David P. Skoner

Efficacy and safety of timothy grass allergy immunotherapy tablets in North American children and adolescents

BACKGROUND Allergy immunotherapy tablet (AIT) treatment might be a safe and convenient form of specific immunotherapy but it has not been investigated in North American children and adolescents. OBJECTIVE We sought to investigate the efficacy and safety of timothy grass AIT treatment in North American children/adolescents with grass pollen-induced allergic rhinoconjunctivitis (ARC) with or without asthma. METHODS Three hundred forty-five subjects (5-17 years old) were randomized to once-daily grass AIT treatment (2,800 bioequivalent allergen units, 75,000 standardized quality tablet, approximately 15 μg of Phl p 5) or placebo approximately 16 weeks before the 2009 grass pollen season (GPS). Treatment continued through the GPS. Daily symptoms and allergy rescue medication use were recorded. The primary end point was the total combined score (TCS) of the daily symptom score (DSS) and daily medication score (DMS) for the entire GPS. DSS, DMS, Rhinoconjunctivitis Quality of Life Questionnaire score, and Phl p 5-specific IgG4 and IgE-blocking factor levels were secondary end points. Safety was assessed through adverse events. RESULTS Eighty-nine percent of subjects were multisensitized. TCS, DSS, DMS, and Rhinoconjunctivitis Quality of Life Questionnaire score versus placebo improved 26% (P = .001), 25% (P = .005), 81% (P = .006), and 18% (P = .04). Phl p 5-specific IgG4 and IgE-blocking factor levels were significantly higher at the peak and end of the GPS (P < .001). Treatment was well tolerated. Adverse events were generally mild and transient. Although no investigator-assessed systemic allergic reactions were reported, 1 grass AIT-treated subject experienced an event indicating a systemic reaction (lip angioedema, dysphagia, and cough). CONCLUSIONS Use of once-daily timothy grass AIT treatment effectively treats timothy grass (cross-reactive with Festucoideae grasses) pollen-induced ARC in North American children 5 years and older. Given its convenient administration, lack of dose build-up requirement, safety profile, and efficacy, AIT treatment might become an important addition to the North American ARC treatment armamentarium.

Sublingual immunotherapy in patients with allergic rhinoconjunctivitis caused by ragweed pollen

BACKGROUND Specific allergen immunotherapy is most often delivered subcutaneously, but sublingual immunotherapy may confer greater benefit in terms of tolerability and safety, accessibility, and improved antigen delivery. OBJECTIVE This randomized, double-blind, placebo-controlled trial was conducted to identify a safe and effective maintenance dose range of sublingual standardized glycerinated short ragweed pollen extract in adults with ragweed-induced rhinoconjunctivitis. METHODS In May 2006, a total of 115 patients with ragweed-induced rhinoconjunctivitis were randomly allocated to placebo (n = 40), medium-dose extract (4.8 microg Amb a 1/d; n = 39), or high-dose extract (48 microg Amb a 1/d; n = 36). In a 1-day (rush) dose-escalation regimen, ragweed pollen extract was administered sublingually in incremental doses until maximum tolerable or scheduled dose was reached and then maintained during the ragweed pollen season. Patient diaries were used to monitor nasal and ocular symptoms and medication. The primary endpoint was symptom score. RESULTS Both active treatment groups achieved a 15% reduction in total rhinoconjunctivitis symptom scores compared with placebo during the entire ragweed pollen season, but the difference was not statistically significant (P > .10) However, in an analysis of covariance correcting for preseasonal symptoms, both mean daily symptom scores (0.19 +/- 1.16 vs 1.00 +/- 2.30) and medication scores (0.0003 +/- 1.64 vs 0.63 +/- 1.06) for the entire pollen season were significantly reduced in the high-dose versus placebo groups, respectively (P <or= .05). Ragweed-specific IgG, IgG(4), and IgA antibodies were increased after treatment in the medium- and high-dose groups and not the placebo group. Frequency of adverse events was similar between the placebo and treatment groups, but oral-mucosal adverse events occurred more often with treatment. CONCLUSION Standardized glycerinated short ragweed pollen extract administered sublingually at maintenance doses of 4.8 to 48 microg Amb a 1/d was safe and can induce favorable clinical and immunologic changes in ragweed-sensitive subjects. However, additional trials are needed to establish efficacy.

Safety and Tolerability of Montelukast in Placebo-Controlled Pediatric Studies and Their Open-Label Extensions

Montelukast is a potent leukotriene‐receptor antagonist administered once daily that provides clinical benefit in the treatment of asthma and allergic rhinitis in children and adults. Because of its wide use as a pediatric controller, there is a need for a further review of the safety and tolerability of montelukast in children.

Effects of Inhaled Mometasone Furoate on Growth Velocity and Adrenal Function: A Placebo-Controlled Trial in Children 4–9 Years Old with Mild Persistent Asthma

Objective. To assess the effects of long-term mometasone furoate delivered via a dry powder inhaler (MF-DPI) on growth velocity and hypothalamic–pituitary–adrenal axis function in children with asthma. Study design. Children aged 4–9 years with asthma (n = 187) were randomized to MF-DPI 100 μg (delivered dose; actuated dose is 110 μg) once daily in the morning (QD AM), 100 μg twice daily (BID), 200 μg QD AM, or placebo for 52 weeks followed by a 3-month follow-up period. The primary outcome was growth velocity calculated from stadiometric heights recorded at each visit. Secondary outcomes included serum and 12-h urinary cortisol, serum osteocalcin, and urinary N-telopeptide. Results. MF-DPI 100 μg QD AM treatment did not significantly affect growth velocity compared with placebo (–0.10 ± 0.31 cm/y, p = 0.76). When the effect of a total daily dose of 200 μg MF-DPI on growth velocity was examined, no significant effect was demonstrated for MF-DPI 100 μg BID compared with placebo (–0.64 ± 0.39 cm/y, p = 0.10), although the change in mean growth velocity with MF-DPI 200 μg QD AM reached statistical significance (–0.70 ± 0.29 cm/y, p = 0.02). The effects of all examined doses of MF-DPI on mean plasma cortisol levels were similar to cortisol changes seen in the placebo group, suggesting an absence of drug-related effects. No differences in 12-h urinary cortisol or other outcomes were observed between groups. Conclusions. One year of treatment with a total daily dose of 100 μg of MF-DPI in the morning resulted in no significant difference, whereas a total daily dose of 200 μg of MF-DPI was associated with some changes in growth velocity when compared with placebo. The differences in growth velocity, and the absence of drug-related cortisol effects, support the use of a total daily dose of 100 μg of MF-DPI in children aged 4–9 years with mild persistent asthma.

New asthma drugs: small molecule inhaled corticosteroids.

Small-particle inhaled corticosteroid (ICS) metered-dose inhalers were recently developed to treat asthma as part of the CFC to HFA propellant switch mandated by the Montreal Protocol. Two such ICS, beclomethasone dipropionate (BDP) and ciclesonide (CIC), are available in the United States and are formulated in HFA solutions. A major advantage of small-particle ICS is that they have improved total lung deposition and consequently, effective asthma control is achieved at lower daily doses than the large-particle ICS. Another advantage of small-particle ICS is that they are able to reach the small airways and consequently, may result in increased efficacy. Indeed, recent studies have demonstrated the effect of small-particle ICS on asthmatic inflammation in the small airways. Another advantage of small-particle ICS is that they may have an improved safety profile. Small-particle inhalers generally deposit decreased amounts of drug in the oropharynx than their CFC counterparts possibly resulting in a lower incidence of oropharyngeal candidiasis. However, growth studies and most HPA studies do not support improved safety on the basis of particle size alone and some studies suggest even higher systemic bioavailability and safety risk with smaller particles, depending on the molecule and the formulation. Further efficacy and safety studies are clearly warranted to determine any potential advantages of small-particle ICS, particularly in long-term disease modification where large-particle ICS have failed, and in infants and pre-schoolers, in whom airway delivery is problematic with current formulations.

Effect on growth of long-term treatment with intranasal triamcinolone acetonide aqueous in children with allergic rhinitis

BACKGROUND Guidelines recommend treatment with intranasal corticosteroids for patients with allergic rhinitis (AR), but concerns remain about possible adverse effects. OBJECTIVE To present the 1- and 2-year growth results for children with AR treated with triamcinolone acetonide aqueous nasal spray. METHODS Thirty-nine children (aged 6.1-14.3 years at study entry) were treated with triamcinolone acetonide aqueous for 1 year, and a subset of 30 children completed a second year of treatment. The dose was physician titered to achieve control over AR symptoms. For each child, statural heights at baseline and at the 1- and 2-year (where available) visits, together with growth rates, were measured and were compared with predicted values. RESULTS There were no significant differences between measured and predicted heights at the 1- and 2-year visits. The mean (SD) measured--predicted difference was 0.3 (2.2) cm (95% confidence interval, -0.4 to 1.0 cm) at the 1-year visit and 0.5 (3.0) cm (95% confidence interval, -0.6 to 1.6 cm) at the 2-year visit. Mean differences in measured and predicted growth rates were nonsignificant at the 1- and 2-year visits. CONCLUSIONS Triamcinolone acetonide aqueous titered to control AR symptoms and given for 1 or 2 years had no significant effect on statural growth in children with AR.

A Randomized, Double-Blind, Parallel-Group, Multicenter, Placebo-Controlled Study of the Safety and Efficacy of Extended-Release Guaifenesin/Pseudoephedrine Hydrochloride for Symptom Relief as an Adjunctive Therapy to Antibiotic Treatment of Acute Respiratory Infections

Abstract Purpose: This study assessed the efficacy and safety of guaifenesin 600 mg and pseudoephedrine hydrochloride 60 mg extended-release bilayer tablets in providing relief of acute respiratory symptoms when used as an adjunct to antibiotics in patients with an acute respiratory infection (ARI). Methods: Adult patients experiencing symptoms of ARI and meeting the physicians usual diagnostic criteria for oral antibiotic treatment were prescribed an antibiotic and randomized to adjunctive guaifenesin/pseudoephedrine hydrochloride or matching placebo twice daily for 7 days. Patients completed symptom diaries and treatment assessments twice daily and attended office visits on Days 4 and 8. Results: The safety/intent-to-treat (ITT) population analysis included 601 patients (guaifenesin/pseudoephedrine, n = 303; placebo, n = 298). Mean symptom scores were lower with guaifenesin/pseudoephedrine from Day 3 for every symptom assessed, with statistically significant improvements in total symptom score from Day 3 (P = 0.026). The greatest effects of treatment with guaifenesin/pseudoephedrine were observed for nasal congestion and sinus headache. Time to overall relief was shorter with guaifenesin/pseudoephedrine (P = 0.038). Significantly more patients reported “the medication was helping during the day” on Day 2 with guaifenesin/pseudoephedrine (P = 0.002). Patient assessments of symptom relief showed a significant preference for guaifenesin/pseudoephedrine versus placebo (P = 0.021). Treatment with guaifenesin/pseudoephedrine was well tolerated. Insomnia (2.6%), nausea (2.3%), and headache (1.3%) were the most common treatment-related adverse effects. Conclusions: As adjunctive therapy for symptom relief for patients taking antibiotics for ARIs, guaifenesin/pseudoephedrine shortened time to relief and improved bothersome respiratory symptoms better than placebo, with greatest effects seen for nasal congestion and sinus headache.

Safety and Efficacy of Inhaled Corticosteroids (ICS) in Children with Asthma

Inhaled corticosteroids (ICS) are the guideline-preferred preventative therapy for persistent asthma of all severity levels and for all ages, including children. While these drugs are unquestionably efficacious, concerns of adverse systemic effects limit patient compliance with treatment regimens and thus the attainable benefits. Suppression of bone growth, bone density, and HPA axis function, in addition to cataract formation and elevated intraocular pressure/glaucoma, have been associated with ICS use. This review will focus on recent developments in the safety and efficacy of ICS as compared to oral CS corticosteroids and the achievement of a balance between risk and benefit in optimizing ICS therapy.