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Topical Sirolimus in Cutaneous Lymphatic Malformations (TOPICAL)

Primary Purpose

Vascular Malformations, Lymphatic Malformation

Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Topical 0.1% Sirolimus
Topical Vehicle
Sponsored by
University Hospital, Tours
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Vascular Malformations focused on measuring Cutaneous Microcystic Lymphatic Malformations

Eligibility Criteria

6 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • ANGERS
  • BORDEAUXRecruiting
  • LYON ADRecruiting
  • LYON PEDRecruiting
  • CAENRecruiting
  • DIJONRecruiting
  • MarseilleRecruiting
  • MontpellierRecruiting
  • NANTESRecruiting
  • NICERecruiting
  • Lariboisiere
  • NECKERRecruiting
  • QUIMPER
  • RENNESRecruiting
  • TOULOUSERecruiting
  • TOURSRecruiting
  • NANCY

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Topical sirolimus

Vehicle

Arm 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.

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.

Outcomes

Primary Outcome Measures

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)

Secondary Outcome Measures

Efficacy 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)
Efficacy of 0.1% topical sirolimus vs vehicle regarding each of the following complications of the CMLM: oozing, bleeding, erythema, and thickness
Assessment by the investigator blinded to treatment with a visual analog scale (VAS) from 0 to 10 (0: no improvement, 10: recovery)
Number of independent experts who correctly identify which area among both received the active treatment for each patient on the basis of standardised photographs
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.
Global self-reported efficacy of topical sirolimus vs vehicle (with help of parents in case of children under 16 years)
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)
Functional and esthetic impairments (self-reported with help of parents in case of children under 16 years)
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no improvement and 10 recovery)
Pain linked to the CMLM (with help of parents in case of children under 16 years)
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no pain and 10 worst imaginable pain)
Effect on quality of life
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)
Evaluation of systemic passage of sirolimus by dosage of serum level of sirolimus
Dosage of serum level of sirolimus
Number of patients with biological adverse events and total number of biological adverse events (to assess the biological tolerance of topical sirolimus)
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 (to assess the clinical tolerance of topical sirolimus)
Number of patients with clinical adverse events and total number of clinical adverse events (record of local and general adverse events)

Full Information

First Posted
May 24, 2019
Last Updated
May 9, 2023
Sponsor
University Hospital, Tours
Collaborators
University Hospital, Angers
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1. Study Identification

Unique Protocol Identification Number
NCT03972592
Brief Title
Topical Sirolimus in Cutaneous Lymphatic Malformations
Acronym
TOPICAL
Official Title
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
Study Type
Interventional

2. Study Status

Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 5, 2019 (Actual)
Primary Completion Date
September 2023 (Anticipated)
Study Completion Date
June 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Tours
Collaborators
University Hospital, Angers

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Vascular Malformations, Lymphatic Malformation
Keywords
Cutaneous Microcystic Lymphatic Malformations

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Split-body randomised, double-blind, vehicle-controlled clinical trial
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
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.
Allocation
Randomized
Enrollment
55 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Topical sirolimus
Arm Type
Experimental
Arm 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.
Arm Title
Vehicle
Arm Type
Placebo Comparator
Arm 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.
Intervention Type
Drug
Intervention Name(s)
Topical 0.1% Sirolimus
Other Intervention Name(s)
Verum
Intervention Description
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
Intervention Name(s)
Topical Vehicle
Other Intervention Name(s)
Placebo
Intervention Description
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.
Primary Outcome Measure Information:
Title
Efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
Description
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)
Time Frame
Week 12
Secondary Outcome Measure Information:
Title
Efficacy of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation versus topical vehicle
Description
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)
Time Frame
Day 1, Week 6, Week 20, Month 12
Title
Efficacy of 0.1% topical sirolimus vs vehicle regarding each of the following complications of the CMLM: oozing, bleeding, erythema, and thickness
Description
Assessment by the investigator blinded to treatment with a visual analog scale (VAS) from 0 to 10 (0: no improvement, 10: recovery)
Time Frame
Day 1, Week 12, Week 20, Month 12
Title
Number of independent experts who correctly identify which area among both received the active treatment for each patient on the basis of standardised photographs
Description
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.
Time Frame
Day1, Week 12
Title
Global self-reported efficacy of topical sirolimus vs vehicle (with help of parents in case of children under 16 years)
Description
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)
Time Frame
Week 12, Week 20, Month 12
Title
Functional and esthetic impairments (self-reported with help of parents in case of children under 16 years)
Description
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no improvement and 10 recovery)
Time Frame
Day1, Week 20, Month 12
Title
Pain linked to the CMLM (with help of parents in case of children under 16 years)
Description
Using a VAS (Visual Analog Scale) from 0 to 10 (0 no pain and 10 worst imaginable pain)
Time Frame
Day1, Week 20, Month 12
Title
Effect on quality of life
Description
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)
Time Frame
Day 1, Week 20, Month 12
Title
Evaluation of systemic passage of sirolimus by dosage of serum level of sirolimus
Description
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)
Title
Number of patients with biological adverse events and total number of biological adverse events (to assess the biological tolerance of topical sirolimus)
Description
Number of patients with biological adverse events and total number of biological adverse events (blood samples at baseline, week 12 and week 20)
Time Frame
Baseline, Week 12, Week 20
Title
Number of patients with clinical adverse events and total number of clinical adverse events (to assess the clinical tolerance of topical sirolimus)
Description
Number of patients with clinical adverse events and total number of clinical adverse events (record of local and general adverse events)
Time Frame
Week 6, Week 12, Week 20

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
MARUANI Annabel
Phone
02 47 47 90 76
Ext
+33
Email
annabel.maruani@univ-tours.fr
First Name & Middle Initial & Last Name or Official Title & Degree
LEDUCQ Sophie
Email
sleducq@hotmail.fr
Facility Information:
Facility Name
ANGERS
City
Angers
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MARTIN Ludovic
Facility Name
BORDEAUX
City
Bordeaux
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
LEAUTE-LABREZE Christine
Facility Name
LYON AD
City
Bron
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
GUIBAUD Laurent
Facility Name
LYON PED
City
Bron
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
PHAN Alice
Facility Name
CAEN
City
Caen
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DOMPMARTIN Anne
Facility Name
DIJON
City
Dijon
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
VABRES Pierre
Facility Name
Marseille
City
Marseille
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MALLET Stéphanie
Facility Name
Montpellier
City
Montpellier
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
BESSIS Didier
Facility Name
NANTES
City
Nantes
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
BARBAROT Sébastien
Facility Name
NICE
City
Nice
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
CHIAVERINI Christine
Facility Name
Lariboisiere
City
Paris
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annouk BISDORFF-BRESSON
Facility Name
NECKER
City
Paris
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
BOCCARA Olivia
Facility Name
QUIMPER
City
Quimper
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
PLANTIN Patrice
Facility Name
RENNES
City
Rennes
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
DROITCOURT Catherine
Facility Name
TOULOUSE
City
Toulouse
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MAZEREEUW-HAUTIER Juliette
Facility Name
TOURS
City
Tours
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
MARUANI Annabel
Facility Name
NANCY
City
Vandoeuvre les nancy
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
BURSZTEJN Anne-Claire

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
31847908
Citation
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.
Results Reference
derived

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Topical Sirolimus in Cutaneous Lymphatic Malformations

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