Topical Sirolimus in Cutaneous Lymphatic Malformations (TOPICAL)

Regional University Hospital Center (CHRU)

Status and phase: Enrolling; Phase 2

Conditions: Vascular Malformations; Lymphatic Malformation

Treatments: Drug: Topical 0.1% Sirolimus; Drug: Topical Vehicle

Study type: Interventional

Funder types: Other

Identifiers

NCT03972592

2018-001359-11 (EudraCT Number)

PHRN17-AM / TOPICAL (DR180115)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 55 estimated patients

Sex: All

Ages: 6+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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55 participants in 2 patient groups, including a placebo group

Topical sirolimus

Experimental group

Description:

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.

Treatment:

Drug: Topical 0.1% Sirolimus

Vehicle

Placebo Comparator group

Description:

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.

Treatment:

Drug: Topical Vehicle