Nathan Segall

Accuracy of IgE antibody laboratory results

BACKGROUND Studies have demonstrated that the magnitude of sensitization as evidenced by specific IgE (sIgE) levels provides significant information as to whether a sensitized individual is likely to be truly reactive. However, it is not clear that quantitative sIgE results provided by different laboratories using different technologies are comparable. OBJECTIVE To investigate whether similar results were obtained from Clinical Laboratory Improvement Act-certified laboratories that used 3 common systems for sIgE antibody determination with serum samples and mouse-human IgE chimeric antibodies with known specificity and quantity. METHODS Sixty samples for peanut and 20 for soy were submitted for sIgE determination on 3 different systems: ImmunoCAP, Immulite, and Turbo radioallergosorbent test (RAST). Mouse-human chimeric IgE antibodies specific for the major birch allergen Bet v 1 and for the dust mite allergen Der p 2 were also included. RESULTS A qualitative evaluation using a cutoff of 0.35 kUA/L showed some differences in the ability to detect sIgE sensitization, with the Turbo RAST being most variable. However, considerable differences were found with quantitative evaluation, with Immulite overestimating and Turbo RAST underestimating sIgE compared with ImmunoCAP. Similar discrepancies were seen with the mouse-human chimeric IgE antibody samples. CONCLUSION These findings have potentially serious clinical implications, since each of these systems is widely used. It is therefore important that all laboratories clarify which system they are using. Just because 2 systems present their results in the same units does not mean that the results are necessarily correct or interchangeable.

Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma.

BACKGROUND Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. OBJECTIVE To compare the efficacy and safety of once-daily (AM) administration of mometasone furoate dry powder inhaler (MF DPI) 200 microg and 400 microg with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. METHODS This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV1 was the primary efficacy variable. RESULTS At endpoint, both doses of MF DPI were significantly more effective than placebo (P < or = .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 microg was more effective than placebo (P < or = .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 microg provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. CONCLUSIONS The results of this study indicate that once-daily (AM) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma.

A dose-ranging study of mometasone furoate aqueous nasal spray in children with seasonal allergic rhinitis

BACKGROUND The efficacy and safety of mometasone furoate aqueous nasal spray (MFNS; Nasonex) 200 microg once daily for the treatment and prophylaxis of seasonal allergic rhinitis (SAR) and treatment of perennial rhinitis have been demonstrated in adults. However, the dose response of MFNS in pediatric patients has not yet been characterized. OBJECTIVE This study was conducted to determine the dose-response relationship of 3 different doses of MFNS in a pediatric population. METHODS This was a multicenter, double-blind, active- and placebo-controlled study of 679 children 6 to 11 years of age with histories of SAR and documented positive skin test responses. Patients were randomized to one of the following treatment groups for 4 weeks: MFNS 25 microgram once daily, MFNS 100 microgram once daily, MFNS 200 microgram once daily, beclomethasone dipropionate 84 microgram twice daily (168 microgram/day), or placebo. Physician evaluations were performed at days 4, 8, 15, and 29, and patient evaluations were analyzed for days 1 to 15 and 16 to 29. RESULTS The mean reduction from baseline in physician-evaluated total nasal symptom scores at day 8 (the primary efficacy variable) was significantly greater in the MFNS and beclomethasone dipropionate groups than in the placebo group (P </=.02). No significant differences were observed among the 3 MFNS groups. However, as treatment continued, symptoms in patients treated with MFNS 100 or 200 microgram once daily continued to improve, whereas those treated with MFNS 25 microgram once daily demonstrated little further improvement. By day 29, MFNS 100 and 200 microgram once daily both were significantly more effective than MFNS 25 microgram once daily in relieving symptoms of SAR, but MFNS 200 microgram provided no additional benefit over MFNS 100 microgram. All doses of MFNS were well tolerated, and cosyntropin stimulation tests performed before and after treatment found no evidence of hypothalamic-pituitary-adrenal axis suppression. CONCLUSION These results indicate that the most appropriate therapeutic dosage of MFNS in the treatment of SAR in children 6 to 11 years of age is 100 microgram once daily. In addition, MFNS at doses up to 200 microgram once daily for 4 weeks was well tolerated and had no detectable effects on hypothalamic-pituitary-adrenal axis function.

A comparison of the actions of H1 and H2 antihistamines on histamine-induced bronchoconstriction and cutaneous wheal response in asthmatic patients

The effect of an H1 antihistamine, an H2 antihistamine, and the combination of the two drugs on both histamine-induced bronchoconstriction and dermal whealing was examined in five patients with mild asthma. Chlorpheniramine 8 mg, cimetidine 300 mg, the combination of both, and placebo were administered orally to each patient for a single dose and for seven consecutive doses given every 6 hr after a double-blind, randomized protocol. The airway response to inhaled histamine and the wheal size induced by the intradermal injection of histamine were determined in every patient 2 hr after the final drug dose. The results indicate that a single dose of chlorpheniramine produces a significant increase in the threshold of histamine-induced bronchoconstriction as measured by the provocative histamine dose producing 20% decrease in 1-sec forced expiratory volume (PD20-FEV1), and this effect was significantly enhanced after seven doses. Cimetidine caused a significant decrease in the threshold of histamine-induced bronchoconstriction, but this was not augmented by seven doses. Only chlorpheniramine, when given for seven doses, improved the baseline FEV1 and forced expiratory flow during middle half of forced vital capacity (FEF25%-75%). Chlorpheniramine in both single and multiple doses and the combination of chlorpheniramine and cimetidine given for seven doses produced a significant inhibition of histamine-induced dermal wheals, whereas cimetidine alone had no effect. These results confirm our previous observation that both H1 and H2 receptors are present in the airways of asthmatic patients and that they mediate opposite effects. We also demonstrated a cumulative effect with the repeated administration of chlorpheniramine but not with cimetidine. Finally, the results suggest that the role of H1 and H2 receptors differs in the bronchi from that seen in the dermal vessels of asthmatic patients and are in contrast to those of normals. The H2 receptor effect on histamine-induced skin wheals appears deficient, further supporting earlier suggestions of the presence of an H2 receptor defect in asthmatic patients.

Efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis: a randomized, placebo-controlled study.

BACKGROUND Levocetirizine, a second-generation antihistamine for symptomatic treatment of allergic rhinitis and chronic idiopathic urticaria, has not been previously studied in US patients. OBJECTIVE To assess the efficacy and safety of levocetirizine in improving symptoms and health-related quality of life in US adults with seasonal allergic rhinitis (SAR). METHODS This multicenter, double-blind trial randomized adults with SAR, sensitized to at least 1 grass allergen, to receive levocetirizine, 5 mg, or placebo once daily in the evening for 2 weeks. The primary end point was the 24-hour reflective Total 5-Symptom Score (T5SS; sum of rhinorrhea, sneezing, nasal congestion, and nasal and ocular pruritus) during the entire treatment period. Secondary assessments included the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), Work Productivity and Activity Impairment-Allergy Specific (WPAI-AS) questionnaire, and Epworth Sleepiness Scale (ESS), each assessed at week 1, week 2, and the end of treatment. RESULTS The intent-to-treat population comprised 287 patients taking levocetirizine and 290 taking placebo, with no significant between-group differences at baseline. Levocetirizine resulted in significantly greater improvement from baseline vs placebo in the T5SS (P < .001), overall RQLQ score (P < .001), general and work-related WPAI-AS subscores (P < .05), and ESS score (P < .001). Overall incidence of treatment-emergent adverse events was 14.4% for levocetirizine and 18.4% for placebo. The incidence of somnolence and fatigue was 0.7% and 1.8% with levocetirizine and 1.0% and 0% with placebo, respectively. CONCLUSIONS Levocetirizine was well tolerated and was significantly more effective than placebo in improving the naso-ocular symptoms and health-related quality of life in US patients with SAR.

Long-Term Tolerability of Fexofenadine in Healthy Volunteers

AbstractObjective: To evaluate the long-term safety of fexofenadine compared with placebo. Design: Two placebo-controlled, double-blind, randomised, parallel-group studies. Setting: Twenty-nine investigational centres in the USA. Patients: Healthy volunteers aged 12 to 65 years. Interventions: In a 6-month study, 436 volunteers received either fexofenadine 60mg twice daily or placebo; in a 12-month study, 477 volunteers received fexofenadine 240mg once daily or placebo. Main Outcome Measures and Results: In both studies, adverse events, 12-lead ECGs, laboratory evaluations and vital signs were recorded. There was no statistically significant difference in the incidence of adverse events when fexofenadine was compared with placebo. The most frequently reported treatment-related adverse event was headache, which occurred with a similar incidence for fexofenadine compared with placebo in both studies. Fexofenadine was not associated with statistically significant changes in 12-lead ECGs or clinically relevant changes in laboratory evaluations or vital signs when compared with placebo. Conclusions: These two long-term studies demonstrate that fexofenadine, at doses up to 240mg once daily for up to 12 months in healthy volunteers, is safe and well tolerated.

Pharmacokinetics, safety and tolerability of an oral suspension of fexofenadine for children with allergic rhinitis.

Allergic rhinitis (AR) is a common chronic condition in children and may impact a childs quality of life. Increasing treatment compliance may improve quality of life. An oral suspension of fexofenadine hydrochloride (HCl) has been developed to ease administration to children and may, therefore, improve treatment compliance. The purpose of this study was to assess the pharmacokinetic behavior, safety, and tolerability of a single dose of fexofenadine HCl oral suspension administered to children aged 2-5 years with allergic rhinitis. Children (aged 2-5 years) with AR were recruited in a multicenter, open-label, single-dose study. Fexofenadine HCl (30 mg) was administered as a 6-mg/mL suspension (5 mL). Plasma samples were collected up to 24 hours postdose. Adverse events (AEs); electrocardiograms (ECGs); vital signs; and clinical laboratory tests for hematology, blood chemistry, and urinalysis were analyzed to evaluate safety and tolerability. Fifty subjects completed the study. Mean maximum plasma concentration of fexofenadine was 224 ng/mL, and mean area under the plasma concentration curve was 898 ng . hour/mL. Treatment-emergent AEs were mild in intensity and reported in a total of seven subjects. No trends or clinically meaningful changes in mean ECG, vital sign, or clinical laboratory test data occurred during the study. In children aged 2-5 years, the exposure after a 30-mg dose of fexofenadine HCl suspension was similar to the exposures previously seen after a 30- and 60-mg dose of fexofenadine HCl in children aged 6-11 years and in adults, respectively. The suspension was also well tolerated.

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.

Once-Daily Treatment with Beclomethasone Dipropionate (BDP) Nasal Aerosol Is Effective in Improving Total Nasal Symptom Scores (TNSS) in Children with Seasonal Allergic Rhinitis (SAR) Regardless of Baseline Symptom Severity

Rationale: Beclomethasone dipropionate (BDP) nasal aerosol (a nonaqueous formulation) is approved for management of seasonal and perennial allergic rhinitis (PAR) in adolescents and adults. This post hoc analysis evaluated the effectiveness of BDP nasal aerosol based on baseline symptom severity in children with PAR. Methods: This 12-week, double-blind, placebo-controlled study evaluated children aged 4–11 years with PAR randomized to BDP nasal aerosol 80 mcg/day; n=362) or placebo (n=185). Efficacy assessments included change from baseline in patientreported average AM and PM reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS) over 6 weeks for children aged 6–11 years (primary variable) evaluated by baseline symptom severity: less severe (baseline rTNSS or iTNSS < baseline median) and more severe (baseline rTNSS or iTNSS ≥ baseline median). Results: Treatment with BDP nasal aerosol improved average AM and PM rTNSS versus placebo in children with more severe baseline symptoms (least squares mean [95% confidence interval] difference: −0.70 [−1.31, −0.08]; P=0.027) and less severe baseline symptoms (−0.64 [−1.20, −0.08]; P=0.026) over the 6 weeks. Treatment with BDP nasal aerosol improved average AM/PM iTNSS versus placebo in children with more severe baseline symptoms (−0.72 [−1.32, −0.12]; P=0.019); however, in children with less severe baseline symptoms, the improvement did not reach statistical significance (80 mcg −0.43 [−0.92, 0.07]; P=0.094). Conclusions: In this post hoc analysis, BDP nasal aerosol treatment in children with PAR resulted in significant improvements versus placebo in rTNSS regardless of baseline symptom severity and in iTNSS in the group with more severe symptoms at baseline.