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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Vabres reported receiving personal fees from Pierre Fabre outside the submitted work. Dr Barbarot reported receiving personal fees from Almirall, Sanofi-Genzyme, AbbVie, Pfizer, LEO Pharma, Lilly, UCB Pharma, and Janssen; nonfinancial support from Novartis; and grants from LEO Pharma outside the submitted work. Dr Bursztejn reported receiving personal fees from Sanofi-Aventis, Lilly, Novartis, Amgen, Pierre Fabre, LEO Pharma, Takeda, and Janssen outside the submitted work. Dr Bourgoin reported receiving grants from French Health Ministry National Programme Hospitalier de Recherche Clinique during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Patients Included in the Study, From Enrollment to Analysis

Figure 2.. Patient-Assessed Pain and Physician-Assessed Efficacy

Pain was assessed by patients on a visual analog scale of 0 to 10 (where 0 indicates no pain and 10 indicates the worst pain imaginable) during the observational period and interventional period for all vascular malformations (A), venous malformations (B), lymphatic malformations (C), and combined malformations (D). Global efficacy was assessed on a visual analog scale of 0 to 10 (where 0 indicates no efficacy and 10 indicates complete resolution) by investigator physicians, patients, and parents, starting from the time of switch to sirolimus to the end of the study for all vascular malformations (A), venous malformations (B), lymphatic malformations (C), and combined malformations (D).