Clinical trial NCT03972592: Topical Sirolimus in Cutaneous Lymphatic Malformations
Official title: 0.1% Topical Sirolimus in the Treatment of Cutaneous Microcystic Lymphatic Malformations in Children and Adults: Phase II, Split-body Randomized, Double-blind, Vehicle-controlled Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Vascular Malformations
Lymphatic Malformation
Keywords: Cutaneous Microcystic Lymphatic Malformations
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
Collaborators: name: University Hospital, Angers
First posted: 2019-06-03
Enrollment: 55
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Split-body randomised, double-blind, vehicle-controlled clinical trial
Primary purpose: TREATMENT

Brief summary: Cutaneous microcystic lymphatic malformations (CMLMs) are rare conditions of children and adults resulting from abnormal embryologic development of lymphatic vessels. They present as clusters of vesicles full of lymph and blood of various extent. They ooze and bleed, inducing maceration, esthetic impairment, scars, pain, bacterial infections and impaired quality of life. Currently, treatments for CMLMs are disappointing, and their management is challenging. Sirolimus is an inhibitor of mammalian target of rapamycin (mTOR), a serine/threonine protein kinase involved in cell growth and proliferation, cellular metabolism, autophagy and angio-lymphangiogenesis. Topical sirolimus, known to be efficient and well tolerated in cutaneous angiofibromas linked to tuberous sclerosis, has recently been reported effective in few reports of patients with CMLMs. The objective of this trial 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.

Detailed description: This blinded multicentre split body randomized controlled phase 2 trial aims to include 50 patients ≥ 6 years old who have a primary CMLM without an underlying malformation.

The CMLM will be divided into 2 equal areas of the same severity that will be randomly allocated to 0.1% topical sirolimus or topical vehicle for 12 weeks. During the double-blind 12-week period, both topical products will be applied by a nurse to avoid inter-group contamination and for better compliance.

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 8 more weeks. Patients will also be seen at week 20 (treatment will be stopped) and at month 12 to evaluate long-term efficacy.

Eligibility criteria: Inclusion Criteria:

* Patients ≥ 6 years
* Updated immunization schedule
* Diagnosis of primary cutaneous microcystic lymphatic malformation (CMLM) confirmed by histopathological or dermoscopic examination, with or without an underlying malformation or a syndromic malformation (Protée syndrome for instance), responsible for impairment (oozing, bleeding and/or pain)
* CMLM ≥ 20 cm2, that can be divided into 2 parts of similar severity
* Informed, written consent of the subject and his/her parents if \< 18 years
* Rights to French social security (including CMU)

Exclusion Criteria:

* Patients with lymphatic malformation requiring a continued background therapy (involving deep organs)
* Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
* Previous treatment with oral or topical mTOR inhibitors within 12 months before inclusion
* Previous treatment with oral or topical steroids within 10 days before inclusion
* Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
* Ongoing neoplasia
* Active chronic infectious disease (Hepatitis B Virus, Hepatitis C Virus, Human Immunodeficiency Virus, etc)
* Local fungal, viral (Herpes Simplex Virus, Varicella Zoster Virus, etc) or bacterial infection on the site of the CMLM (based on clinical examination)
* Skin necrosis
* Known allergy to one of the components of the topical sirolimus preparation or vehicle
* Women of child-bearing potential (including teenagers) not using a reliable contraceptive method until the end of the study
* Pregnant or breastfeeding women
* Subject already involved in another therapeutic trial

Primary outcomes:
measure: Efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
timeFrame: Week 12
Secondary outcomes:
measure: Efficacy of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
timeFrame: Day 1, Week 6, Week 20, Month 12
measure: Efficacy of 0.1% topical sirolimus vs vehicle regarding each of the following complications of the CMLM: oozing, bleeding, erythema, and thickness
timeFrame: Day 1, Week 12, Week 20, Month 12
measure: Number of independent experts who correctly identify which area among both received the active treatment for each patient on the basis of standardised photographs
timeFrame: Day1, Week 12
measure: Global self-reported efficacy of topical sirolimus vs vehicle (with help of parents in case of children under 16 years)
timeFrame: Week 12, Week 20, Month 12
measure: Functional and esthetic impairments (self-reported with help of parents in case of children under 16 years)
timeFrame: Day1, Week 20, Month 12
measure: Pain linked to the CMLM (with help of parents in case of children under 16 years)
timeFrame: Day1, Week 20, Month 12
measure: Effect on quality of life
timeFrame: Day 1, Week 20, Month 12
measure: Evaluation of systemic passage of sirolimus by dosage of serum level of sirolimus
timeFrame: Week 6, Week 12, Week 20, +/- Week 16 (if CMLM ≥ 30*30 cm and/or ≥900 cm2)
measure: Number of patients with biological adverse events and total number of biological adverse events (to assess the biological tolerance of topical sirolimus)
timeFrame: Baseline, Week 12, Week 20
measure: Number of patients with clinical adverse events and total number of clinical adverse events (to assess the clinical tolerance of topical sirolimus)
timeFrame: Week 6, Week 12, Week 20
Other outcomes:
Locations:
city: Angers
country: France
facility: ANGERS
city: Bordeaux
country: France
facility: BORDEAUX
city: Bron
country: France
facility: LYON AD
city: Bron
country: France
facility: LYON PED
city: Caen
country: France
facility: CAEN
city: Dijon
country: France
facility: DIJON
city: Marseille
country: France
facility: Marseille
city: Montpellier
country: France
facility: Montpellier
city: Nantes
country: France
facility: NANTES
city: Nice
country: France
facility: NICE
city: Paris
country: France
facility: Lariboisiere
city: Paris
country: France
facility: NECKER
city: Quimper
country: France
facility: QUIMPER
city: Rennes
country: France
facility: RENNES
city: Toulouse
country: France
facility: TOULOUSE
city: Tours
country: France
facility: TOURS
city: Vandoeuvre les nancy
country: France
facility: NANCY
Study officials:
References:
citation: Leducq S, Caille A, Barbarot S, Beneton N, Bessis D, Boccara O, Bursztejn AC, Chiaverini C, Dompmartin A, Droitcourt C, Gissot V, Goga D, Guibaud L, Herbreteau D, Le Touze A, Leaute-Labreze C, Lorette G, Mallet S, Martin L, Mazereeuw-Hautier J, Phan A, Plantin P, Quere I, Vabres P, Bourgoin H, Giraudeau B, Maruani A; Groupe de Recherche de la Societe Francaise de Dermatologie Pediatrique. 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. Trials. 2019 Dec 17;20(1):739. doi: 10.1186/s13063-019-3767-8.