Annabel Maruani1,2,3, Elsa Tavernier1,3, Olivia Boccara4, Juliette Mazereeuw-Hautier5, Sophie Leducq1,2, Didier Bessis6, Laurent Guibaud7, Pierre Vabres8, Virginie Carmignac8, Stéphanie Mallet9, Sébastien Barbarot10, Christine Chiaverini11, Catherine Droitcourt12, Anne-Claire Bursztejn13, Céline Lengellé14, Jean-Baptiste Woillard15, Denis Herbreteau16, Anne Le Touze17, Aline Joly18, Christine Léauté-Labrèze19, Julie Powell20, Hélène Bourgoin21, Valérie Gissot3, Bruno Giraudeau1,3, Baptiste Morel22. 1. University of Tours, University of Nantes, Institut National de la Santé et de la Recherche Médicale, SPHERE U1246, Tours, France. 2. Centre Hospitalier Régional Universitaire Tours, Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée-Tours), Tours, France. 3. Centre Hospitalier Régional Universitaire Tours, Institut National de la Santé et de la Recherche Médicale Clinical Investigation Center 1415, Tours, France. 4. Department of Dermatology and Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée-Necker), University Hospital Necker-Enfants Malades, Paris, France. 5. Department of Dermatology, University Hospital Center of Toulouse, Toulouse, France. 6. Department of Dermatology, University Hospital Center of Montpellier, Montpellier, France. 7. University Hospital Center of Lyon, Consultation Multidisciplinaire Lyonnaise des Angiomes, Lyon, France. 8. Department of Dermatology, University Hospital Center of Dijon, Dijon, France. 9. Department of Dermatology, University Hospital Center of Marseille, Marseille, France. 10. Department of Dermatology, University Hospital Center of Nantes, Nantes, France. 11. Department of Dermatology, University Hospital Center of Nice, Nice, France. 12. Department of Dermatology, University Hospital Center of Rennes, Rennes, France. 13. Department of Dermatology, University Hospital Center of Nancy, Nancy, France. 14. Centre Hospitalier Régional Universitaire Tours, Department of Clinical Pharmacology, Regional Pharmacovigilance Center, Tours, France. 15. Centre Hospitalier Universitaire Limoges, Department of Pharmacology and Toxicology, University of Limoges, Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 850, Limoges, France. 16. University of Tours, Centre Hospitalier Régional Universitaire Tours, Department of Neuroradiology, Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée-Tours), Tours, France. 17. Centre Hospitalier Régional Universitaire Tours, Department of Pediatric Surgery, Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée-Tours), Tours, France. 18. Centre Hospitalier Régional Universitaire Tours, Department of Pediatric Maxillofacial Surgery, Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée-Tours), Tours, France. 19. Department of Dermatology, University Hospital Center of Bordeaux, Bordeaux, France. 20. Department of Pediatric Dermatology, Hospital Sainte-Justine, Montréal, Québec, Canada. 21. Centre Hospitalier Régional Universitaire Tours, Department of Pharmacy, Tours, France. 22. University of Tours, Centre Hospitalier Régional Universitaire Tours, Department of Pediatric Radiology, Tours, France.
Abstract
IMPORTANCE: Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking. OBJECTIVE: To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. DESIGN, SETTING AND PARTICIPANTS: This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020. INTERVENTIONS: Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety. RESULTS: Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]). CONCLUSIONS AND RELEVANCE: This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.
IMPORTANCE: Sirolimus is increasingly being used to treat various vascular anomalies, although evidence of its efficacy is lacking. OBJECTIVE: To assess the efficacy and safety of sirolimus for children with slow-flow vascular malformations to better delineate the indications for treatment. DESIGN, SETTING AND PARTICIPANTS: This multicenter, open-label, observational-phase randomized clinical trial included 59 children aged 6 to 18 years with a slow-flow vascular malformation who were recruited between September 28, 2015, and March 22, 2018, in 11 French tertiary hospital centers. Statistical analysis was performed on an intent-to-treat basis from December 4, 2019, to November 10, 2020. INTERVENTIONS: Patients underwent an observational period, then switched to an interventional period when they received oral sirolimus (target serum levels, 4-12 ng/mL). The switch time was randomized from month 4 to month 8, and the whole study period lasted 12 months for each patient. MAIN OUTCOMES AND MEASURES: The primary outcome was change in the volume of vascular malformations detected on magnetic resonance imaging scan (with centralized interpretation) per unit of time (ie, between the interventional period and the observational period). Secondary outcomes included subjective end points: pain, bleeding, oozing, quality of life, and safety. RESULTS: Among the participants (35 girls [59.3%]; mean [SD] age, 11.6 [3.8] years), 22 (37.3%) had a pure venous malformation, 18 (30.5%) had a cystic lymphatic malformation, and 19 (32.2%) had a combined malformation, including syndromic forms. Variations in the volume of vascular malformations detected on magnetic resonance imaging scans associated with the duration period were not overall significantly different between the interventional period and the observational period (all vascular malformations: mean [SD] difference, -0.001 [0.007]; venous malformations: mean [SD] difference, 0.001 [0.004]; combined malformations: mean [SD] difference, 0.001 [0.009]). However, a significant decrease in volume was observed for children with pure lymphatic malformations (mean [SD] difference, -0.005 [0.005]). Overall, sirolimus had positive effects on pain, especially for combined malformations, and on bleeding, oozing, self-assessed efficacy, and quality of life. During sirolimus treatment, 56 patients experienced 231 adverse events (5 serious adverse events, none life-threatening). The most frequent adverse event was an oral ulcer (29 patients [49.2%]). CONCLUSIONS AND RELEVANCE: This observational-phase randomized clinical trial allows for clarifying the goals of patients and families when starting sirolimus therapy for children older than 6 years. Pure lymphatic malformations seem to be the best indication for sirolimus therapy because evidence of decreasing lymphatic malformation volume per unit of time, oozing, and bleeding and increasing quality of life was found. In combined malformations, sirolimus significantly reduced pain, oozing, and bleeding. Benefits seemed lower for pure venous malformations than for the 2 other subgroups, also based on symptoms. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02509468; clinicaltrialsregister.eu Identifier: 2015-001096-43.