Patient progress through the trial. AE indicates adverse event.
Schlessinger J, Miller B, Gilbert RD, Plott RT. An Open-label Adrenal Suppression Study of 0.1% Fluocinonide Cream in Pediatric Patients With Atopic Dermatitis. Arch Dermatol. 2006;142(12):1568-1572. doi:10.1001/archderm.142.12.1568
Copyright 2006 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2006
To assess the potential of a superhigh-potency 0.1% fluocinonide cream to suppress the hypothalamic-pituitary-adrenal (HPA) axis in pediatric patients with atopic dermatitis.
A multicenter, multiple-dose, open-label safety study in 4 age cohorts with 0.1% fluocinonide cream applied once or twice daily for 2 weeks.
Clinical outpatient setting.
Patients with moderate to severe atopic dermatitis with 20% or more of the body surface area involved were included in the study. Each cohort began only after evaluation of the preceding cohort: ages 12 to younger than 18 years (cohort 1); 6 to younger than 12 years (cohort 2); 2 to younger than 6 years (cohort 3); and 3 months to younger than 2 years (cohort 4).
Main Outcome Measures
Assessment of HPA axis suppression, local and systemic adverse events, and change in disease status from baseline.
Suppression of the HPA axis was not observed in any patient treated once daily for the 2 youngest cohorts. Suppression was observed in 1 (7%) of 15 and 2 (12%) of 16 patients in the fluocinonide twice-daily group in cohorts 1 and 2, respectively. In all 4 cohorts, more than 90% of patients in the fluocinonide once-daily and twice-daily groups showed improvement in their disease status.
Once-daily treatment with 0.1% fluocinonide cream for 2 weeks does not result in HPA axis suppression under the conditions of this study. Once-daily applications provided similar or better efficacy as twice-daily applications with a lower risk of HPA axis suppression. The frequency of HPA axis suppression is no greater in younger children than in older children.
isrctn.org Identifier: ISRCTN71227633
The interdependent feedback mechanism of the hypothalamus (responsible for secretion of corticotropin-releasing factor), pituitary gland (responsible for secretion of adrenocorticotropic hormone), and adrenal cortex (which secretes cortisol)1 is called the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis may be suppressed by applying topical corticosteroids.2,3 The extent of adrenal suppression is generally related to the potency of the topical corticosteroids, the frequency of application, the patient's body surface area (BSA), and the skin's ability to act as a barrier.4 The present study was undertaken to assess the systemic safety (ie, ability) of a superhigh-potency (class I) 0.1% fluocinonide cream5,6 to suppress the HPA axis when applied once or twice daily for 2 weeks in pediatric patients with atopic dermatitis.
A multicenter, multiple-dose, open-label study to assess the safety of a new superhigh-potency (class I) formulation of 0.1% fluocinonide cream (Vanos; Medicis Pharmaceutical Corp, Scottsdale, Ariz) was performed in pediatric patients with clinically diagnosed atopic dermatitis. The study was performed in accordance with the ethical principles put forth in the Declaration of Helsinki,7 with the approval of an appropriately constituted institutional review board. At screening (baseline), each qualified patient was assessed for a normally functioning HPA axis. Male or female patients with clinically diagnosed atopic dermatitis that involved 20% or more of the BSA were randomized to receive either once- or twice-daily treatment in 4 sequential age cohorts: ages 12 to younger than 18 years (cohort 1); 6 to younger than 12 years (cohort 2); 2 to younger than 6 years (cohort 3); and 3 months to younger than 2 years (cohort 4).
Patient demographics and visit schedules are summarized in Table 1. Patients who met the inclusion and exclusion criteria were randomized to receive topical fluocinonide either once or twice daily in an outpatient setting. Patients and/or their guardians were instructed to apply a thin layer of the study product to all treatable areas once or twice daily for 2 weeks. At the end of weeks 1, 2, and 4, patients returned to the study site for the investigator (J.S. or B.M.) to perform all designated evaluations.
The potential of fluocinonide to suppress the HPA axis was assessed by determining the rate of incidence of suppression, when suppression was defined as a serum cortisol level of 18 μg/dL or less (≤497 nmol/L) 30 minutes after intravenous cosyntropin stimulation. For a patient to be evaluable for HPA axis suppression, the patient must have received at least 2 full weeks of fluocinonide treatment before the cosyntropin challenge. Blood samples taken before and after cosyntropin stimulation were obtained between 7:30 and 8:30 AM and at the baseline and week 2 visits as directed in the package insert.8 At the end of the 2-week treatment period, any patient with a poststimulation cortisol level of 18 μg/dL or less was retested at week 4 and once every 4 weeks thereafter until the poststimulation levels were within normal limits. Specific skin safety evaluations were performed at each study visit with regard to all treated lesions by noting the presence or absence of the following 8 signs and symptoms of skin atrophy: telangiectasia, transparency, loss of elasticity, loss of normal skin markings, thinning, striae, pigmentation changes, and bruising. Adverse events were coded using Medical Dictionary for Regulatory Activities terminology and were described according to their intensity, duration, and relationship to the study product. Efficacy was assessed by observing the change in the severity of atopic dermatitis from baseline to weeks 2 and 4 as “clear/almost clear,” “improved (but less than clear/almost clear),” “no improvement,” or “worsened.”
Demographic characteristics are summarized by cohort for all treated patients in Table 1. Patient disposition is summarized in the Figure. At baseline, the mean percentage of BSA affected by atopic dermatitis (BSA involvement) ranged from approximately 34% in the cohort 1 fluocinonide twice-daily group to 43% in the cohort 4 fluocinonide once-daily group.
Serum cortisol level data after cosyntropin stimulation for the evaluable patients are summarized for all cohorts in Table 2. One (7%) of 15 patients in the cohort 1 fluocinonide twice-daily group met the criterion for HPA axis suppression, with a poststimulation serum cortisol level of 17.6 μg/dL (485.6 nmol/L) (screening value of 20.4 μg/dL [562.8 nmol/L]) at week 2. At the week 4 visit (2 weeks after treatment), the value was normal at 18.9 μg/dL (521.4 nmol/L).
Two (12%) of 16 patients in the cohort 2 fluocinonide twice-daily group met the criterion for HPA axis suppression. At week 2, the poststimulation serum cortisol level of the first patient was 17.2 μg/dL (474.6 nmol/L) (screening value of 32.1 μg/dL [885.6 nmol/L]). At the week 4 visit (2 weeks after treatment), the value for this patient was normal at 28.7 μg/dL (791.3 nmol/L). At week 2, the poststimulation serum cortisol level for the second patient was 16.7 μg/dL (460.8 nmol/L) (screening value of 20.5 μg/dL [565.6 nmol/L]). At an unscheduled visit 8 days after the end of treatment, the value for this patient was normal at 22.4 μg/dL (618.0 nmol/L).
One (7%) of 15 patients in the cohort 3 fluocinonide twice-daily group met the criterion for HPA axis suppression at the week 2 visit. At week 2, the poststimulation serum cortisol level for the patient was 9.1 μg/dL (251.1 nmol/L) compared with the prestimulation level of 28.0 μg/dL (772.5 nmol/L). Because the prestimulation cortisol level was higher than the poststimulation level, it was suspected that the prestimulation and poststimulation samples were reversed and that the HPA axis response to cosyntropin stimulation in this patient was normal. Poststimulation values at screening and week 4 were 40.0 μg/dL (1103.6 nmol/L) and 30.3 μg/dL (836.0 nmol/L), respectively. Because the prestimulation value was greater than 18 μg/dL (496.6 nmol/L), this patient cannot be said to have suppression of the HPA axis.
In 1 or 2 patients in each of the 4 cohorts and treatment groups, 1 or more signs of skin atrophy, such as loss of elasticity, loss of normal skin markings, skin thinning, striae, and pigmentation changes, were observed after baseline but were considered unrelated to the treatment with fluocinonide. Table 3 provides a summary of the skin safety assessment of all treated patients. Thus, no age-related or dose-related differences were found in the incidence of these effects.
Forty-five (35.7%) of 126 patients treated in this study reported at least 1 treatment emergent adverse event. No age-related trends were evident with regard to the incidence of treatment-related adverse events. One patient in the cohort 1 fluocinonide once-daily group was withdrawn from the study because of an adverse event (moderate urticaria). No patients were withdrawn because of adverse events in cohorts 2, 3, or 4.
In cohorts 1 and 2, all of the patients in the fluocinonide once-daily group and most patients (>90%) in the fluocinonide twice-daily group were rated by the investigator as showing an improvement in their disease status or as clear or almost clear of disease at the end of the treatment period compared with baseline. In cohorts 3 and 4, more than 90% of the once- and twice-daily groups were rated by the investigator as showing an improvement in their disease status or as clear or almost clear of disease at the end of the treatment period. At the 2-week follow-up visit, more than 90% of the patients in each dosage group in cohort 4, more than 80% of patients in each dosage group in cohorts 1 and 3, and more than 70% of patients in each dosage group in cohort 2 continued to show an improvement of clear or almost clear compared with baseline.
This study investigated the systemic and topical safety of a superhigh-potency (class I) topical corticosteroid used for 2 weeks in the treatment of children with moderate to severe atopic dermatitis. The results of this trial were surprising and thus provide several important lessons for the safe use of superhigh-potency products in children. From previous studies conducted with the drug in adults with atopic dermatitis, once-daily treatment has been shown to be as effective as twice-daily treatment. The efficacy results in this pediatric population confirmed once-daily treatment as the lowest effective dosing frequency. Patients treated in the study had severe atopic dermatitis with a mean of 40% BSA involvement. Thirty-seven percent of the patients treated in the trial achieved clear or almost clear status at the end of the 2 weeks of treatment.
The systemic safety of once-daily applications of this class I potency product produced no HPA axis suppression. This finding suggests that the potential for HPA axis suppression when the product is used as studied is low. Drug labeling for this class I 0.1% fluocinonide cream indicates that it is not recommended beyond 2 consecutive weeks and that the total dosage should not exceed 60 g/wk in children younger than 12 years.5
This study provides evidence that younger patients may not have an increased risk of HPA axis suppression when treated with potent topical corticosteroids as previously thought. In the youngest and the oldest cohorts, the mean response to intravenous cosyntropin challenge stayed the same after treatment with fluocinonide once daily, whereas in all cohorts treated twice daily, the mean response to cosyntropin decreased slightly. Suppression of the HPA axis was observed in 1 (7%) of 15 patients in the fluocinonide twice-daily group in cohort 1 and in 2 (12%) of 16 patients in the fluocinonide twice-daily group in cohort 2. Current topical corticosteroid labeling suggests that pediatric patients may be more susceptible to HPA axis suppression because of the larger skin surface–to–body mass ratio. In our study, there is no evidence of greater susceptibility in younger patients, even when treating large portions of diseased body surfaces.
In conclusion, 0.1% fluocinonide cream, a class I potency product, used once daily for 2 weeks does not result in suppression of the HPA axis in patients 3 months old to younger than 18 years under the conditions of this study. Once-daily treatment provided similar or better efficacy to twice-daily applications with a lower risk of HPA axis suppression. There was no increase in risk observed for younger children and infants compared with adolescents for HPA axis suppression by this superhigh-potency product under the conditions of this study.
Correspondence: R. Todd Plott, MD, Medicis Pharmaceutical Corp, 8125 N Hayden Rd, Scottsdale, AZ 85258.
Financial Disclosure: None reported.
Accepted for Publication: May 14, 2006.
Author Contributions: Drs Schlessinger, Miller, Gilbert, and Plott participated sufficiently in the work to take public responsibility for part of the content and acquisition of data; provided critical revision of the manuscript for important intellectual content, administrative, technical or material support, and supervision; and have no affiliation with or financial involvement with any organization or entity discussed in the manuscript and no relevant financial interest in the manuscript. Study concept and design: Gilbert and Plott. Acquisition of data: Schlessinger and Miller. Analysis and interpretation of data: Gilbert and Plott. Drafting of the manuscript: Gilbert. Critical revision of the manuscript for important intellectual content: Schlessinger, Miller, Gilbert, and Plott. Statistical analysis: Gilbert. Obtained funding: Plott. Administrative, technical, and material support: Schlessinger, Miller, Gilbert, and Plott. Study supervision: Schlessinger, Miller, and Plott.
Members of the Vanos Study Group (participating clinical investigators and contributors in addition to the authors): Lester Fahrner, MD, Champaign, Ill; Michael Gold, MD, Nashville, Tenn; David Pariser, MD, Norfolk, Va; Craig Leonardi, MD, and Elaine Siegfried, MD, St Louis, Mo; Dow Stough, MD, Hot Springs, Ark; and Cindy Lamerson, MD, Reno, Nev.
Funding/Support: Funding, design, and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript was provided by Medicis, The Dermatology Company. Yogesh Mawal, PhD, served as medical writer.