Topical Sirolimus in Cutaneous Lymphatic Malformations

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Vascular Malformations, Lymphatic Malformation

Intervention / Treatment
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* Drug: Topical 0.1% Sirolimus
* Drug: Topical Vehicle


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Split-body randomised, double-blind, vehicle-controlled clinical trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Topical sirolimus<br>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<br>* 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.<br>* Other names: Verum;|
| Placebo Comparator: Vehicle<br>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<br>* 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.<br>* Other names: Placebo;|

What is the study measuring?
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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 | 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 | 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 | 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 | 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) | 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) | 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) | 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 | 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 | 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) | 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) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cutaneous Microcystic Lymphatic Malformations