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* ClinTrials of Orange County, Orange, California
Child First Pediatrics, Englewood, Colorado
Allergy & Clinical Immunology Associates, Pittsburgh, Pennsylvania
¶ Nemours Children’s Clinic, Jacksonville, Florida
|| GlaxoSmithKline, Research Triangle Park, North Carolina
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. Patients ages 2 to 3 years with symptoms of allergic rhinitis were administered FP 200 µg/day (FP200 QD) or vehicle placebo for 6 weeks.
Results. The FP200 QD group (n = 33) was equivalent to the placebo group (n = 32) in mean change from baseline in the primary safety measure of 12-hour creatinine-corrected urinary-free cortisol concentration (geometric mean difference [standard error; SE] for placebo—FP200 QD = 0.96 [1.20]; 95% confidence interval 0.66, 1.39) at the end of the treatment period. The adjusted geometric mean change from baseline value was 0.98 for FP200 QD (SE = 1.14) and 0.94 for placebo (SE = 1.15); a value of 1.0 reflects no change from baseline. Cough and fever were the most common adverse events reported in either group.
Conclusions. FP200 QD was equivalent to placebo with respect to effects on HPA axis function measured by 12-hour urinary-free cortisol in 2- and 3-year-old patients. FP200 QD was well-tolerated in these very young children with allergic rhinitis.
Key Words: FP200 QD nasal spray • HPA axis • children <4 years old • allergic rhinitis
Abbreviations: HPA, hypothalamic-pituitary-adrenal • FP, fluticasone propionate aqueous nasal spray • FP200 QD, fluticasone propionate aqueous nasal spray 200 µg/day • SD, standard deviation • SE, standard error
Well-tolerated and effective, intranasal corticosteroids are the cornerstone of pharmacotherapy for allergic rhinitis in older children, adolescents, and adults,1–3 but they have not been thoroughly studied in young children (ie, younger than 4 years). In establishing the safety profile of intranasal corticosteroids in very young children, evaluation of potential systemic exposure is important in light of the well-documented effects of systemic corticosteroids on hypothalamic-pituitary-adrenal (HPA) axis function.4 Although data from older children and adults demonstrate that the intranasal corticosteroids at therapeutic doses are well-tolerated and do not suppress HPA axis function,5 these findings have not been verified prospectively in young children.
The efficacy and tolerability of the intranasal corticosteroid fluticasone propionate formulated as an aqueous nasal spray have been extensively studied in patients as young as 4 years with allergic rhinitis.6–21 With a systemic bioavailability of <2%,22 fluticasone propionate aqueous nasal spray (FP) 100 µg or 200 µg daily for 2 to 12 weeks had no clinically significant effect on HPA axis function in 5 published randomized, double-blind, placebo-controlled or active-comparator studies in 
700 children 4 to 11 years of age.6–9 Moreover, FP at daily doses of 200 µg for periods ranging from 2 weeks to 1 year had no clinically significant effect on HPA axis function in 12 randomized, double-blind, placebo-controlled studies of 1500 patients ages 12 years and older.10–21 Considered together, these data show no systemic effects, as assessed by HPA axis measures, of FP in either adults or children 4 years and older; however, the effects of FP on HPA axis function in children younger than 4 years have not been previously reported. This randomized, double-blind, placebo-controlled study of FP 200 µg/day, referred to hereafter as FP200 QD (the highest recommended dose in pediatric patients) was conducted to evaluate its potential systemic effects as measured by 12-hour urinary-free cortisol levels in patients 2 to 3 years of age.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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2 but <4 years of age at the initiation of treatment were eligible for the study if they were toilet-trained or partially toilet-trained and if they met the following criteria suggesting that they suffered from allergic rhinitis and may have benefited from an intranasal corticosteroid: 1) a positive skin test (ie, wheal diameter 3 mm greater than that of diluent control using 1:20 w:v glycerinated solution) to at least 1 perennial or seasonal allergen within 1 year before screening; and 2) presence of nasal symptoms for >1 hour daily on most days or the use of rhinitis medication on most days during the relevant allergen exposure period. Exclusion criteria included a requirement for antibiotics within 14 days of randomization; a history of symptomatic asthma involving at least 2 exacerbations requiring medical attention and corticosteroid therapy within 1 year before screening; recent use of any medication that might directly affect skin test results; current use of intranasal sodium cromoglycate or nedocromil sodium; and use of inhaled, intranasal, oral, optical, injectable, or topical steroids with the exception of intermittent use of 
1% hydrocortisone within 6 months of the screening visit. Written informed consent was obtained from patients’ parents and/or guardians.
Procedures
The protocol for this randomized, double-blind, parallel-group, placebo-controlled, multicenter study (GlaxoSmithKline protocol FNM40183) was approved by institutional review boards for each of the study sites. The study comprised a 2- to 7-day screening period and a 6-week treatment period. Clinic visits occurred at screening, on the first day of treatment, and at the end of weeks 1, 3, 5, and 6 of treatment.
Patients meeting eligibility criteria at the screening visit and having an evaluable 12-hour urine sample (see below) were randomly assigned to receive FP200 QD (administered as 2 sprays per nostril once daily in the morning) or placebo (consisting of the vehicle for FP) for 6 weeks. The maximum recommended daily dose of FP (200 µg once daily) was selected for this study. To ensure that the age distribution of patients was similar between the FP200 QD group and the placebo group, randomization was stratified by age at enrollment (2 years and <3 years for stratum 1 and 3 years and <4 years for stratum 2).
Twelve-hour urine samples (beginning at 8 PM and ending at 8 AM the following day) were collected by the parent or guardian in the patient’s home before the patient was randomized to treatment and at the end of the treatment period. Evaluable samples, defined as those collected within the appropriate time interval and having a documented start time, stop time, total urine volume, and no missed voids, were stored with boric acid in brown collection jugs and returned to the clinic within 40 hours of the start of the collection interval. For each evaluable 12-hour urine sample, the total urine volume was documented. A 25-mL aliquot was labeled and frozen at –20°C before it was shipped in dry ice to a laboratory for analysis.
Routine clinical laboratory tests for chemistry, hematology, and electrolytes were performed at screening and at the last visit of the treatment period.
Medications known to affect the HPA axis were prohibited throughout the treatment period. Vaccinations and antirhinitis medications, with the exception of those administered intranasally, were permitted throughout the study.
Measures and Data Analyses
All patients randomized to receive study medication were included in the data analyses. The primary measure of safety was mean change from baseline in 12-hour creatinine-corrected urinary-free cortisol at the end of the 6-week treatment period. The power calculation indicated that a sample size of 24 patients per group would provide at least 85% power to show equivalence within ±20 µg/g between the FP200 QD group and the placebo group in the mean change from baseline in 12-hour creatinine-corrected urinary-free cortisol. This calculation was based on a 2-sided t test, an 
of .05, and the assumption that the standard deviation (SD) of the mean change from baseline in 12-hour creatinine-corrected urinary-free cortisol in either treatment group would be 20 µg/g.11
Twelve-hour creatinine-corrected urinary-free cortisol was derived by dividing the 12-hour urinary cortisol value (µg/dL) by the urinary creatinine value (mg/dL) and multiplying the resulting ratio by 1000 so that the quantity was in micrograms per gram, the same units as the prospectively defined equivalence limit (–20 µg/g, 20 µg/g). Analysis of covariance adjusted for baseline, patients’ age at enrollment, and study site was used to assess differences between the FP200 QD group and the placebo group with urinary cortisol data from both strata pooled. Because the data were not normally distributed as required for analysis of covariance, cortisol values were log-transformed before analysis and reported as geometric means. Note that conversion back to a natural log scale is required before any arithmetic operations can be performed on these results, and that exponentiation back to the original units is required after such operations. In addition to being analyzed with data from both strata pooled, 12-hour urinary-free cortisol data were also summarized for each stratum separately, but no formal statistical hypothesis testing was conducted for the separate strata.
Secondary safety measures included the incidence of clinically significant changes in results of clinical laboratory tests and the incidence of adverse events, defined as any untoward medical occurrence regardless of its suspected causality. These secondary measures were summarized using descriptive statistics, but no statistical hypothesis testing was conducted. No efficacy measures were included in this study.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Mean values in original units (ie, not log-transformed or adjusted for baseline) for cortisol, creatinine, and urine volume are listed in Table 2. Values for all of these variables were comparable between the FP200 QD group and the placebo group.
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Clinical Laboratory Tests
The incidence of posttreatment clinical laboratory tests outside predetermined threshold values was extremely low, and no patterns suggesting an effect of study medication were observed. There was 1 incident of elevated serum creatinine and 1 incident of low red blood cell count in the FP200 QD group.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of the range of measures of HPA axis function, 12-hour urinary cortisol levels were chosen as the primary endpoint for this study because they are sensitive to the systemic presence of corticosteroids even during short-term use of corticosteroid medications.5 HPA axis stimulation tests such as the cosyntropin test are most useful for detecting clinically significant corticosteroid effects, such as adrenal insufficiency, that potentially occur after long-term systemic exposure.5 The use of the 12-hour urinary cortisol level as a primary outcome measure in the current study was also appropriate from the standpoint that it involves reliable, noninvasive techniques that can be successfully employed in very young patients. This study is the first to the authors’ knowledge to gather urine samples for 12-hour urinary cortisol measures in rhinitic children this young.
The data from the current study corroborate and extend findings of several studies evaluating the potential HPA axis effects of FP200 QD in children 4 to 11 years of age. Four of the studies—3 of which were conducted in patients 4 to 11 years of age6–8 and the fourth of which was conducted in patients 5 to 11 years of age9—were placebo-controlled trials with treatment periods ranging from 2 to 4 weeks. No differences between FP 100 µg or 200 µg daily and placebo were observed for morning plasma cortisol levels at the beginning or the end of the treatment period (4 studies6–9) or in 24-hour urinary-free cortisol or 17-ketogenic steroid levels (1 study7). Similarly, in a double-blind trial comparing FP 100 µg or 200 µg daily with beclomethasone dipropionate aqueous nasal spray 200 µg daily in patients 6 to 11 years of age, morning plasma cortisol levels were not significantly different between treatments either before or after a 12-week course of therapy.10
The HPA axis findings in children are consistent with results of adult studies that show no evidence of a clinically significant effect of FP200 QD on the HPA axis in patients with allergic rhinitis.10–21 The consistency of the data across numerous studies renders the findings compelling. Although isolated statistically significant effects of FP200 QD on HPA axis function have been observed in 2 studies in healthy adults,23,24 the validity of both studies has been called into question.25,26 A 2002 healthy-volunteer study that corrected some of the limitations of the latter 2 investigations showed no effect of FP (200 µg/d for 4 days) or triamcinolone acetonide nasal spray (200 µg/d for 4 days) compared with placebo on 12-hour urinary cortisol excretion or overnight urinary cortisol/creatinine excretion.26
The current study is the first to examine the HPA axis effects of an intranasal corticosteroid in 2-year-olds with allergic rhinitis. In the only other study to assess HPA axis effects of an intranasal corticosteroid in patients as young as 3 years, cortisol responses to the cosyntropin stimulation test did not differ among 3- to 5-year old patients (mean age 4.1 years) treated with the intranasal corticosteroid mometasone furoate (50 µg, 100 µg, or 200 µg) compared with placebo after 2 weeks of therapy.27 Although the cosyntropin test is considered a valid measure of HPA axis effects after long-term systemic exposure to corticosteroids, it is relatively insensitive for detecting systemic presence of corticosteroids with short-term use.5
The adverse-event data from the current study show that FP was well-tolerated in very young children. Adverse events were reported with similar frequency in the FP200 QD group and the placebo group with the exception of vomiting and gastric pain, which were reported in more FP200 QD-treated patients. These data are similar to those from previous studies in children and adults.6–20 The most common adverse events, such as cough and fever, were considered by the investigators to be unrelated to study medication. Furthermore, few clinically meaningful changes in clinical laboratory parameters were observed in these young patients given FP200 QD for 6 weeks.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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ACKNOWLEDGMENTS |
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The authors acknowledge the following investigators for their participation in this clinical study: Edwin A. Bronsky (Salt Lake City, UT), Roger A. Friedman (Columbus, OH), David B. K. Golden (Baltimore, MD), Anne-Marie Irani (Richmond, VA), John D. Jeppson (Boise, ID), Kenneth T. Kim (Long Beach, CA), Jeffrey G. Leflein (Ypsilanti, MI), Arden L. Levy (Spartanburg, SC), David Lee Miller (Pittsburgh, PA), and Michael J. Noonan (Portland, OR). The authors acknowledge Jane Saiers, PhD, for assistance with writing the manuscript.
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FOOTNOTES |
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Reprint requests to (S.P.G.) ClinTrials of Orange County, 1201 West La Veta, Ste 501, Orange, CA 92868. E-mail: drgalant{at}galantandlin.com
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This article has been cited by other articles:
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  B. Q. Lanier Use of Intranasal Corticosteroids in the Management of Congestion and Sleep Disturbance in Pediatric Patients With Allergic Rhinitis Clinical Pediatrics, June 1, 2008; 47(5): 435 - 445. [Abstract] [PDF]
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