Topical Sirolimus in Cutaneous Lymphatic Malformations

NCT03972592 | Completed Phase 2 DMC

• 2 other identifiers: PHRN17-AM / TOPICAL (DR180115)2018-001359-11
• Study Type: interventional
• Target: 55
• Locations: 1 country
• Sites: 17

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.

Conditions

Vascular Malformations; Lymphatic Malformation

Keywords

Cutaneous Microcystic Lymphatic Malformations

Outcome Measures

Primary Outcomes (1)

• Efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle

  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)

  Week 12

Secondary Outcomes (10)

• Efficacy of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle

  Day 1, Week 6, Week 20, Month 12

• Efficacy of 0.1% topical sirolimus vs vehicle regarding each of the following complications of the CMLM: oozing, bleeding, erythema, and thickness

  Day 1, Week 12, Week 20, Month 12

• Number of independent experts who correctly identify which area among both received the active treatment for each patient on the basis of standardised photographs

  Day1, Week 12

• Global self-reported efficacy of topical sirolimus vs vehicle (with help of parents in case of children under 16 years)

  Week 12, Week 20, Month 12

• Functional and esthetic impairments (self-reported with help of parents in case of children under 16 years)

  Day1, Week 20, Month 12

Study Arms (2)

Topical sirolimus

EXPERIMENTAL

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.

Drug: Topical 0.1% Sirolimus

Vehicle

PLACEBO COMPARATOR

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.

Drug: Topical Vehicle

Interventions

Topical 0.1% Sirolimus DRUG

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.

Also known as: Verum

Topical sirolimus

Topical Vehicle DRUG

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.

Also known as: Placebo

Vehicle

Eligibility Criteria

• Age: 6 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)

You may not qualify if:

• Patients with lymphatic malformation requiring a continued background therapy (involving deep organs)
• Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
• 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

Sponsors & Collaborators

• University Hospital, Tours: lead
• University Hospital, Angers: collaborator

Study Sites (17)

ANGERS

Angers, France

Location

BORDEAUX

Bordeaux, France

Location

LYON AD

Bron, France

Location

LYON PED

Bron, France

Location

CAEN

Caen, France

Location

DIJON

Dijon, France

Location

Marseille

Marseille, France

Location

Montpellier

Montpellier, France

Location

NANTES

Nantes, France

Location

NICE

Nice, France

Location

Lariboisiere

Paris, France

Location

NECKER

Paris, France

Location

QUIMPER

Quimper, France

Location

RENNES

Rennes, France

Location

TOULOUSE

Toulouse, France

Location

TOURS

Tours, France

Location

NANCY

Vandœuvre-lès-Nancy, France

Location

Related Publications (1)

• 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.

  PMID: 31847908 DERIVED

MeSH Terms

Conditions

Vascular Malformations; Lymphatic Abnormalities

Interventions

Sirolimus; calcium D-pantothenate, L-cysteine drug combination

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lymphatic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Split-body randomised, double-blind, vehicle-controlled clinical trial

Study Record Dates

• First Submitted: May 24, 2019
• First Posted: June 3, 2019
• Study Start: June 5, 2019
• Primary Completion: August 14, 2024
• Study Completion: August 14, 2024
• Last Updated: February 13, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

FR (17)