Vascular Malformation Clinical Trial
— PERFORMUSOfficial title:
Treatment of Superficial Voluminous Complicated Slow-flow Vascular Malformations With Sirolimus: a Phase 2 Trial in Children Observational-phase Designed
Verified date | September 2019 |
Source | University Hospital, Tours |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
The most recent classification, adopted by International Society for the Study of Vascular
Anomalies (ISSVA) in 1996, and updated in Melbourne in 2014, divides these lesions into two
broad categories: vascular tumors and vascular malformations. Vascular malformations (VMs)
are subdivided into high-flow VM and slow-flow VM.
Slow-flow VMs consist of congenital anomalies which may involve abnormal capillaries vessels,
venous vessels, lymphatic vessels or combination of several of them. They can be superficial
(involving cutaneous and subcutaneous tissues) and/or may have visceral involvement. They can
be limited or diffuse, and are sometimes components of genetic hypertrophic syndromes.
The diagnosis of slow-flow VMs is performed on physical examination (biopsy may be required
for confirmation), and is completed with imaging (ultrasonography and magnetic resonance
imaging (MRI)). Slow-flow VMs may be particularly voluminous; associated with underlying
hypertrophy responsible for functional impairment; painful; associated with seepage or
continuous cutaneous bleeding; complicated with visceral signs or hematologic disturbances
(anemia, thrombopenia). Management requires dedicated multispecialty care. There are no
guidelines for treatment, and management may include no intervention - but natural history of
these VMs is progressive worsening -, compression by physical bandage, sclerotherapy,
resection (when feasible),anti-inflammatory or anti-coagulation drugs.
Case reports and series have provided evidence for supporting the need for a clinical trial
of sirolimus by reporting successful treatment on several children with complicated vascular
anomalies. The choice of sirolimus is rational. Mammalian target of rapamycin (mTOR) is a
serine/threonine kinase regulated by phosphoinositide-3-kinase involved in cell mobility,
cell growth and angiogenesis. Sirolimus inhibits mTOR, which induces inhibition of
angiogenesis, in particular lymphangiogenesis, which has been demonstrated in several models.
Status | Completed |
Enrollment | 63 |
Est. completion date | March 2019 |
Est. primary completion date | March 2019 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 6 Years to 18 Years |
Eligibility |
- Patients aged from 6 years to 18 years - With a slow-flow vascular malformation confirmed by MRI, included or not into a genetic disorder, among the following: - microcystic lymphatic malformation - mixed micro- and macrocystic malformation - venous malformation - combined lymphatic and venous malformation - Malformation voluminous and complicated (pain, functional impairment, bleeding, seepage) - Extended to the underlying subcutaneous tissue, to the fascias, the muscles and/or the underlying bone - MRI of the VM performed within 8 months - Vaccination schedule updated - Informed, written consent of the subject's parents or the 18 years old subject - Cooperative parent or subject, aware of the necessity and duration of controls so that perfect adhesion to the protocol could be expected - Subjects or subject's parents covered by or having the rights to social security. Exclusion criteria: - Slow-flow VMs which are only macrocystic lymphatic malformations - Visceral life-threatening involvement - Patients who received prior per os treatment with an mTOR inhibitor - Immunosuppression (immunosuppressive disease or immunosuppressive treatment) - Known chronic infectious disease - History of cancer in the 2 previous years - Brest feeding or pregnant women, or women on childbearing age without effective contraception, up to 12 weeks after treatment discontinuation - Known allergy to mTOR inhibitor - Concomitant treatment that inhibits or activates CYP3A4, and P-gp glycoprotein, cytotoxic drugs, antilymphocyte immunoglobulines and metoclopramide - Intolerance to fructose, intolerance or malabsorption to glucose, galactose, metabolic insufficiency in sucraseisomaltase, metabolic defect in lactase - Known allergy to peanuts or soyabean - Liver insufficiency (elevated transaminases > 2.5 N) - Anemia with Hb < 9 g/dl - Leukopenia < 1000/mm3 - Thrombocytopenia < 80 000/mm3 - Hypercholesterolemia (LDL-cholesterol = 2g/l) - Patients with risk of opportunistic infections - Contraindication of MRI - Known allergy to lidocaïne - Live attenuated vaccine up to 3 months after sirolimus discontinuation - Subject already participating to a therapeutic study |
Country | Name | City | State |
---|---|---|---|
France | Service de dermatologie, CHU Angers | Angers | |
France | Service de dermatologie, Hôpital du Bocage, CHU Dijon | Dijon | |
France | Explorations Médecine Vasculaire Hôpital A. Michallon, CHU de Grenoble | Grenoble | |
France | Service de radiologie Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon | Lyon | |
France | Service de Dermatologie, vénéréologie et cancérologie cutanée, Hôpital La Timone APHM | Marseille | |
France | Service de Dermatologie, Hôpital St Eloi, CHU Montpellier | Montpellier | |
France | Service de Dermatologie, Hôpital Hôtel-Dieu, CHU Nantes | Nantes | |
France | Service de dermatologie, CHU Nice | Nice | |
France | Service de dermatologie, APHP Necker | Paris | |
France | Service de Dermatologie, Hôpital Pontchaillou, CHU RENNES | Rennes | |
France | Service de dermatologie, Hôpital Larrey, CHU Toulouse | Toulouse | |
France | Consultations externes de Dermatologie, Hôpital Clocheville, CHU Tours | Tours |
Lead Sponsor | Collaborator |
---|---|
University Hospital, Tours |
France,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | Change of volume of the Vascular Malformation | Primary outcome will be based on the volume of the VMs on MRI. Three MRI will be performed: one at baseline (M0), one at the date of switch from the observational period to the sirolimus period (MS) and one at the end of follow-up (M12). Relative change of volume, standardized by the duration period, will define the outcome. Thus, for the observational period, the primary outcome is defined as {(VMS - V0)/V0}/(MS-M0) where V0 and VMS are the volumes assessed at baseline and month S, respectively, and (MS-M0) corresponds to the duration of the observational period. For the sirolimus period, the outcome is defined in the same way as {(V12 - VMS)/VMS}/(M12-MS), where V12 is the volume assessed at month 12 and (M12-MS) corresponds to the duration of the sirolimus period. Interpretation of the MRI will be centralized and performed by a radiologist blinded from physical assessment and from treatment period. |
at baseline, at date of switch from the observational period to the sirolimus period (between 4 and 8 month) and at 12 months | |
Secondary | Efficacy of study treatment measured on digital photographs | Qualitative assessment of efficacy on digital photographs | inclusion, switch from the observational period to the sirolimus period (between 4 and 8 month), switch+1month, 12 month | |
Secondary | Self assessment of efficacy of study treatment | Patient self assessment or proxy (parents) self assessments using visual analogic scale (0-10): Global treatment efficacy on a visual analogic scale (0-10) Skin complications/symptoms (seepage, bleeding, skin tension, functional impairment) Pain Quality of life by the dermatological quality of life scale (DLQI and DLQI adapted to children) |
Participants will be followed during 12 months | |
Secondary | Dermatologist's assessment of efficacy of study treatment | Dermatologist's global assessment of efficacy using a visual analogic scale (0-10) | Participants will be followed during 12 months | |
Secondary | Efficacy of study treatment | Decrease of vascular endothelium growth factor (VEGF) and Tissue Factor (TF) plasma levels Platelet count, and fibrinogen, D-dimers, factor V levels supporting the presence and disappearance of an abnormal intravascular coagulation consumption | Participants will be followed during 12 months | |
Secondary | Adverse events and safe adverse events will be compared | Adverse events and safe adverse events will be compared using the Mc Nemar test, if applicable. Otherwise, descriptive statistics (percentages) will be estimated. | Participants will be followed during 12 months | |
Secondary | Organic collection of skin and blood samples | From the organic collection (including blood and skin samples), genetic analysis of several genes involved in vasculogenesis (currently TIE2 and PIK3CA) will be performed. A genotype/phenotype study will be carried out. | at 5 month or 6 month or 7 month or 8 month or 9 month after inclusion |
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