Journal Article

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

Droitcourt, Catherine, Boccara, Olivia, le Touze, Anne, Chiaverini, Christine, Jonville-Bera, Annie-Pierre, Blaise, Sophie, Mazereeuw-Hautier, Juliette, Maruani, Annabel, Vabres, Pierre, Leducq, Sophie, Giraudeau, Bruno, Mallet, Stéphanie, Goga, Dominique, Guibaud, Laurent, Woillard, Jean-Baptiste, Gruel, Yves, Rollin, Jérome, Barbarot, Sébastien, Herbreteau, Denis, Tavernier, Elsa, Martin, Ludovic, Lorette, Gérard, Morel, Baptiste, Bessis, Didier, Gissot, Valérie

2018

Overview

Background Slow-flow superficial vascular malformations (VMs) are rare congenital anomalies that can be responsible for pain and functional impairment. Currently, we have no guidelines for their management, which can involve physical bandages, sclerotherapy, surgery, anti-inflammatory or anti-coagulation drugs or no treatment. The natural history is progressive and worsening. Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that acts as a master switch in cell proliferation, apoptosis, metabolism and angio/lymphangiogenesis. Sirolimus directly inhibits the mTOR pathway, thereby inhibiting cell proliferation and angio/lymphangiogenesis. Case reports and series have reported successful use of sirolimus in children with different types of vascular anomalies, with heterogeneous outcomes. Objective The objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs. Methods/design This French multicenter randomized observational-phase, phase 2 trial aims to include 50 pediatric patients 6 to 18 years old who have slow-flow (lymphatic, venous or lymphatico-venous) voluminous complicated superficial VM. Patients will be followed up for 12 months. All patients will start with an observational period (no treatment). Then at a time randomly selected between month 4 and month 8, they will switch to the experimental period (switch time), when they will receive sirolimus until month 12. Each child will undergo MRI 3 times: at baseline, at the switch time, and at month 12. For both periods (observational and treatment), we will calculate the relative change in volume of the VM divided by the study period duration. This relative change weighted by the study period duration will constitute the primary endpoint. VM will be measured by MRI images, which will be centralized and interpreted by the same radiologist who will be blinded to the study period. Hence, each patient will be his/her own control. Secondary outcomes will include assessment of safety and efficacy by viewing standardized digital photographs and according to the physician, the patient or proxy; impact on quality of life; and evolution of biological makers (coagulation factors, vascular endothelial growth factor, tissue factor). Discussion The main benefit of the study will be to resolve uncertainty concerning the efficacy of sirolimus in reducing the volume of VMs and limiting related complications and the safety of the drug in children with slow-flow VMs. This trial design is interesting in these rare conditions because all included patients will have the opportunity to receive the drug and the physician can maintain it after the end of the protocol if is found efficient (which would not be the case in a classical cross-over study). Trial registration ClinicalTrials.gov Identifier: NCT02509468 , first received: 28 July 2015. EU Clinical Trials Register EudraCT Number: 2015-001096-43.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adolescent / Age Factors / Analysis / Anemia / Biomedicine / Blood circulation disorders / Blood Flow Velocity / Care and treatment / Child / Children / Clinical trials / Clinical Trials, Phase II as Topic / Contraindications / Coronary Circulation - drug effects / Data collection / Drug dosages / Female / France / Genetic disorders / Health aspects / Health Sciences / Human health and pathology / Humans / Kinases / Life Sciences / Lymphatic malformations / Magnetic Resonance Imaging / Male / Mammalian target of rapamycin inhibitors / Medicine / Medicine & Public Health / Metabolism / Multicenter Studies as Topic / Observational Studies as Topic / Patients / Pediatrics / Pharmacokinetics / Protein Kinase Inhibitors - adverse effects / Protein Kinase Inhibitors - therapeutic use / Quality of life / Randomized Controlled Trials as Topic / Sclerotherapy / Sirolimus / Sirolimus - adverse effects / Sirolimus - therapeutic use / Statistics for Life Sciences / Study Protocol / Time Factors / Treatment Outcome / Vascular anomalies / Vascular Malformations - diagnostic imaging / Vascular Malformations - drug therapy / Vascular Malformations - physiopathology / Venous malformations