Related Experiment Video
Updated: Jul 11, 2025
Author Spotlight: Utilizing Venoplasty Balloon Model in Rodents to Simulate Surgical Interventions for Deep Veins
Published on: May 24, 2024
Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular
Emmanuel Seront1,2, An Van Damme1,3, Catherine Legrand4
1Center for Vascular Anomalies, Cliniques universitaires Saint-Luc, University of Louvain, VASCERN VASCA European Reference Centre, Brussels, Belgium.
Abstract:
BACKGROUNDSlow-flow vascular malformations frequently harbor activating mutations in the PI3K/AKT/mTOR cascade. Phase II trials pinpointed sirolimus effectiveness as a drug therapy. Efficacy and safety of sirolimus thus need to be evaluated in large prospective phase III trials.METHODSThe Vascular Anomaly-Sirolimus-Europe (VASE) trial, initiated in 2016, is a large multicentric prospective phase III trial (EudraCT 2015-001703-32), which evaluates efficacy and safety of sirolimus for 2 years in pediatric and adult patients with symptomatic slow-flow vascular malformations. In this interim analysis, we studied all patients enrolled up to October 2021 who received sirolimus for 12 or more months or who prematurely stopped the treatment.RESULTSThirty-one pediatric and 101 adult patients were included in this analysis; 107 completed 12 or more months of sirolimus, including 61 who were treated for the whole 2-year period. Sirolimus resulted in a clinical improvement in 85% of patients. The efficacy appeared within the first month for the majority of them. Grade 3-4 adverse events were observed in 24 (18%) patients; all resolved after treatment interruption/arrest. Sirolimus increased feasibility of surgery or sclerotherapy in 20 (15%) patients initially deemed unsuitable for intervention. Among the 61 patients who completed the 2-year treatment, 33 (54%) reported a recurrence of symptoms after a median follow-up of 13 months after sirolimus arrest. While there was no difference in efficacy, clinical improvement was faster but subsided more rapidly in PIK3CA-mutated (n = 24) compared with TIE2-mutated (n = 19) patients.CONCLUSIONSirolimus has a high efficacy and good tolerance in treatment of slow-flow vascular malformations in children and adults.TRIAL REGISTRATIONClinicalTrials.gov NCT02638389 and EudraCT 2015-001703-32.FUNDINGThe Fonds de la Recherche Scientifique (FNRS grants T.0247.19, P.C005.22, T.0146.16, and P.C013.20), the Fund Generet managed by the King Baudouin Foundation (grant 2018-J1810250-211305), the Walloon Region through the FRFS-WELBIO strategic research programme (WELBIO-CR-2019C-06), the MSCA-ITN network V.A. Cure no. 814316, the Leducq Foundation Networks of Excellence Program grant "ReVAMP" (LFCR grant 21CVD03), the European Union's Horizon 2020 research and innovation programme under grant agreement no. 874708 (Theralymph), the Swiss National Science Foundation under the Sinergia project no. CRSII5_193694, and a Pierre M. fellowship.
Insights
Sirolimus effectively treats slow-flow vascular malformations in adults and children, showing high clinical improvement rates. While generally well-tolerated, symptom recurrence after treatment cessation occurs in over half of patients.
Area of Science:
- Vascular Biology
- Pharmacology
- Genetics
Background:
- Slow-flow vascular malformations often involve PI3K/AKT/mTOR pathway mutations.
- Previous Phase II trials demonstrated sirolimus's effectiveness.
- Large-scale Phase III trials are needed to confirm efficacy and safety.
Purpose of the Study:
- To evaluate the efficacy and safety of sirolimus in treating symptomatic slow-flow vascular malformations.
- To assess sirolimus treatment over two years in pediatric and adult patients.
- To analyze patient responses and adverse events in a prospective trial.
Main Methods:
- The Vascular Anomaly-Sirolimus-Europe (VASE) trial is a multicentric, prospective Phase III study.
- 132 patients (31 pediatric, 101 adult) received sirolimus for at least 12 months or until premature cessation.
- Data were analyzed from patients enrolled up to October 2021.
Main Results:
- Sirolimus achieved clinical improvement in 85% of patients, with effects often seen within the first month.
- Grade 3-4 adverse events occurred in 18% of patients but resolved upon treatment cessation.
- Sirolimus facilitated surgery or sclerotherapy in 15% of patients and symptom recurrence was observed in 54% after treatment cessation.
Conclusions:
- Sirolimus demonstrates high efficacy and good tolerance for treating slow-flow vascular malformations in both children and adults.
- Treatment benefits may be more rapid but less sustained in PIK3CA-mutated compared to TIE2-mutated patients.
- Long-term safety and management strategies, including addressing recurrence, are important considerations.
