Vascular Malformation Clinical Trial
Official title:
Treatment of Superficial Voluminous Complicated Slow-flow Vascular Malformations With Sirolimus: a Phase 2 Trial in Children Observational-phase Designed
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.
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"
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