Hydrocortisone butyrate 0.1% lotion in the treatment of atopic dermatitis in pediatric subjects

Robert Matheson

Introduction

Topical corticosteroids have become the cornerstone of treatment for a variety of inflammatory dermatoses, including atopic dermatitis (AD), eczema, and psoriasis. A wide selection of topical corticosteroid products is available and the potency of these formulas depends on several factors, including the inherent activity of the steroid molecule, concentration of the active ingredient, duration of treatment, and nature of the vehicle.

Hydrocortisone butyrate (HCB) is a synthetic, nonfluorinated, glucocorticoid developed in the early 1970s. Hydrocortisone butyrate in other semi-solid dosage forms has been found to be a midpotency topical corticosteroid. Hydrocortisone butyrate 0.1% lotion may provide physicians with a formulation that is easier to apply to extensive areas of disease than creams and ointments.

Methods

Objectives

The primary objective of this study was to evaluate efficacy of a twice-daily application of HCB 0.1% lotion as compared to the vehicle in infants and children aged 3 months to less than 18 years diagnosed with mild to moderate AD. The secondary objective was to evaluate the safety of HCB 0.1% lotion as compared to the vehicle by evaluating reported and observed adverse events.

Design

This multicenter, randomized, parallel group, vehicle controlled study was designed to demonstrate statistical significance of the HCB 0.1% lotion in comparison to its vehicle. The vehicle used in this study was a matched vehicle containing all of the same components of the drug product exclusive of the active ingredient, HCB.

Subjects were assigned to either HCB 0.1% lotion or to the vehicle treatment group in a 1:1 ratio according to a computer-generated randomization scheme. Treatments were randomly assigned to consecutive subject numbers using permuted blocks with a random block size of 4. Upon enrollment into the study, the investigator dispensed subject kits to those determined by the inclusion/exclusion criteria. Each kit was labeled with the subject number and contained 6 double-blind labeled bottles of study treatment. The investigators, subjects, and study sponsor were blinded to the treatment assignments throughout the conduct of the study.

The treatment duration was 4 weeks. Subjects were scheduled for a screening and 5 visits: baseline (day 1), 3 interim visits (days 8, 15, and 22), and a final visit (day 29). Dosing was twice-daily of the HCB 0.1% or vehicle lotion without occlusive dressing to the areas affected by AD. A review of adverse events and concomitant medications was performed at each visit. If a subject achieved total clearing, Physician Global Assessment (PGA)=0, as determined by the investigator at the day 22 visit, treatment was discontinued at that time. Regardless of the duration of the treatment, all subjects returned on day 29 for a final assessment of the condition of the disease.

Clinical assessments for overall disease condition, individual signs and symptoms, and body surface area (BSA) involvement were performed at days 1, 8, 22, and 29 as outlined below:

1. Overall disease severity using a 5-point ordinal PGA scale (0=clear to 4=severe).

2. Physician's assessment of severity of individual signs (erythema, induration/papulation, lichenification, excoriation, and oozing/crusting) of the overall body and of each body region (head/neck, upper limbs, trunk, and lower limbs) using a 4-point ordinal scale (0=none to 3=severe).

3. Physician's assessment of percent BSA involvement by body region (head/neck, upper limbs, trunk, and lower limbs). Overall percent BSA was computed using the weighted body region percent scores.

4. Eczema Area and Severity Index (EASI) scores were computed as described by Hanifin et al. (1)

5. Subject self-assessment of the intensity of pruritus over the previous 24-hour period using a 4-point scale (0=none to 3=severe). (Assessment was done by subject's parent/legal guardian, if applicable).

Subject enrollment was monitored closely during the study to ensure adequate and approximately equal representation across all age groups and subjects with moderate disease. Weekly monitoring and real-time reporting of screening and enrollment was used and, if necessary, general measures were taken to encourage sites to shift enrollment to study subjects of specific age ranges or severity.

Participants

Male and female subjects aged 3 months to less than 18 years who presented with a clinical diagnosis of stable mild to moderate AD using the Hanifin and Rajka criteria for diagnosing atopic dermatitis, (2) a PGA score of 2 or 3, and at least a 10% BSA involvement were eligible for the study. With the exception of the disease being studied, subjects were to be in general good health and have agreed to the requirements and restrictions of the study: consistent usage of soap, moisturizers, lotions, creams, ointments, sunscreens, or other skin products; consistent usage of hair products (eg, shampoo); and urine pregnancy testing for female subjects of child-bearing potential at the baseline and final visits. Pregnant or lactating subjects, immunocompromised subjects, and subjects with extensive disease which could not be reasonably controlled with topical corticosteroid therapy were ineligible to participate in the study.

Subjects requiring any medications or disease-specific therapies that could affect the course of their AD were also ineligible. Subjects who had used systemic corticosteroids, immunomodulators, ultraviolet light therapy, or who were treated with another investigational device or drug within 30 days prior to study enrollment were excluded from participation. However, if subjects were on stable maintenance therapy (ie, 30 days or more of use prior to enrollment), oral antihistamines and nasal sprays containing corticosteroids for treatment of bronchial asthma or allergic rhinitis, and antibiotics for treatment of acne were allowed. Use of topical therapies for the treatment of AD including corticosteroids, immunomodulators, calcipotriene or other vitamin D preparations, retinoids, antihistamines (eg, doxepin), and antibiotics within 14 days prior to entering the study was prohibited, as was the use of systemic antibiotic therapy within 7 days prior to study entry. Subjects with known hypersensitivity to any component of the study medication, subjects with a history or evidence of other conditions that would interfere with the evaluation of the study medication, and subjects desiring excessive or prolonged exposure to UV light (eg, sunlight, tanning beds) during the study were also excluded.

This study was conducted in accordance with the Declaration of Helsinki and in accordance with Good Clinical Practice guidelines. Study sites included academic institutions, private medical practices, and clinical research centers. Principal investigators at each site were board certified dermatologists or pediatricians.

Before initiation of the trial, the investigators submitted the protocol and all required information to their institutional review board (IRB) for review and approval. The majority of the study was managed by a Quorum Review IRB, with the exception of those sites that required the use of their own IRB. Written IRB-approved informed consent was obtained from each subject's parent or legal guardians and written IRB-approved consent was obtained from subjects aged 7 years or older before any study-related procedures were performed.

Endpoints

Efficacy

The primary efficacy endpoint was the percentage of subjects who achieved "treatment success" based upon the dichotomized physician's global evaluation at the final day 29 visit using the 5-point ordinate PGA. Treatment success was defined as those subjects with a final, day 29 PGA score of 0 or 1 who had a 2-point or more reduction in the PGA score from baseline to day 29. The secondary efficacy endpoint was the change from baseline in pruritus at day 29. The percent change from baseline in EASI scores at day 29 was also assessed.

Descriptive statistics and figures were used to summarize the percent change in percentage BSA and the change from baseline in the severity of erythema, induration/papulation, lichenification, excoriation, oozing/crusting, and pruritus at each postbaseline evaluation.

Safety

Safety was assessed by monitoring and reporting adverse events that occurred during the study. Topical steroid-specific events of telangiectasia, skin atrophy, and striae were evaluated as absent or present at each assessment.

Statistical Methods

All statistical processing was performed using SAS[R] software unless otherwise stated. Statistical significance was based on 2-sided hypothesis testing resulting in P values of 0.05 or less. No adjustments of P values for multiple comparisons were made. The Last Observation Carried Forward (LOCF) method was used to extrapolate data, which were missing. A sensitivity analysis was conducted for the day 29 dichotomized PGA score wherein a subject was considered a "failure" for a missing evaluation. Efficacy and safety analyses were conducted on the intent-to-treat (ITT) population. Efficacy analyses were also conducted on the per-protocol (PP) population (excluding pooling).

Primary Efficacy Analysis

An efficacy analysis of HCB 0.1% lotion over its vehicle was conducted for the primary variable, the dichotomized PGA at day 29, which was analyzed with a Cochran-Mantel-Haenszel (CMH) test stratified by an analysis center.

Secondary Efficacy Analysis

Change from baseline in pruritus at day 29 was analyzed with a CMH test stratified by analysis center.

Other Efficacy Analyses

The Shapiro-Wilk test was used for testing normality. Failure to meet the normality assumption was indicated if the P value of the Shapiro-Wilk test was less than 0.05. An analysis of variance with factors of treatment and analysis center was used to analyze percent change in EASI scores at day 29 if the data met the normality assumption; otherwise, the analysis was based on absolute change provided that it met the normality assumption. If the absolute change failed to meet the assumption of normality, then the analysis of EASI scores was based on a nonparametric approach of ranking the percent change in EASI scores and then submitting the ranked data to an ANOVA.

Descriptive statistics and figures were used to summarize the percent change in percentage BSA and the change from baseline in the severity of erythema, induration/papulation, lichenification, excoriation, oozing/crusting and pruritus at each postbaseline evaluation. The frequencies and percentages of PGA scores at baseline and days 8, 22, and 29 and dichotomized PGA scores at each postbaseline evaluation were presented by treatment group to characterize the clinical effect of the study drug.

Results

Disposition of Study Subjects

Two hundred eighty-four (284) subjects were enrolled in the study (Table 1). One hundred thirty-nine (139) subjects were randomized to HCB 0.1% lotion and 145 subjects were randomized to vehicle. All 284 subjects enrolled in the study were included in the ITT population. Thirty-five subjects in the HCB 0.1% lotion group and 40 subjects in the vehicle group were excluded from the PP analyses. Results are summarized for the ITT population. The results of the PP analyses were consistent with those of the ITT. Baseline characteristics are presented in Table 2.

Primary Endpoint: Treatment Success at Day 29

Analysis of the day 29 dichotomized PGA scores demonstrated that the HCB 0.1% lotion treatment effect was significantly greater than vehicle (P<.001). Figure 1 demonstrates the change in the dichotomized PGA scores during the study period; at day 8, only 16/139 (12%) ITT subjects in the HCB 0.1% lotion group and only 2/145 (1%) of the vehicle-treated subjects were considered successes. At day 29, 68/139 (49%) ITT in the HCB 0.1% lotion group were considered a success compared to 35/145 subjects (24%) in the vehicle group. Results of the PP analyses were consistent (P<.001) with the ITT analyses. Additionally, sensitivity analyses were conducted in which (1) "failure" was imputed for missing day 29 evaluations, and (2) "success" was imputed for missing day 29 evaluations. Results of these analyses were also consistent with the primary analyses in which a significant treatment effect was shown in favor of the HCB 0.1% lotion group for both the ITT and PP populations.

Secondary Endpoints: Change in Pruritus at Day 29

Change from baseline in pruritus scores indicated a significant treatment effect (P<.001) in favor of the HCB 0.1% lotion. In the HCB 0.1% lotion group, change in pruritus averaged 1.4 compared to the vehicle group which averaged 0.7 (Table 3).

EASI Scores

Percent change in EASI scores from baseline to day 29 indicated a significant treatment effect (P<.001) in favor of the HCB 0.1% lotion. In the HCB 0.1% lotion group, percent change in EASI scores averaged 74.5% compared to the vehicle group which averaged 41.5% (Table 4).

Signs and Symptoms of Atopic Dermatitis

Descriptive statistics summarized the percent change from baseline in the severity of erythema, induration/papulation, lichenification, excoriation, oozing/crusting, scaling, and BSA affected at each postbaseline evaluation. The results demonstrated progressive improvement in each of these signs and symptoms from day 8 through to day 29 evaluation in the HCB 0.1% lotion group compared to the vehicle group.

Adverse Events

Thirty-five percent (35%) of subjects in the HCB 0.1% lotion group and 39% of subjects in the vehicle group reported adverse events. Most adverse events reported during the study were mild to moderate in intensity and not related to study medication. A classification of these adverse events is depicted in Table 5. Within the HCB 0.1 % lotion group, the most common adverse events reported were nasopharyngitis (5%), pyrexia (4%), upper respiratory tract infection (4%), and ear infection (3%). Within the vehicle group, the most common adverse events reported were application site burning (6%), nasopharyngitis (6%), pyrexia (5%), application site pruritus (3%), upper respiratory tract infection (3%), and cough (3%).

All other adverse events reported within the HCB 0.1% lotion and vehicle groups were reported by no more than 2% of subjects. The number of subjects who reported adverse events, classified as "general disorders and administration site conditions," was significantly different (P=.001) with a greater proportion of subjects in the vehicle group (25/145, 17%) reporting events compared to the HCB 0.1% lotion group (7/139, 5%).

A significant difference between treatment groups was also noted for the comparison of the specific event of a burning sensation at the application site (P=.036). A significantly greater proportion of subjects in the vehicle group (8/145, 6%) reported the event compared to the HCB 0.1% lotion group (1/139, 1%). No other significant differences in reported adverse events between treatment groups were noted.

One serious adverse event was reported by a subject in the vehicle group: acute eczema exacerbation, requiring brief hospitalization, was reported approximately a week after the subject had discontinued from the study due to treatment failure. It resolved with therapy and was considered moderate in severity.

Topical Steroid Specific Evaluations

Topical steroid-related side effects (eg, telangiectasia, skin atrophy, and striae) were not observed in subjects in either the HCB 0.1% lotion or vehicle group.

Discussion and Conclusion

This study in 284 pediatric subjects (ages 3 months to less than 18 years) suggests that HCB 0.1% in a lotion base applied 2 times daily is a safe and effective therapy for the treatment of mild to moderate AD in pediatric patients. Efficacy analyses showed a significant treatment effect in favor of hydrocortisone butyrate 0.1% lotion (P<.001) with global improvement in all evaluated disease-related signs and symptoms. The safety profile of the HCB 0.1% lotion was also favorable. No topical steroid-related side effects (eg, telangiectasia, skin atrophy, and striae) were observed on the treated areas.

Conventional treatment with topical corticosteroids is well established for the management of AD. While the wide selection of cream and ointment formulations of topical corticosteroids is useful, there are times when a lotion formulation may be preferred to treat large body surface or hair bearing areas. The ease of application and convenience of a lotion dosage form may also be preferred by some patients or parents that assist in managing children with AD.

Disclosure

This study was sponsored by Ferndale Laboratories. The investigating authors were compensated for performing the clinical research study. Editorial support for the authors of this manuscript was provided by employees of Therapeutics Inc and data analysis support was provided by employees of QST Consulting Inc. The authors have no other conflict of interest to disclose.

References

1. Hanifin JM, Thurston M, Omoto M, et al. The eczema area and severity index (EASI): assessment of reliability of atopic dermatitis. EASI Evaluator Group. Exp Dermatol. 2001;10:11-18.

2. Rajka G, Langeland T Grading of the severity of atopic dermatitis. Acta Derm Venereol Suppl (Stockh). 1989;144:13-14.

ADDRESS FOR CORRESPONDENCE

Dan Piacquadio MD

Therapeutics Inc

9025 Balboa Avenue, Suite 100

San Diego, CA 92123

Phone: 858-571-1800 x107

Fax: 858-571-1234

e-mail: danp@therapeuticsinc.com

Robert Matheson MD, (a) Steven Kempers MD, (b) Debra Breneman MD, (c) Zoe Draelos MD, (d) Candice E. Johnson MD PhD, (e) Robert Loss MD, (f) Daniel J. Hogan MD, (g) Robert Schoenfeld MD, (h) Scott Checketts MD, (i) Leon Kircik MD, (j) David Fivenson MD, (k) Adelaide A. Hebert MD, (l) Judith Williams MD, (m) Regina Hamlin MD, (n) Daniel Groisser MD, (o) Dan Piacquadio MD (p)

a. Oregon Medical Research Center PC, Portland, OR

b. Minnesota Clinical Study Center, Fridley, MN

c. University of Cincinnati, Department of Dermatology, Cincinnati, OH

d. Dermatology Consulting Services, High Point, NC

e. The Children's Hospital, Denver, CO

f. Dermatology Associates of Rochester PC, Rochester, NY

g. Louisiana State University Health Sciences Center, Shreveport, LA

h. Wayne State University Department of Dermatology, Detroit, MI

i. Tanner Memorial Clinic, Layton, UT

j. DermResearch PLLC, Louisville, KY

k. David Fivenson MD, Dermatology PLLC, Ann Arbor, MI

l. University of Texas Health Science Center-Houston, Houston, TX

m. Children's Hospital of The King's Daughters, Norfolk, VA

n. Associates in Research, Inc., Fresno, CA

o. The Dermatology Group PC, Verona, NJ

p. University of California, San Diego, Division of Dermatology, San Diego, CA; Therapeutics Inc, San Diego, CA

Table 1. Summary of subject completion/discontinuation.

                                      HCB 0.1% lotion  Vehicle  Total

Number of Subjects Enrolled           139              145      284
Number of Subjects Who Completed the  132              120      252
  Study
Number of Subjects Who Prematurely      7               25       32
  Discontinued

Reason for Premature Discontinuation
  Subject Request                       2                7        9
  Lost to Follow-up                     5                5       10
  Lack of Efficacy                      0                6        6
  Adverse Event                         0                5        5
  Other                                 0                2        2

Figure 1. Treatment success summary.

           Treatment Success (% Subjects)
Visit Day  HCB Lotion  Vehicle

Day 8      12           1
Day 22     39           8
Day 29     49          24

Note: Table made from bar graph.

Table 2. Baseline characteristics of intent-to-treat (ITT) population.

                                     HCB 0.1% Lotion
Characteristic                       (n=139)          Vehicle (n=145)

Age
Overall Mean                          7.31             6.97
  Standard                            5.32             5.09
  Range                               0.3-17.8         0.4-17.6
3 months to <2 years                 32               29
2 years to <6 years                  32               40
6 years to <12 years                 38               47
12 years to <18 years                37               29

Gender
Male                                 64 (46%)         79 (54%)
Female                               75 (54%)         66 (46%)

Race
White                                92 (66%)         93 (64%)
Black/ African American              40 (29%)         52 (36%)
Asian                                 9 (6%)           4 (3%)
Native Hawaiian or Pacific Islander   0 (0%)           2 (1%)
American Indian or Alaska Native      2 (1%)           2 (1%)

PGA Score
Mild (Score = 2)                     65 (47%)         69 (48%)
Moderate (Score = 3)                 74 (53%)         75 (52%)
Severe (Score = 4)                    0 (0%)           1 (1%)

Pruritus
None                                  3 (2%)           4 (3%)
Mild                                 42 (30%)         42 (29%)
Moderate                             64 (46%)         68 (47%)
Severe                               30 (22%)         31 (21%)

Table 3. Change from baseline in severity of pruritus at day 29.

                       Change from Baseline
          HCB 0.1% Lotion (n=139)  Vehicle (n=145)
          LSMean  LSSTD            LSMean  LSSTD    P value*

Pruritus  1.4     1.0              0.7     1.0      <.001

*Last observation carried forward was used to impute missing data prior
to analysis. P value and least squares means and standard deviations
resulted from analysis of variance with factors of treatment and
analysis center.

Table 4. Percent change from baseline in EASI score at day 29.

                         Change from Baseline
            HCB 0.1% Lotion (n=139)  Vehicle (n=145)
            Mean   Standard          Mean   Standard  P value*

EASI Score  74.5%  37.5%             41.5%  53.4%     <.001

*Last observation carried forward was used to impute missing data prior
to analysis. P value resulted from a ranked analysis of variance with
factors of treatment and analysis center.

Table 5. Summary of adverse event characteristics.

                            HCB 0.1% lotion (N=139)  Vehicle (N=145)

Number of Events Reported   69                       85
Number of Subjects          48 (35%)                 56 (39%)
  Reporting >1 Event

Severity of Event
  Mild                      60 (87%)                 64 (75%)
  Moderate                   9 (13%)                 19 (22%)
  Severe                     0 (%)                    2 (2%)

Relationship to Study Drug
  Not assessable             3 (4%)                   1 (1%)
  Not Related               61 (88%)                 62 (73%)
  Possible                   5 (7%)                   6 (7%)
  Probable                   0 (0%)                   7 (8%)
  Certain                    0 (0%)                   9 (11%)

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