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Proactive disease management with 0·03% tacrolimus ointment for children with atopic dermatitis: results of a randomized, multicentre, comparative study

Authors

  • D. Thaçi,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • S. Reitamo,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • M.A. Gonzalez Ensenat,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • C. Moss,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • V. Boccaletti,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • T. Cainelli,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • P. Van Der Valk,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • H. Buckova,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • M. Sebastian,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • M.L. Schuttelaar,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • T. Ruzicka,

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • for the European Tacrolimus Ointment Study Group

    1. Department of Dermatology and Venerology, J. W. Goethe University, Theodor-Stern-Kai 7, Frankfurt, D-60596 Germany
      *Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland
      †Hospital Sant Joan de Deu, Barcelona, Spain
      ‡Birmingham Children’s Hospital, Birmingham, U.K.
      §Department of Dermatology, Parma University Hospital, Parma, Italy
      ¶Ospedali Riuniti di Bergamo, Bergamo, Italy
      **Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
      ††Children’s Hospital of Faculty Hospital, Brno, Czech Republic
      ‡‡Group Practice, Dermatology, Mahlow, Germany
      §§Department of Dermatology, University Medical Centre Groningen, Groningen, The Netherlands
      ¶¶Heinrich-Heine University, Duesseldorf, Germany
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  • Conflicts of interest
    Astellas Pharma GmbH, manufacturer of tacrolimus ointment, provided support to perform the study. D.T., S.R., M.A.G.E., P.V. and T.R. have received fees/sponsorship for speaking/chairing meetings on behalf of Astellas. D.T., S.R., P.V., M.A.G.E. and T.R. have served as advisers to Astellas. All other authors declare that they have no conflicts of interest.

  • Trial registration number NCT00480896 (registered at http://www.ClinicalTrials.gov).

  • 1

    Additional members of the European Tacrolimus Ointment Study Group are listed in the Appendix.

Diamant Thaçi.
E-mail: thaci@em.uni-frankfurt.de
Tel.: +49 69 6301 6556
Fax: +49 69 6301 7375

Summary

Background  Long-term treatment for atopic dermatitis (AD) using low-dose, intermittent, topical anti-inflammatory agents may control acute disease and prevent exacerbations.

Objectives  This 12-month, European, multicentre, randomized study investigated if proactive, twice-weekly application of 0·03% tacrolimus ointment can keep AD in remission and reduce the incidence of disease exacerbation (DE) in children.

Patients and methods  During the initial open-label period, 267 children with AD applied 0·03% tacrolimus ointment twice daily for up to 6 weeks to all affected areas. When an Investigator Global Assessment (IGA) score of ≤ 2 was achieved, the patient entered the disease control period (DCP) and was randomized to receive tacrolimus (= 125) or vehicle ointment (= 125) twice weekly for 12 months. Exacerbations were treated with 0·03% tacrolimus ointment twice daily until an IGA ≤ 2 was regained, then randomized treatment was restarted.

Results  The outcome measure was the number of DEs during the DCP that required substantial therapeutic intervention. Proactive application of 0·03% tacrolimus ointment significantly reduced the number of DEs during the DCP that required substantial therapeutic intervention (median difference: 1·0; < 0·001; Wilcoxon rank-sum test), the percentage of DE treatment days (median difference: 6·2; < 0·001; Wilcoxon rank-sum test), and increased the time to first DE requiring intervention (median: 173 vs. 38 days; < 0·001; stratified log-rank test). Differences in quality of life scores were not significant between groups. The adverse event profile was similar for both treatment approaches.

Conclusions  Twice-weekly proactive application of 0·03% tacrolimus ointment over 12 months was effective for most paediatric study patients in preventing, delaying and reducing the occurrence of AD exacerbations.

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