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

• Register: EUCTR
• Last refreshed on: 30 April 2019
• Main ID: EUCTR2018-001359-11-FR
• Date of registration: 23/07/2018
• Prospective Registration: Yes
• Primary sponsor: CHRU TOURS
• Public 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
• Scientific 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 - TOPICAL
• Date of first enrolment: 22/02/2019
• Target sample size: 55
• Recruitment status: Authorised-recruitment may be ongoing or finished
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2018-001359-11
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: no; Single blind: no; Double blind: yes; Parallel group: no; Cross over: no; Other: yes; Other trial design description: Intra-individual comparison test; If controlled, specify comparator, Other Medicinial Product: no; Placebo: yes; Other: no; Number of treatment arms in the trial: 1
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France

Contacts

• Name: ARC DRCI - Estelle BOIVIN
• Affiliation: CHRU TOURS

• Name: ARC DRCI - Estelle BOIVIN
• Affiliation: CHRU TOURS

Key inclusion & exclusion 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)
Are the trial subjects under 18? yes
Number of subjects for this age range: 30
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 25
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
- Patients with lymphatic malformation requiring a continued backround 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 (HBV, HCV, HIV, etc)
- Local fungal, viral (HSV, VZV, 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


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Cutaneous microcystic lymphatic malformations (CMLM) in children and adults
MedDRA version: 20.0 Level: LLT Classification code 10003229 Term: Arteriovenous malformations System Organ Class: 100000004850

Intervention(s)

Product Name: Sirolimus 0,1% crème
Pharmaceutical Form: Cream
INN or Proposed INN: SIROLIMUS
CAS Number: 53123-88-9
Concentration unit: % (W/W) percent weight/weight
Concentration type: equal
Concentration number: 0.1-
Pharmaceutical form of the placebo: Cream
Route of administration of the placebo: Cutaneous use

Primary Outcome(s)

Main Objective: To evaluate the efficacy of a 12-week application period of 0.1% topical sirolimus in cutaneous microcystic lymphatic malformation in children and adults, versus topical vehicle.

Secondary Objective: To evaluate the efficacy of a 6-week application period of 0.1% topical sirolimus, versus topical vehicle, and of a 12-week, 20-week application period :
- by comparing times W0 and W12 on photographs
- regarding each of the following complications of the CMLM at W12 and W20
- by assessing the global self-reported efficacy of topical sirolimus vs vehicle at W12 and W20
- by assessing the global efficacy by the physician at W12 and W20
- by assessing functional and esthetic impairments at W20
- by evaluating pain linked to the CMLM at W20
- by evaluating a the effect on quality of life
To measure systemic passage of sirolimus at W12 and W20
To evaluate tolerance of 0.1% topical sirolimus at W12 and W20
To measure the long-term efficacy by the investigator and the patient at M12

Primary end point(s): The primary outcome will consist in the PGA score (Physician Global Assessment) 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).

Timepoint(s) of evaluation of this end point: At week 12

Secondary Outcome(s)

Secondary end point(s): - Efficacy by PGA score
- Efficacy by two independent experts on the basis of standardized photographs (instructions will be given for standardizing photographs) on each area of the CMLM. 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
- Efficacy by the investigator blinded to treatment regarding severity of oozing, bleeding, erythema, and thickness on both areas (treated with topical sirolimus and topical vehicle), with a visual analog scale (VAS) from 0 to 10
- Self-assessment by the subject (and parents in case of children under 16) of the global improvement of CMLM in both areas using a VAS from 0 to 10
- Self-assessment of functional and esthetic impairments (by the patient and parents if patient < 16, using a 0 to 10 VAS)
- Self-assessment of pain by the patient on a 0 to 10 VAS linked to the CMLM (a VAS adapted to children will be used for subjects under 16 years)
- Self-assessment of quality of life using the validated DLQI scale (Dermatology Life Quality Index), or Child-DLQI for children
- Evaluation of systemic passage of sirolimus
- Tolerance of topical sirolimus: record of local side effects in both areas treated with topical sirolimus and vehicle ; record of general side effects
- Biological safety (we will perform biological measurements that are required for assessing safety of oral sirolimus: blood cell count, liver and renal functions, ionogram, lipids [cholesterol and triglycerides] and glycemia)

Timepoint(s) of evaluation of this end point: - PGA at baseline, W6, W20 and M12
- Photographs at baseline and W12
- VAS for severity of oozing, bleeding, erythema, and thickness on both areas at baseline, W12, W20 and M12
- Self-assessment by the subject at W12, W20 and M12
- VAS for functional and esthetic impairments at baseline, W20 and M12
- VAS for pain at baseline, W20 and M12
- DLQI or Child-DLQI scale at baseline, W20 and M12
- Dosage of serum level of sirolimus at W6, W12 and W20
- Biological safety at baseline, W12 and W20
W12 is the end of the double-blinded period
W20 is the end of the open application of 0.1% topical sirolimus on the whole CMLM

Secondary ID(s)

PHRN17-AM-TOPICAL/DR180115

Source(s) of Monetary Support

DGOS

Ethics review

Status: Approved
Approval date:
Contact: