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

Abstract

BackgroundSlow-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.ObjectiveThe objective of this trial is to evaluate the efficacy and safety of sirolimus in children with complicated superficial slow-flow VMs.Methods/designThis 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).DiscussionThe 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 registrationClinicalTrials.gov Identifier: NCT02509468, first received: 28 July 2015.EU Clinical Trials Register EudraCT Number: 2015-001096-43.Electronic supplementary materialThe online version of this article (10.1186/s13063-018-2725-1) contains suppl...

Analysis of mTOR pathway expression in lymphatic malformation and related diseases

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“…The mTOR inhibitor sirolimus (also called rapamycin) is used for the treatment of unresectable and locally advanced lymphatic anomalies. Preclinical trials have been conducted to test the efficacy of mTOR inhibitor in lymphatic anomalies 12,13 . However, little is known about the expression of mTOR pathway components in lymphatic anomalies.…”

Sirolimus: A Successful Medical Treatment for Head and Neck Lymphatic Malformations

“…Diffuse malformations present significant challenges due to the morbidity of interventional treatments to achieve local control. There are currently no guidelines for treatment of LMs [3]. mTOR inhibitors, such as sirolimus, have recently been used for their antilymphangiogenic properties in treating LMs [4].…”

Fibro-adipose vascular anomaly (FAVA): three case reports with an emphasis on the mammalian target of rapamycin (mTOR) pathway

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