Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis

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1 Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis Sakari Reitamo, MD, a Edwin J. M. Van Leent, MD, b Vincent Ho, MD, c John Harper, FRCP, d Thomas Ruzicka, MD, e Kirsti Kalimo, MD, f Frédéric Cambazard, MD, g Malcolm Rustin, MD, h Alain Taïeb, MD, i David Gratton, MD, j Daniel Sauder, MD, k Graham Sharpe, FRCP, l Catherine Smith, FRCP, m Michael Jünger, MD, n and Yves de Prost, MD, o for the European/Canadian Tacrolimus Ointment Study Group* Helsinki and Turku, Finland, Amsterdam, The Netherlands, Vancouver, British Columbia, Montreal, Quebec, and Toronto, Ontario, Canada, London and Liverpool, United Kingdom, Dusseldorf and Tuebingen, Germany, Saint Etienne, Bordeaux, and Paris, France, and Baltimore, Md From a the Department of Dermatology, Hospital for Skin and Allergic Diseases, University of Helsinki, Helsinki; b the Department of Dermatology, University of Amsterdam, Amsterdam; c the Division of Dermatology, Vancouver; d the Department of Paediatric Dermatology, Great Ormond Street Hospital for Children, London; e Heinrich-Heine-Universität, Hautklinik, Düsseldorf; f the Department of Dermatology, University Hospital of Turku, Turku; g Hôpital Nord, Service de Dermatologie, St Etienne; h Royal Free Hospital, London; i Unite de Dermatologie Pediatrique, Hôpital Pellegrin-Enfants, Bordeaux; j private practice, Montreal; k the Division of Dermatology, University of Toronto (present address: Johns Hopkins University, Johns Hopkins Outpatient Carrier, Baltimore, MD); l the Department of Dermatology, The University of Liverpool, Liverpool; m Skin Therapy Research Unit, Department of Dermatology, University Hospital Lewisham, London; n Universitaetsklinikum Tuebingen, Hautklinik, Tuebingen; o Service de Dermatologie, Hôpital Necker-Enfants Malades, Paris. *Additional members of the European/Canadian Tacrolimus Ointment Study Group are listed in the Appendix. Supported by Fujisawa GmbH, Munich, Germany. Received for publication July 2, 2001; revised November 16, 2001; accepted for publication November 19, Reprint requests: Sakari Reitamo, MD, the Department of Dermatology, Hospital for Skin and Allergic Diseases, University of Helsinki, Meilahdentie 2, Helsinki, Finland. Copyright 2002 by Mosby, Inc /2002 $ /85/ doi: /mai Background: Vehicle-controlled studies have demonstrated the efficacy and safety of tacrolimus ointment in the treatment of patients with atopic dermatitis (AD). Objective: This study was undertaken to compare 0.03% and 0.1% tacrolimus ointment with 1% hydrocortisone acetate ointment in children 2 to 15 years of age with moderate-tosevere AD. Methods: Treatment was twice daily to affected areas for 3 weeks in this multicenter, randomized, double-blind, parallelgroup study. The primary endpoint was the modified eczema area and severity index (measi) mean area under the curve (mauc) as a percentage of baseline. Results: Five hundred sixty patients were randomized and received at least one application of ointment. Discontinuations included 21 of 189 patients from the 0.03% tacrolimus group, 13 of 186 patients from the 0.1% tacrolimus group, and 20 of 185 patients from the hydrocortisone acetate group. The median measi mauc as a percentage of baseline showed 0.03% and 0.1% tacrolimus to be significantly more effective than 1% hydrocortisone acetate (P <.001) and 0.1% tacrolimus to be more effective than 0.03% tacrolimus (P =.006). The measi mauc as a percentage of baseline was 44.8%, 39.8%, and 64.0% for patients who received 0.03% tacrolimus, 0.1% tacrolimus, and 1% hydrocortisone acetate, respectively. Transient skin burning was the only adverse event to show a higher incidence in the tacrolimus treatment groups than in the hydrocortisone acetate group (P <.05). Laboratory parameters showed no treatment differences and no marked changes over time. Conclusion: Tacrolimus, 0.03% and 0.1%, was significantly more effective than 1% hydrocortisone acetate and 0.1% tacrolimus was more effective than 0.03% tacrolimus in the treatment of moderate-to-severe AD in children. No safety concerns were identified. (J Allergy Clin Immunol 2002;109: ) Key words: Tacrolimus, FK506, atopic dermatitis, efficacy, safety, ointment, topical Atopic dermatitis (AD) is a chronically relapsing inflammatory skin disease. It is characterized by episodes of intense pruritus, multiple lesions with erythema, excoriations, erosions accompanied by a serous exudate, lichenification, papules, dry skin, and a susceptibility to cutaneous infections. 1 AD tends to run in families and often coexists with other atopic diseases, such as rhinitis, asthma, and allergic conjunctivitis. The immune pathology of AD is not precisely understood. Skin lesions have infiltrates of eosinophils and cells of the mononuclear phagocyte lineage and T cells. Elevated IgE is found in 60% to 80% of patients with AD. Patients also usually have elevated eosinophil counts. Topical corticosteroids and emollients represent the standard treatment for acute lesions of AD. 2 Repeated use of topical corticosteroids carry a risk of local side effects, such as skin atrophy and striae, as well as systemic side effects. Given their ratio of skin surface area to body mass, young children are at particular risk for hypothalamic-pituitary-adrenal axis suppression. Thus 539

2 540 Reitamo et al J ALLERGY CLIN IMMUNOL MARCH 2002 Abbreviations used AD: Atopic dermatitis BSA: Body surface area EASI: Eczema area and severity index mauc: Mean area under the curve measi: Modified eczema area and severity index mild topical corticosteroids are generally recommended for treatment of children. More potent topical corticosteroids should be especially avoided on regions of skin that are particularly thin and more susceptible to skin atrophy, such as the face and intertriginous areas. The efficacy of mild topical corticosteroids is generally not adequate for moderate-to-severe AD; however, in consideration of the risk of side effects, stronger preparations must be used with special care in children. Tacrolimus ointment, formulated for the treatment of AD, is the first in a class of topical immunomodulators. Its mechanism of action is based on calcineurin inhibition. Tacrolimus inhibits the phosphatase activity of calcineurin and thereby the dephosphorylation of the nuclear factor of activated T-cell protein, a transcription factor necessary for the expression of inflammatory cytokines. 3,4 Downregulation of the expression of the high-affinity IgE receptor in Langerhans cells and inhibition of the release of inflammatory mediators from mast cells and basophils by tacrolimus may also serve as targets in the immune therapy of AD. 5-7 Large, multicenter, randomized, vehicle-controlled studies in adults and children have shown that tacrolimus ointment is effective and safe in the treatment of AD The safety and efficacy of tacrolimus ointment monotherapy has been demonstrated for periods of up to 1 year in adults and children. 13,14 Unlike topical corticosteroids, tacrolimus ointment does not interfere with collagen synthesis or cause skin atrophy. 15 Like topical corticosteroids, it is associated with a reduction in staphylococcal skin colonization in AD lesions. 16 Systemic absorption is minimal. 17 The present study was undertaken to compare the efficacy and safety of tacrolimus ointment with a topical corticosteroid reference therapy. The reference therapy chosen, 1% hydrocortisone acetate, is classified as a mild topical corticosteroid and is a standard therapy for AD in children. 18 Although used in clinical practice on a caseby-case basis, more potent topical corticosteroids are contraindicated in some countries 19 and are used only with reluctance and with much consideration elsewhere. METHODS Study design The primary focus of this phase III, comparative, multicenter, randomized, double-blind, parallel-group study was to assess the efficacy and safety of 0.03% and 0.1% tacrolimus ointment and 1% hydrocortisone acetate ointment in children with moderate-to-severe AD. The study was performed at 27 centers in 6 European countries and Canada; the ethics committee from each center reviewed the protocol and granted approval of the study before its implementation. The study consisted of a screening visit within 7 days before the baseline visit, a baseline (day 0, treatment allocation) visit, visits on days 3 and 7 and weeks 2 and 3 of treatment, and a follow-up visit 2 weeks after treatment was completed (week 5). Patient selection Male and female patients, 2 to 15 years old, with a diagnosis of AD on the basis of the criteria of Hanifin and Rajka 20 were eligible for study participation. Patients were also required to have an AD severity grading of moderate to severe according to the criteria of Rajka and Langeland 21 and disease involvement of at least 5% but no more than 60% of the total body surface area (BSA). The main exclusion criterion was a serious skin disorder other than AD that required treatment. Patients with a history of eczema herpeticum were excluded. Each parent (and the patient when he or she was old enough to understand the study) gave written informed consent. Randomization and blinding Patients were randomized in parallel groups (1:1:1) to receive 0.03% tacrolimus ointment, 0.1% tacrolimus ointment, or a commercial preparation of 1% hydrocortisone acetate ointment (Lichtenstein N Cortisol Ointment, Koblenz, Germany). Randomization was stratified by center and patient age (2-6 years vs 7-15 years). The sponsor (Fujisawa GmbH, Munich) supplied each center with a unique block of sequentially ordered patient numbers from a randomization list. Randomization (assignment of a patient number) occurred in the order that patients passed the selection criteria on the baseline visit. For treatment allocation, an ointment supply box bearing a unique patient number was dispensed. Study ointments were provided in identical tubes to safeguard blinding, and the ointment supply boxes bore no information that might have revealed the identity of the study ointment. Treatment Treatment consisted of a thin layer of ointment applied twice daily to areas of actively diseased skin. Treatment of cleared lesions was to be stopped 7 days after clearance. Prohibited therapies during the study were topical and systemic corticosteroids, antimicrobials and antihistamines, coal tar, topical nonsteroidal anti-inflammatory drugs, nonsteroidal immunosuppressants, UV light treatments (UVA and UVB), hypnotics and sedatives, and other investigational drugs. Wash-out periods for these therapies ranged from 5 days to 6 weeks. Inhaled or intranasal corticosteroids were limited to 1 mg/d. Bath oil and nonmedicated emollients were allowed. Assessments At baseline (day 0), days 3 and 7 and weeks 2 and 3 of treatment, and 2 weeks after completing treatment (week 5), investigators rated erythema, edema-induration-papulation, excoriations, and lichenification on a scale of 0 to 3 and estimated the percentage of the total BSA affected by AD (0%-100%) for 4 body regions (head and neck, trunk, upper limbs, and lower limbs). Patients assessed the intensity of itching experienced during the previous 24 hours using a 10-cm visual analogue scale, with 0 cm indicating no itch and 10 cm indicating worst itch imaginable. These assessments were used to calculate the modified eczema area and severity index (measi). The measi is a variant of the eczema area and severity index (EASI) developed by Hanifin et al. 22 The measi is identical to the EASI, except that in the latter an assessment of itching is not included. Itching was included in the measi because it is considered a primary symptom of AD. 14 Both the EASI and the measi have the advantage of including severity scores for individual symptoms of AD weighted according to the extent of affected BSA. For

3 J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 3 Reitamo et al 541 TABLE I. Demographics and baseline characteristics and reasons for withdrawal of patients Tacrolimus Hydrocortisone acetate 1% 0.03% 0.1% No Age, y (years ± SD) All patients 7.2 ± ± ± y 4.0 ± 1.3 (n = 97) 3.8 ± 1.4 (n = 92) 4.0 ± 1.3 (n = 94) 7-15 y 10.7 ± 2.7 (n = 88) 11.1 ± 2.7 (n = 96) 10.5 ± 2.8 (n = 92) Male/female ratio, % 51.4/ / /48.4 White, No. (%) 150 (81.1) 140 (74.1) 144 (77.4) Duration of current episode, mo (median) Moderate-severe AD, % 51.4/ / /45.7 Percentage affected BSA (median) Affected body region, No. (%) Head and neck 160 (86.5) 164 (86.8) 164 (88.2) Upper limbs 183 (98.9) 187 (98.9) 184 (98.9) Trunk 155 (83.8) 143 (75.7) 154 (82.8) Lower limbs 176 (95.1) 181 (95.8) 181 (97.3) Withdrawn from study, No. (%) 20 (10.8) 21 (11.1) 13 (7.0) Reason for withdrawal, No. (%) Lack of efficacy 7 (3.8) 3 (1.6) 1 (0.5) Adverse event 4 (2.2) 3 (1.6) 3 (1.6) Prohibited therapy 3 (1.6) 7 (3.7) 2 (1.1) Withdrawal of consent 1 (0.5) 2 (1.1) 0 Administrative (eg, noncompliance, lost to follow-up, 5 (2.7) 6 (3.2) 7 (3.8) violation of selection criteria) each body region (head and neck, upper limbs, trunk, and lower limbs), the following steps were carried out: (1) an affected area score of 0 to 6 was assigned for the percentage of affected BSA (0%-100%); (2) the individual ratings for erythema, edemainduration-papulation, excoriations, and lichenification were summed (0-3 for each of the 4 symptoms); (3) the sum for the individual symptoms (maximum = 12) was multiplied by the affected area score (maximum = 6), for a maximum of 72; (4) for 2- to 6- year-olds, the head and neck subtotal was multiplied by 0.2, the upper limb subtotal by 0.2, the trunk subtotal by 0.3, and the lower limb subtotal by 0.3; (5) for 7- to 15-year-olds, the head and neck subtotal was multiplied by 0.1, the upper limb subtotal by 0.2, the trunk subtotal by 0.3, and the lower limb subtotal by 0.4; (6) all components were summed (maximum EASI = 72); and (7) the patient s assessment of itching was converted to an ordinal scale of 0 to 3 and then multiplied by the investigator s total affected area score (0-6), for a maximum itching score of 18. The EASI was summed with the itching score, for a maximum measi of 90 (the sum of 72 and 18). In principle this system of scoring AD is similar to the SCORAD (for scoring AD) index developed by the European Task Force on Atopic Dermatitis. 23 Investigators also assessed overall clinical improvement in the physician s global evaluation of clinical response. Cleared indicated improvement of 100%, excellent indicated improvement of 90% to 99%, marked indicated improvement of 75% to 89%, moderate indicated improvement of 50% to 74%, slight indicated improvement of 30% to 49%, no appreciable improvement indicated improvement of 0% to 29%, and worse indicated improvement of less than 0%. Adverse events were monitored on an ongoing basis. An adverse event was defined as any undesirable experience that occurred to a patient during the clinical trial, regardless of whether it was considered related to the study drug. Causally related adverse events were those assessed by the investigator as having a highly probable, probable, possible, or not assessable relationship to the study drug or adverse events for which such an assessment was not made. Except where noted, adverse event data are presented irrespective of the causality assessment. Laboratory assessments (haematology and clinical chemistry, including assessments for renal and hepatic function) were performed at the screening visit, the end of treatment (week 3), and the end of the study (week 5). Investigators were instructed to collect whole-blood samples at the screening visit and on days 3 and 7 and week 3 of treatment to allow measurement of tacrolimus concentrations in whole blood. For days 3 and 7, finger-prick and venous puncture samples were taken. On the screening visit and at week 3, only venous puncture samples were taken. Whole-blood samples were assayed for the tacrolimus concentration by using a validated HPLC method with repeated mass spectrometry. 24 Statistical analyses The primary population was an intent-to-treat population, which comprised all patients who were randomized and received at least one application of study ointment. The primary endpoint was the measi mean area under the curve (mauc) as a percentage of baseline. Based on a phase II study (which used a different efficacy parameter), 8 it was estimated that about 180 patients per treatment group would be required for an ANOVA with an α value of.05 and a power of 90% to detect a difference of 15% among the 3 treatment groups. Before unblinding of the data, it was discovered that the data did not have a normal distribution; thus a nonparametric method (the Wilcoxon rank sum test) was adopted. All continuous variables (the measi mauc as a percentage of baseline, as well as the percentage decrease of measi, EASI, pruritus, and affected BSA from baseline to the end of treatment) were tested with the Wilcoxon rank sum test. The χ 2 test was used to compare treatment groups for the physician s global evaluation of clinical response. A global dictionary, based on COSTART (coding symbols for thesaurus of adverse reaction terms), was used to code investigator

4 542 Reitamo et al J ALLERGY CLIN IMMUNOL MARCH 2002 patients from the 0.03% tacrolimus group, 13 (7.0%) of 186 patients from the 0.1% tacrolimus group, and 20 (10.8%) of 185 patients from the hydrocortisone acetate group. Reasons for withdrawal were similar among treatment groups but with slightly more patients withdrawing because of lack of efficacy in the hydrocortisone acetate group (Table I). Patient demographic and baseline characteristics were similar among treatment groups (Table I). The affected BSA was extensive at baseline (a median of approximately 25% of the total BSA across treatment groups), and most patients had active disease on all body regions, including the head and neck. FIG 1. Median percentage decreases from baseline (and upper and lower quartiles) in measi and affected BSA. The measi considers the affected BSA and the severity of erythema, edema, excoriations, lichenification, and itching. At the end of treatment, the greater improvement with either tacrolimus concentration compared with 1% hydrocortisone acetate was significant (P.001), as was the greater improvement with 0.1% compared with 0.03% tacrolimus (P <.05). terms. The term skin burning was used to refer to the sensation of skin burning or smarting. Flu syndrome was used to code investigator terms such as cold, common cold, flu, influenza, and upper respiratory tract infection. Adverse events were summarized by frequency counts, with treatment groups compared by using the Fisher exact test. RESULTS Patients A total of 560 patients were randomized and received at least one application of study ointment (intent-to-treat population). By mistake, a 20-year-old patient was randomized into the 0.03% tacrolimus group; this patient was included in the analysis that included all patients but was excluded in the separate analyses of younger (2-6 years old) and older (7-15 years old) children. Approximately 90% of patients across treatment groups completed the study; withdrawals included 21 (11.1%) of 189 Efficacy The measi mauc as a percentage of baseline showed 0.03% and 0.1% tacrolimus ointment to be significantly more effective than 1% hydrocortisone acetate ointment (P <.001, Wilcoxon rank sum test) and 0.1% tacrolimus ointment to be more effective than 0.03% tacrolimus ointment (P =.006, Wilcoxon rank sum test). Averaged over the 3-week course of treatment, patients had a median improvement of 55.2% with 0.03% tacrolimus (ie, from 100.0% at baseline to a median measi mauc of 44.8% over the entire treatment period), 60.2% with 0.1% tacrolimus (ie, from 100% at baseline to a median of 39.8% over the entire treatment period), and 36.0% with hydrocortisone acetate (ie, from 100% at baseline to a median of 64.0% over the entire treatment period). A separate analysis of the head and neck showed the same overall results as the main analysis, with a median measi mauc improvement of 62.5% for 0.03% tacrolimus, 75.2% for 0.1% tacrolimus, and 43.3% for hydrocortisone acetate. Findings for younger (2-6 years old) and older (7-15 years old) children were essentially the same (data not shown). For all 3 treatment groups, improvement as assessed with percentage decreases in the measi and size of the affected BSA was apparent 3 days after starting treatment (Fig 1). Whereas further improvement over time was observed in the tacrolimus treatment groups, it had reached a plateau at week 1 in the hydrocortisone acetate group. After 7 days of treatment, median decreases in measi and the affected BSA were about twice as large in the tacrolimus treatment groups as in the hydrocortisone group, with further decreases at weeks 2 and 3. At the end of treatment (week 3 or discontinuation visit), the greater improvement with either tacrolimus concentration compared with 1% hydrocortisone acetate was associated with descriptive P values (P <.001, Wilcoxon rank sum test), as was the greater improvement with 0.1% tacrolimus compared with the 0.03% concentration (P <.05, Wilcoxon rank sum test). Findings for percentage decreases in the EASI and pruritus (data not shown) were similar to those for the measi and affected BSA. In the physician s global evaluation of clinical response, only 15.7% of patients who received hydrocortisone acetate experienced excellent improvement or

5 J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 3 Reitamo et al 543 clearance ( 90% improvement) by the end of treatment compared with 38.5% of patients who received 0.03% tacrolimus and 48.4% of patients who received 0.1% tacrolimus. The difference between either tacrolimus concentration and hydrocortisone acetate was statistically significant (P =.001, χ 2 test), but the difference between 0.03% and 0.1% tacrolimus was not (P =.055, χ 2 test). At least marked improvement was observed for 32.4%, 62.6%, and 73.9% of patients who received hydrocortisone acetate, 0.03% tacrolimus, and 0.1% tacrolimus, respectively (Fig 2). At least moderate improvement was observed in 51.4%, 80.2%, and 85.3% of patients, respectively. Patients who had a rating of moderate improvement at the end of treatment and continued therapy restrictions were assessed 2 weeks after stopping treatment (week 5). In all 3 treatment groups, only about half of the patients maintained a moderate improvement after 2 weeks without treatment (Fig 2). Follow-up for other efficacy endpoints showed similar findings, with patients, on average, showing a better condition at follow-up than at baseline but a worse condition than observed at the end of treatment (data not shown). Safety Adverse events at the application site experienced by at least 4 patients in any treatment group are presented in Table II. Skin burning was the only adverse event to show a significantly higher incidence in the tacrolimus treatment groups than in the hydrocortisone acetate group (P <.05, Fisher exact test). Local pruritus was also common. These signs of local irritation were transient, decreasing in prevalence over time (Table III). Most cases were mild or moderate. Flu syndrome and fever were the most common adverse events not occurring at the application site (Table IV). Fever (lowest in the 0.1% tacrolimus group), rhinitis (lowest in the 0.03% tacrolimus group), and diarrhea (lowest in the 0.03% tacrolimus group) were associated with significant P values (P <.05, Fisher exact test), but the direction of the differences in incidence did not suggest a relationship to treatment with tacrolimus ointment. No treatment-related age differences in safety profile were apparent between 2- and 6-year-olds and older children (Table IV). Three patients experienced a serious adverse event during treatment: 1 patient with hematomas and 1 patient with lack of drug effect in the hydrocortisone acetate group and 1 patient with an allergic reaction to food in the 0.1% tacrolimus group. These were considered serious because the patients were hospitalized. Only the lack of drug effect in the hydrocortisone acetate group was considered to be causally related to the study ointment by the investigator. An adverse event that led to treatment discontinuation was experienced by 4 patients in the hydrocortisone group (1 patient with folliculitis and urticaria, 1 patients with skin infection, 1 patient with a reaction at the application site, and 1 patient with maculopapular rash and pruritus), 3 patients in the 0.03% tacrolimus group (1 FIG 2. Physician s global evaluation of clinical response at the end of treatment and the end of follow-up. The population for analysis at the end of treatment was an intent-to-treat population, with 185, 187, and 184 patients included in the 1% hydrocortisone acetate group, the 0.03% tacrolimus group, and the 0.1% tacrolimus groups, respectively. The difference in the proportion of patients who had clearance or excellent improvement was significant between tacrolimus and hydrocortisone acetate (P =.001) but not between 0.03% and 0.1% tacrolimus (P =.055). The population for analysis of follow-up included only patients who had moderate improvement at the end of treatment and continued prohibited therapy restrictions, with 88, 134, and 144 patients, respectively. patient with skin infection, 1 patient with pruritus, and 1 patient with skin burning and pain), and 3 patients in the 0.1% tacrolimus group (2 patients with chicken pox and 1 patient with an allergic reaction to food). As expected for a population of patients with AD, 1,25 laboratory measurements showed mean eosinophil counts and lactate dehydrogenase concentrations above the normal range at baseline and all study visits. There were no meaningful differences among treatment groups for these parameters. All other mean laboratory values were within normal range during the study and showed no marked changes over time and no differences among treatment groups. Abnormal laboratory values reported as adverse events comprised 1 patient with a transient

6 544 Reitamo et al J ALLERGY CLIN IMMUNOL MARCH 2002 TABLE II. Incidence of the most common adverse events at the application site, irrespective of causality Tacrolimus COSTART term Hydrocortisone acetate 0.03% 0.1% No Skin burning, No. (%) 13 (7.0) 35 (18.5) 38 (20.4) Pruritus, No. (%) 14 (7.6) 25 (13.2) 21 (11.3) Folliculitis, No. (%) 5 (2.7) 11 (5.8) 8 (4.3) Skin infection, No. (%) 4 (2.2) 6 (3.2) 4 (2.2) Skin erythema, No. (%) 3 (1.6) 4 (2.1) 1 (0.5) TABLE III. Prevalence of skin burning and pruritus at the application site over time Tacrolimus Hydrocortisone acetate 1% 0.03% 0.1% n Patients (%) n Patients (%) n Patients (%) Skin burning Days (6.5) (17.5) (19.9) Days (2.7) (4.9) (4.4) Week (2.3) (1.6) (5.0) Week (1.2) (1.1) (5.6) Pruritus Days (4.9) (12.2) (9.7) Days (5.5) (5.9) (3.8) Week (4.5) (3.8) (3.9) Week (3.5) (2.9) (2.3) increase in aspartate transaminase and alanine transaminase activities in the 0.03% tacrolimus group, 1 patient with a slight decrease in calcium in the 0.1% tacrolimus group (no follow-up was available), and 1 patient with anemia and 1 patient with an increased creatinine level in the hydrocortisone acetate group. The investigator considered the transient increase in liver function enzyme activity (0.03% tacrolimus) and the increased creatinine level (hydrocortisone acetate) to be possibly related to the study drug. Systemic exposure It was discovered that blood samples collected by means of the finger-prick test had a high likelihood of ointment contamination from the skin. Thus only tacrolimus determinations from venous puncture samples are presented (Table V). Only 1.6% (3/188) of patients who received 0.03% tacrolimus and 11.3% (21/186) of patients who received 0.1% tacrolimus experienced a tacrolimus concentration of 1 ng/ml or greater at some time during the study, and none of the patients experienced a concentration of 5 ng/ml or greater (Table V). Concentrations of 1 ng/ml or greater were transient (data not shown). The highest value experienced by any patient was 2.8 ng/ml, which occurred on day 3 in a patient who received 0.1% tacrolimus. DISCUSSION Much consideration was given to selection of the reference therapy in this study, and a mild topical corticosteroid was determined to be the most appropriate in terms of standard medical practice. Treatment of children is generally conservative to avoid the risk of side effects associated with topical corticosteroids. If possible, topical corticosteroids are avoided, with emollients being preferred. When topical corticosteriods are necessary, mild preparations, such as 1% hydrocortisone acetate ointment, are recommended for pediatric patients. 18 Twice daily treatment for an uninterrupted period of 3 weeks with a more potent topical steroid is not generally considered safe for children, especially considering that the face and neck (where skin is thin and more vulnerable to atrophy) were not excluded and that treatment of up to 60% of the total BSA was allowed (increasing the risk of systemic steroidal side effects, such as hypothalamic-pituitary-adrenal axis suppression). Thus compared with a relevant reference therapy, 0.03% and 0.1% tacrolimus ointment were demonstrated to be effective and safe in the treatment of moderate-tosevere AD in children 2 to 15 years of age. This was demonstrated with the primary endpoint, measi mauc as a percentage of baseline, and all secondary endpoints.

7 J ALLERGY CLIN IMMUNOL VOLUME 109, NUMBER 3 Reitamo et al 545 TABLE IV. Incidence of the most common adverse events not at the application site, irrespective of causality Tacrolimus COSTART term Hydrocortisone acetate 0.03% 0.1% All patients (n) Flu syndrome (eg, flu, cold, upper respiratory tract infection) 16 (8.6) 15 (7.9) 14 (7.5) Fever 8 (4.3) 9 (4.8) 1 (0.5) Rhinitis 4 (2.2) 0 6 (3.2) Pharyngitis 6 (3.2) 2 (1.1) 1 (0.5) Diarrhea 2 (1.1) 0 5 (2.7) 2-6 y (n) Flu syndrome (eg, flu, cold, upper respiratory tract infection) 7 (7.2) 9 (9.8) 8 (8.5) Fever 7 (7.2) 8 (8.7) 1 (1.1) Cough increased 2 (2.1) 3 (3.3) 2 (2.1) Rhinitis 3 (3.1) 0 3 (3.2) Pharyngitis 3 (3.1) 1 (1.1) 0 Diarrhea 1 (1.0) 0 5 (5.3) 7-15 y (n) Flu syndrome (eg, flu, cold, upper respiratory tract infection) 9 (10.2) 6 (6.3) 6 (6.5) Abdominal pain 0 1 (1.0) 3 (3.3) Rhinitis 1 (1.1) 0 3 (3.3) Pharyngitis 3 (3.4) 1 (1.0) 1 (1.1) Headache 3 (3.4) 1 (1.0) 3 (3.3) TABLE V. Tacrolimus blood concentrations (in nanograms per milliliter) Descriptive statistics Frequency, No. of patients (%) n Median Range <LOQ LOQ-<1 1-<5 0.03% Tacrolimus Day (29.0) 69 (69.0) 2 (2.0) Day (32.0) 66 (66.0) 2 (2.0) Week (41.1) 89 (58.9) 0 Maximum per patient* (23.4) 141 (75.0) 3 (1.6) 0.1% Tacrolimus Day (14.3) 58 (69.0) 14 (16.7) Day (15.8) 74 (77.9) 6 (6.3) Week (17.4) 124 (80.0) 4 (2.6) Maximum per patient* (12.4) 142 (76.3) 21 (11.3) LOQ, Limit of quantification. *Maximum value (highest individual value) at any time during the study. Both concentrations of tacrolimus were significantly more effective than 1% hydrocortisone acetate ointment, and the 0.1% concentration of tacrolimus was found to be more effective than the 0.03% concentration. Improvement was apparent 3 days after starting treatment for all 3 treatment groups. The greater efficacy of the tacrolimus ointments compared with the hydrocortisone acetate ointment was apparent after 1 week of treatment. The quick onset of efficacy is consistent with phase II and phase III vehicle-controlled studies This study was not designed to assess relapse or rebound; however, the average condition of patients at the followup visit was better than that recorded at baseline. Because tacrolimus ointment offers a potential advantage to topical corticosteroids for the treatment of skin of the face and intertriginous areas (tacrolimus ointment does not reduce collagen synthesis or skin thickness 15 ), separate analyses for the head and neck were carried out. These analyses showed similar efficacy and safety results for the head and neck compared with those for the combined body regions. Long-term efficacy without evidence of skin atrophy or other safety risks has been shown in a noncomparative study in which 255 children with moderate-to-severe AD received 0.1% tacrolimus ointment for up to 1 year. 14 The long-term efficacy and safety of tacrolimus ointment monotherapy is of particular benefit for children with persistent disease, for whom long-term treatment with topical corticosteroids would be inappropriate because of an unacceptable risk of local and systemic side effects. The results of this study indicate that short-term treatment with 0.03% and 0.1% tacrolimus ointment in young children (2-6 years of age) and older children (7-15 years of age) is safe. The only adverse event that showed a significantly higher incidence in the tacrolimus treatment groups than in the hydrocortisone acetate group was skin burning. The prevalence of this adverse event largely decreased by the fourth day of treatment. Other studies

8 546 Reitamo et al J ALLERGY CLIN IMMUNOL MARCH 2002 have shown that the actual episode of skin burning lasts only about 10 minutes. 11,14 The decrease in the prevalence of skin burning after the first few days of treatment is probably related to skin healing. There were no causally related serious adverse events in any patient who received tacrolimus ointment. Except for 1 patient with skin burning and pain and 1 patient with pruritus (presumably related to skin irritation) in the 0.03% tacrolimus group, adverse events that led to treatment discontinuation in the 0.03% and 0.1% treatment groups were related to AD (skin infection) or atopy in general (allergic reaction to food) or were common childhood infections (chicken pox). The tacrolimus blood concentrations observed were consistent with no or minimal systemic absorption of tacrolimus. We conclude that 0.03% and 0.1% tacrolimus ointment are significantly more effective than 1% hydrocortisone acetate ointment. Clinical improvement was greater for 0.1% tacrolimus compared with 0.03% tacrolimus. Other than transient skin irritation, the safety profiles of tacrolimus ointment and hydrocortisone acetate ointment were similar over the 3-week treatment period. This new treatment option offers an alternative to topical corticosteroids for children with moderate-to-severe AD. We thank Connie Grogan for editorial support and Ulrich Beyer and Ruthild Sautermeister for support in the statistical analyses. REFERENCES 1. Leung DYM. Atopic dermatitis: new insights and opportunities for therapeutic intervention. J Allergy Clin Immunol 2000;105: Leung DYM, Hanifin JM, Charlesworth EN, et al. Disease management of atopic dermatitis: a practice parameter. Ann Allergy 1997;79: Goto T, Kino T, Hatanaka H, at al. Discovery of FK-506, a novel immunosuppressant isolated from Streptomyces tsukubaensis. Transplant Proc 1987;19: Tocci MJ, Markovich DA, Collier KA, et al. The immunosuppressant FK506 selectively inhibits expression of early T cell activation genes. J Immunol 1989;143: Panhans-Groß A, Novak N, Kraft S, Bieber T. Human epidermal Langerhans cells are targets for the immunosuppressive macrolide tacrolimus (FK506). J Allergy Clin Immunol 2001;107: De Paulis A, Stellato C, Cirillo R, Ciccarelli A, Oriente A, Marone G. Anti-inflammatory effect of FK506 on human skin mast cells. J Invest Dermatol 1992;99: Reitamo S. Tacrolimus: a topical immunomodulatory therapy for atopic dermatitis [editorial]. J Allergy Clin Immunol 2001;107: Ruzicka T, Bieber T, Schoepf E, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337: Boguniewicz M, Fiedler VC, Raimer S, et al. A randomized, vehiclecontrolled trial of tacrolimus ointment for the treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102: Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E, the Tacrolimus Ointment Study Group. 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Tacrolimus ointment does not affect collagen synthesis: results of a single-center randomized trial. J Invest Dermatol 1998;111: Remitz A, Kyllönen H, Granlund H, Reitamo S. Tacrolimus ointment reduces staphylococcal colonization of atopic dermatitis lesions [letter]. J Allergy Clin Immunol 2001;107: Alaiti S, Kang S, Fiedler VC. Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 1998;38: Bos JD, Sillevis Smitt JH. Continuing medical education: atopic dermatitis. J Eur Acad Dermatol Venereol 1996;7: British national formulary. London: British Medical Association and Royal Pharmacological Society of Great Britain; Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980;92: Rajka G, Langeland T. Grading of the severity of atopic dermatitis. Acta Derm Venereol (Stockh) 1989;144: Hanifin JM, Thurston M, Ornoto M, Cherill R, Tofte SJ, Graeber M. 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J Dermatol 1990;17: APPENDIX Additional members of the European/Canadian Tacrolimus Ointment Study Group: Linda de Reave, MD (AZV Universiteit Brussel, Brussels, Belgium); Micheline Song, MD (Clinique Dermatologique ULB, Brussels, Belgium); Bernice Krafchik, MD (Hospital for Sick Children, Toronto, Canada), Thomas Diepgen, MD, and Manige Fartasch, MD (Dermatologische Universitaets Klinik, Erlangen, Germany); Enno Christophers, MD (Dermatologische Universitaetsklinik, Kiel, Germany); Ingrid Moll, MD, and Barbara Kunz, MD (Universitaet Eppendorf Hautklinik, Hamburg, Germany); Thomas Luger, MD (Hautklinik Muenster, Muenster, Germany); Kristina Turjanmaa, MD (Tampere University Central Hospital, Tampere, Finland); Louis Dubertret, MD (Hôpital Saint-Louis, Paris, France); Jean-Francois Stalder (Hôpital Hotel-Dieu, Nantes, France); Gerard Guillet, MD (Hôpital A. Morvan, Brest, France); Gerard Lorette, MD (Hôpital Trousseau, Tours, France); John Berth-Jones, MD (Walgrave Hospital, Coventry, United Kingdom), J. L. Perrot (Hôpital Nord, St Etienne, France); Jan D. Bos, MD (University of Amsterdam, Amsterdam, The Netherlands); Franck Boralevi (Hôpital Pellegrin-Enfants, Bordeaux, France); Adrian Green, MD (Great Ormond Street Hospital for Children, London, United Kingdom); and Håkan Granlund, MD, and Anita Remitz, MD (Hospital for Skin and Allergic Diseases, University of Helsinki, Helsinki, Finland).