Fluticasone furoate nasal spray did not suppress the function of the hypothalamic-pituitary-adrenal [HPA] axis in teens and adults with allergic rhinitis (AR), according to the results of a short-term, double-blind, randomized study reported in the May issue of Annals of Allergy & Asthma Immunology.
"Intranasal corticosteroids are recommended as first-line therapy for [AR], and because of their pharmacologic class, [HPA] axis function is evaluated," write Deepen Patel, MD, from Allied Research International Inc, in Mississauga, Ontario, Canada, and colleagues. "Fluticasone furoate is a novel enhanced-affinity glucocorticoid that has been developed for the treatment of AR. Phase 2 studies have demonstrated that fluticasone furoate nasal spray has low systemic bioavailability and does not significantly affect serum cortisol (SC) or urinary cortisol (UC) levels."
The goal of this study was to determine whether treatment with fluticasone furoate nasal spray, 110 μg once daily for 6 weeks in patients 12 years and older with perennial AR (PAR), suppressed cortisol production as a measure of HPA axis function vs vehicle placebo and prednisone.
In this placebo- and active-controlled (prednisone), parallel-group study, outpatients aged 12 to 65 years with PAR for 2 years or more were enrolled from 1 US center and 1 Canadian center. During 24-hour overnight clinic visits, pharmacodynamic and pharmacokinetic samples were collected for measurements of change from baseline in 24-hour SC weighted mean and 24-hour urinary free cortisol excretion, total 24-hour urinary free cortisol excretion and 6-ß hydroxycortisol excretion, and plasma concentration of fluticasone furoate.
Of 183 patients enrolled, 112 were randomized. In terms of the ratio from baseline in SC weighted mean, fluticasone furoate was noninferior to placebo (treatment ratio, 0.98; 95% confidence interval, 0.89 – 1.07). However, the group randomly assigned to prednisone, 10 mg once daily, had a significant decrease in the ratio from baseline vs placebo. Change from baseline in 24-hour UC excretion was similar in the fluticasone furoate and placebo groups, and plasma levels of fluticasone furoate were undetectable after 6 weeks of treatment.
"Fluticasone furoate nasal spray, 110 µg once daily, was not associated with HPA axis suppression in patients 12 years and older with [PAR]," the study authors write. "These results are likely to be attributable to low systemic exposure."
Limitations of this study include lack of 24-hour UC data for patients in the prednisone control group because of assay interference from the prednisone urinary metabolite.
"Although patients younger than 12 years were not included in the present trial, it is anticipated that fluticasone furoate, with its very low systemic bioavailability, will also have an excellent tolerability profile relative to these older agents," the study authors conclude. "As reflective of any short-term safety trial investigating HPA axis function, it is difficult to determine whether the reported findings would be predictive of any potential long-term effects of fluticasone furoate in patients with PAR. However, a recently published long-term safety study conducted in adult and adolescent patients with PAR showed no evidence of clinically relevant systemic corticosteroid exposure with up to 12 months' treatment with fluticasone furoate."
GlaxoSmithKline R&D Ltd supported this study and employs 4 of its authors.
Ann Allergy Asthma Immunol. 2008;100:490-496.
Clinical Context
According to Patel and colleagues, symptoms of PAR include nasal and ocular symptoms, and intranasal corticosteroids have been well tolerated in children and adults with good symptom relief, but there are concerns about HPA function suppression as assessed by plasma cortisol concentrations and urinary free cortisol excretion over 24 hours. Newer nasal corticosteroids compared with older ones have been found to have low systemic bioavailability and may be associated with lower likelihood of HPA suppression, according to the authors.
This is a randomized, double-blind, placebo-controlled trial to compare the effects of fluticasone furoate (a newer corticosteroid nasal spray) 110 µg twice daily with placebo and oral prednisone on the HPA axis in adult patients with PAR.
Study Highlights
* Included were patients from 1 US and 1 Canadian center aged 12 to 65 years with PAR for at least 2 years with documented positive skin prick test to a perennial allergen or in vitro results for specific immunoglobulin E in the last 12 months.
* All patients had a minimum reflective total nasal symptom score (rTNSS) of 5 or more (total score, 12) on 4 of 7 days.
* rTNSS scores were based on symptoms of rhinorrhea, nasal congestion, nasal itching, and sneezing.
* Excluded were those patients who had medical conditions affecting rhinitis, who were currently receiving corticosteroids, or who had abnormal electrocardiogram or laboratory findings.
* 112 patients were randomly assigned in a 4:4:1 ratio to receive fluticasone furoate nasal spray 110 µg twice daily or placebo for 6 weeks, or prednisone 10 mg tablet daily for the last 7 days during the 6 weeks, using a dummy blinding method.
* Diary cards were used for compliance, symptom scores, medication use, and adverse events.
* The spray devices were also weighed to determine compliance.
* A 4-point scale was used to assess symptoms on the rTNSS for the past 12 hours and at specific time points.
* Primary end point was change from baseline in 24-hour SC weighted mean.
* Secondary end points were change from baseline for 24-hour urinary free cortisol excretion, total 24-hour UC excretion, and 6-β hydroxycortisol excretion.
* Urine samples were taken in a controlled domiciled setting immediately before randomization and at 6 weeks.
* Safety was recorded by diaries, monitoring of vital signs, and detailed physical and nasal examination at visits.
* Baseline SC levels were similar in all 3 groups.
* Fluticasone furoate was not inferior to placebo for ratio from baseline in 24-hour SC weighted mean and the predefined noninferiority bound of 0.8 (treatment ratio, 0.98).
* For the prednisone active group, geometric mean SC concentrations at week 6 showed a marked reduction from baseline compared with placebo (treatment ratio, 0.49).
* Fluticasone furoate and placebo were similar in change from baseline UC excretion except for 2 patients.
* Results for total 24-hour urinary free cortisol and 6-β hydroxycortisol excretion were also similar between fluticasone furoate and placebo.
* At the week 6 domiciled visit, fluticasone furoate levels were not quantifiable in any patient.
* Mean compliance ranged from 98.4% to 99.1% across treatment groups.
* Adverse effects were reported by 63% and 53% of fluticasone furoate vs placebo patients, with headache most common and similar in both (17% and 16%, respectively).
* Epistaxis occurred in 15% of fluticasone furoate vs 4% of placebo patients.
* The authors concluded that use of fluticasone furoate nasal spray twice daily for 6 weeks in patients with PAR was not associated with HPA axis suppression or systemic exposure.
Pearls for Practice
* Use of fluticasone furoate nasal spray 110 µg twice daily for 6 weeks is not associated with HPA axis suppression in patients with PAR.
* There is insignificant systemic exposure after 6 weeks of use of fluticasone furoate nasal spray 110 µg twice daily in patients with PAR.
Reviewed by Dr. Ramaz Mitaishvili
Glendale, CA
