TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN (TOPGUN)

November 28, 2023 updated by: University Hospital, Tours

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).

Study Overview

Status

Recruiting

Conditions

Intervention / 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

Study Type

Interventional

Enrollment (Estimated)

12

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • France
      • Paris, France, 75015
        • Active, not recruiting
        • Hospital NECKER -AP-HP - Dermatology
    • Indre Et Loire
      • Tours, Indre Et Loire, France, 37044
        • Recruiting
        • Univsersity of TOURS _ Service de Dermatologie
        • Contact:
        • Contact:
        • Principal Investigator:
          • Annabel MARUANI, MD-PhD
        • Sub-Investigator:
          • Sophie LEDUCQ, MD
        • Sub-Investigator:
          • Aline JOLY, MD-PhD
    • Loiret
      • Orléans, Loiret, France, 45000
        • Withdrawn
        • REGIONAL Hospital of ORLEANS -Service de Dermatologie

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

3 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Sirolimus 1mg/mL
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, the experimental intervention versus usual care (no treatment), the control condition.
Drug: Sirolimus Oral Liquid Product 1mg/mL
0.5 mL to 1 mL according to the size of the lesion, once daily, on lingual microcystic lymphatic malformation
Other Names:
  • Experimental treatment
No Intervention: Control condition
Usual care, i.e. no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Physical Global Assessment (PGA) after topical application of Sirolimus for 12 weeks
Time Frame: 12 weeks

The primary outcome will consist in the evaluation of global severity of the LMLM using PGA (Physical Global Assessment) 0 to 5 score, by three independent blinded experts, on monthly standardized photographs.

A 1-point improvement versus baseline in PGA scale would already have a clinical relevance.

Our primary analysis will focus on change in PGA after topical application of Sirolimus for 12 weeks
12 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Investigator-assessed PGA
Time Frame: at weeks 0, 4, 8, 12, 16, 20 and 24
Investigator-assessed PGA (Physical Global Assessment)
at weeks 0, 4, 8, 12, 16, 20 and 24
Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort,
Time Frame: at weeks 0, 4, 8, 12, 16, 20 and 24.
Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort, each using a numeric scale from 0 to 10 (0: clear, 10: very severe), at weeks 0, 4, 8, 12, 16, 20 and 24
at weeks 0, 4, 8, 12, 16, 20 and 24.
Global evolution assessed by the patient
Time Frame: at weeks 4, 8, 12, 16, 20 and 24.
Global evolution assessed by the patient from -10 to 10 (-10 = severe worsening, 0 = no change, 10 = complete recovery), at weeks 4, 8, 12, 16, 20 and 24.
at weeks 4, 8, 12, 16, 20 and 24.
Global Quality of life assessment
Time Frame: at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
(DLQI or children's DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and week 24.
at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
Measurements of the lesion
Time Frame: at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
by the investigator, at baseline, time of switch to treatment and week 24.
at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
Time to obtain optimal results
Time Frame: up to 24 weeks
i.e. time from switch to treatment to time reaching the minimal PGA score
up to 24 weeks
Assessment of tolerance of topical sirolimus:
Time Frame: from the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
record of local side effects at each visit after the patient has crossed over to the intervention, up to 24 weeks
from the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
General side effects
Time Frame: rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
Follow-up of general side effects
rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
Assessment of sirolimus blood passage
Time Frame: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
Evaluation of biological safety
Time Frame: after 8,16 and up to 24 weeks
Number of participants with at least one biological abnormality treatment-related adverse events as assessed by CTCAE v4.0
after 8,16 and up to 24 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital, Tours

Investigators

  • Study Director: Annabel MARUANI, MD-PhD, University Hospital of TOURS;INSERM 1246 SPHERE

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 14, 2020

Primary Completion (Estimated)

February 13, 2025

Study Completion (Estimated)

July 31, 2025

Study Registration Dates

First Submitted

September 24, 2019

First Submitted That Met QC Criteria

October 15, 2019

First Posted (Actual)

October 16, 2019

Study Record Updates

Last Update Posted (Actual)

November 29, 2023

Last Update Submitted That Met QC Criteria

November 28, 2023

Last Verified

November 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DR190041-TOPGUN
  • 2019-001530-33 (EudraCT Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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