Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants

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1 Onset of action of pimecrolimus cream 1% in the treatment of atopic eczema in infants Roland Kaufmann, MD, a Regina Fölster-Holst, MD, b Peter Höger, MD, c Diamant Thacxi, MD, a Helena Löffler, MD, d Doris Staab, MD, e and Matthias Bräutigam, PhD, d for the CASM981CDE04-Study Group Frankfurt am Main, Kiel, Hamburg, Nürnberg, and Berlin, Germany Background: Data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce, as in previous studies, the first postbaseline assessment was performed only after 1 week. Objective: We sought to investigate the onset of action of pimecrolimus cream 1% in infants with mild to very severe atopic eczema. Methods: We used pimecrolimus cream 1% (n = 129) or vehicle cream (n = 66) administered in a double-blind manner for 4 weeks and then open-label pimecrolimus cream 1% for 12 weeks, with a 4-week follow-up period. Results: Pimecrolimus cream 1% reduced the mean Eczema Area and Severity Index at 4 weeks by 71.5% compared with an increase of 19.4% with vehicle (P <.001). The reduction in the Eczema Area and Severity Index with pimecrolimus cream 1% was significant at day 4 (38.5% vs 17.6% increase with vehicle). Significant improvements in caregivers assessments of pruritus and sleep loss were observed with pimecrolimus cream 1% by day 2 (P <.03) and day 3 (P =.002), respectively, compared with vehicle. Responses to pimecrolimus cream 1% From a Johann Wolfgang Goethe-Universität, Hautklinik, Frankfurt am Main; b Christian-Albrechts-Universität, Hautklinik, Kiel; c the University of Hamburg, Department of Dermatology, Division of Paediatric Dermatology, Hamburg; d Novartis Pharma GmbH, Clinical Research, Nürnberg; and e Charite-Virchow Klinikum, Kinderklinik und Poliklinik, Berlin. Supported by Novartis Pharma GmbH. Conflict of interest statement: The following have a financial interest-relationship as follows. R. Kaufmann: grant-research support from Amgen, Aventis, Basilea, Biofrontera, Biogen, Centocor, Fumapharm, Fujisawa, Galderma, Genmab, Henkel, Hermal, Infectopharm, Leo, Medigene, Medimmune, Novartis, Schering, Schering-Plough, Serono, Smith & Nephew, and Versicor. D. Thacxi: grant-research support from Amgen, Aventis, Basilea, Biofrontera, Biogen, Centocor, Fumapharm, Fujisawa, Galderma, Genmab, Henkel, Hermal, Infectopharm, Leo, Medigene, Medimmune, Novartis, Schering, Schering-Plough, Serono, Smith & Nephew, Versicor; lecture honoraria from Novartis, Biogen, Fumedica, Hermal, Leo; consultant for Novartis and Fujisawa. R. Fölster-Holst: grant-research support from Novartis, Fujisawa, Hartmann and Stallergen; lecture honoraria from Novartis and Fujisawa; consultant for Novartis. P. Höger: grant-research support from Novartis; consultant for Novartis. D. Staab: grant-research support from Novartis and Fujisawa; lecture honoraria from Novartis. H. Löffler and M. Bräutigam are employees of Novartis Pharma GmbH. Received for publication May 11, 2004; revised August 6, 2004; accepted for publication August 6, Available online October 7, Reprint requests: Roland Kaufmann, MD, Johann Wolfgang Goethe University Hospital, Department of Dermatology and Venereology, Theodor-Stern-Kai 7, Frankfurt am Main, Germany. kaufmann@em.uni-frankfurt.de /$30.00 Ó 2004 American Academy of Allergy, Asthma and Immunology doi: /j.jaci were sustained during the open-label phase, and pimecrolimus cream 1% was well tolerated. Symptoms of atopic eczema returned gradually after discontinuation. Conclusion: Pimecrolimus cream 1% was well tolerated and effective in patients with mild to very severe atopic eczema, with rapid onset of action and no disease rebound after discontinuation. (J Allergy Clin Immunol 2004;114: ) Key words: Pimecrolimus, infants, atopic eczema, dermatitis Atopic eczema (also known as atopic dermatitis) is a common skin disorder affecting 10% to 15% of children less than 5 years of age in Western countries. 1 Approximately 48% to 75% of these individuals present with signs and symptoms of the disease during the first 6 months of life. 2,3 Poor control of atopic eczema during early life is not simply a burden for patients and their caregivers but is also associated with an increased risk of persistent disease in later childhood and adulthood 4 and the development of other atopic diseases, such as asthma and allergic rhinitis. Traditional management of atopic eczema in infants and young children consists of the exclusion of atopic triggers and irritants from the child s environment, the use of emollients to maintain skin hydration, and the use of topical corticosteroids to treat flares. 5,6 This approach is deficient because topical corticosteroids can only be used for a limited period without risking local adverse reactions, most importantly skin atrophy. 7-9 In infants and young children there is also a higher body surface area/weight ratio and therefore a greater risk of adverse systemic effects with extensive corticosteroid use, such as suppression of the hypothalamic-pituitary-adrenal axis Pimecrolimus is a nonsteroid inhibitor of inflammatory cytokines formulated as a 1% cream for the treatment of atopic eczema and other inflammatory skin diseases. 13 Pimecrolimus works by selectively inhibiting the expression of inflammatory cytokines by inflammatory T cells and preventing the release of proinflammatory mediators by mast cells As a consequence of this selective mode of action, pimecrolimus cream 1% (Elidel) does not cause skin atrophy or other local, steroid-like adverse effects and has no significant systemic effects. 15,17 Prevention of flares and effective long-term control of atopic eczema were demonstrated in 3 large, multicenter, controlled studies with pimecrolimus cream 1% However, in previous studies the first postbaseline assessment was performed only after 1 week, and hence 1183

2 1184 Kaufmann et al J ALLERGY CLIN IMMUNOL NOVEMBER 2004 Abbreviations used EASI: Eczema Area and Severity Index IGA: Investigators Global Assessment data on the efficacy of pimecrolimus cream 1% within the first days of treatment are scarce. Acute atopic eczema is usually associated with bothersome itching and sleep disturbances, which can lead to an impaired well-being and decreased quality of life for patients and their caregivers. 4 In this situation the doctor is expected to prescribe drugs that provide rapid itch relief. Here we present the results of a multicenter, vehiclecontrolled study of the efficacy and safety of pimecrolimus cream 1% in infants with mild to very severe atopic eczema, with the primary objective being the assessment of the speed of response within the first days of treatment. METHODS Study design This was a 20-week, randomized, controlled, multicenter study, comprising 3 phases. The first was a double-blind, vehicle-controlled, parallel-group phase, during which patients were randomly assigned 2:1 to receive either pimecrolimus cream 1% or vehicle equivalent for 4 weeks. This phase was followed by a 12-week open-label extension phase, during which all patients received pimecrolimus cream 1%. Patients could be switched to open-label pimecrolimus cream 1% treatment after 2 weeks of the double-blind phase if they achieved total disease clearance or if they did not show any improvement. The third phase was a 4-week follow-up period in which active treatment was discontinued in all patients to enable the return of symptoms to be assessed. The study design was approved by the participating hospitals institutional review boards and was conducted according to the Declaration of Helsinki and the standards of Good Clinical Practice. 21 Patients The study included pediatric patients aged 3 to 23 months with a clear diagnosis of atopic eczema 22 affecting 5% or more of the body surface area and with a baseline Investigators Global Assessment (IGA) score of 2 (mild disease severity) or greater on the basis of the degree of erythema and infiltration-papulation. Eligible patients also had atopic eczema affecting the face. Patients with insufficient washout periods (ie, <1 month for systemic corticosteroids and phototherapy, <2 weeks for antibiotics, and <1 week for topical steroids or other topical therapies that might have an effect on atopic eczema) were excluded. Patients with concomitant diseases that might have interfered with the study, including severe concurrent skin disease in the study area and active viral or bacterial infections, were also excluded. Other excluded groups were immunocompromised patients or those with a known hypersensitivity to the study drug. Written informed consent by the patient s legal guardian was required. The study was conducted between June 2001 and July 2002 at a total of 19 centers in Germany. Treatment Primary caregivers were instructed to apply pimecrolimus cream 1% or the corresponding vehicle equivalent to the patient twice daily during the double-blind phase. Applications were made approximately 12 hours apart (typically 8 AM and 8 PM) as a thin film on all areas affected by atopic eczema. Unaffected areas or previously affected skin areas that were clear of disease were not treated with the study medication. During the 4-week double-blind phase, emollients were only applied to areas not treated with study medication. However, during the 12-week open-label phase and the 4-week discontinuation phase, the use of emollients was permitted, as required, on all body areas. Application onto treated areas was allowed only after the study medication had been fully absorbed. Assessments The primary efficacy parameter was the Eczema Area and Severity Index (EASI). 23 This is a validated tool for objectively assessing the severity of eczema, taking into account both the severity of symptoms and surface area involvement. 24 It assesses erythema, infiltrationpapulation, excoriation, and lichenification separately in the head and neck region, trunk, upper limbs, and lower limbs. Proportionate values are assigned to each of these 4 body regions, and the figures are combined to yield an overall EASI score ranging from 0 (no disease present) to 72 (all signs of disease rated severe and present over 100% of body surface). The severity of disease was also assessed with the IGA, a 6-point scale from 0 (clear) to 5 (very severe disease). 25 This scale measures disease severity on the basis of morphology, without reference to the baseline state. The IGA also enabled the proportion of patients with a severe flare, defined by an IGA score of 4 or 5 (severe or very severe disease), to be determined at each assessment. The patient s primary caregiver was asked to assess the degree of disease control over the previous 7 days by using a 4-point scale from 0 (complete disease control) to 3 (uncontrolled disease). Caregivers also assessed both pruritus and sleep loss in a daily diary, using visual analog scales of 0 to 10, as specified in the Severity Scoring of Atopic Dermatitis (SCORAD) assessment tool for atopic eczema. 26,27 Adverse events were monitored and recorded throughout the study, together with regular measurement of vital signs and physical examinations. Blinding and statistical analysis Patients were assigned to treatment according to a computergenerated blinded randomization list. The double-blind status of the initial phase of the study was maintained by the use of study medication and vehicle of identical appearance and odor. Efficacy was analyzed in the intention-to-treat population by using the lastobservation-carried-forward method for patients who discontinued participation. The primary efficacy variable was the change in EASI at end point, defined as the end of the double-blind treatment phase or the last postbaseline assessment in the case of early discontinuation. The primary statistical null hypothesis (ie, no differences in changes in EASI between the pimecrolimus cream 1% and vehicle control treatment groups) was performed with an adjusted analysis of covariance model. The baseline for changes in pruritus and sleep loss was the last day before commencing treatment with study medication. Safety was assessed by comparing the incidence of adverse events between the treatment groups. A time-to-event analysis was performed to determine the adjusted incidence of adverse events to account for the difference in duration of followup in the 2 treatment groups. RESULTS Patients In total, 201 patients were included in the study at 19 centers; 196 of these patients were allocated to randomized treatment, 130 with pimecrolimus cream 1%

3 J ALLERGY CLIN IMMUNOL VOLUME 114, NUMBER 5 Kaufmann et al 1185 TABLE I. Baseline demographics and disease characteristics Pimecrolimus cream 1% (n = 129) Vehicle (n = 66) Age, mo (mean 6 SD) Sex, n (%) Male 81 (62.8) 47 (71.2) Female 48 (37.2) 19 (28.8) Ethnicity, n (%) White 117 (90.7) 61 (92.4) Black 2 (1.6) 0 (0) Asian 7 (5.4) 4 (6.1) Other 3 (2.3) 1 (1.5) Height, cm (mean 6 SD) Weight, kg (mean 6 SD) IGA score, n (%) 2 (Mild) 12 (9.3) 8 (12.1) 3 (Moderate) 75 (58.1) 39 (59.1) 4 (Severe) 34 (26.4) 17 (25.8) 5 (Very severe disease) 8 (6.2) 2 (3.0) EASI score (mean 6 SD) and 66 with vehicle. The patients progression through the successive phases of the study is summarized in Fig E1 in the Journal s Online Repository at One hundred seventeen (90%) patients from the pimecrolimus group and 41 (62.1%) patients from the vehicle group completed the double-blind phase. One hundred eighty-eight patients entered the open-label phase, and 162 entered the follow-up phase. The baseline demographic and clinical characteristics in the intention-to-treat population are summarized in Table I. Efficacy Double-blind phase. Pimecrolimus cream 1% was effective and fast acting in reducing the signs and symptoms of atopic eczema during the double-blind phase. The mean 6 SD EASI score decreased by 71.5% (from at baseline to at day 29) in the pimecrolimus group but increased by 19.4% (from to ) in the vehicle group (P<.001) at the end of week 4. The response to pimecrolimus cream 1% treatment was rapid, with a reduction of 6.5 points, or 38.5%, in mean EASI score by day 4 (the first ontreatment visit) compared with an increase of 1.8 points, or 17.6%, in the vehicle group (P <.001). The treatment difference between the 2 groups continued to increase throughout the double-blind phase of the study (Fig 1). Pimecrolimus cream 1% was highly effective in patients with severe atopic eczema. Patients with severe baseline disease (IGA 4) experienced a statistically significant mean reduction in EASI score compared with vehicle of 74.7% (from to ) over the course of the double-blind phase (P <.001). Similar responses were observed in patients with mild or moderate baseline disease (IGA 3), who had a mean decrease of 70% in EASI score (from to , P<.001, Fig 2) at the end of week 4. FIG 1. Improvement in clinical symptoms of atopic eczema as assessed by EASI score during the double-blind and open-label phases. When the response to treatment was assessed in the head and neck region alone, the rate and overall magnitude of the response, as measured on the basis of the EASI score, were similar to those observed for the body as a whole. In the pimecrolimus group the mean EASI score for the head and neck decreased by 40.1% (from at baseline to ) at day 4 and was reduced by 73.1% to a mean score of at day 29. In contrast, in the vehicle group the mean EASI score increased by 34.7% (from at baseline to ) by day 29. Marked improvements in the overall severity of disease were also observed in terms of IGA score. Treatment success (IGA = 0 [clear] or IGA = 1 [almost clear]) was achieved by 69 (53.5%) patients in the pimecrolimus group at day 29 compared with 7 (10.6%) patients treated with vehicle (P<.001 for the between-group comparison, Cochran-Mantel-Haenszel test). In the pimecrolimus group 42 (32.6%) patients had a severe flare (as defined by an IGA score of 4 or 5) at baseline, but this decreased to 10 (7.7%) patients by day 4 and 7 (5.5%) patients by day 8 and remained less than 5% at days 15 and 29. In contrast, 19 (28.8%) patients in the vehicle group had a flare at baseline, and this figure remained greater than 30% in all postbaseline assessments. The primary caregivers assessment of disease response was similar to that of physicians. At day 29, disease control was assessed by primary caregivers to be good or complete in 104 (80.6%) patients in the pimecrolimus group and in 15 (22.7%) patients in the vehicle group (P<.001). As assessed by primary caregivers, pruritus and sleep loss in patients also showed rapid and substantial improvement after treatment with pimecrolimus cream 1%. In the pimecrolimus group the mean pruritus score decreased from at baseline to at day 29, whereas in the vehicle group it increased from at baseline to at day 29 (P <.001 for the between-group comparison, Fisher exact test). Similarly, the mean sleep-loss score decreased from to in the pimecrolimus group but increased from to by day 29 in the vehicle group (P<.001 for the between-group comparison, Fisher exact test).

4 1186 Kaufmann et al J ALLERGY CLIN IMMUNOL NOVEMBER 2004 FIG 3. Percentage of patients with an improvement of at least 50% from baseline according to the primary caregiver s assessment (visual analog scale). A, Pruritus. B, Sleep loss. FIG 2. Improvement in clinical symptoms of atopic eczema in patients treated with pimecrolimus cream 1% during the doubleblind phase. Mean total EASI score in patients with mild or moderate disease (IGA = 2-3; A) compared with that seen in patients with severe or very severe disease (IGA = 4-5; B). The percentage of patients with an improvement in pruritus and sleep-loss scores from baseline of at least 50% increased rapidly with pimecrolimus cream 1% treatment, with a statistically significant pruritus treatment effect in favor of pimecrolimus cream 1% by day 2 and a significant improvement in sleep loss by day 3 (P<.001, Fig 3). From day 4 on, more than 60% of patients treated with pimecrolimus cream 1% had an improvement from baseline in pruritus and sleep-loss scores of at least 50%. In contrast, less than 15% of patients treated with vehicle had an improvement in pruritus score of 50% or greater and less than 30% in terms of sleep loss after day 4 (Fig 3). Open-label extension phase. The significant improvements in atopic eczema observed in the pimecrolimus group during the double-blind phase were sustained throughout the 12 weeks of open-label treatment. By the end of the open-label phase, disease severity in this group had improved to the same degree as in the group that had received pimecrolimus cream 1% in both treatment phases (Fig 1). Follow-up phase. The final 4-week follow-up phase began after the discontinuation of pimecrolimus cream 1% treatment in all patients. During this phase, there was a gradual increase in the severity of atopic eczema. After 2 weeks without active treatment, the mean EASI score increased from at the end of the open-label phase to When 4 weeks without active treatment had elapsed, a further slight deterioration in the signs and symptoms of atopic eczema occurred, and the mean EASI score increased to This represented a much lower disease severity than at study baseline, where the mean EASI score for the population that entered the follow-up phase was Safety Double-blind phase. A total of 83 (63.8%) patients in the pimecrolimus group and 40 (60.6%) patients in the vehicle group experienced at least one adverse event during the double-blind phase. Most of the adverse events in both groups were mild to moderate in severity. Three (2.3%) patients in the pimecrolimus group and 2 (3.0%) patients in the vehicle group experienced a treatmentrelated adverse event. These were application-site burning (1 patient in each treatment group), impaired healing (1 patient in the pimecrolimus group), burning sensation (1 patient in the pimecrolimus group), and erythema (1 patient in the vehicle group). In addition, 2 (1.5%) patients from the pimecrolimus group and 1 (1.5%) patient from the vehicle group experienced a treatment-related serious adverse event resulting in discontinuation from the study. One discontinuation from each group was due to a superinfection (together with aggravated atopic eczema in the vehicle group), and the third patient had a moderate case of eczema herpeticum. The most common adverse events in both groups were typical childhood ailments (Table II). After correcting for the length of time in the study, there was no overall difference in the occurrences of these common ailments between the 2 treatment groups. Local tolerability of pimecrolimus cream 1% was excellent. Parents reports of application-site burning were very uncommon, occurring in only one patient in each group. There were no clinically significant differences between the groups in the occurrence of any skin infections or infestations. Open-label and follow-up phases. During the openlabel phase, 138 (73.4%) patients experienced at least one

5 J ALLERGY CLIN IMMUNOL VOLUME 114, NUMBER 5 Kaufmann et al 1187 adverse event. Most of these were mild to moderate in severity, and almost all (132/138 patients) were considered unrelated to the study drug and to be common childhood ailments (as in the double-blind phase). A total of 9 patients had severe adverse events; 6 patients had a suspected treatment-related adverse event, including 4 cases of infection (2 cases of impetigo, 1 of herpes simplex dermatitis, and 1 of varicella) and one case each of asthma, aggravated atopic eczema, and exacerbated eczema. Three patients discontinued the study because of adverse events (teething, pyrexia, and rash). Local tolerability of pimecrolimus cream 1% was excellent, with only one patient experiencing a mild burning sensation. TABLE II. Adjusted incidence rates of common adverse events ($5% for any group) in the double-blind phase Adverse event Pimecrolimus cream 1%, (n = 130), % Vehicle (n = 66), % P value Nasopharyngitis Pyrexia Rhinitis NOS Diarrhea NOS Cough Bronchitis NOS Contact dermatitis Gastroenteritis NOS NOS, Not otherwise specified. Discussion This study has demonstrated that pimecrolimus cream 1% is highly effective and has a good safety profile in the treatment of atopic eczema of all severities in infants aged 3 to 23 months. A rapid response was observed, with a statistically significant treatment difference in EASI score emerging between the pimecrolimus and vehicle groups from day 4 on (the first on-treatment visit), when a decrease of almost 40% in the clinical symptom score could already be observed. Most of the full treatment effect was achieved by day 8, after which the level of improvement was sustained. The improvement in EASI score was confirmed by other assessments, including IGA and caregivers assessment. The response to pimecrolimus cream 1% was sustained during the 12 weeks of open-label therapy, and patients who had received vehicle during the double-blind phase rapidly achieved a comparable level of response when switched to open-label pimecrolimus cream 1%. 25,28 An important finding of the study was that pimecrolimus cream 1% was at least as effective in patients with severe and very severe disease as it was in patients with milder disease. Approximately 30% of patients in each treatment group had an IGA score at baseline of 4 or 5, corresponding to severe or very severe disease, and these patients had a greater absolute reduction in EASI score than patients with mild or moderate disease during the course of the study. However, the improvement, when expressed as a percentage of baseline EASI score, was comparable for patients of all baseline disease severities. The rate of improvement in terms of pruritus and patient sleep loss, as assessed by caregivers, was even more rapid than the improvement in EASI score. Sleep loss (caused by pruritus) has been shown to be very common when a child is experiencing a flare of atopic eczema, 29 and rapid alleviation of pruritus can have significant effects on the quality of life of both the child and the caregiver. Statistically significant differences between the pimecrolimus and vehicle groups in the percentage of patients with at least a 50% improvement from baseline were observed as early as day 2 for pruritus and day 3 for sleep loss. As with the EASI score, the full benefits of treatment were largely achieved within 1 week and sustained thereafter. An important issue addressed by this study was the possibility of disease rebound after discontinuation of active treatment. The effects of treatment cessation were investigated in the final 4-week phase of the study, during which no active treatment was given. During this phase, there was a gradual increase in the signs and symptoms of atopic eczema; however, by the end of the study period, the overall severity of disease remained considerably lower than at study baseline. Disease rebound can occur after topical corticosteroids are discontinued 7 and hence can compromise corticosteroid-based management because indefinite treatment with steroids to maintain disease control is not a safe option. In contrast, pimecrolimus cream 1% maintains a good safety profile when used for extended periods and, as shown by this study, can be discontinued when clinically appropriate, without any risk of disease rebound. Treatment with pimecrolimus cream 1% was well tolerated throughout the course of the study. All the common adverse events recorded during the study were typical childhood ailments, none of which were considered by investigating physicians to be related to treatment, and after correction for time on the study, the incidence of side effects was no higher with pimecrolimus cream 1% than with vehicle. The discontinuation rate during the double-blind phase was higher in the vehicle group (37.9%) than in the pimecrolimus group, in which only 10.4% of patients discontinued treatment early. Local skin infections occurred at similar frequencies in the pimecrolimus cream 1% and vehicle groups, and there was no evidence of skin atrophy, which is consistent with the nonsteroid mode of action of pimecrolimus. In conclusion, pimecrolimus cream 1%, given twice daily, is an effective and well-tolerated treatment for controlling atopic eczema of all severities in infants aged 3 to 23 months. The response is rapid, with clinically significant improvements in pruritus and the clinical signs of atopic eczema evident within 2 and 3 days, respectively, compared with vehicle. Sleep loss is also rapidly improved. Pimecrolimus cream 1% retains its clinical effectiveness in long-term use, and there is no rebound effect when it is discontinued. These findings suggest that

6 1188 Kaufmann et al J ALLERGY CLIN IMMUNOL NOVEMBER 2004 the treatment of atopic eczema with pimecrolimus cream 1% constitutes an important advance in the management of this disease in infants. We thank the following investigators: Ulrich Wahn, Christiane Bayerl, Martin Hartmann, Andrea von Berg, Alexander Kapp, Hans Merk, Michael Meurer, Uwe Schauer, Johannes Forster, Klaus Deichmann, Michael Sebastian, Wolfgang Kamin, Volker Wahn, Rüdiger Szczepanski, Frank Friedrichs, Heidelore Hofmann, Udo Amann, and Margarita Meisel-Stosiek. Additional thanks are also extended to Stefan Bruns, Kathrin Krüger-Barvels Sabine Nowak, Sabine Stegner, and Doris Weber for their assistance with study administration and statistical analysis. REFERENCES 1. Schultz LF. The epidemiology of atopic dermatitis. Monogr Allergy 1993;31: Kay J, Gawkrodger DJ, Mortimer MJ, Jaron AG. The prevalence of childhood atopic eczema in a general population. 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