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Ethanol

The standard TAE, without TVE, is used in patient allocated standard treatment.

The arterial approach will consist of at least one attempted catheterization for trans-arterial injection of liquid embolic.

Patients incompletely treated at the time of the final embolization procedure are adjudicated a failure to reach the primary outcome and can be treated using alternative standard options (including surgery, radiation therapy, conservative management). In addition, patients of the control group can also be offered TVE, if still feasible, once the TAE has been adjudicated to be a failure.

If the operator deems, on the table, for a trans-arterial injection to be too dangerous, no arterial injection is necessary. Treatment, where indicated, can be completed through other means.

The experimental treatment is an attempt to completely occlude the AVM using venous catheterization and retrograde EVOH injection during the final session. TAE can be performed to prepare for final TVE during the same or one previous preparatory session, or TAE can be used to rescue an incomplete TVE. In some patients, balloon catheterization is used trans-arterially to assist TVE.

It will be permissible to perform more than one treatment session when deemed necessary (occasionally to treat an AVM through the trans-venous route requires a two-stage approach, with a single trans-arterial attempt to decrease AVM filling prior to the definitive trans-venous approach, and this will be permitted).

The trans-venous strategy will consist of at least one transvenous injection of ethyl vinyl alcohol (EVOH), with the choice of delivery microcatheters and other technical details left to the individual operator's discretion).

The standard TAE, without TVE, is used in patient allocated standard treatment. The arterial approach will consist of at least one attempted catheterization for trans-arterial injection of liquid embolic.

If the operator deems, on the table, for a trans-arterial injection to be too dangerous, no arterial injection is necessary. Treatment, where indicated, can be completed through other means.

Standard Trans-Arterial Embolization (TAE)

The experimental treatment is an attempt to completely occlude the AVM using venous catheterization and retrograde EVOH injection during the final session.

The trans-venous strategy will consist of at least one transvenous injection of ethyl vinyl alcohol (EVOH), with the choice of delivery microcatheters and other technical details left to the individual operator's discretion.

Trans-Venous Embolization (TVE)

A new endovascular route for the treatment of brain AVMs may be possible in some cases: Trans-Venous Embolization (TVE). The technique uses microcatheters to navigate to the draining veins of AVM, to reach and then fill the AVM nidus retrogradely with liquid embolic agents until the lesion is occluded. This technique has the potential to improve on some of the problems with the arterial approach to AVM embolization, such as a low overall occlusion rate. However, by occluding the vein first, and filling the lesion with the embolic agent in a retrograde fashion, the method transgresses a widely held dogma in the surgical or endovascular treatment of AVMs: to preserve the draining vein until all afferent vessels have been occluded. Nevertheless, the initial case series have shown promising results, with high occlusion rates, and few technical complications.

The method is increasingly used in an increasing number of centers, but there is currently no research protocol to guide the use of this promising but still experimental treatment in a prudent fashion. Care trials can be designed to offer such an experimental treatment, taking into account the best medical interests of patients, in the presence of rapidly evolving indications and techniques.

Transvenous Approach for the Treatment of Cerebral Arteriovenous Malformations

Transvenous Approach for the Treatment of Cerebral Arteriovenous Malformations (TATAM): A Randomized Controlled Trial and Registry

Angiographic evidence of residual AVM at time of confirmatory catheter angiography

Failure to reach a safe and effective microcatheter position for embolization.

Any procedural complication leading to transient new neurological deficit.

Any procedural complication leading to new neurological deficit.

Any treatment-related complication that prolongs hospitalization by ≥5 days.

Incidence of new ischemia following treatment (Brain MR imaging prior to discharge with diffusion sequences).

Incidence of new admission to hospital during follow-up.

Incidence of intracranial hemorrhage during follow-up.

Incidence of residual AVM on confirmatory catheter angiography at 3(+/-1) months post-treatment.

Centre hospitalier de l'Université de Montréal (CHUM)

Patients with unruptured BAVMs will receive symptomatic medical management alone.

Patients with unruptured BAVMs will receive symptomatic medical management with invasive therapies (any combination of surgery, endovascular embolization, or radiotherapy).

All interventional procedures are standard of care for the treatment of AVMs. They are not experimental. A patient randomized to interventional therapy is expected to begin interventional therapy within 3 months following randomization. Interventional therapy consists of endovascular attempts at occlusion of the nidus and feeding vessels, coiling or microsurgery for feeding artery aneurysms, microsurgery for BAVM itself, and radiosurgery, these alone or in various combinations and timings.

Interventional therapy

Patients participating in the trial will receive the best medical management possible for the disorder being tested in the trial and for any general medical illnesses they are demonstrated to have. One important consideration in the medical management of patients in this trial is stroke risk factor reduction.

Medical management

J.P. Mohr, MS, MD

Alan J. Moskowitz, MD

Michael Parides, PhD

Christian Stapf, MD

Eric Vicaut, MD

Claudia S. Moy, PhD

The purpose of this study is to determine if medical management is better than invasive therapy for improving the long-term outcome of patients with unruptured brain arteriovenous malformations.

Brain arteriovenous malformations (BAVMs) are an infrequent but important cause of stroke, particularly in a young population. Current invasive treatment strategies are varied and include endovascular procedures, neurosurgery, and radiotherapy. All of these treatments are administered on the assumption that they can be achieved at acceptably minor complication rates, decrease the risk of subsequent hemorrhage, and lead to better long-term outcomes.

Recent data from the literature comparing initial presentation and outcome for patients with ruptured and unruptured BAVMs have raised the possibility that such elective invasive treatment for unruptured BAVMs may yield worse outcomes than managing patients symptomatically with therapy. Unfortunately, no controlled clinical trials have yet been undertaken for management of unruptured BAVMs to address these concerns. Therefore, the goal of this randomized controlled trial is to determine if the long-term outcomes of patients who receive medical management for symptoms (e.g., headache, seizures) associated with an unruptured BAVM are superior to those who receive medical management and invasive therapy to eradicate the BAVM.

Participants will be randomly assigned to receive either symptomatic medical management alone or such management with invasive therapies (any combination of surgery, endovascular embolization, or radiotherapy). Functional assessment will be carried out at the time of randomization, pre-intervention and 48-hour post-intervention, and for all participants at 1 month, and at 6 month intervals throughout the follow up period which will be a minimum of 5 years.

A Randomized Trial of Unruptured Brain AVMs

A Randomized Trial of Unruptured Brain Arteriovenous Malformations

The hypothesis to be tested is that there is no difference between medical management and interventional therapy in the time to stroke or death from any cause.

The hypothesis to be tested is that early intervention decreases the risk of death or clinical impairment at 5 years post-randomization. (Rankin Score \>/= 2)

National Institute of Neurological Disorders and Stroke (NINDS)

Columbia University

Daniel Sciarra Professor of Neurology

Interventional therapies include:

neurosurgery (surgical resection when the lesion is considered by a multidisciplinary team to be safely 'operable'); radiation therapy (when the AVM is smaller than 3 cm, and considered to not be safely 'operable'); radiosurgery, alone or in combination, with or without endovascular procedure; curative embolization (when the lesion is considered curable by embolization).

Patients with AVMs that the multidisciplinary team judges could potentially benefit from endovascular treatment prior to surgical resection or radiation therapy will then also be pre-randomly allocated to embolization or to no embolization.

The conservative, or medical management arm, involves pharmacological therapy as deemed appropriate for medical symptoms as determined by the treating investigator. Should patients in the conservative management arm develop hemorrhage or infarction related to their AVM, they then potentially become candidates for interventional therapy.

Surgical resection to be used when the lesion is considered by a multidisciplinary team to be safely 'operable'.

Neurosurgery

when the AVM is smaller than 3 cm, and considered to not be safely 'operable'.

Radiation therapy

Curative embolization, when the lesion is considered curable by embolization.

Embolization

Daniel Roy, MD

Tim Darsaut, MD

Rabih Tawk, MD

Thanh Nguyen, MD

Andrew Carlson, MD

Iuri Martins, MD

George Nunes Mendes, MD

Luciana Alves Oliveira Silva, MD

Gisele Sampaio, MD

Tim Darsaut, MD, PhD

Ruby Klink, PhD

Alain Weill, MD

Michel Bojanowski, MD

Chiraz Chaalala, MD

Jean-Paul Bahary, MD

David Roberge, MD

Laura Masucci, MD

Cynthia Ménard, MD

Rodrigo Rivera Miranda, MD

Daniel Eduardo Mantilla Garcia, MD

Andres Felipe Ortiz Giraldo, MD

Elsa Magro, MD

Jean-Christophe Gentric, MD

Alessandra Biondi, MD

Xavier Barreau, MD

Patrick Courtheoux, MD

Emmanuel Chabert, MD

Frédéric Ricolfi, MD

Laurent Spelle, MD

Charble Mounayer, MD

Isabelle Pelissou-Guyotat, MD

Pierre-Hugues Roche, MD

Vincent Costalat, MD

Serge Bracard, MD

Hubert Desal, MD

Philippe Cornu, MD

Michel Piotin, MD

Denis Trystram, MD

Xavier Morandi, MD

Christine Papagiannaki, MD

François Proust, MD

Christophe Cognard, MD

Denis Herbreteau, MD

The objectives of this study and registry are to offer the best management possible for patients with brain arteriovenous malformations (AVMs) (ruptured or unruptured) in terms of long-term outcomes, despite the presence of uncertainty. Management may include interventional therapy (with endovascular procedures, neurosurgery, or radiotherapy, alone or in combination) or conservative management.

The trial has been designed to test a) whether medical management or interventional therapy will reduce the risk of death or debilitating stroke (due to hemorrhage or infarction) by an absolute magnitude of about 15% (over 10 years) for unruptured AVMs (from 30% to 15%); and, b) to test if endovascular treatment can improve the safety and efficacy of surgery or radiation therapy by at least 10% (80% to 90%).

As for the nested trial on the role of embolization in the treatment of Brain AVMs by other means: the pre-surgical or pre-radiosurgery embolization of cerebral AVMs can decrease the number of treatment failures from 20% to 10%. In addition,embolization of cerebral AVMs can be accomplished with an acceptable risk, defined as permanent disabling neurological complications of 8%.

Intracranial arteriovenous malformations (AVMs) are relatively uncommon but increasingly discovered lesions that can lead to significant neurological disability or death.1 Population-based data suggest that the annual incidence of discovery of a symptomatic AVM is approximately 1.1 per 100 000 population.7. AVMs commonly present following an intracranial hemorrhage or seizure, although with contemporary brain imaging techniques, an increasing number of incidental lesions are found.2

Intracranial AVMs are typically diagnosed before the age of 40 years old, with more than 50% of patients presenting following an intracranial hemorrhage, the most feared sequelae of harbouring an AVM.3 An AVM-related seizure is reported as the presenting feature in 20-25% of cases4, 5 and although these can sometimes be successfully managed with anti-epileptic agents, some AVMs lead to intractable seizures in spite of medication. Other presentations include headaches, focal neurological deficits, or pulsatile tinnitus.1

The available natural history studies indicate an overall risk of initial hemorrhage of approximately 2% to 4% per year, although the long-term consequences in terms of the probability of death or long-term disability following intracranial hemorrhage remains unclear.6-8 Mortality from the first hemorrhage has been reported to occur between 10-30% of patients with a ruptured AVM, although some more recent data suggest that the mortality rate may be lower and only 10-20% of survivors have long-term disability.9-11 Hemorrhagic presentation is considered the most reliable risk factor for a repeat hemorrhage.6, 8 Unfortunately, the natural history data available is not of sufficient quality (Level V) to support making management recommendations.

Over the last decade, there have been substantial developments in the management of intracranial AVMs. There has been an evolution of microsurgical as well as endovascular and radiosurgical techniques to treat these lesions. As the management options have evolved, individual and combined modality treatment protocols have been developed in different institutions for the management of AVMs. Current interventional therapy for brain arteriovenous malformations (BAVMs) is varied and includes open neurosurgical resection, radiosurgery, and endovascular management, either alone or in combination. The choice of management is largely dependent on the decisions of the local physicians that make up the treatment team, and a recent survey has demonstrated substantial variability in decision-making for almost all AVMs.12

Interventional therapies, when they are performed, are assumed to decrease the risk of initial or subsequent hemorrhage and therefore lead to better long-term outcomes, an assumption that has yet to be proven.

Although the question of which AVM treatment modality is the most appropriate first choice (surgery, radiosurgery, or embolization) remains controversial, consensus can be reached in several circumstances. Surgical evacuation of a hematoma exerting significant mass effect is an uncontested appropriate management, although many patients with a hemorrhagic presentation do not necessarily meet this threshold for surgical indication. Almost all other management choices remain debatable.13, 14 A systematic review has proposed that approximately 7.1% of surgical candidates, 6.6% of endovascular candidates, and 5.1% of radiosurgical candidates were facing permanent neurological deficits after treatment.15 The epidemiological study of Davies et al, using the Nationwide Inpatient Sample (NIS) data base and surrogates such as location at discharge, showed worse outcomes for surgical and endovascular management of both ruptured and unruptured AVMs.16

Current choices of interventional therapy for brain arteriovenous malformations are varied, with decisions made on a case-by-case basis, by the local clinical team. Often these decisions will change as the results of one particular attempted treatment modality become available. All interventional therapies are performed with the assumption that they will decrease the risk of initial or subsequent hemorrhage and lead to better long-term patient outcomes. Despite these laudable goals, there is no reliable evidence that interventional management of unruptured bAVMs is beneficial, and in patients judged to need interventional therapy, such as those patients presenting with ruptures, there is no randomized evidence that embolization is beneficial. Although no clinical trial data exist on the effect of interventional therapy even after AVM hemorrhage, the most contentious issue at present is whether interventional therapy should be considered for patients with incidentally discovered AVMs, whose lesions have not bled. In patients with unruptured AVMs, the best management strategy remains unknown, and interventions should be proposed only in the context of a randomized trial.

The potential role of embolization: Although endovascular AVM embolization can occasionally eradicate lesions without surgery or radiation therapy in selected cases, and although embolization may potentially improve the safety and efficacy of surgical or radiosurgical treatments in some other cases, it remains a contentious issue whether it is worth accepting the additional risks of endovascular treatment for a greater overall benefit for patients with brain AVMs that are treatable by surgery or radiation therapy. Some series have reported satisfactory results.20 It is possible that the overall morbidity and mortality of the combined interventional management strategy is increased when embolization is added to a surgical or radiosurgical procedure.17 Therefore, pre-surgical or pre-radiosurgical embolization can be offered, but only as a randomized allocation between embolization and no embolization, within the context of a trial.

Primary objective: In the spirit of care trials, the primary objective of the trial and accompanying registry is to offer the best management possible for patients with brain AVMs (ruptured or unruptured) in terms of long-term outcomes, despite the presence of uncertainty. Management may include interventional therapy (neurosurgery, or radiosurgery, alone or in combination, with or without endovascular procedures, alone or combined) or conservative management. An expert multidisciplinary study group will review patients on an individual basis to determine eligibility for the trial or registry parts of the study. The trial has been designed to test whether conservative management or interventional therapy will reduce the risk of disabling stroke or death.

Secondary objectives: To determine if interventional management is effective in the prevention of neurological events during 10 years. To determine the morbidity and mortality related to therapy. To follow-up and record the neurological events and the neurological status of all patients with brain AVMs recruited and managed in our institutions, regardless of management strategy chosen.

Hypotheses

A) Randomized comparison of interventional treatment and conservative management:

Primary hypothesis: Treatment of cerebral AVMs can decrease the number of disabling neurological events caused by the presence of the AVM (excluding peri-operative complications) from 30 to 15% within 10 years. (n = 266 minima) Secondary hypothesis: Treatment of cerebral AVMs can be accomplished with an acceptable up-front risk, defined as the occurrence of a permanent disabling neurological complication in less than 15% of patients)

B) Nested trial on the Role of embolization in the treatment of Brain AVMs by other means Primary hypothesis: Pre-surgical or pre-radiosurgery embolization of cerebral AVMs can decrease the number of treatment failures (failure to achieve angiographic cure) from 20% to 10% (n= 440).

Secondary hypothesis: Embolization of cerebral AVMs can be accomplished with an acceptable risk, defined as permanent disabling neurological complications of 8% (3.4 to 12.6%, 95% C.I.).

The study design is a prospective, multi-center, randomized, controlled trial and registry. Treatment assignment will not be masked; Interim study results will be kept confidential. The primary outcome is the composite event of death from any cause or disabling stroke (hemorrhage or infarction revealed by imaging and resulting in mRS \>2). Functional outcome status will be measured by the Rankin Scale, a widely used outcome measure for stroke. The secondary measures of outcome include adverse events, ruptures, and angiographic occlusion of the lesion.

Treatment of Brain AVMs (TOBAS) Study

Treatment of Brain AVMs (TOBAS) Study: A Randomized Controlled Trial and Registry

death or disabling stroke due to hemorrhage or infarction as revealed by imaging and resulting in mRS \>2.

The incidence of permanent (more than 3 months) disabling (mRS \>2) peri-operative (within 31 days) complications

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Transvenous Approach for the Treatment of Cerebral Arteriovenous Malformations	NCT03691870	Arteriovenous M... Unruptured Brai... Ruptured Brain ...	Standard Trans-... Trans-Venous Em...	-	Centre hospitalier de l'Université de Montréal (CHUM)
Transvenous Approach for the Treatment of Cerebral Arteriovenous Malformations	NCT03691870	Arteriovenous M... Unruptured Brai... Ruptured Brain ...	Standard Trans-... Trans-Venous Em...	-	Centre hospitalier de l'Université de Montréal (CHUM)
A Randomized Trial of Unruptured Brain AVMs	NCT00389181	Arteriovenous M...	Interventional ... Medical managem...	18 Years -	Columbia University
Treatment of Brain AVMs (TOBAS) Study	NCT02098252	Unruptured Brai... Ruptured Brain ... Arteriovenous M... AVM BAVM	Neurosurgery Radiation thera... Embolization	5 Years -	Centre hospitalier de l'Université de Montréal (CHUM)
A Randomized Trial of Unruptured Brain AVMs	NCT00389181	Arteriovenous M...	Interventional ... Medical managem...	18 Years -	Columbia University

Spots Global Cancer Trial Database for unruptured brain arteriovenous malformation