Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2023 Nov 8;8(21):e173095.
doi: 10.1172/jci.insight.173095.

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations

Emmanuel Seront  1   2 , An Van Damme  1   3 , Catherine Legrand  4 , Annouk Bisdorff-Bresson  5 , Philippe Orcel  6 , Thomas Funck-Brentano  6 , Marie-Antoinette Sevestre  7 , Anne Dompmartin  8 , Isabelle Quere  9 , Pascal Brouillard  10 , Nicole Revencu  1   11 , Martina De Bortoli  10 , Frank Hammer  1   12 , Philippe Clapuyt  1   13 , Dana Dumitriu  1   13 , Miikka Vikkula  1   10   14 , Laurence M Boon  1   10   15
Affiliations
Clinical Trial

Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations

Emmanuel Seront et al. JCI Insight. .

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.

Keywords: Angiogenesis; Clinical Trials; Genetic diseases; Lymphomas.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest: The authors have declared that no conflict of interest exists.

Figures

Figure 1
Figure 1. CONSORT diagram.
Figure 2
Figure 2. Evolution of symptoms on sirolimus.
Change in pain (A), pain exacerbation frequency (B), pain exacerbation intensity (C), and functional limitation (D) from baseline to 1, 3, 6, and 12 months after start of sirolimus treatment. Change is expressed for pain (A) and pain exacerbation intensity (C), as increase (I), stabilization (S), small decrease (SD, 1 to 3 points), medium decrease (MD, 4 to 6 points), and large decrease (LD, 7 to 10 points) in pain score. For pain exacerbation frequency (B), the change is expressed as I, S, SD of 1 to 3 crises per month, MD of 4 to 6 crises per month, and LD of 7 to 10 crises per month. For functional limitation (D), change is expressed as I, S, SD (1 to 3 points), MD (4 to 6 points), and LD (7 to 10 points) in functional limitation score. Patients with missing information or out of study were grouped under “No available information” (NA).
Figure 3
Figure 3. Evolution of patients after the 2-year sirolimus treatment.
Figure 4
Figure 4. Representative clinical and radiological evolution on sirolimus.
(A) Evolution of malformations before (left) and after sirolimus treatment (right). Evolution after 3 months of sirolimus treatment of an extensive capillary venous malformation of the lower extremity responsible for daily bleeding and severe consumptive coagulopathy with low fibrinogen and high D-dimer (3-month-old girl). Within 1 month of sirolimus treatment, daily bleeding ceased; surgical resection became possible after 4 months of sirolimus treatment. (B) Evolution after 3 months of sirolimus treatment of a tongue venous malformation (20-year-old girl). (C and D) MRI axial (C) and sagittal view (D) showing the evolution of a venous malformation of the fourth cervical body that caused cervico-brachialgia in a 34-year-old man (left). Two-year sirolimus treatment showing regression of the malformation and restoration of the anatomy of the medullary canal (middle). He is currently treatment free 2 years after sirolimus arrest (right).
See this image and copyright information in PMC

References

    1. Wassef M, et al. Vascular anomalies classification: recommendations from the International Society for the Study of vascular anomalies. Pediatrics. 2015;136(1):e203–e214. doi: 10.1542/peds.2014-3673. - DOI - PubMed
    1. Boon LM, et al. Pathogenesis of vascular anomalies. Clin Plast Surg. 2011;38(1):7–19. doi: 10.1016/j.cps.2010.08.012. - DOI - PMC - PubMed
    1. Mulliken JB, Glowacki J. Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Plast Reconstr Surg. 1982;69(3):412–422. doi: 10.1097/00006534-198203000-00002. - DOI - PubMed
    1. Greene AK, et al. Vascular anomalies in 5621 patients: guidelines for referral. J Pediatr Surg. 2011;46(9):1784–1789. doi: 10.1016/j.jpedsurg.2011.05.006. - DOI - PubMed
    1. Cahill AM, et al. Pediatric vascular malformations: pathophysiology, diagnosis, and the role of interventional radiology. Cardiovasc Intervent Radiol. 2011;34(4):691–704. doi: 10.1007/s00270-011-0123-0. - DOI - PubMed

Publication types

Associated data