy of inhaled zanamivir in preventing influenza. OBJECTIVE: This study investigated the efficacy and safety of zanamivir in preventing influenza in community-dwelling adult and adolescent subjects at high risk for complications of influenza. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in community-dwelling subjects aged >or=12 years who were at high risk for developing complications of influenza, were able to use the Diskhaler device (Glaxo Group Limited, Research Triangle Park, North Carolina), and were able to take the first dose of study medication within 5 days of laboratory-confirmed local influenza activity. Eligible subjects were randomized to receive inhaled zanamivir 10 mg or placebo once daily for 28 days. The primary end point was the proportion of randomized subjects who developed symptomatic influenza during prophylaxis, as confirmed by culture and/or serology. All adverse events (AEs) occurring after the first dose of study medication were recorded. RESULTS: The study enrolled 3363 subjects, of whom 58% were female and 93% were white; the mean age of participants was 60.4 years (range, 12-94 years), and 4% were adolescents. Significantly fewer zanamivir-treated subjects developed symptomatic, laboratory- confirmed influenza during prophylaxis compared with placebo recipients (4/1678 vs 23/1685, respectively), representing a relative risk (RR) of 0.17 (95% CI, 0.07-0.44; P < 0.001) and a protective efficacy of 83%. The incidence of complications was reduced in zanamivir-treated subjects compared with placebo recipients (1/1678 and 8/1685), representing an RR of 0.12 (95% CI, 0.02-0.73; P = 0.042) and a protective efficacy of 88%. The numbers of zanamivir recipients (151/1678 [9%]) and placebo recipients (169/1685 [ 10 % ] ) who developed symptomatic influenza-like illness regardless of laboratory confirmation did not differ significantly (RR = 0.86; 95% CI, 0.70-1.06), indicating that zanamivir was not effective in preventing influenza-like illness that was not caused by influenza infection. Similarly, there was no significant difference in the numbers of zanamivir and placebo recipients who developed laboratory-confirmed infection regardless of symptoms (39/1678 [2%] and 52/1685 [3%], respectively; RR = 0.76; 95% CI, 0.50-1.15). Of these, 64 subjects (35 and 29) were asymptomatic; seroconversion occurred in all but 1 subject, indicating that zanamivir prophylaxis did not prevent asymptomatic seroconversion. During prophylaxis, 51% of subjects in both treatment groups reported at least 1 AE. There were no major differences in the frequency or nature of AEs between groups. The most commonly reported AEs (>or=3% of subjects in each treatment group) were consistent with upper respiratory viral infection (headache: 17% zanamivir, 18% placebo; cough: 14% and 15%, respectively; throat and tonsil discomfort/pain: 13% and 14%). There were no differences between groups in the overall incidence of viral respiratory infections (5% in both groups) or ear, nose, and throat infections (2% in both groups). None of the analyzed isolates from confirmed cases of influenza exhibited reduced susceptibility to zanamivir or genotypic evidence of resistance. CONCLUSIONS: Zanamivir, administered once daily for 28 days, was efficacious in preventing infection with the predominant circulating strains in the 2000- 2001 influenza season in the Northern Hemisphere (influenza A/New Calendonia/20/99-1ike and influenza B/ Sichuan/379/99-like) in these high-risk community- dwelling subjects aged >or=12 years. Zanamivir was well tolerated, with a safety profile comparable to that of placebo. No emergence of resistant virus was detected.

Efficacy and safety of setipiprant in seasonal allergic rhinitis: results from Phase 2 and Phase 3 randomized, double-blind, placebo- and active-referenced studies.

BACKGROUND: Antagonism of chemoattractant receptor-homologous molecule on T-helper type-2 cells (CRTH2), a G-protein coupled receptor for prostaglandin D2, could be beneficial for treating allergic disorders. We present findings on the efficacy and safety/tolerability of a CRTH2 antagonist (setipiprant) in participants with seasonal allergic rhinitis (AR) in a real-life setting over 2 weeks. METHODS: A Phase 2 trial and a Phase 3 trial were conducted at seven centers in Texas, USA during the Mountain Cedar pollen season. Both were prospective, randomized, double-blind, placebo- and active-referenced (cetirizine) studies. The Phase 2 trial assessed setipiprant 100-1000 mg b.i.d. and 1000 mg o.d. versus placebo in adult and elderly participants. The Phase 3 trial assessed setipiprant 1000 mg b.i.d. in adolescent, adult, and elderly participants. Efficacy was assessed using daytime nasal symptom scores (DNSS), night-time nasal symptom scores (NNSS) and daytime eye symptom scores (DESS). RESULTS: 579 participants were randomized in the Phase 2 trial (mean age 41.6-43.4 years); 630 were randomized in the Phase 3 trial (mean age 37.5-40.7 years). A statistically significant, dose-related improvement in mean change from baseline DNSS was observed over 2 weeks with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 trial (-0.15 [95% CI -0.29, -0.01]; p = 0.030). Setipiprant 1000 mg b.i.d. had no significant effect on this endpoint in the Phase 3 trial (-0.02 [95% CI -0.12, 0.07]; p = 0.652). Total and individual NNSS and DESS symptom scores were significantly improved with setipiprant 1000 mg b.i.d. versus placebo in the Phase 2 but not the Phase 3 trial. Setipiprant showed a favorable safety/tolerability profile. CONCLUSIONS: The Phase 2 trial was the first large clinical study to assess a CRTH2 antagonist in seasonal AR in a real-life setting. Setipiprant dose-related efficacy in the Phase 2 trial was not confirmed during Phase 3. Setipiprant was well tolerated in both studies. Trial registration NCT01241214 and NCT01484119.

Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults.

AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax(®) (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: (1) AV7909 on Days 0/14; (2) AV7909 on Days 0/28; (3) AV7909 on Days 0/14/28; (4) half dose AV7909 on Days 0/14/28; and (5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2-4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥0.56) to be ≥40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.

Once-daily budesonide inhalation powder (Pulmicort Turbuhaler) improves health-related quality of life in adults previously receiving inhaled corticosteroids.

In the treatment of asthma, the conventional measures used to monitor a patient's progress and health status do not address the impact of functional impairments associated with the disease that may affect the patient's daily life. Unlike those measures, health-related quality of life (HRQL) reflects the physical, psychological, and social difficulties a patient perceives on a day-to-day basis. This study was conducted to determine the effects of once-daily budesonide inhalation powder via the Pulmicort Turbuhaler on the HRQL in adult patients with asthma previously treated with other inhaled corticosteroids. A total of 184 patients 18 to 70 years of age who previously received inhaled corticosteroids were enrolled in this double-blind, placebo-controlled, parallel-group, multicenter study. Patients were randomly assigned to budesonide 400 microg once daily or to placebo for 12 weeks. Each patient's HRQL was assessed at randomization and at weeks 4 and 12 with the Asthma Quality of Life Questionnaire (AQLQ). More patients receiving budesonide than those receiving placebo reported statistically significant (P < or = .05) improvements in HRQL at weeks 4 and 12. With the exception of the domain pertaining to exposure to environmental stimuli, differences from placebo in overall AQLQ scores and individual domain scores were clinically important (> or = 0.5 units). In addition, 2.4 patients needed to be treated with once-daily budesonide for 1 patient to demonstrate clinically important improvement. Budesonide 400 microg administered once daily via the Pulmicort Turbuhaler provides statistically significant and clinically important HRQL benefit in adult patients with asthma previously receiving inhaled corticosteroids.

Double-blind, placebo-controlled study of azelastine and fluticasone in a single nasal spray delivery device.

BACKGROUND: A proof-of-concept study suggested that combination therapy with commercial azelastine hydrochloride nasal spray and fluticasone propionate nasal spray significantly improved nasal symptoms of seasonal allergic rhinitis compared with either agent alone. OBJECTIVE: To compare an azelastine-fluticasone combination nasal spray administered in a single-delivery device with a commercially available azelastine nasal spray and fluticasone nasal spray. METHODS: This 14-day, multicenter, randomized, double-blind study was conducted during the Texas mountain cedar season. After a 5-day placebo lead-in, 610 patients with moderate-to-severe nasal symptoms were randomized to treatment with (1) azelastine nasal spray, (2) fluticasone nasal spray, (3) combination azelastine and fluticasone nasal spray, or (4) placebo nasal spray. All treatments were given as 1 spray per nostril twice daily. The primary efficacy variable was the change from baseline in the total nasal symptom score (TNSS), consisting of nasal congestion, runny nose, itchy nose, and sneezing. RESULTS: All 3 active groups were statistically superior (P

Safety and tolerability of fexofenadine for the treatment of allergic rhinitis in children 2 to 5 years old.

BACKGROUND: The safety of fexofenadine has been examined extensively in adults and school-age children. However, the safety of fexofenadine in children younger than 6 years has not been reported to date. OBJECTIVE: To compare the safety and tolerability of twice-daily fexofenadine hydrochloride, 30 mg, and placebo in preschool children aged 2 to 5 years with allergic rhinitis. METHODS: This was a multicenter, double-blind, randomized, placebo-controlled, parallel-group study, conducted between February 29, 2000, and June 14, 2001. Participants were randomized to either fexofenadine hydrochloride, 30 mg, or placebo twice daily for a 2-week period. To facilitate dosing, capsule content was mixed with applesauce (approximately 10 mL). Safety assessments depended on date of entry into the study because of an amendment to the protocol. Before the amendment, assessments included physical examination, vital signs reporting (oral temperature, heart rate, and respiratory rate), and adverse event (AE) reporting. After the amendment, safety assessments included laboratory testing (blood chemistry and hematology profiles), physical examination, 12-lead electrocardiography, and vital signs (oral temperature, blood pressure, heart rate, and respiratory rate) and AE reporting. RESULTS: Treatment-emergent AEs were observed in 116 of 231 participants receiving placebo and 111 of 222 receiving fexofenadine. These AEs were possibly related to study medication in 19 (8.2%) and 21 (9.5%) of the participants receiving placebo and fexofenadine, respectively, and most frequently involved the digestive system. No clinically relevant differences in laboratory measures, vital signs, and physical examinations were observed. CONCLUSIONS: The findings show that fexofenadine hydrochloride, 30 mg, is well tolerated and has a good safety profile in children aged 2 to 5 years with allergic rhinitis.

Safety and tolerability of fexofenadine hydrochloride, 15 and 30 mg, twice daily in children aged 6 months to 2 years with allergic rhinitis.

BACKGROUND: Antihistamines are an established first-line treatment for allergic rhinitis and are widely prescribed in infants for allergic symptoms. OBJECTIVE: To establish the safety and tolerability of fexofenadine hydrochloride in children aged 6 months to 2 years in 2 studies (T/3001 and T/3002). METHODS: Both studies had a multicenter, randomized, placebo-controlled design. Mean treatment duration was 8 days. Subjects were randomized (T/3001, n = 174; and T/3002, n = 219) to twice-daily fexofenadine hydrochloride, 15 or 30 mg, or placebo mixed with a standard vehicle. RESULTS: In the combined population, the incidence of treatment-emergent adverse events (TEAEs) was comparable between groups (placebo, 48.2% [96/199]; fexofenadine hydrochloride, 15 mg, 40.0% [34/85]; and fexofenadine hydrochloride, 30 mg, 35.2% [38/108]). Vomiting was the most common TEAE (placebo, 13.6%; fexofenadine hydrochloride, 15 mg, 14.1%; and fexofenadine hydrochloride, 30 mg, 5.6%). Most TEAEs were unrelated to study medication, as evaluated by investigators; those possibly related to study medication were mild or moderate in intensity. No clinical differences were seen between fexofenadine and placebo for vital signs, electrocardiographic results, or physical examination results. CONCLUSION: Fexofenadine hydrochloride, 15 or 30 mg, given for a mean duration of 8 days is well tolerated, with a good safety profile, in children aged 6 months to 2 years.

Optimal dose selection of fluticasone furoate nasal spray for the treatment of seasonal allergic rhinitis in adults and adolescents.

Efficacy and safety of fluticasone furoate nasal spray, administered using a unique side-actuated device, were evaluated in patients > or =12 years of age with seasonal allergic rhinitis to determine the optimal dose. A randomized, double-blind, parallel-group, placebo-controlled, dose-ranging study was performed on 641 patients who received placebo (n=128) or fluticasone furoate, 55 microg (n=127), 110 microg (n=127), 220 microg (n=129), or 440 microg (n=130), once daily for 2 weeks. Fluticasone furoate was significantly more effective than placebo for mean changes from baseline over the 2-week treatment period in daily reflective total nasal symptom score (primary end point; p < 0.001 each dose vs. placebo), morning predose instantaneous total nasal symptom score (p < 0.001 each dose versus placebo), daily reflective total ocular symptom score (p < or = 0.013 each dose versus placebo), and morning predose instantaneous total ocular symptom score (p < or = 0.019 for three highest doses versus placebo). The onset of action for fluticasone furoate nasal spray versus placebo was observed 8 hours after the first. dose of study medication in the 110 and 440 microg treatment groups (p < or = 0.032). The incidence of adverse events, results of clinical laboratory tests, and changes in 24-hour urinary cortisol values were similar between active treatment groups and placebo. The preliminary profile of fluticasone furoate is that of a rapidly effective therapy that confers 24-hour efficacy for both nasal and ocular symptoms with once-daily dosing. The 110-microg dose was chosen for phase III development because it achieved statistically significant and clinically meaningful results for all efficacy end points and provided the optimal risk-benefit ratio.

Comparison of fluticasone propionate aqueous nasal spray and oral montelukast for the treatment of seasonal allergic rhinitis symptoms.

BACKGROUND: Few studies have directly compared the efficacy of intranasal corticosteroids with that of leukotriene receptor antagonists for the treatment of daytime and nighttime symptoms of seasonal allergic rhinitis (SAR). OBJECTIVE: To compare fluticasone propionate aqueous nasal spray, 200 microg daily, with oral montelukast, 10 mg daily, for the relief of SAR symptoms. METHODS: Patients with SAR 15 years or older were randomized to receive either fluticasone propionate (n = 367) or montelukast (n = 369) in this double-blind, double-dummy, parallel-group study. The primary efficacy measure was the mean change from baseline in daytime total nasal symptom scores (TNSSs) (the sum of 4 daytime individual nasal symptom scores [INSSs] assessing nasal congestion, itching, rhinorrhea, and sneezing), averaged across weeks 1 and 2. Secondary efficacy measures included the 4 daytime INSSs, nighttime TNSSs (the sum of 3 nighttime INSSs assessing congestion on awakening, difficulty going to sleep, and nighttime awakenings), and the 3 nighttime INSSs averaged across weeks 1 and 2. RESULTS: Mean changes from baseline in daytime TNSSs (P < .001), all daytime INSSs (P < .001), nighttime TNSSs (P < .001), and all nighttime INSSs (P < or = .02) showed significant differences favoring fluticasone propionate over montelukast across 2 weeks of treatment. CONCLUSION: Compared with montelukast, fluticasone propionate provided significantly greater improvement in daytime and nighttime SAR symptoms.