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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Background  Pimecrolimus cream 1%, a cell-selective inhibitor of inflammatory cytokines, has been shown to be effective in treating atopic dermatitis (AD). This report examines the effect of ethnic origin and baseline disease severity on treatment outcomes in pediatric patients with AD treated with pimecrolimus cream 1%.

Methods  The analysis included 589 patients aged 3 months to 17 years from three 6-week, randomized, multicenter studies of similar design. Patients were treated with pimecrolimus cream 1% or vehicle twice daily. Efficacy, safety and tolerability in Caucasian and non-Caucasian groups were compared. In addition, the effect of baseline disease severity on treatment outcome was investigated.

Results  A total of 321 Caucasian and 268 non-Caucasian patients [Blacks, Asians and others (including Hispanics)] with mild, moderate or severe disease at baseline were included. Baseline characteristics were comparable between the pimecrolimus and vehicle control groups and between Caucasian and non-Caucasian groups. Significantly higher efficacy [measured by Investigators’ Global Assessment and Eczema Area and Severity Index (EASI) scores] was achieved in the pimecrolimus-treated group, compared with the vehicle group, irrespective of ethnic origin. Baseline disease severity had no effect on treatment outcome: patients with both mild and moderate AD responded well to pimecrolimus (absolute change from baseline in EASI score −2.60 and −5.48, respectively; both P < 0.001). Pimecrolimus cream 1% was safe and well tolerated in all ethnic groups and at all levels of disease severity.

Conclusions  Ethnic origin and baseline disease severity had no effect on treatment outcome with pimecrolimus cream 1% in patients with AD.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

The ascomycin macrolactam derivative pimecrolimus is a cell-selective inhibitor of inflammatory cytokines, developed specifically to treat inflammatory skin conditions, such as atopic dermatitis (AD), also known as atopic eczema.1,2

Three large pediatric clinical studies of similar design have demonstrated that pimecrolimus cream 1% (Elidel®; Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) has a good safety profile, and is effective and well tolerated in infants, children and adolescents with AD.3,4 Two factors not considered in these studies were the influences of ethnic origin and baseline severity on the treatment outcomes with pimecrolimus.

Several population-based studies have suggested that AD is more prevalent in non-Caucasians (particularly Blacks) than in Caucasians5–7 or that non-Caucasians are more likely to seek medical attention for their disease than Caucasians.8 Although results from prevalence studies of AD in different ethnic groups have been reported in the literature, there has been very little investigation into the influence of ethnic origin on treatment outcome in AD. Indeed, the present study is the first, to our knowledge, to formally investigate such a hypothesis.

Another potential influence on treatment outcome is the impact of baseline disease severity (mild, moderate or severe). Several scoring systems have been developed for the assessment of disease severity in AD, and these have been reviewed in the literature.9,10 An accurate evaluation of disease severity and extent is important for baseline assessment and subsequent monitoring of the course of the disease and the effect of treatment.

Consequently, two factors that could help determine the clinical treatment outcome in patients are their ethnic origin and initial (baseline) disease severity. In order to evaluate the effects of these two factors on treatment outcome, we analyzed the efficacy, safety and tolerability data from three large, double-blind, 6-week pediatric studies of patients treated with pimecrolimus cream 1%.

Patients and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

In three multicenter clinical trials of almost identical design, the efficacy and safety of pimecrolimus cream 1% were evaluated in children (2–17 years old) and infants (3–23 months of age) with predominantly mild or moderate AD. Each of the studies comprised a 6-week, double-blind, vehicle-controlled phase, where subjects were randomized 2 : 1 to receive either pimecrolimus cream 1% or corresponding vehicle control, to be applied twice daily to affected areas. Other than the age of patients recruited, the studies differed slightly such that the patients in the infants’ study could discontinue from the double-blind phase of the study after 3 weeks and enroll into the 20-week, open-label extension. The individual results from these studies have been reported separately elsewhere.3,4 The recruitment and randomization were not stratified by race; the patient's ethnicity was entered as Caucasian, Black, Oriental (subsequently referred to as Asian) or Other on the case report form.

Patients with AD who had an Investigators’ Global Assessment (IGA) score of 2 (mild disease) or 3 (moderate disease) affecting at least 5% of the total body surface area were included.3,4 The IGA is an overall evaluation of the patient's AD on a 6-point ordinal scale of disease severity, ranging from 0 (clear of disease) to 5 (very severe disease).11

The primary efficacy outcome was the proportion of patients achieving treatment success, defined as an IGA score of 0 or 1 (clear or almost clear of disease), after completion of the 6-week treatment phase. The main secondary efficacy assessment utilized the Eczema Area and Severity Index (EASI)12 which incorporates severity of dermatitis and surface area involvement, with a possible score total ranging from 0 to 72.

Statistical analyses

All efficacy analyses were conducted on the pooled intention- to-treat (ITT) population from the three studies, comparing treatment groups using a two-sample test of proportions at the 5% two-sided significance level. A 25% difference in efficacy parameter score was taken as a minimum clinically relevant difference. Primary efficacy endpoint data, stratified by clinical center, were analyzed using the Cochran-Mantel-Haenszel (CMH) test. EASI data were subjected to an analysis of covariance (ANCOVA), with the EASI score at endpoint as the responding variable and the EASI baseline score and center as covariates.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Data from a total of 589 pediatric patients (including 186 infants) were included in the analyses; 390 and 199 patients were randomized to pimecrolimus cream 1% and vehicle treatments, respectively. The baseline demographics of patients in the individual studies were similar, and are reported elsewhere.3,4 At baseline, 93.8% of Caucasian and 92.7% of non-Caucasian patients in the pimecrolimus-treated group, and 95.4 and 88.8%, respectively, in the vehicle group had IGA severity ratings of 2 or 3. Baseline EASI scores were also comparable across the treatment groups, with mean values of 12.0 and 12.8 in the pimecrolimus group vs. 10.1 and 14.1 in the vehicle group for the Caucasian and non-Caucasian groups, respectively. Patients’ baseline disease severity and ethnic origin are summarized in Table 1.

Table 1.  Patients’ baseline disease severity and ethnic origin
 Pimecrolimus cream 1%[n (%)] (n = 390)Vehicle [n (%)] (n = 199)
  1. EASI, Eczema Area and Severity Index; IGA, Investigators’ Global Assessment.

Baseline IGA
0 (clear)  0  0
1 (almost clear)  0  0
2 (mild)120 (31) 64 (32)
3 (moderate)244 (63)120 (60)
4/5 (severe/very severe disease) 26 (7) 15 (8)
Baseline EASI (score-range)
≤ 8163 (42) 94 (47)
> 8–15115 (29) 53 (27)
> 15112 (29) 52 (26)
Ethnic group
Caucasian211 (54.1)110 (55.3)
Non-Caucasian179 (45.9) 89 (44.7)
Black 73 (18.7) 39 (19.6)
Asian 21 (5.4) 10 (5.0)
Other 85 (21.8) 40 (20.1)

Effect of ethnic origin on treatment outcome

For the purpose of the efficacy analyses, patients were categorized into two main groups: Caucasian (n = 321) and non-Caucasian (n = 268). Patients in the non-Caucasian group were further divided into three subgroups: 112 (41.8%) were Black; 31 (11.6%) were Asian; and 125 (46.6%) were categorized as being of “Other” ethnic origin (mainly Hispanic).

Efficacy

Significantly higher efficacy outcomes, as assessed by the IGA (Table 2) and EASI (Table 3) scores, were achieved in the patient group treated with pimecrolimus cream 1%, compared with those receiving vehicle, irrespective of ethnic origin. The treatment success rates, derived from analyses of the IGA scores, were statistically significant in both main ethnic groups of patients, for pimecrolimus cream 1% vs. vehicle: Caucasian (45.0 vs. 23.6%, respectively; P < 0.05), and non-Caucasian (36.3 vs. 15.7%; P < 0.001). Furthermore, for both these ethnic groups, the 95% confidence intervals (CIs) for the treatment effects overlapped significantly, showing that there was no difference in the magnitude of these effects between Caucasian and non-Caucasian patients: 21.4% (95% CI: 0.03, −0.41) vs. 20.6% (95% CI: 0.09, −0.30), respectively (Table 2).

Table 2.  Influence of ethnic origin on Investigators’ Global Assessment (IGA) treatment success at day 43
 CaucasianNon-Caucasian
Pimecrolimus cream 1% (n = 211)Vehicle (n = 110)Pimecrolimus cream 1% (n = 179)Vehicle (n = 89)
  • a

    Treatment success defined as IGA, 0 (clear) or 1 (almost clear of disease).

  • b

    Treatment effect and 95% CI (pimecrolimus cream 1% vs. vehicle) based on the difference in percentages; Cochran–Mantel–Haenszel general association test stratified by center; overall treatment success estimated using the weighted noniterative estimator.13

Treatment successa[n (%)]95 (45.0)26 (23.6)65 (36.3)14 (15.7)
Treatment effect (%) (95% CI)b21.4 (0.03, 0.41) 20.6 (0.09, 0.30) 
Treatment effect P-valueb0.02 < 0.001 
Table 3.  Influence of ethnic origin on Eczema Area and Severity Index (EASI)
 CaucasianNon-Caucasian
Pimecrolimus cream 1% (n = 211)Vehicle (n = 110)Pimecrolimus cream 1% (n = 179)Vehicle (n = 89)
  • a

    Overall treatment effect estimated using the weighted noniterative estimator.13

  • b

    Treatment effect and 95% CI based on the difference in means (pimecrolimus cream 1% vs. vehicle). Based on an ancova model of EASI score (pimecrolimus cream 1% vs. vehicle). The mean difference is adjusted for baseline.

Mean (± SD) change in EASI
 from baseline−6.56 ± 8.24−1.22 ± 6.04−5.83 ± 7.90−0.49 ± 9.34
Treatment effecta (95% CI)−4.35 (−5.65, −3.04) −5.37 (−7.44, −3.29) 
Treatment effect P-valueb< 0.001 < 0.001 

Since the non-Caucasian group comprised individuals of distinct ethnic origins, a subgroup analysis of the IGA scores was carried out on each ethnic group as defined by the case report form. The treatment success rate followed the same trend as found in the overall non-Caucasian grouping, with 34.2% (25/73) vs. 20.5% (8/39) of Black patients, 42.9% (9/21) vs. 0% of Asian patients, and 36.5% (31/85) vs. 15.0% (6/40) of other patients demonstrating an IGA of clear or almost clear in the pimecrolimus and vehicle groups, respectively. Due to the small numbers of patients in some of the groups, statistical comparisons across the ethnic groups could not be made.

The mean changes (± SD) in EASI from baseline to study endpoints also demonstrated highly significant (P < 0.001) treatment effects of pimecrolimus cream 1% compared with vehicle in both Caucasian (−6.56 ± 8.24 vs. −1.22 ± 6.04) and non-Caucasian (−5.83 ± 7.90 vs. −0.49 ± 9.34) patients (Table 3). Again, the 95% CI for the treatment effects showed significant overlap between the Caucasian and non-Caucasian groups: −4.4 (95% CI: −5.65, −3.04) vs. −5.4 (95% CI: −7.44, −3.29), respectively (Table 3), indicating that the magnitude of the treatment effects is comparable in these ethnic groups. A similar response was seen when the EASI scores were separated into each ethnic grouping within the non-Caucasian category for pimecrolimus and vehicle [mean ± SD changes from baseline: Black, −3.85 ± 7.41 (n = 73) vs. 0.28 ± 8.70 (n = 39); Asian, −6.33 ± 8.63 (n = 21) vs. −0.32 ± 10.61 (n = 10); Other, −7.41 ± 7.83 (n = 85) vs. 0.75 ± 9.85 (n = 40), respectively]. Again, due to the small numbers of patients in some of the groups, statistical comparisons across the ethnic groups could not be made.

Safety and tolerability

Pimecrolimus cream 1% was well tolerated in both infants and children, irrespective of their ethnic origin. The incidence of application-site burning, the most common cutaneous adverse event, was very low and comparable between the treatment groups as well as between the ethnic groups in both the pimecrolimus (9.0% of Caucasian patients, compared with 5.6% of non-Caucasian patients) and vehicle (9.1% of Caucasian patients, compared with 10.1% of non-Caucasian patients) treatment groups. There was no significant difference in the incidences of application-site burning between Caucasian and non-Caucasian patients (9.0% vs. 7.1%, respectively; P = 0.4506, Fisher's exact test). The majority of application-site reactions were of short duration and occurred early in treatment in all groups. Furthermore, there were no adverse events in these studies indicative of systemic toxicity of pimecrolimus.3,4

Influence of baseline disease severity on treatment outcome

The severity of disease at baseline, expressed in terms of IGA or EASI scores, was comparable in the two treatment groups (Table 1); 62.6% of patients treated with pimecrolimus cream 1% and 60.3% of patients using the vehicle control had moderate disease (IGA = 3), and 30.8 vs. 32.2%, respectively, had mild disease (IGA = 2). Mean EASI scores at baseline were similar between the respective treatment groups: 11.9 (pimecrolimus cream 1%) vs. 12.3 (vehicle).

Patients with mild (IGA = 2) or moderate (IGA = 3) disease at baseline responded well to pimecrolimus cream 1%, as determined by IGA scores during the study, with a similar treatment effect in both the mild- and moderate-disease groups (absolute difference of 19.2 and 23.3%, respectively; P < 0.01 vs. vehicle) (Table 4). There were too few patients with severe or very severe AD (IGA = 4 or 5, respectively) to permit meaningful analysis; however, there was a trend showing a higher treatment efficacy in these worst-affected disease categories in patients receiving pimecrolimus cream 1%, compared with patients receiving vehicle only.

Table 4.  Influence of baseline disease variablesa on Investigators’ Global Assessment (IGA) treatment success at day 43
Baseline variableIndexTreatment success [n/N (%)]bVehicleTreatment effectcTreatment effect P-valued
Pimecrolimus cream 1%
  • a

    Baseline disease expressed as Investigators’ Global Assessment (IGA) and Eczema Area and Severity Index (EASI); the endpoint is the last postbaseline assessment in the double-blind phase, up to and including day 43.

  • b

    Treatment success defined as IGA = 0 (clear) or 1 (almost clear).

  • c

    Overall treatment effect estimated using the weighted noniterative estimator.13

  • d

    Treatment effect (pimecrolimus cream 1% vs. vehicle) is based on the difference in proportion of successes.

IGA2 (mild)70/120 (58.3) 25/64 (39.1)0.200.009
3 (moderate)87/244 (35.7)15/120 (12.5)0.230.006
4/5 (severe/very severe)  3/26 (11.5)  0/15 (–)0.110.068
EASI 891/163 (55.8) 32/94 (34.0)0.230.012
> 8–1548/115 (41.7)  6/53 (11.3)0.300.008
> 1521/112 (18.8)  2/52 (3.8)0.130.006

For the purpose of analysis, the baseline EASI data were merged into three score-ranges (≤ 8, > 8–15, and > 15) so that each contained approximately one-third of the patient population. Patients within all three baseline EASI score-ranges also improved while using pimecrolimus cream 1%, as indicated by IGA scores (Table 4), with a statistically significant treatment effect being noted in all disease-severity categories (P < 0.02 for all comparisons).

Analysis of changes in EASI assessments demonstrated that patients with mild or moderate AD clearly responded well to treatment with pimecrolimus cream 1%, with a significant treatment effect (absolute change from baseline in EASI score −2.60 and −5.48, respectively; both P < 0.001) in both these disease-severity categories (Table 5). Again, since the studies evaluated patients with primarily mild to moderate disease, there were too few patients within the severe or very severe disease categories to permit a meaningful analysis, although there is a trend towards a greater treatment effect as severity increased (Table 5).

Table 5.  Influence of baseline disease variablesa on Eczema Area and Severity Index (EASI)
Baseline variableIndexChange from baseline in EASITreatment effectcTreatment effect P-valued
Pimecrolimus cream 1%Vehicle
nMean ± SDnMean ± SD
  • a

    Baseline disease expressed as Investigators’ Global Assessment (IGA) and Eczema Area and Severity Index (EASI).

  • b

    Overall treatment effect estimated using the weighted noniterative estimator.13

  • c

    Treatment effect based on the difference in means (pimecrolimus cream 1% vs. vehicle).

IGA2 (mild)120 −3.33 ± 4.19 64−0.04 ± 5.12−2.60< 0.001
3 (moderate)244 −6.85 ± 7.99120−1.06 ± 7.16−5.48< 0.001
4/5 (severe/very severe) 26−13.68 ± 14.49 15−3.21 ± 16.47−8.59    0.146
EASI 8163 −2.44 ± 3.66 94  0.09 ± 5.24−2.71< 0.001
> 8–15115 −6.20 ± 4.38 53−0.51 ± 7.4−5.93< 0.001
> 15112−11.76 ± 11.73 52−3.08 ± 10.79−7.92< 0.001

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Assigning individuals to specific ethnic groups is often based on personal observations, rather than scientific objectivity, so there is an element of scientific imprecision involved in placing individuals into specific ethnic groups. However, differences in responses to drug treatments in patients of differing ethnic origin and genetic background have been observed.14 Pimecrolimus is a topical drug that acts within the skin to suppress the inflammation responsible for AD lesions.15–17 There is no evidence of differences between ethnic groups with respect to skin structure or properties, and because pimecrolimus is absorbed to a negligible degree, systemic exposure is minimal.18 Hence, there should be no expectation of any differences among ethnic groups in the efficacy and safety profile of pimecrolimus cream 1% and, indeed, no such differences have been found to date.

The studies reported in the literature, and cited in this report, involved a substantial number of non-Caucasian patients, including those of Asian background. The analyses reported here show that treatment with pimecrolimus cream 1% rapidly and markedly improves the disease presentation of AD in infants, children and adolescents, compared with vehicle control, irrespective of the patient's ethnic origin. In addition, the treatment was well tolerated in the Caucasian patients, as well as in those in the Black, Asian and other non-Caucasian (including Hispanic) ethnic groups, with no evidence of a difference in tolerability associated with ethnic origin in any group. In retrospectively grouping patients into ethnic categories, this study was not prospectively designed to characterize a population with specifically defined racial demographics but was, rather, an attempt to explore, within this extensive database, whether racial characteristics (under the broad categorization of patients as either Caucasian or non-Caucasian) could affect the treatment outcomes with pimecrolimus cream 1%. The finding that there were no differences between such groups of patients suggests that ethnic origin has no influence on treatment outcomes with this agent.

The incidence of application-site reactions in these pediatric studies was very low and was comparable in patients treated with pimecrolimus cream 1% and vehicle. Furthermore, no adverse events indicative of systemic toxicity were detected in patients of any ethnic origin.

It is also important that new therapeutic modalities for AD are effective in patients, irrespective of the severity of the disease. Assessment of the disease before treatment, and thereafter at appropriate intervals during treatment, enables an effective evaluation of treatment outcome.9 In the present study, disease severity assessments were made using the EASI12 and IGA11 evaluation systems. In assessing AD by two different scoring systems, we have demonstrated that patients with higher baseline disease severity showed improved treatment effects over corresponding controls when treated with pimecrolimus cream 1%.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

Pimecrolimus cream 1% is an efficacious and well-tolerated treatment for infants and children with AD, irrespective of their ethnic origin. Moreover, pimecrolimus cream 1% is efficacious in all disease-severity groups studied, which makes it a promising new therapy for the clinical care of pediatric AD patients.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References

The authors would like to thank the following participating investigators: A. Halbert (Australia); F. Alonso, S. Cestari, A. Sittart, and R. Takaoka (Brazil); A. Gupta, V. Ho, and K. Papp (Canada); K. Deichmann, R. Foelster-Holst, H. Hamm, P. Hoger, and D. Thaçi (Germany); M. Groenwald, P. Jeena, D. Patel, P. Potter, N. Raboobee, and S. Reyneke (South Africa); M. Casado, J. Escudero, J. Hermosa, and F. Vanaclocha (Spain); M. Boguniewicz, D. Butler, I. Caro, A. Gottlieb, J. Hanifin, A. Hebert, P. Honig, M. Jarratt, I. Katz, J. Koo, N. Korman, A. Lane, M. Ling, A. Paller, D. Pariser, L. Schachner, D. Stewart, M. Stiller, E. Tschen, and K. Washenik (USA).

Researchers from Novartis included: B. Abrams, C. Bush, R. Cherill, M. Graeber, S. Hedgecock, K. Marshall, C. Paul, and M. Thurston.

This study was supported by a research grant from Novartis Pharmaceuticals Corporation, East Hanover, NJ.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and Methods
  5. Results
  6. Discussion
  7. Conclusions
  8. Acknowledgments
  9. References