suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS

NCT ID: NCT02509468

Last Updated: 2025-12-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 63 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-09-30
• Study Completion Date: 2019-03-31

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"

Conditions

Vascular Malformation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Observational

Patients will first be included in an observational period, then, at a randomized time different from one to another, will all receive the experimental treatment (i.e. sirolimus).

This design has been defined a the "randomized placebo-phase design" (Feldman et al. J Clin Epidemiol. 2001 Jun;54(6):550-7)

Group Type: NO_INTERVENTION

No interventions assigned to this group

Experimental

At a randomized date, patients will start treatment with sirolimus (beginning dose: 0.08mg/kg/day)

Group Type: EXPERIMENTAL

Sirolimus

Intervention Type: DRUG

• 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

Interventions

Sirolimus

• 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

Intervention Type: DRUG

Other Intervention Names

rapamune

Eligibility Criteria

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

• Minimum Eligible Age: 6 Years
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Tours

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Annabel Maruani, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

CHRU TOURS

Locations

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, , France

Countries

France

References

Maruani A, Tavernier E, Boccara O, Mazereeuw-Hautier J, Leducq S, Bessis D, Guibaud L, Vabres P, Carmignac V, Mallet S, Barbarot S, Chiaverini C, Droitcourt C, Bursztejn AC, Lengelle C, Woillard JB, Herbreteau D, Le Touze A, Joly A, Leaute-Labreze C, Powell J, Bourgoin H, Gissot V, Giraudeau B, Morel B. Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial. JAMA Dermatol. 2021 Nov 1;157(11):1289-1298. doi: 10.1001/jamadermatol.2021.3459.

Reference Type: RESULT

PMID: 34524406 (View on PubMed)

Maruani A, Boccara O, Bessis D, Guibaud L, Vabres P, Mazereeuw-Hautier J, Barbarot S, Chiaverini C, Blaise S, Droitcourt C, Mallet S, Martin L, Lorette G, Woillard JB, Jonville-Bera AP, Rollin J, Gruel Y, Herbreteau D, Goga D, le Touze A, Leducq S, Gissot V, Morel B, Tavernier E, Giraudeau B; Groupe de Recherche de la Societe Francaise de Dermatologie Pediatrique. Treatment of voluminous and complicated superficial slow-flow vascular malformations with sirolimus (PERFORMUS): protocol for a multicenter phase 2 trial with a randomized observational-phase design. Trials. 2018 Jun 27;19(1):340. doi: 10.1186/s13063-018-2725-1.

Reference Type: DERIVED

PMID: 29945674 (View on PubMed)

Other Identifiers

PHRN14-AM/PERFORMUS

Identifier Type: -

Identifier Source: org_study_id

2015-001096-43

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id