Topical sirolimus 0.1% for treating cutaneous microcystic lymphatic malformations in children and adults (TOPICAL): protocol for a multicenter phase 2, within-person, randomized, double-blind, vehicle-controlled clinical trial
Sophie Leducq,
Agnès Caille,
Sébastien Barbarot,
Nathalie Bénéton,
Didier Bessis,
Olivia Boccara,
Anne-Claire Bursztejn,
Christine Chiaverini,
Anne Dompmartin,
Catherine Droitcourt,
Valérie Gissot,
Dominique Goga,
Laurent Guibaud,
Denis Herbreteau,
Anne Le Touze,
Christine Léauté-Labrèze,
Gérard Lorette,
Stéphanie Mallet,
Ludovic Martin,
Juliette Mazereeuw-Hautier,
Alice Phan,
Patrice Plantin,
Isabelle Quéré,
Pierre Vabres,
Hélène Bourgoin,
Bruno Giraudeau,
Annabel Maruani,
Groupe de Recherche de la Société Française de Dermatologie Pédiatrique
Affiliations
Sophie Leducq
INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours
Agnès Caille
INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours
Sébastien Barbarot
Department of Dermatology, University Hospital Center of Nantes
Nathalie Bénéton
Department of Dermatology, Hospital Center of le Mans
Didier Bessis
Department of Dermatology, University Hospital Center of Montpellier
Olivia Boccara
Department of Dermatology and Reference center for genodermatoses and rare skin diseases (MAGEC), University Hospital Necker-Enfants Malades
Anne-Claire Bursztejn
Department of Dermatology, University Hospital Center of Nancy
Christine Chiaverini
Department of Dermatology, University Hospital Center of Nice
Anne Dompmartin
Department of Dermatology, University Hospital Center of Caen
Catherine Droitcourt
Department of Dermatology, University Hospital Center of Rennes
Valérie Gissot
Clinical Investigation Center, INSERM 1415, CHRU Tours
Dominique Goga
Department of Maxillo-Facial surgery, CHRU Tours
Laurent Guibaud
University Hospital Center of Lyon, Consultation Multidisciplinaire Lyonnaise des Angiomes
Denis Herbreteau
Department of Neuroradiology, CHRU Tours
Anne Le Touze
Department of Pediatric Surgery, CHRU Tours
Christine Léauté-Labrèze
Department of Dematology, Pellegrin Children’s Hospital
Gérard Lorette
Department of Dermatology and Reference Center for Rare Diseases and Vascular Malformations (MAGEC), CHRU Tours
Stéphanie Mallet
Department of Dermatology, University Hospital Center of Marseille
Ludovic Martin
Department of Dermatology, University Hospital Center of Angers
Juliette Mazereeuw-Hautier
Reference center for rare skin diseases, Department of Dermatology, University Hospital Center of Toulouse, Paul Sabatier University
Alice Phan
Department of Dermatology, University Hospital Center of Lyon
Patrice Plantin
Department of Dermatology, Hospital Center of Quimper
Isabelle Quéré
Departement of Vascular Medicine, National Reference Centre for Rare Vascular Diseases, EA 2992 Research Team, University of Montpellier, University Hospital Center of Montpellier
Pierre Vabres
Department of Dermatology, University Hospital Center of Dijon
Hélène Bourgoin
Department of Pharmacy, University Hospital Center of Tours
Bruno Giraudeau
INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours
Annabel Maruani
INSERM U1246 -SPHERE « MethodS in Patients-centered outcomes and HEalth REsearch », University of Nantes, University of Tours
Groupe de Recherche de la Société Française de Dermatologie Pédiatrique
Abstract Background Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions in children and adults. They present as clusters of vesicles full of lymph and blood to various extents, inducing maceration, esthetic impairment, pain, and impaired quality of life. The treatment is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR) involved in angio-lymphangiogenesis. Topical sirolimus has recently been reported as effective in a few reports of patients with CMLMs. The objective is to compare the efficacy and safety of a 12-week application of 0.1% topical sirolimus versus topical vehicle in CMLMs in children and adults. Methods This French blinded multicenter within-person randomized controlled phase 2 trial aims to include 55 patients aged ≥ 6 years who have a primary CMLM. The CMLM will be divided into two equal areas that will be randomly allocated to 0.1% topical sirolimus or topical vehicle applied for 12 weeks. At the end of the 12-week period, the patient/parent will treat the whole area of CMLM with 0.1% topical sirolimus on remaining lesions, for eight more weeks. Patients will be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy. The primary outcome will be improvement of the CMLM in the area treated with topical sirolimus compared to the area treated with topical vehicle by the investigator physician (blinded to the treatment) with the Physician Global Assessment score at week 12. Secondary outcomes will include: assessment of efficacy by independent experts on the basis of standardized photographs; impact on quality of life; efficacy for oozing, bleeding, erythema, and thickness evaluated by the investigators; and global efficacy as well as efficacy for functional and aesthetic impairment evaluated by the patient. Systemic passage of sirolimus will be measured at weeks 6, 12, and 20, and at week 16 for CMLMs ≥ 900 cm2. Discussion For patients with CMLMs, topical sirolimus could be a non-invasive and well-tolerated therapeutic option. If the trial demonstrates efficacy and safety of this treatment, this result will lead to a real change in the management of this condition, and 0.1% sirolimus cream would become the first-line treatment. Trial registration ClinicalTrials.gov, NCT03972592. Registered on 3 June 2019. EU Clinical Trials Register EudraCT, 2018–001359-11.
