Mapping the global clinical trial landscape of targeted therapy for vascular malformations

Vascular malformations originate from defective early vascular morphogenesis and dysregulated angiogenesis, including capillary, lymphatic, venous, arteriovenous, and mixed subtypes^[1,2^]. These are frequently associated with germline or somatic mutations activating key signaling cascades, such as PI3K-AKT-mTOR, RAS-MAPK-ERK, and G-protein coupled receptor pathways, exhibiting pathogenic overlaps with oncogenic alterations^[3^]. Historically, therapeutic approaches like sclerotherapy and surgery have demonstrated limited efficacy in complicated malformations^[4^]. Therefore, antiangiogenic drugs have continued to gain attention^[5^]. However, the evidence base is fragmented across registration platforms and dominated by small, early-phase, often single-arm studies, with varied eligibility criteria. Given disease rarity and heterogeneity, a consolidated registry-level map is needed to reveal the potential of these drugs. Therefore, we profiled registered pharmacological studies across vascular-malformation subtypes to inform the design of future pragmatic trials.

This study analyzed 67 clinical trials (excluding non-pharmacological treatments) from ClinicalTrials.gov (https://clinicaltrials.gov) and Trialtrove (https://clinicalintelligence.citeline.com) using search term “Disease: Vascular Malformations” on 18 April 2025. ClinicalTrials.gov is the largest publicly accessible registry of clinical studies, whereas Trialtrove is a curated commercial database that integrates clinical trial information from multiple public registries and other sources. All retrieved data were then manually screened to include interventional targeted therapy and to exclude non-pharmacological treatments such as sclerotherapy, embolization, surgery, and radiotherapy. After screening, 59 eligible trials were retained from ClinicalTrials.gov and 33 from Trialtrove, while 25 were registered in both databases. Subsequent analyses were conducted on pivotal information, including geographic distribution, phases, status, study design, drugs, and diseases. The study is compliant with the TITAN Guidelines 2025^[6^].

Globally, 35 (42%) clinical trials were conducted in North America, followed by Europe (37%) and Asia (15%; Supplemental Digital Content Figure S1, available at: http://links.lww.com/JS9/G805). The United States leads with 31 cases, followed by France and China (13 and 9; Fig. 1G). Most are in preliminary stages (only 11% phase III, 3% phase IV), with rising numbers in recent years (Fig. 1A). Academic institutions dominate sponsorship, though pharmaceutical involvement is growing (Supplemental Digital Content Figure S2, available at: http://links.lww.com/JS9/G805).

Figure 1.

Analysis and trends in clinical trials of vascular malformations (VMs) drugs. (A) Annual distribution of VMs drugs clinical trials by phase. (B) Distribution of diseases in VMs drugs clinical trials and corresponding trial status. (C) Drugs with their classification and related studied diseases in VMs clinical trials. (D) Bubble chart of VMs drugs and their matching targets in clinical trials. Only values greater than 3 are labeled in the figure. (E) Annual distribution of different targets in VMs drugs clinical trials. (F) Distribution of patient age groups with different diseases in VMs drugs clinical trials. (G) Overview of countries’ distribution worldwide. The numbers reflect countries’ participation in VMs drugs trials as trial sites: a trial with multiple sites across different countries is thus counted multiple times on the map, while a trial with several sites within the same country is counted as just one. Antarctica is not shown. AVM, arteriovenous malformation; BAVM, brain arteriovenous malformation; BRBNS, blue rubber bleb nevus syndrome; CCM, cerebral cavernous malformations; CLOVES, congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies; CM, capillary malformation; C-VMs, complicated/complex vascular malformations; HHT, hemorrhagic hereditary telangiectasia; KTS, Klippel trenaunay syndrome; LM, lymphatic malformation; M-CM, megalencephaly-CM; PROS, PIK3CA-related overgrowth spectrum; PS, Proteus syndrome; U-VMs, unspecified vascular malformation; VM, venous malformations. ADAR, adrenergic receptor; FKBP, FK506 binding proteins; MMP, matrix metalloproteinase; MoAb, recombinant monoclonal antibodies; PDE5, phosphodiesterase type 5; PIK3CA = PI3Kα, Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha; SERM, steroid receptor modulator; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor.

With respect to study design, across all included trials, planned enrollment was available in 28 studies with a median of 47 participants (IQR 27–75), while actual enrollment was reported in 38 studies with a median of 23 (IQR 7–53). Additionally, 33 (49%) were single-arm, 25 (37%) two-arm, and 7 (10%) included ≥3 arms (Supplemental Digital Content Figure 3A, available at: http://links.lww.com/JS9/G805). Among the 27 trials with a comparator arm, placebo was used in 12 (44%), active in 4 (15%), 7 (26%) incorporated both active and placebo comparators, and no-intervention comparators were reported in 4 (15%) trials (Supplemental Digital Content Figure 3B, available at: http://links.lww.com/JS9/G805). Interventional models were predominantly single group (34, 51%) and parallel (25, 37%) assignment, with few sequential (3, 5%) or crossover designs (2, 3%). Parallel assignment trials were mostly randomized (23, 92%), whereas single group studies were typically reported without an explicit allocation method (unknown in 29/34, 85%; Supplemental Digital Content Figure 3C, available at: http://links.lww.com/JS9/G805).

Lymphatic malformation (LM) is the most investigated condition, with six clinical trials recruiting, most of which focused on Sirolimus (Fig. 1B and 1C). Trials investigating hereditary hemorrhagic telangiectasia (HHT) exhibit the highest completion rates, primarily evaluating VEGF/VEGFR-targeted agents (Fig. 1B and 1D). Despite ongoing efforts, approximately one-third of clinical trials have been suspended, terminated, closed, or remain with unknown status.

Drugs evaluated in the clinical trials exhibit diverse mechanisms of action, among which those targeting VEGF, mTOR, and PI3Kα are the most prevalent (Fig. 1D). VEGF-related drugs, including Thalidomide, Bevacizumab, Propranolol, etc. (Fig. 1D), are tested in diverse diseases, such as HHT, cerebral cavernous malformation, and brain arteriovenous malformation. They mainly focus on bleeding control, such as epistaxis, gastrointestinal bleeding, and lesion bleeding. Sirolimus, a representative mTOR inhibitor, has been tested for slow-flow and complex vascular malformations over 15 years (Fig. 1E). To date, Sirolimus remains the most prominent mTOR inhibitor for the treatment of vascular malformations. PI3Kα inhibitors have only begun to gain attention in the past 5 years, which are all recently developed agents, including Alpelisib, Taselisib, ART-001, RLY-2608, and VT30 (Fig. 1E). They are primarily used for the treatment of combined slow-flow VMs, including PROS, KTS, and CLOVES (Fig. 1C).

Since many vascular malformations have their onset in childhood, the dosage, safety, and tolerability of medications are of significance. More than half of the trials involve children, particularly those with LM, complex vascular malformations or anomalies, and capillary malformation (Fig. 1F).

In summary, due to the rarity of vascular malformations, related clinical trials remain limited and early phase. LM is the most studied disease, HHT has the highest completion rate, Sirolimus has received the most extensive study, and VEGF is the top target. Pediatric involvement is high, requiring attention to dosage and safety for early intervention potential. A key limitation is the potential under-representation of trials registered exclusively in regional databases not captured by our sources, which may bias geographic distributions and leave certain investigational agents or patient populations unreflected in this landscape.

By delineating global patterns in trial design, targeted agents, disease subtypes, age groups, and geographic distribution, this landscape can support the planning of future multicenter, pragmatic trials, including realistic expectations for sample size and completion and the selection of clinically relevant comparators. It may also help prioritize under-studied regions, diseases, and targets when allocating resources and designing collaborative studies in rare vascular malformations.

Ethical approval

Not applicable.

Consent

No patients are included. All authors have approved the content of this manuscript and agreed to its publication.

Sources of funding

None.

Author contributions

X.J. collected the data, finished the data analysis, and wrote the paper. J.L. finished the figures and helped with the paper writing. L.H. and H.C. helped by revising the manuscript. X.Y. and X.L. validated the paper, reviewed the manuscript, and provided the funding resources.

Conflicts of interest disclosure

None reported.

Research registration unique identifying number (UIN)

Not applicable.

Guarantor

Xiaoxi Lin.

Provenance and peer review

Not commissioned.

Data availability statement

Datasets being used are available upon reasonable request.