suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS
Condition: Vascular Malformation
MeSH terms: Vascular Malformations; Congenital Abnormalities
Study type: Interventional
Phase: Phase 2

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"
    

Intervention name(s): Sirolimus
Intervention type(s): Drug
Intervention description(s): each patient will be followed during a 12-month-period
each patient will start by an observational period and 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
Other intervention name(s): rapamune
Intervention MeSH terms: Sirolimus
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Outcomes Assessor)
Primary purpose: Treatment