Topical Sirolimus in Cutaneous Lymphatic Malformations

NCT ID: NCT03972592

Last Updated: 2023-05-10

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE2
• Total Enrollment: 55 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-06-05
• Study Completion Date: 2024-06-30

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.

Conditions

Vascular Malformations; Lymphatic Malformation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Topical sirolimus

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.

Group Type: EXPERIMENTAL

Topical 0.1% Sirolimus

Intervention Type: 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.

Vehicle

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.

Group Type: PLACEBO_COMPARATOR

Topical Vehicle

Intervention Type: 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.

Interventions

Topical 0.1% Sirolimus

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.

Intervention Type: DRUG

Topical Vehicle

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.

Intervention Type: DRUG

Other Intervention Names

Verum; Placebo

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

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Angers

OTHER_GOV

Sponsor Role: collaborator

University Hospital, Tours

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

ANGERS

Angers, , France

Site Status: NOT_YET_RECRUITING

BORDEAUX

Bordeaux, , France

Site Status: RECRUITING

LYON AD

Bron, , France

Site Status: RECRUITING

LYON PED

Bron, , France

Site Status: RECRUITING

CAEN

Caen, , France

Site Status: RECRUITING

DIJON

Dijon, , France

Site Status: RECRUITING

Marseille

Marseille, , France

Site Status: RECRUITING

Montpellier

Montpellier, , France

Site Status: RECRUITING

NANTES

Nantes, , France

Site Status: RECRUITING

NICE

Nice, , France

Site Status: RECRUITING

Lariboisiere

Paris, , France

Site Status: NOT_YET_RECRUITING

NECKER

Paris, , France

Site Status: RECRUITING

QUIMPER

Quimper, , France

Site Status: NOT_YET_RECRUITING

RENNES

Rennes, , France

Site Status: RECRUITING

TOULOUSE

Toulouse, , France

Site Status: RECRUITING

TOURS

Tours, , France

Site Status: RECRUITING

NANCY

Vandœuvre-lès-Nancy, , France

Site Status: NOT_YET_RECRUITING

Countries

France

Central Contacts

MARUANI Annabel

Role: CONTACT

annabel.maruani@univ-tours.fr

02 47 47 90 76 ext. +33

LEDUCQ Sophie

Role: CONTACT

sleducq@hotmail.fr

Facility Contacts

MARTIN Ludovic

Role: primary

LEAUTE-LABREZE Christine

Role: primary

GUIBAUD Laurent

Role: primary

PHAN Alice

Role: primary

DOMPMARTIN Anne

Role: primary

VABRES Pierre

Role: primary

MALLET Stéphanie

Role: primary

BESSIS Didier

Role: primary

BARBAROT Sébastien

Role: primary

CHIAVERINI Christine

Role: primary

Annouk BISDORFF-BRESSON

Role: primary

BOCCARA Olivia

Role: primary

PLANTIN Patrice

Role: primary

DROITCOURT Catherine

Role: primary

MAZEREEUW-HAUTIER Juliette

Role: primary

MARUANI Annabel

Role: primary

BURSZTEJN Anne-Claire

Role: primary

References

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.

Reference Type: DERIVED

PMID: 31847908 (View on PubMed)

Other Identifiers

2018-001359-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

PHRN17-AM / TOPICAL (DR180115)

Identifier Type: -

Identifier Source: org_study_id