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

Maruani et al. Trials (2018) 19:340 https://doi.org/10.1186/s13063-018-2725-1 STUDY PROTOCOL Open Access 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 Annabel Maruani1,2,3* , Olivia Boccara4, Didier Bessis5, Laurent Guibaud6, Pierre Vabres7, Juliette Mazereeuw-Hautier8, Sébastien Barbarot9, Christine Chiaverini10, Sophie Blaise11, Catherine Droitcourt12, Stéphanie Mallet13, Ludovic Martin14, Gérard Lorette2, Jean-Baptiste Woillard15, Annie-Pierre Jonville-Bera1,16, Jérome Rollin17, Yves Gruel17, Denis Herbreteau18, Dominique Goga19, Anne le Touze20, Sophie Leducq2, Valérie Gissot3, Baptiste Morel21, Elsa Tavernier1,3, Bruno Giraudeau1,3 and Groupe de Recherche de la Societé Française de Dermatologie Pédiatrique Abstract 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. (Continued on next page) * Correspondence: 1 University of Tours, University of Nantes, INSERM, SPHERE U1246, Tours, France 2 Department of Dermatology, Unit of Pédiatric Dermatology, CHRU Tours, 37044 Tours Cedex 9, France Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Maruani et al. Trials (2018) 19:340 Page 2 of 9 (Continued from previous page) 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 slowflow 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. Keywords: Vascular anomalies, Lymphatic malformations, Venous malformations, Children, Sirolimus, Mammalian target of rapamycin inhibitors, Randomized placebo-phase design Background Background and rationale Vascular anomalies (VAs) include a heterogeneous group of disorders occurring most frequently in newborns and children. Infantile hemangiomas are common (10% of infants), are generally not complicated and are easily managed, but most other VAs are rare (< 2% altogether) and we have no guidelines for management. The updated classification from the International Society for the Study of Vascular Anomalies (ISSVA), divides VAs into 2 broad categories: vascular tumors and vascular malformations (VMs) [1]. VMs are usually present at birth, although they are not always apparent at this stage; they are distinguished by their hemodynamic flow as high-flow and slow-flow VMs. Slow-flow VMs involve abnormal capillaries vessels (i.e., port-wine stains), venous vessels, lymphatic vessels (including macrocystic, microcystic or mixed lymphatic malformations) or a combination of these. They can be superficial (involving cutaneous and subcutaneous tissues, underlying fasciae and muscles) or may have visceral involvement. They can be limited or diffuse and are sometimes components of genetic syndromes (e.g., Protée, Klippel-Trenaunay, Bean syndrome) [2]. They are always due to defective embryologic vasculogenesis [3]. Slow-flow VMs are diagnosed on physical examination, but a biopsy might be required for confirmation. Diagnosis is always completed with imaging, including duplex ultrasonography for screening, and MRI for definitive diagnosis and diagnosis of extension [4]. Recent molecular findings have allowed for a better understanding of VMs, in particular those for which somatic mutations of genes were identified, especially PIK3CA, causing overgrowth tissue associated with the VM [5, 6]. Slow-flow superficial VMs might induce functional impairment because they can be voluminous, painful, associated with underlying overgrowth tissue, or complicated by seepage or continuous cutaneous bleeding. Visceral VMs can be life-thr (...truncated)