MedPath

suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS

Phase 2
Completed
Conditions
Vascular Malformation
Interventions
Registration Number
NCT02509468
Lead Sponsor
University Hospital, Tours
Brief Summary

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.

Detailed Description

Vascular anomalies include a heterogeneous group of disorders of newborns and children. While infantile hemangioma are common (10% of infants), generally not complicated and easily managed, the majority of other vascular anomalies are rare (\<2% altogether) and have no guidelines for management. The most recent classification, adopted by International Society for the Study of Vascular Anomalies (ISSVA) in 1996, 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. They always result from defective embryologic vasculogenesis.

The diagnosis of slow-flow VMs is performed on physical examination - a biopsy may be required for confirmation -, and is completed with imaging, which includes ultrasonography and magnetic resonance imaging (MRI). Slow-flow VMs may be simple to manage or can be complicated for several reasons: they 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.

The vast majority of literature reporting medical therapies consists of paediatric case reports, and is complicated by publication bias, inconsistent use of nomenclature and absence of clinical trials. 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.

Randomized observational-phase design (Feldman et al. J Clin Epidemiol 2001;54:550-557):

* each patient will be followed during a 12-month-period

* each patient will start by an observational period and will end being treated by sirolimus

* at a random date (between month 4 and month 8), each patient will switch from the observational period to the sirolimus period Therefore, each patient will be his/her own control, as in a cross-over trial (but the difference is that the cross-over is all in one direction, from observational period to treatment period). This explains why variation in volume will be standardized by period durations.

As specified by Feldman et al, the randomized placebo-phase design is well adapted in situations where "a placebo controlled study would be perceived as being unacceptable by enrolling physicians and by patient" and "may be especially useful when highly potent therapies for rare diseases"

Recruitment & Eligibility

Status
COMPLETED
Sex
All
Target Recruitment
63
Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type
INTERVENTIONAL
Study Design
CROSSOVER
Arm && Interventions
GroupInterventionDescription
ExperimentalSirolimusAt a randomized date, patients will start treatment with sirolimus (beginning dose: 0.08mg/kg/day)
Primary Outcome Measures
NameTimeMethod
Change of volume of the Vascular Malformationat baseline, at date of switch from the observational period to the sirolimus period (between 4 and 8 month) and at 12 months

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.

Secondary Outcome Measures
NameTimeMethod
Efficacy of study treatment measured on digital photographsinclusion, switch from the observational period to the sirolimus period (between 4 and 8 month), switch+1month, 12 month

Qualitative assessment of efficacy on digital photographs

Self assessment of efficacy of study treatmentParticipants will be followed during 12 months

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)

Organic collection of skin and blood samplesat 5 month or 6 month or 7 month or 8 month or 9 month after inclusion

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.

Dermatologist's assessment of efficacy of study treatmentParticipants will be followed during 12 months

Dermatologist's global assessment of efficacy using a visual analogic scale (0-10)

Efficacy of study treatmentParticipants will be followed during 12 months

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

Adverse events and safe adverse events will be comparedParticipants will be followed during 12 months

Adverse events and safe adverse events will be compared using the Mc Nemar test, if applicable. Otherwise, descriptive statistics (percentages) will be estimated.

Trial Locations

Locations (12)

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

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Service de dermatologie, CHU Angers
🇫🇷Angers, France

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