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, 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

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.

Keywords: Cutaneous microcystic lymphatic malformation; Lymphangiectasia; Mammalian target of rapamycin inhibitor; Rapamycin; Sirolimus; Topical rapamycin; Vascular malformation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Example of a CMLM of the leg: the investigator will define two areas of similar size and severity by using a ruler, with a separation area of at least 2 cm between both areas (5 points will be drawn on the patient to define the two areas to apply the product in a reproducible way by the nurse and to avoid inter-area contamination). CMLM cutaneous microcystic lymphatic malformation
Fig. 2
Fig. 2
Flow chart of the study procedure. CMLM cutaneous microcystic lymphatic malformation

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