Topical Sirolimus in Cutaneous Lymphatic Malformations

Vascular Malformations Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03972592
• Other study ID #: PHRN17-AM / TOPICAL (DR180115)
• Secondary ID: 2018-001359-11
• Status: Recruiting
• Phase: Phase 2
• Start date: June 5, 2019
• Est. completion date: June 2024

Study information

• Verified date: May 2023
• Source: University Hospital, Tours
• Contact: MARUANI Annabel
• Phone: 02 47 47 90 76
• Email: annabel.maruani[@]univ-tours.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 55
• Est. completion date: June 2024
• Est. primary completion date: September 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 6 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Congenital Abnormalities
• Lymphangioma
• Lymphatic Abnormalities
• Lymphatic Malformation
• Vascular Malformations

Intervention

Drug:
• 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.
• 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.

Locations

Country	Name	City	State
France	ANGERS	Angers
France	BORDEAUX	Bordeaux
France	LYON AD	Bron
France	LYON PED	Bron
France	CAEN	Caen
France	DIJON	Dijon
France	Marseille	Marseille
France	Montpellier	Montpellier
France	NANTES	Nantes
France	NICE	Nice
France	Lariboisiere	Paris
France	NECKER	Paris
France	QUIMPER	Quimper
France	RENNES	Rennes
France	TOULOUSE	Toulouse
France	TOURS	Tours
France	NANCY	Vandoeuvre les nancy

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Tours	University Hospital, Angers

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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