Maureen P. Briscoe

Cetirizine, loratadine, or placebo in subjects with seasonal allergic rhinitis: Effects after controlled ragweed pollen challenge in an environmental exposure unit ☆ ☆☆ ★ ★★

BACKGROUND Allergic rhinitis affects nearly one in 10 Americans. Cetirizine is a newer once-daily selective H1-antagonist. In traditional clinical trials, cetirizine has been shown to be safe and effective for the treatment of seasonal and perennial allergic rhinitis and chronic idiopathic urticaria. OBJECTIVE To better characterize the efficacy and onset of action of cetirizine in a more controlled but clinically relevant setting, this agent was compared with loratadine and placebo in patients with symptomatic seasonal allergic rhinitis undergoing controlled pollen challenge in an environmental exposure unit (EEU). METHODS This was a double-blind, randomized, parallel-group study. After screening, patients were exposed to ragweed pollen (primed) in the EEU (up to six exposures), and those with qualifying symptom scores were randomized to controlled pollen exposure (two periods of 5.5 to 6.5 hours over 2 days) and once-daily treatment with 10 mg cetirizine (n = 67), 10 mg loratadine (n = 67), or placebo (n = 68). The mean ragweed pollen level was 3480 +/- 350 grains/m3 (standard deviation). The primary efficacy variables were the total symptom complex (TSC) and the major symptom complex (MSC) scores. Symptoms were evaluated every half hour in the EEU throughout the study. RESULTS Cetirizine produced a 36.7% mean reduction in TSC scores overall versus 15.4% with loratadine and 12.0% with placebo (p < or = 0.01). Cetirizine also produced a 37.4% mean reduction in MSC scores overall versus 14.7% with loratadine and 6.7% with placebo (p < or = 0.01). Onset of action as assessed by reductions in TSC and MSC scores versus placebo was evident within 1 hour with cetirizine (p < or = 0.02) and 3 hours with loratadine (p < or = 0.03). The incidence of treatment-related side effects was similar among groups, with headache reported most commonly in each group. CONCLUSION Cetirizine is well tolerated and effective in reducing symptoms of seasonal allergic rhinitis in patients undergoing controlled pollen challenge.

Comparative clinical efficacy, onset and duration of action of levocetirizine and desloratadine for symptoms of seasonal allergic rhinitis in subjects evaluated in the Environmental Exposure Unit (EEU)

The Environmental Exposure Unit, an indoor pollen challenge system to test anti‐allergic medications, was used to compare the onset and duration of action and the efficacy of levocetirizine and desloratadine, two recently developed H1‐antagonists. In this double‐blind, placebo‐controlled, parallel‐group study, qualified subjects were randomised to once‐daily levocetirizine 5 mg (n = 141), desloratadine 5 mg (n = 140) or placebo (n = 92) and exposed to ragweed pollen on two consecutive days (7 h and 6 h). Symptoms were self‐rated every 30 min. On both days, levocetirizine produced a greater improvement in the major symptom complex score (primary efficacy variable) than desloratadine (p = 0.015); both were better than placebo (p < 0.001). Levocetirizine acted earlier (1 h vs. 3 h) and produced greater symptom relief at 24 h than desloratadine (p = 0.003). Levocetirizine also alleviated nasal obstruction better than desloratadine (p = 0.007) on day 1; and better than placebo (p = 0.014) after the second dose on day 2, which was not observed with desloratadine. Levocetirizine and desloratadine were safe and well tolerated.

Onset of Action, Efficacy, and Safety of a Single Dose of Fexofenadine Hydrochloride for Ragweed Allergy Using an Environmental Exposure Unit

BACKGROUND Fexofenadine hydrochloride is the active acid metabolite of terfenadine. Fexofenadines anti-allergic properties require confirmation in a clinical setting. OBJECTIVE The purpose of this study was to characterize the time to onset of clinically important relief of symptoms of allergic rhinitis in subjects taking single doses of either 60 mg or 120 mg fexofenadine HCl, or placebo, after exposure to ragweed pollen in a controlled environment. Other objectives were to assess the efficacy and safety of single doses of fexofenadine HCl. METHODS One hundred forty-six ragweed-sensitive subjects were primed in the off-season with ragweed pollen in the environmental exposure unit. One hundred thirty-six subjects who adequately responded to priming entered a single-dose placebo phase. Placebo-responders were disqualified from the study, leaving 99 subjects with adequate symptoms to be randomized and given a single dose of either fexofenadine HCl 120 mg (33), 60 mg (33) or placebo (33), after 60 minutes of allergen exposure. Exposure continued over five hours and subjects recorded symptoms every 20 minutes. This study was of a randomized, placebo-controlled, double-blind, parallel design. RESULTS Median time to onset for relaxed criteria clinically important relief was 60 minutes for both fexofenadine treatment groups, and 100 minutes for placebo (P = .018). The proportion with relief was 82% at 60 mg, 85% at 120 mg, and 64% for placebo. Treated groups had reductions in symptom scores double that of placebo. CONCLUSIONS Fexofenadine is safe and efficacious at single doses of 60 mg and 120 mg. Average time to onset was 60 minutes using controlled pollen exposure in an environmental exposure unit.

A randomized, double-blind, placebo-controlled, controlled antigen delivery study of the onset of action of aerosolized triamcinolone acetonide nasal spray in subjects with ragweed-induced allergic rhinitis

BACKGROUND Clinically apparent relief of nasal symptoms of allergic rhinitis is generally recognized to occur within 3 days to 1 week when intranasal corticosteroids are used. OBJECTIVE A study was designed to evaluate the onset of action of triamcinolone acetonide (TA) in patients with ragweed-induced allergic rhinitis with an environmental exposure unit (EEU). METHODS Eighty-five adults with ragweed-induced allergic rhinitis were primed with ragweed allergen in the EEU. Symptoms were recorded during a baseline exposure in the EEU, and subjects were randomized with a 5:1 ratio to receive either TA 400 micrograms (n = 71) or its propellant (n = 14). Subjects received study medication for 7 days under supervision in the morning and returned to the EEU in the evening for ragweed allergen challenge and symptom assessment. Clinically apparent onset of action was defined as a 25% decrease in symptom scores from baseline. RESULTS A mean reduction in nasal congestion from baseline of greater than 25% (onset of action) was observed in the TA group, but not in the placebo group, by 10 hours. This was also observed for itching of the nose or palate and a combined measure of symptoms. In addition, the proportion of subjects with less nasal congestion after 1 day of treatment was greater in the TA group (41%) than in the placebo group (7%) (p less than 0.05). CONCLUSION The unexpected early relief of symptoms observed in the TA group and, to a lesser extent in the placebo group, has important clinical implications in the treatment of allergic rhinitis.

Environmental exposure unit: a system to test anti-allergic treatment

LEARNING OBJECTIVES Reading this article will enable readers to recognize the Environmental Exposure Unit (EEU), its historic development and its current role as a system to test anti-allergic treatment; to recognize clinical relevance of this test system and its relationship with other pollen challenge methods of evaluation of anti-allergic medication; and, to recognize variables associated with standard clinical studies of anti-allergic medication. Readers will review four studies of antihistamines tested in the Environmental Exposure Unit, three studies on nasal corticosteroids, one on topical eye drops and one on immunotherapy conducted in the EEU. DATA SOURCES The EEU has been in operation since 1985 preceded by a prototype challenge system to assess respiratory effects of urea formaldehyde foam insulation. A number of studies on the onset of action and efficacy of different antihistamines and nasal corticosteroids as well as other treatments have been completed producing accurate and consistent results influenced to some extent by study designs. STUDY SELECTION Studies of commonly used antihistamines and nasal corticosteroids are discussed in detail and represent several of the studies undertaken to date in the EEU. RESULTS Controlled ragweed pollen exposure using the EEU has shown that some antihistamines demonstrate an onset of action within 30 minutes while others have taken up to 3 hours to produce significant effect. Nasal corticosteroids evidenced the onset of clinical improvement at 5 to 6 hours with significance over placebo between 6 and 12 hours depending on dose. CONCLUSION The EEU is an effective pollen delivery system that accurately and consistently determines the onset of action and efficacy of anti-allergic treatment in large groups of subjects. It eliminates variables associated with various other methods of evaluation of these medications but does not supplant the need for such evaluations.

Intranasal fluticasone propionate versus loratadine in the treatment of adolescent patients with seasonal allergic rhinitis

Fluticasone propionate (FP) is a topical corticosteroid with minimal systemic activity. We examined safety and compared the efficacy of FP aqueous nasal spray, 200 micrograms every day with loratadine tablets, 10 mg by mouth every day in 240 adolescents with ragweed pollen-induced seasonal allergic rhinitis for 4 weeks in a randomized, double-blind, parallel-group study. Nasal and eye symptoms were recorded daily on a 4-point (0 to 3) scale. A higher percentage of symptom-free days was observed for nasal blockage on waking during treatment with FP (p < 0.0001). Significant results were also obtained for all other nasal symptoms when analyzed for both symptom-free days and symptom scores. No differences were found for eye irritation symptoms (p = 0.14). Morning and evening nasal peak inspiratory flow (PIF) was recorded daily by 57 subjects. FP treatment was associated wit significantly higher PIF values than loratadine both morning (p = 0.0051) and evening (p = 0.0036). A greater improvement over 4 weeks was observed for PIF morning values in the FP group (p = 0.008) but not for evening values (p = 0.358). Statistically significant correlations were found for nasal blockage and PIF in the morning (r = -0.54, p = 0.0001) and in the evening (r = -0.46, p = 0.008).

Efficacy of Immunotherapy to Ragweed Antigen Tested by Controlled Antigen Exposure

BACKGROUND Immunotherapy is a recognized component in the management of allergic rhinitis. Its efficacy has been evaluated in a number of clinical field trials. These methods of evaluation are limited by control of antigen exposure. OBJECTIVE A study was designed to evaluate the efficacy of immunotherapy in ragweed-induced rhinoconjunctivitis using an environmental exposure unit. METHODS Forty-three subjects were grouped into (1) immunotherapy group: ragweed-allergic subjects on maintenance ragweed immunotherapy for at least 2 years (N = 16), (2) positive control group: ragweed-allergic subjects who had never received immunotherapy (n = 16), and (3) negative control group: ragweed-nonallergic subjects (N = 11). Ragweed specific skin tests and ragweed IgE levels were obtained prior to exposure. The study was done in a room where levels of 2,500 to 3,000 grains m3 of ragweed were maintained over three hours. Symptoms were recorded every 15 minutes. RESULTS Nasal symptoms in the immunotherapy group were significantly less than in the positive control group after 45 minutes (P = .025). Significant differences were not observed for ocular symptoms. Combined nasal and ocular scores were 50% less in the immunotherapy group than in the positive control group by 75 minutes (P = .039). Ragweed-specific skin tests and IgE were significantly less in the immunotherapy group than in the positive control group. Rhinoconjunctivitis symptoms in the negative control group were absent throughout. CONCLUSIONS Controlled ragweed pollen exposure in this setting demonstrated that ragweed immunotherapy significantly reduced symptoms of ragweed-allergic rhinitis but had no significant effect on ocular symptoms. This system presents opportunities for additional studies on immunotherapy for allergic respiratory conditions.

A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis

BACKGROUND Decrements in cognitive performance are associated with the use of sedating antihistamines. Most, but not all, second-generation antihistamines have been found to be nonsedating. OBJECTIVE To examine the central nervous system (CNS) profile of a new second-generation antihistamine, desloratadine. METHODS Subjects with ragweed-induced allergic rhinitis (aged 18-60 years) who demonstrated a predetermined severity of symptoms after priming with ragweed pollen in the Environmental Exposure Unit were randomized to receive a single dose of desloratadine, 5 mg; diphenhydramine, 50 mg; or placebo. A comprehensive battery of repeatable, automated neuropsychological tests was administered to subjects before treatment (symptomatic baseline) and 90 minutes after taking study medication. RESULTS Both desloratadine (P = .04) and diphenhydramine (P < .01) alleviated the symptoms of allergic rhinitis compared with placebo, but treatment with diphenhydramine was associated with clinically meaningful decrements on all vigilance parameters (P < .05 for desloratadine-diphenhydramine contrasts). Also, subjects treated with diphenhydramine performed significantly worse than subjects given desloratadine or placebo across all cognitive domains evaluated. Most effect sizes for the mean desloratadine and diphenhydramine differences were between 0.4 and 0.8 (moderate to high). Stanford Sleepiness Scale scores also indicated significantly more somnolence with diphenhydramine vs desloratadine or placebo (P < .001). There were no significant differences on any of the cognitive parameters between subjects treated with desloratadine and those given placebo. CONCLUSIONS Desloratadine improved ragweed-induced allergic rhinitis symptoms without adversely affecting performance. Diphenhydramine improved allergic rhinitis symptoms but caused significant decrements in vigilance and cognitive functioning. Thus, efficacy of antihistamine treatment must be balanced against the associated effects on CNS functioning.

Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal allergic rhinitis in the Environmental Exposure Unit.

Levocetirizine dihydrochloride, a potent H1-receptor antagonist, and montelukast sodium, a selective leukotriene receptor antagonist, have been approved for the treatment of seasonal allergic rhinitis (SAR), but target two different pathways that cause SAR symptoms. The study objective was to compare the efficacy of levocetirizine (LCTZ), 5 mg, and montelukast (MLKT), 10 mg, in reducing SAR symptoms in ragweed-sensitive adults exposed to ragweed pollen in the Environmental Exposure Unit (EEU). This randomized, double-blind, placebo-controlled, parallel-group study of 418 adult subjects with SAR to ragweed compared the efficacy of LCTZ, MLKT, and placebo administered once daily (11:00 A.M.) for 2 consecutive days in the EEU. There were three evaluation periods: period I, 0-5 hours after first dose; period II, 22.5-24 hours after first dose; and period III, 0-4.5 hours after second dose. The primary efficacy variable was the Major Symptom Complex (MSC) score (six symptoms) over period I. Both active drugs significantly improved the MSC score compared with placebo in all periods. The adjusted mean MSC score difference between LCTZ and MLKT was -0.93 (p = 0.100) in period I, -3.11 (p < 0.001) in period II, -2.42 (p < 0.001) in period III, and -1.88 (p < 0.001) over the total treatment period. The same trends were observed for the Total Symptom Complex score (10 symptoms) and most individual symptoms. Subject-reported global satisfaction was greater for LCTZ compared with MLKT and placebo. All treatments had a favorable safety profile. LCTZ, 5 mg, was more effective than MLKT, 10 mg, in subjects with SAR and had better subject-reported global satisfaction.

Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit

BACKGROUND Nasal congestion is considered to be one of the most bothersome symptoms of allergic rhinitis (AR) and often the most difficult to treat. Oral therapies providing safe, effective, and reliable relief of AR symptoms, including nasal congestion, are limited. OBJECTIVE To evaluate the efficacy of a single dose of loratadine-montelukast (10 mg/10 mg) vs placebo and phenylephrine (10 mg) in relieving nasal congestion over 6 hours after ragweed pollen exposure in the environmental exposure unit at the Kingston General Hospital. METHODS After a screening visit and up to 6 priming visits, patients who met minimum symptom requirements during ragweed pollen exposure were randomized to receive loratadine-montelukast, phenylephrine, or placebo. Patients evaluated nasal congestion and other symptoms of AR and measured peak nasal inspiratory flow before dosing and at 20-minute intervals during the subsequent 8 hours of pollen exposure. RESULTS During the first 6 hours after treatment (primary end point), loratadine-montelukast treatment resulted in greater improvement in the mean nasal congestion score vs placebo (P = .007) and phenylephrine (P < .001). Loratadine-montelukast was more effective than placebo (P < or = .02) and phenylephrine (P < or = .002) in relieving total symptoms, nasal symptoms, and nonnasal symptoms and in improving peak nasal inspiratory flow. There were no statistically significant differences between phenylephrine and placebo for any measures. Fewer patients in the loratadine-montelukast group (3.9%) reported adverse events than in the phenylephrine (7.9%) and placebo (7.1%) groups; most adverse events were mild or moderate. CONCLUSIONS Loratadine-montelukast was more effective than placebo and phenylephrine in relieving nasal congestion and other nasal and nonnasal symptoms resulting from ragweed pollen exposure. There was no statistically significant difference between phenylephrine and placebo.