Clinical trial NCT04128722: TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
Official title: TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Lingual Microcystic Lymphatic Malformations
Keywords: LMLM
Sirolimus
Lead sponsor: University Hospital, Tours
Sponsor class: OTHER
First posted: 2019-10-16
Enrollment: 12
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Individually randomized stepped wedge
Primary purpose: TREATMENT

Brief summary: Lingual microcystic lymphatic malformations (LMLMs) are rare congenital vascular malformations, presenting as clusters of cysts filled with lymph fluid or blood. They are responsible for a heavy burden even with small well-limited lesions because of oozing, bleeding, infections, or even speech, chewing or breathing impairment. Pain and aesthetic prejudice are also frequently reported. The natural history of LMLMs is progressive worsening. LMLMs complex management requires multidisciplinary care in specialised centres, and the "wait-and-see" approach is frequently used. In complicated lymphatic malformations, whatever the location, treatment with oral sirolimus, an mTOR (mammalian Target of Rapamycin) inhibitor, is often used.

Topical sirolimus is a known effective treatment for some cutaneous conditions such as angiofibromas in tuberous sclerosis. Topical applications of sirolimus on the buccal mucosae have been reported in erosive lichen planus and oral pemphigus vulgaris with good tolerance and none to slight detectable blood sirolimus concentrations.

The objective of this study is to evaluate the efficacy and safety of a 1mg/mL sirolimus solution applied once daily on mild to moderate lingual microcystic lymphatic malformation in children and adults after 4, 8, 12, 16, 20 and 24 weeks of treatment as compared to usual care (no treatment).

Detailed description: This is a randomized, open-labelled, multicenter pilot study using an individually randomized stepped wedge design over a 24 weeks period to evaluate topical application of 1 mg/mL sirolimus solution, 0.5 mL to 1 mL according to the size of the lesion, once daily, on lingual microcystic lymphatic malformation that do not require systemic treatment, the experimental intervention versus usual care (no treatment), the control condition.

In this design, subjects are included in a cohort where at a randomized time (W0, W4, W8 or W12), they switch from an observational period to the interventional period.

All subjects will be followed for 24 weeks

Eligibility criteria: Inclusion Criteria:

* Participants ≥ 5 years of age
* Lingual microcystic lymphatic malformation that does not require systemic treatment, assessed by clinical examination and head-and-neck MRI imaging prior to study enrolment, with or without underlying syndromic malformation (CLAPO for instance)
* Participants covered by or having the rights to social security
* Written informed consent obtained from participant and participant's legal representative if participant is under 18
* Ability for participant to comply with the requirements of the study

Exclusion Criteria:

* Patients with a lymphatic malformation requiring a continued background therapy (involving deep organs)
* Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
* Previous treatment with systemic or topical mTOR (mammilian target of rapamycin) inhibitors within 12 months before inclusion (half-life of oral sirolimus is 60 days in adults).
* Previous treatment with oral or topical steroids within 10 days before inclusion (half-life of corticosteroids is 12-36 hours)
* Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
* Ongoing neoplasia
* Active chronic infectious disease (Hepatitis-B virus, Hepatitis-C virus, HIV, etc)
* Local necrosis
* Local fungal, viral (herpes simplex virus, varicella zoster virus, etc) or bacterial infection on the site of the LMLM (based on clinical examination)
* Known allergy to one of the components of the sirolimus solution
* Soy bean or Peanut allergy
* Pregnant or breastfeeding women
* Women of child-bearing potential (including teenagers) not using a reliable contraceptive method until the end of the study and three month after the end of the study or sirolimus discontinuation.
* Already involved in another therapeutic trial

Primary outcomes:
measure: Change in Physical Global Assessment (PGA) after topical application of Sirolimus for 12 weeks
timeFrame: 12 weeks
Secondary outcomes:
measure: Investigator-assessed PGA
timeFrame: at weeks 0, 4, 8, 12, 16, 20 and 24
measure: Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort,
timeFrame: at weeks 0, 4, 8, 12, 16, 20 and 24.
measure: Global evolution assessed by the patient
timeFrame: at weeks 4, 8, 12, 16, 20 and 24.
measure: Global Quality of life assessment
timeFrame: at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
measure: Measurements of the lesion
timeFrame: at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
measure: Time to obtain optimal results
timeFrame: up to 24 weeks
measure: Assessment of tolerance of topical sirolimus:
timeFrame: from the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
measure: General side effects
timeFrame: rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
measure: Assessment of sirolimus blood passage
timeFrame: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
measure: Evaluation of biological safety
timeFrame: after 8,16 and up to 24 weeks
Other outcomes:
Locations:
city: Tours
country: France
facility: Univsersity of TOURS _ Service de Dermatologie
state: Indre Et Loire
city: Orléans
country: France
facility: REGIONAL Hospital of ORLEANS -Service de Dermatologie
state: Loiret
city: Paris
country: France
facility: Hospital NECKER -AP-HP - Dermatology
Study officials:
affiliation: University Hospital of TOURS;INSERM 1246 SPHERE
name: Annabel MARUANI, MD-PhD
role: STUDY_DIRECTOR
References:
citation: Marchand A, Caille A, Gissot V, Giraudeau B, Lengelle C, Bourgoin H, Largeau B, Leducq S, Maruani A. Topical sirolimus solution for lingual microcystic lymphatic malformations in children and adults (TOPGUN): study protocol for a multicenter, randomized, assessor-blinded, controlled, stepped-wedge clinical trial. Trials. 2022 Jul 8;23(1):557. doi: 10.1186/s13063-022-06365-y.