Diseases and Abnormalities at or Before Birth

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Lymphatic Diseases

Lymphatic Malformations

Microcystic Lymphatic Malformation

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Sirolimus

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Tannic Acid

The experimental group will consist in one area of the CMLM (almost half of it) that will receive 0.1% sirolimus preparation. This product will be applied 1/day on the randomly allocated area, by a nurse at home, during 12 weeks.

The control group will consist in the other half area of the CMLM, that will receive the same vehicle than the one used in the topical 0.1% sirolimus preparation. It will be applied 1/day in the corresponding area by a nurse, at home, during 12 weeks.

The formulation is 0.03 g rapamycin, 1.5 g Transcutol, Quantum Satis (QS) 30g Excipial® hydrocream, corresponding to a concentration at 0.1%. The cream will be packaged in 30 ml aluminium tubes.

Topical 0.1% Sirolimus

The same vehicle than the one used in the topical 0.1% sirolimus preparation will be used for the other half area of CMLM, i.e. Excipial® hydrocream. It will be packaged to maintain the double blind way of this trial and will be undistinguishable from the sirolimus cream.

Topical Vehicle

MARUANI Annabel

LEDUCQ Sophie

MARTIN Ludovic

LEAUTE-LABREZE Christine

GUIBAUD Laurent

PHAN Alice

DOMPMARTIN Anne

VABRES Pierre

MALLET Stéphanie

BESSIS Didier

BARBAROT Sébastien

CHIAVERINI Christine

Annouk BISDORFF-BRESSON

BOCCARA Olivia

PLANTIN Patrice

DROITCOURT Catherine

MAZEREEUW-HAUTIER Juliette

BURSZTEJN Anne-Claire

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.

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.

Split-body randomised, double-blind, vehicle-controlled clinical trial

Patients, parents, nurses and investigators will be blinded for the treatment allocated to each area of the CMLM, during the first step of the study (until week 12, where primary endpoint will be assessed). To ensure the double blinding, both areas will be randomized, and the topical treatments (sirolimus and vehicle) to be applied will have similar packaging. Their appearance is similar, thus the active drug (topical sirolimus) and vehicle cannot be distinguished at drug allocation. Furthermore, the consistency of the creams is similar.

Topical Sirolimus in Cutaneous Lymphatic Malformations

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

PGA (Physician Global Assessment) score assessed by the investigator physician (blinded from the treatment). PGA score ranges from 0 (clear) to 5 (severe lesions), and is commonly used in several dermatologic conditions. For each patient, PGA of the area treated with the intervention (0.1% topical sirolimus) will be compared to PGA of the area treated with topical vehicle (inactive comparator)

Assessment by the investigator blinded to treatment with a visual analog scale (VAS) from 0 to 10 (0: no improvement, 10: recovery)

Standardized photographs will be performed at baseline and week 12: the experts will have to identify, at the end of the study, which area among both received the active treatment. In case of disagreement, a consensus will be reached between both experts; if consensus is not reached, a third expert will be sought for final decision. Interpretation by dermatologic experts (i.e correct identification of intervention/vehicle treated area) will be considered as correct or false, and the proportion of correct interpretation will be estimated. The proportion of correct interpretation will be compared to the theoretical 50% value, corresponding to a random assessment. Five photographs will be taken: 1) one of the patient including the malformation 2) one of the malformation (distance of 50 cm), 3) one of the malformation (distance of 15 cm), 4) profile photography and finally 5) three quarter view.

Self-assessment of the global improvement of CMLM in both areas using a VAS (Visual Analog Scale) from 0 to 10 (0 no improvement and 10 recovery)

Using a VAS (Visual Analog Scale) from 0 to 10 (0 no improvement and 10 recovery)

Using a VAS (Visual Analog Scale) from 0 to 10 (0 no pain and 10 worst imaginable pain)

Self-assessment of quality of life using the validated DLQI (Dermatology Life Quality Index) scale, or Child-DLQI for children (equal ou under 16 years old) from 0 to 30 (0 no impact on quality of life and 30 maximum impact on quality of life)

Number of patients with biological adverse events and total number of biological adverse events (blood samples at baseline, week 12 and week 20)

Number of patients with clinical adverse events and total number of clinical adverse events (record of local and general adverse events)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Topical Sirolimus in Cutaneous Lymphatic Malformations	NCT03972592	Vascular Malfor... Lymphatic Malfo...	Topical 0.1% Si... Topical Vehicle	6 Years -	University Hospital, Tours
Topical Sirolimus in Cutaneous Lymphatic Malformations	NCT03972592	Vascular Malfor... Lymphatic Malfo...	Topical 0.1% Si... Topical Vehicle	6 Years -	University Hospital, Tours

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