Back to resultsTOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN (TOPGUN)
Primary Purpose
Lingual Microcystic Lymphatic Malformations
Status
Recruiting
Phase
Phase 2
Locations
France
Study Type
Interventional
Intervention
Sirolimus Oral Liquid Product 1mg/mL
Sponsored by
About this trial
This is an interventional treatment trial for Lingual Microcystic Lymphatic Malformations focused on measuring LMLM, Sirolimus
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
Sites / Locations
- Univsersity of TOURS _ Service de DermatologieRecruiting
- REGIONAL Hospital of ORLEANS -Service de Dermatologie
- Hospital NECKER -AP-HP - Dermatology
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
No Intervention
Arm Label
Sirolimus 1mg/mL
Control condition
Arm Description
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.
Usual care, i.e. no intervention
Outcomes
Primary Outcome Measures
Change in Physical Global Assessment (PGA) after topical application of Sirolimus for 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
Secondary Outcome Measures
Investigator-assessed PGA
Investigator-assessed PGA (Physical Global Assessment)
Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort,
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
Global evolution assessed by the patient
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.
Global Quality of life assessment
(DLQI or children's DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and week 24.
Measurements of the lesion
by the investigator, at baseline, time of switch to treatment and week 24.
Time to obtain optimal results
i.e. time from switch to treatment to time reaching the minimal PGA score
Assessment of tolerance of topical sirolimus:
record of local side effects at each visit after the patient has crossed over to the intervention, up to 24 weeks
General side effects
Follow-up of general side effects
Assessment of sirolimus blood passage
by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
Evaluation of biological safety
Number of participants with at least one biological abnormality treatment-related adverse events as assessed by CTCAE v4.0
Full Information
NCT ID
NCT04128722
First Posted
September 24, 2019
Last Updated
May 12, 2023
Sponsor
University Hospital, Tours
1. Study Identification
Unique Protocol Identification Number
NCT04128722
Brief Title
TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
Acronym
TOPGUN
Official Title
TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
Study Type
Interventional
2. Study Status
Record Verification Date
May 2023
Overall Recruitment Status
Recruiting
Study Start Date
February 14, 2020 (Actual)
Primary Completion Date
August 13, 2023 (Anticipated)
Study Completion Date
January 28, 2024 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Tours
4. Oversight
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
Data Monitoring Committee
Yes
5. Study Description
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
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lingual Microcystic Lymphatic Malformations
Keywords
LMLM, Sirolimus
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Model Description
Individually randomized stepped wedge
Masking
Outcomes Assessor
Masking Description
Primary outcome is assessed on anonymised photographs by an adjudication committee blinded from treatment allocation
Allocation
Randomized
Enrollment
12 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Sirolimus 1mg/mL
Arm Type
Experimental
Arm Description
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.
Arm Title
Control condition
Arm Type
No Intervention
Arm Description
Usual care, i.e. no intervention
Intervention Type
Drug
Intervention Name(s)
Sirolimus Oral Liquid Product 1mg/mL
Other Intervention Name(s)
Experimental treatment
Intervention Description
0.5 mL to 1 mL according to the size of the lesion, once daily, on lingual microcystic lymphatic malformation
Primary Outcome Measure Information:
Title
Change in Physical Global Assessment (PGA) after topical application of Sirolimus for 12 weeks
Description
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
Time Frame
12 weeks
Secondary Outcome Measure Information:
Title
Investigator-assessed PGA
Description
Investigator-assessed PGA (Physical Global Assessment)
Time Frame
at weeks 0, 4, 8, 12, 16, 20 and 24
Title
Assessment by the patient regarding severity of oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort,
Description
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
Time Frame
at weeks 0, 4, 8, 12, 16, 20 and 24.
Title
Global evolution assessed by the patient
Description
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.
Time Frame
at weeks 4, 8, 12, 16, 20 and 24.
Title
Global Quality of life assessment
Description
(DLQI or children's DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and week 24.
Time Frame
at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
Title
Measurements of the lesion
Description
by the investigator, at baseline, time of switch to treatment and week 24.
Time Frame
at baseline, at time of switch to the intervention (either week 0, week 4, week 8 or week 12) and week 24.
Title
Time to obtain optimal results
Description
i.e. time from switch to treatment to time reaching the minimal PGA score
Time Frame
up to 24 weeks
Title
Assessment of tolerance of topical sirolimus:
Description
record of local side effects at each visit after the patient has crossed over to the intervention, up to 24 weeks
Time Frame
from the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
Title
General side effects
Description
Follow-up of general side effects
Time Frame
rom the switch to intervention up to the end of the study, i.e a maximum of 24 weeks.
Title
Assessment of sirolimus blood passage
Description
by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
Time Frame
after 4 weeks of treatment, then 8 weeks, then every 8 weeks until week 24
Title
Evaluation of biological safety
Description
Number of participants with at least one biological abnormality treatment-related adverse events as assessed by CTCAE v4.0
Time Frame
after 8,16 and up to 24 weeks
10. Eligibility
Sex
All
Minimum Age & Unit of Time
5 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Annabel MARUANI, MD-PhD
Phone
+33 247479076
Email
annabel.maruani@univ-tours.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Wiebe de JONG, MSc
Phone
+33 247474680
Email
w.dejong@chu-tours.fr
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Annabel MARUANI, MD-PhD
Organizational Affiliation
University Hospital of TOURS;INSERM 1246 SPHERE
Official's Role
Study Director
Facility Information:
Facility Name
Univsersity of TOURS _ Service de Dermatologie
City
Tours
State/Province
Indre Et Loire
ZIP/Postal Code
37044
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Annabel MARUANI, MD-PhD
Phone
+33247479076
Email
annabel.maruani@univ-tours.fr
First Name & Middle Initial & Last Name & Degree
Wiebe de JONG, MSc
Phone
+33247474680
Email
w.dejong@chu-tours.fr
First Name & Middle Initial & Last Name & Degree
Annabel MARUANI, MD-PhD
First Name & Middle Initial & Last Name & Degree
Sophie LEDUCQ, MD
First Name & Middle Initial & Last Name & Degree
Aline JOLY, MD-PhD
Facility Name
REGIONAL Hospital of ORLEANS -Service de Dermatologie
City
Orléans
State/Province
Loiret
ZIP/Postal Code
45000
Country
France
Individual Site Status
Active, not recruiting
Facility Name
Hospital NECKER -AP-HP - Dermatology
City
Paris
ZIP/Postal Code
75015
Country
France
Individual Site Status
Active, not recruiting
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
35804404
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.
Results Reference
derived
Learn more about this trial
TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
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