Topical Sirolimus in Cutaneous Lymphatic Malformations (TOPICAL)

May 9, 2023 updated by: University Hospital, Tours

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

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.

Study Overview

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.

Study Type

Interventional

Enrollment (Anticipated)

55

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

      • Angers, France
        • Not yet recruiting
        • ANGERS
        • Contact:
          • MARTIN Ludovic
      • Bordeaux, France
        • Recruiting
        • Bordeaux
        • Contact:
          • LEAUTE-LABREZE Christine
      • Bron, France
        • Recruiting
        • LYON AD
        • Contact:
          • GUIBAUD Laurent
      • Bron, France
        • Recruiting
        • LYON PED
        • Contact:
          • PHAN Alice
      • Caen, France
        • Recruiting
        • Caen
        • Contact:
          • DOMPMARTIN Anne
      • Dijon, France
        • Recruiting
        • Dijon
        • Contact:
          • VABRES Pierre
      • Marseille, France
        • Recruiting
        • Marseille
        • Contact:
          • MALLET Stéphanie
      • Montpellier, France
        • Recruiting
        • Montpellier
        • Contact:
          • BESSIS Didier
      • Nantes, France
        • Recruiting
        • Nantes
        • Contact:
          • BARBAROT Sébastien
      • Nice, France
        • Recruiting
        • Nice
        • Contact:
          • CHIAVERINI Christine
      • Paris, France
        • Not yet recruiting
        • Lariboisiere
        • Contact:
          • Annouk BISDORFF-BRESSON
      • Paris, France
        • Recruiting
        • NECKER
        • Contact:
          • BOCCARA Olivia
      • Quimper, France
        • Not yet recruiting
        • QUIMPER
        • Contact:
          • PLANTIN Patrice
      • Rennes, France
        • Recruiting
        • Rennes
        • Contact:
          • DROITCOURT Catherine
      • Toulouse, France
        • Recruiting
        • Toulouse
        • Contact:
          • MAZEREEUW-HAUTIER Juliette
      • Tours, France
        • Recruiting
        • Tours
        • Contact:
          • MARUANI Annabel
      • Vandoeuvre les nancy, France
        • Not yet recruiting
        • Nancy
        • Contact:
          • BURSZTEJN Anne-Claire

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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.
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.
Other Names:
  • Verum
Placebo Comparator: 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.
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.
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
Time Frame: Week 12
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 Outcome Measures

Outcome Measure
Measure Description
Time Frame
Efficacy of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
Time Frame: Day 1, Week 6, Week 20, Month 12
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)
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
Time Frame: Day 1, Week 12, Week 20, Month 12
Assessment by the investigator blinded to treatment with a visual analog scale (VAS) from 0 to 10 (0: no improvement, 10: recovery)
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
Time Frame: Day1, Week 12
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.
Day1, Week 12
Global self-reported efficacy of topical sirolimus vs vehicle (with help of parents in case of children under 16 years)
Time Frame: Week 12, Week 20, Month 12
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)
Week 12, Week 20, Month 12
Functional and esthetic impairments (self-reported with help of parents in case of children under 16 years)
Time Frame: Day1, Week 20, Month 12
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no improvement and 10 recovery)
Day1, Week 20, Month 12
Pain linked to the CMLM (with help of parents in case of children under 16 years)
Time Frame: Day1, Week 20, Month 12
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no pain and 10 worst imaginable pain)
Day1, Week 20, Month 12
Effect on quality of life
Time Frame: Day 1, Week 20, Month 12
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)
Day 1, Week 20, Month 12
Evaluation of systemic passage of sirolimus by dosage of serum level of sirolimus
Time Frame: Week 6, Week 12, Week 20, +/- Week 16 (if CMLM ≥ 30*30 cm and/or ≥900 cm2)
Dosage of serum level of sirolimus
Week 6, Week 12, Week 20, +/- Week 16 (if CMLM ≥ 30*30 cm and/or ≥900 cm2)
Number of patients with biological adverse events and total number of biological adverse events (to assess the biological tolerance of topical sirolimus)
Time Frame: Baseline, Week 12, Week 20
Number of patients with biological adverse events and total number of biological adverse events (blood samples at baseline, week 12 and week 20)
Baseline, Week 12, Week 20
Number of patients with clinical adverse events and total number of clinical adverse events (to assess the clinical tolerance of topical sirolimus)
Time Frame: Week 6, Week 12, Week 20
Number of patients with clinical adverse events and total number of clinical adverse events (record of local and general adverse events)
Week 6, Week 12, Week 20

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 5, 2019

Primary Completion (Anticipated)

September 1, 2023

Study Completion (Anticipated)

June 1, 2024

Study Registration Dates

First Submitted

May 24, 2019

First Submitted That Met QC Criteria

May 31, 2019

First Posted (Actual)

June 3, 2019

Study Record Updates

Last Update Posted (Actual)

May 10, 2023

Last Update Submitted That Met QC Criteria

May 9, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Vascular Malformations

Clinical Trials on Topical 0.1% Sirolimus

3
Subscribe