TOPical sirolimus in linGUal microkystic lymphatic malformation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Regional Universitaire De Tours

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

4 Feb 2020 → 8 Jan 2025

Decision date (initial)

2024-08-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2024-515955-39-01

EudraCT number

2019-001530-33

ClinicalTrials.gov

NCT04128722

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

To evaluate the efficacy and safety of a 1mg/mL sirolimus solution applied once daily on the anterior part of lingual microcystic lymphatic malformation of any stage in children and adults after 4, 8, 12, 16, 20 and 24 weeks of treatment as compared to usual care (no treatment).

Secondary objectives 5

1. To evaluate patient-reported global efficacy of the application of 1mg/mL sirolimus solution on mild to moderate lingual microcystic lymphatic malformation in children and adults.
2. To evaluate patient-reported specific efficacy of the application of 1mg/mL sirolimus solution on mild to moderate LMLM in children and adults, versus usual care, on the following symptoms: oozing, bleeding, sialorrhea, eating impairment, taste modification, aesthetic impairment, pain and global discomfort.
3. To evaluated quality of life of patients before and after treatment with topical sirolimus.
4. To assess time to optimal results.
5. Safety: by measuring systemic passage of sirolimus and assessing tolerance (local tolerance and general safety data).

Conditions and MedDRA coding

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

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 6

1. ≥ 5 years of age
2. Lingual microcystic lymphatic malformation of any stage (Wiegand 2009) assessed by clinical examination and head-and-neck MRI imaging prior to study enrolment, with or without underlying syndromic malformation (CLAPO for instance)
3. Participants covered by or having the rights to social security
4. Written informed consent obtained from participant and participant’s legal representative if participant is under 18
5. Ability for participant to comply with the requirements of the study
6. Compliance with the French mandatory immunization program

Exclusion criteria 14

1. Patients with a lymphatic malformation requiring a continued background therapy (involving deep organs)
2. Secondary lymphatic malformations (lymphangiectasia post-radiotherapy, etc)
3. Previous treatment with systemic or topical mTOR inhibitors within 6 months before inclusion (half-life of oral sirolimus is 60 hours in adults according to Rapamune ® Summary of Product Characteristics)
4. Previous treatment with oral or topical steroids within 10 days before inclusion (half-life of corticosteroids is 12-36 hours)
5. Immunosuppression (immunosuppressive disease or immunosuppressive treatment)
6. Ongoing neoplasia
7. Active chronic infectious disease (HBV, HCV, HIV, etc)
8. Local necrosis
9. Local fungal, viral (HSV, VZV, etc) or bacterial infection on the site of the LMLM (based on clinical examination)
10. Known allergy to one of the components of the sirolimus solution
11. Soy bean or Peanut allergy
12. Pregnant or breastfeeding women
13. 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
14. Already involved in another therapeutic trial

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 10

1. Investigator-assessed PGA at weeks 0, 4, 8, 12, 16, 20 and 24
2. 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 compared to baseline, 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 (DLQI or children’s DLQI for minors aged 5 to 16), at baseline, time of switch to treatment and W24
5. Measurement of the lesion (length, width, thickness) by the investigator, at baseline, time of switch to treatment and W24
6. Time to obtain optimal results
7. Safety: Assessment of tolerance of topical sirolimus: record of local adverse events at each visit, before and after the patient has crossed over to the intervention
8. Safety : record of general adverse events at each visit, before and after the patient has crossed over to the intervention, physical examination, systolic and diastolic blood pressure measurement
9. Safety: Assessment of sirolimus blood passage by measuring residual sirolimus blood concentration: after 4 weeks of treatment, then 8 weeks, then every 8 weeks until W24
10. Safety: Evaluation of biological safety at weeks 8, 16 and 24 of exposure compared to baseline (we will perform biological measurements that are required for assessing safety of oral sirolimus: complete blood count, liver (ASAT, ALAT, GGT) and renal (serum creatinine) functions, lipids [cholesterol i.e. total cholesterol, HDL and LDL calculation according to Friedwald's formula and triglycerides] and glycaemia)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Regional Universitaire De Tours

Sponsor organisation

Centre Hospitalier Regional Universitaire De Tours

Address

2 Boulevard Tonnelle

City

Tours Cedex 9

Postcode

37044

Country

France

Scientific contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Pr Annabel MARUANI

Public contact point

Organisation

Centre Hospitalier Regional Universitaire De Tours

Contact name

Pr Annabel MARUANI

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

1 submissions — initial application plus substantial / non-substantial modifications