Table 1.

Schedule of enrolment, interventions, and assessments

	Study period
	Screening	Inclusion	Follow-up
	V0	D1 (V1)	W6 (V2)	W12 (V3)	W20 (V4)	M12 (V5)
Timepoint	14–28 days before treatment initiation	–	±3 days	±3 days	±3 days	±5 days
Drug administration		Once daily
Enrollment
Eligibility screening	X
Informed consent	X
Control of inclusion/exclusion criteria	X
Randomization		X
Physical examination		X	X	X	X	X
Height and weight measurement		X
Vital signs (cardiac frequency, arterial pressure)		X	X	X	X	X
Photographs		X		X
Location and measure of the CMLM	X
Definition of the two areas		X
Urinary pregnancy test for womena	X	X	Once a month until S20		X
Blood sample for toleranceb		X		X	X
Serum level of sirolimusc			X	X	X
Cutaneous effects			X	X	X
Adverse events			X	X	X
Delivery of nursing notebook		X	X	X
Interventionsd
Delivery of topical sirolimus		X	X	X
Delivery control		X	X
Treatment returns			X	X	X
Assessments
PGA score		X	X	X	X	X
Dermatological quality of life scale – DLQI		X			X	X
VAS for self-assessment of pain		X			X	X
VAS for assessment of efficacy by the investigator on oozing, bleeding, erythema, thickness		X		X	X	X
VAS for self-assessment of global efficacy				X	X	X
VAS for self-assessment of functional and esthetic impairments		X			X	X

CMLM cutaneous microcystic lymphatic malformation, PGA Physician Global Assessment, VAS visual analog scale

^a If detectable sirolimus level: monthly pregnancy test for three additional months

^b Blood count, ionogram, liver function (ASAT, ALAT, gamma-GT), renal function (creatinine), lipids (cholesterol, triglycerides), glycemia. Local analysis

^c With CMLM ≥ 30 × 30 cm and/or ≥ 900 cm², a blood sample for evaluation of systemic passage of sirolimus (residual serum level of sirolimus) will be performed at W16

^d Application of both topical preparations (intervention or inactive comparator) by a nurse