suPERficial Slow-flow Vascular malFORMations Treated With sirolimUS

NCT02509468 | Completed Phase 2 DMC

• 2 other identifiers: PHRN14-AM/PERFORMUS2015-001096-43
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 12

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.

Conditions

Vascular Malformation

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Efficacy of study treatment measured on digital photographs

  inclusion, switch from the observational period to the sirolimus period (between 4 and 8 month), switch+1month, 12 month

• Self assessment of efficacy of study treatment

  Participants will be followed during 12 months

• Dermatologist's assessment of efficacy of study treatment

  Participants will be followed during 12 months

• Efficacy of study treatment

  Participants will be followed during 12 months

• Adverse events and safe adverse events will be compared

  Participants will be followed during 12 months

Study Arms (2)

Observational

NO INTERVENTION

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)

Experimental

EXPERIMENTAL

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

Drug: Sirolimus

Interventions

Sirolimus 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

Also known as: rapamune

Experimental

Eligibility Criteria

• Age: 6 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may not qualify if:

• 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

Sponsors & Collaborators

• University Hospital, Tours: lead

Study Sites (12)

Service de dermatologie, CHU Angers

Angers, 49933, France

Location

Service de dermatologie, Hôpital du Bocage, CHU Dijon

Dijon, 21079, France

Location

Explorations Médecine Vasculaire Hôpital A. Michallon, CHU de Grenoble

Grenoble, 38700, France

Location

Service de radiologie Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon

Lyon, 69000, France

Location

Service de Dermatologie, vénéréologie et cancérologie cutanée, Hôpital La Timone APHM

Marseille, 13000, France

Location

Service de Dermatologie, Hôpital St Eloi, CHU Montpellier

Montpellier, 34000, France

Location

Service de Dermatologie, Hôpital Hôtel-Dieu, CHU Nantes

Nantes, 44000, France

Location

Service de dermatologie, CHU Nice

Nice, 06202, France

Location

Service de dermatologie, APHP Necker

Paris, 75743, France

Location

Service de Dermatologie, Hôpital Pontchaillou, CHU RENNES

Rennes, 35000, France

Location

Service de dermatologie, Hôpital Larrey, CHU Toulouse

Toulouse, 31059, France

Location

Consultations externes de Dermatologie, Hôpital Clocheville, CHU Tours

Tours, 37000, France

Location

Related Publications (2)

• 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.

  PMID: 34524406 RESULT

• 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.

  PMID: 29945674 DERIVED

MeSH Terms

Conditions

Vascular Malformations

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Annabel Maruani, MD, PhD

  CHRU TOURS

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 15, 2015
• First Posted: July 28, 2015
• Study Start: September 30, 2015
• Primary Completion: March 1, 2019
• Study Completion: March 1, 2019
• Last Updated: December 22, 2025

Record last verified: 2019-09

Locations

FR (12)