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Original Investigation
September 15, 2021

Sirolimus (Rapamycin) for Slow-Flow Malformations in Children: The Observational-Phase Randomized Clinical PERFORMUS Trial

Author Affiliations
  • 1University of Tours, University of Nantes, Institut National de la Santé et de la Recherche Médicale, SPHERE U1246, Tours, France
  • 2Centre Hospitalier Régional Universitaire Tours, Department of Dermatology, Reference Center for Genodermatoses and Rare Skin Diseases (Maladies Génétiques rares à Expression Cutanée–Tours), Tours, France
  • 3Centre Hospitalier Régional Universitaire Tours, Institut National de la Santé et de la Recherche Médicale Clinical Investigation Center 1415, Tours, France
  • 4Department 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
  • 5Department of Dermatology, University Hospital Center of Toulouse, Toulouse, France
  • 6Department of Dermatology, University Hospital Center of Montpellier, Montpellier, France
  • 7University Hospital Center of Lyon, Consultation Multidisciplinaire Lyonnaise des Angiomes, Lyon, France
  • 8Department of Dermatology, University Hospital Center of Dijon, Dijon, France
  • 9Department of Dermatology, University Hospital Center of Marseille, Marseille, France
  • 10Department of Dermatology, University Hospital Center of Nantes, Nantes, France
  • 11Department of Dermatology, University Hospital Center of Nice, Nice, France
  • 12Department of Dermatology, University Hospital Center of Rennes, Rennes, France
  • 13Department of Dermatology, University Hospital Center of Nancy, Nancy, France
  • 14Centre Hospitalier Régional Universitaire Tours, Department of Clinical Pharmacology, Regional Pharmacovigilance Center, Tours, France
  • 15Centre 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
  • 16University 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
  • 17Centre 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
  • 18Centre 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
  • 19Department of Dermatology, University Hospital Center of Bordeaux, Bordeaux, France
  • 20Department of Pediatric Dermatology, Hospital Sainte-Justine, Montréal, Québec, Canada
  • 21Centre Hospitalier Régional Universitaire Tours, Department of Pharmacy, Tours, France
  • 22University of Tours, Centre Hospitalier Régional Universitaire Tours, Department of Pediatric Radiology, Tours, France
JAMA Dermatol. Published online September 15, 2021. doi:10.1001/jamadermatol.2021.3459
Key Points

Question  Is sirolimus effective for vascular malformations in children?

Findings  This observational-phase randomized clinical trial of 59 children aged 6 to 18 years found no evidence on magnetic resonance imaging of the efficacy of sirolimus for reducing the volume of slow-flow vascular malformations. Overall, sirolimus was efficient for painful symptoms, especially among patients with combined malformations, and for bleeding, oozing, and quality of life associated with the malformations.

Meaning  This study allows for clarifying the goals of the patient and family when starting sirolimus therapy: reducing pain, bleeding, oozing, and volume only for those with pure lymphatic malformations.

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

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