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

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ClinicalTrials.gov Identifier: NCT04128722
Recruitment Status : Not yet recruiting
First Posted : October 16, 2019
Last Update Posted : November 1, 2019
Sponsor:
Information provided by (Responsible Party):
University Hospital, Tours

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).


Condition or disease Intervention/treatment Phase
Lingual Microcystic Lymphatic Malformations Drug: Sirolimus Oral Liquid Product 1mg/mL Phase 2

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


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: Individually randomized stepped wedge
Masking: Single (Outcomes Assessor)
Masking Description: Primary outcome is assessed on anonymised photographs by an adjudication committee blinded from treatment allocation
Primary Purpose: Treatment
Official Title: TOPical Sirolimus in linGUal Microcystic Lymphatic Malformation -TOPGUN
Estimated Study Start Date : November 15, 2019
Estimated Primary Completion Date : November 15, 2020
Estimated Study Completion Date : February 28, 2021


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 Name: Experimental treatment

No Intervention: Control condition
Usual care, i.e. no intervention



Primary Outcome Measures :
  1. 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



Secondary Outcome Measures :
  1. Investigator-assessed PGA [ Time Frame: at weeks 0, 4, 8, 12, 16, 20 and 24 ]
    Investigator-assessed PGA (Physical Global Assessment)

  2. 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

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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

  10. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   5 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04128722


Contacts
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Contact: Annabel MARUANI, MD-PHD +33 247479076 annabel.maruani@univ-tours.fr
Contact: Wiebe de JONG, MSc +33 247474680 w.dejong@chu-tours.fr

Locations
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France
Univsersity of TOURS _ Service de Dermatologie Not yet recruiting
Tours, Indre Et Loire, France, 37044
Contact: Annabel MARUANI, MD-PHD    +33247479076    annabel.maruani@univ-tours.fr   
Contact: Wiebe de JONG, Msc    +33247474680    w.dejong@chu-tours.fr   
Principal Investigator: Annabel MARUANI, MD-PHD         
REGIONAL Hospital of ORLEANS -Service de Dermatologie Not yet recruiting
Orléans, Loiret, France, 45000
Contact: Wiebe de JONG, Msc    +33247474680    w.dejong@chu-tours.fr   
Principal Investigator: Antoine FINON, MD-PHD         
Sponsors and Collaborators
University Hospital, Tours
Investigators
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Study Director: Annabel MARUANI, MD-PHD University Hospital of TOURS;INSERM 1246 SPHERE

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Responsible Party: University Hospital, Tours
ClinicalTrials.gov Identifier: NCT04128722     History of Changes
Other Study ID Numbers: DR190041-TOPGUN
2019-001530-33 ( EudraCT Number )
First Posted: October 16, 2019    Key Record Dates
Last Update Posted: November 1, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by University Hospital, Tours:
LMLM
Sirolimus
Additional relevant MeSH terms:
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Lymphangioma
Lymphatic Abnormalities
Congenital Abnormalities
Lymphatic Vessel Tumors
Neoplasms by Histologic Type
Neoplasms
Lymphatic Diseases
Sirolimus
Everolimus
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs