- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04128722
TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN (TOPGUN)
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
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
Enrollment (Estimated)
Phase
- Phase 2
Contacts and Locations
Study Contact
- Name: Annabel MARUANI, MD-PhD
- Phone Number: +33 247479076
- Email: annabel.maruani@univ-tours.fr
Study Contact Backup
- Name: Wiebe de JONG, MSc
- Phone Number: +33 247474680
- Email: w.dejong@chu-tours.fr
Study Locations
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Paris, France, 75015
- Active, not recruiting
- Hospital NECKER -AP-HP - Dermatology
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Indre Et Loire
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Tours, Indre Et Loire, France, 37044
- Recruiting
- Univsersity of TOURS _ Service de Dermatologie
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Contact:
- Annabel MARUANI, MD-PhD
- Phone Number: +33247479076
- Email: annabel.maruani@univ-tours.fr
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Contact:
- Wiebe de JONG, MSc
- Phone Number: +33247474680
- Email: w.dejong@chu-tours.fr
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Principal Investigator:
- Annabel MARUANI, MD-PhD
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Sub-Investigator:
- Sophie LEDUCQ, MD
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Sub-Investigator:
- Aline JOLY, MD-PhD
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Loiret
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Orléans, Loiret, France, 45000
- Withdrawn
- REGIONAL Hospital of ORLEANS -Service de Dermatologie
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
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
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.
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0.5 mL to 1 mL according to the size of the lesion, once daily, on lingual microcystic lymphatic malformation
Other Names:
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No Intervention: Control condition
Usual care, i.e. no intervention
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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
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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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Investigator-assessed PGA
Time Frame: at weeks 0, 4, 8, 12, 16, 20 and 24
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Investigator-assessed PGA (Physical Global Assessment)
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at weeks 0, 4, 8, 12, 16, 20 and 24
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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.
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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
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at weeks 0, 4, 8, 12, 16, 20 and 24.
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Global evolution assessed by the patient
Time Frame: at weeks 4, 8, 12, 16, 20 and 24.
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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.
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at weeks 4, 8, 12, 16, 20 and 24.
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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.
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(DLQI or children's DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and week 24.
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at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
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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.
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by the investigator, at baseline, time of switch to treatment and week 24.
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at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
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Time to obtain optimal results
Time Frame: up to 24 weeks
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i.e. time from switch to treatment to time reaching the minimal PGA score
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up to 24 weeks
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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.
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record of local side effects at each visit after the patient has crossed over to the intervention, up to 24 weeks
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from the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
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General side effects
Time Frame: rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
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Follow-up of general side effects
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rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
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Assessment of sirolimus blood passage
Time Frame: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
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by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
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after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
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Evaluation of biological safety
Time Frame: after 8,16 and up to 24 weeks
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Number of participants with at least one biological abnormality treatment-related adverse events as assessed by CTCAE v4.0
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after 8,16 and up to 24 weeks
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Collaborators and Investigators
Sponsor
Investigators
- Study Director: Annabel MARUANI, MD-PhD, University Hospital of TOURS;INSERM 1246 SPHERE
Publications and helpful links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Estimated)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Lymphatic Diseases
- Lymphatic Vessel Tumors
- Congenital Abnormalities
- Lymphangioma
- Lymphatic Abnormalities
- Physiological Effects of Drugs
- Anti-Infective Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Anti-Bacterial Agents
- Antibiotics, Antineoplastic
- Antifungal Agents
- Sirolimus
Other Study ID Numbers
- DR190041-TOPGUN
- 2019-001530-33 (EudraCT Number)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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