In Situ Injection of Anti-angiogenics in Patients With Brain Arteriovenous Malformations Not Eligible for Exclusion Treatment

NCT07075757 | Not Yet Recruiting Phase 1 DMC

• 2 other identifiers: APHP2110332023-506991-28-00
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 5

Brief Summary

Brain arteriovenous malformations (bAVMs) are rare aggressive vascular malformations affecting mostly young and healthy adults. The most frequent revealing condition (in almost 50% of cases) is an intra-cerebral hemorrhage, which is a considerable source of disability and mortality. The only way to prevent a bleeding or a rebleeding is to perform an exclusion treatment (endovascular embolization, microsurgery, stereotactic radiosurgery, or a combination of these techniques). The major drawback of these treatments is the risk of severe complications, which can reach 20%, especially in patients presenting a bAVM with complex angio-architecture (i.e., grade IV to V in the Spetzler Martin grading scale). There is a growing evidence about the strong implication of angiogenesis (mainly mediated by the type A vascular endothelial growth factor \[VEGF-A\]) on the size and growth of the bAVM and even in the occurrence of bleeding events. Our hypothesis is that an in situ injection of bevacizumab, a monoclonal antibody inhibiting VEGF-A, in patients with bAVM deemed not suitable for exclusion treatment may be safe and help to reduce the nidus volume.

Conditions

Brain Arteriovenous Malformations

Keywords

Brain arteriovenous malformations (bAVM), in situ intra-arterial injection, Bevacizumab

Outcome Measures

Primary Outcomes (1)

• Dose limiting toxicity

  Dose limiting toxicity defined as the occurrence within 30 days of the in situ injection of bevacizumab of one of the following events: * Symptomatic venous/arterial thromboembolic events : pulmonary embolism, deep venous thrombosis, ischemic stroke, related to an arterial occlusion * Severe cytopenia defined as:Anemia defined as hemoglobin level less than 8.0 g/dL grade ≥ III,Thrombocytopenia \< 50 G/L grade ≥ III * Neutropenia \< 1000/μ L grade ≥ IV * Hypertension grade ≥ III * Symptomatic intracranial hemorrhage, resulting in transient/permanent neurological deficit * Any bleeding requiring transfusion * Leukoencephalopathy grade ≥ III * Onset of intractable seizures ≥ Grade III * Thrombo-embolic complication during the procedure leading to permanent deficit/death * Intracranial arterial perforation with the microcatheter/ microguide wire resulting in symptomatic hemorrhage causing any disability/death. * Any other serious adverse reaction resulting in any disability or death

  Days 0 (day of the injection) to day 30

Secondary Outcomes (4)

• Tolerance of escalating doses (3+3) of an in situ intra-arterial injection of bevacizumab

  Days 0 (day of the injection) to 12 months

• Reduction of the nidus volume

  at 6 and 12 months

• Occurrence of an intra-cerebral bleeding event

  Days 0 (day of the injection) to 12 months

• Occurrence of at least one seizure

  Days 0 (day of the injection) to 12 months

Study Arms (1)

Single in situ intra-arterial injection of bevacizumab

EXPERIMENTAL

3 Escalating doses of an in situ intra-arterial injection of Bevacizumab (5 mg/kg, 7.5 mg/kg, 10 mg/kg)

Drug: Single in situ intra-arterial injection of bevacizumab

Interventions

Single in situ intra-arterial injection of bevacizumab DRUG

3 Escalating doses of an in situ intra-arterial injection of Bevacizumab (5 mg/kg, 7.5 mg/kg, 10 mg/kg)

Single in situ intra-arterial injection of bevacizumab

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• bAVM (i.e.: located in the brain, brain stem or cerebellum)
• History of rupture and/or with intractable symptoms related to the bAVM (i.e.: intractable seizure, steal phenomenon, compressive symptoms)
• Hemoglobin (Hb) levels more than 13.5 g/dL in males and Hb levels more than 12.5 g/dL in females.
• Platelet count ≥ 150 G/L
• Leukocytes count ≥ 3000/μL
• Neutrophils count ≥ 1500/μL
• Complete COVID-19 vaccinal scheme, according to the French recommendations
• Affiliation to French Healthcare system (AME excluded)
• Signed informed consent

You may not qualify if:

• Diffuse bAVM (like proliferative angiopathy) that cannot be assessed in terms of volume by cross-sectional imaging on MRI
• Inability/contraindication to undergo MRI (Pacemaker, iron metallic items, cochlear implants, claustrophobia)
• Coagulation disorders (prothrombin time \< 50% or Platelet count \< 150 G/L)
• Any congenital predisposition to coagulation disorder
• Any disease requiring full anticoagulation
• History of cancer, except baso-cellular carcinoma
• Congestive cardiac failure
• Pre-existing coronary disease
• Unstable medical or psychiatric illness
• Any history of clinically significant thrombotic episode within the last 6 months
• Any history of atrial fibrillation
• Proteinuria (albumin excretion rate \> 30 mg/day)
• Blood hypertension grade ≥ II (CTACE v5.0, 2017)
• Past history of a gastro-intestinal fistula
• Past history of a vaginal fistula

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (5)

CHU de Limoges, Hôpital Dupuytren

Limoges, 87000, France

Location

CHU de Nancy, Hôpital Central

Nancy, 54000, France

Location

APHP, Hôpital Pitié-Salpêtrière

Paris, 75013, France

Location

Centre Hospitalier Sainte-Anne

Paris, 75014, France

Location

CHU de Rouen, Hôpital Charles-Nicolle

Rouen, 76000, France

Location

MeSH Terms

Conditions

Intracranial Arteriovenous Malformations

Interventions

Single Person

Condition Hierarchy (Ancestors)

Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Central Nervous System Vascular Malformations; Nervous System Malformations; Arteriovenous Malformations; Vascular Malformations; Cardiovascular Abnormalities; Cardiovascular Diseases; Vascular Diseases; Intracranial Arterial Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Intervention Hierarchy (Ancestors)

Marital Status; Family Characteristics; Demography; Population Characteristics; Socioeconomic Factors

Study Officials

• Frédéric Clarençon, Professor

  Pitié-Salpêtrière Hospital, AP-HP - Neuroradiology department

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Frédéric Clarençon, Professor

CONTACT

(+33)1 42 16 35 43; frederic.clarencon@aphp.fr

Marthe Mahi, Project manager

CONTACT

(+33)1 42 16 16 99; marthe.mahi@aphp.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 10, 2025
• First Posted: July 20, 2025
• Study Start: October 1, 2025
• Primary Completion (Estimated): November 1, 2028
• Study Completion (Estimated): November 1, 2028
• Last Updated: July 20, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor
• Access Criteria: Researchers who provide a methodologically sound proposal.

Locations

FR (5)