Treatment of Brain AVMs (TOBAS) Study

Sponsor

Centre hospitalier de l'Université de Montréal (CHUM) (Other)

Overall Status

Recruiting

CT.gov ID

NCT02098252

Collaborator

Centre Hospitalier Régional et Universitaire de Brest (Other)

1,000

Enrollment

Locations

Arms

260

Duration (Months)

34.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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,

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%.

Condition or Disease	Intervention/Treatment	Phase
Unruptured Brain Arteriovenous Malformation Ruptured Brain Arteriovenous Malformation Arteriovenous Malformations AVM BAVM	Procedure: Neurosurgery Radiation: Radiation therapy Procedure: Embolization	N/A

Detailed Description

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)

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

1000 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

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

Study Start Date :

May 1, 2014

Anticipated Primary Completion Date :

Jan 1, 2035

Anticipated Study Completion Date :

Jan 1, 2036

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Interventional therapy 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.	Procedure: Neurosurgery Surgical resection to be used when the lesion is considered by a multidisciplinary team to be safely 'operable'. Radiation: Radiation therapy when the AVM is smaller than 3 cm, and considered to not be safely 'operable'. Procedure: Embolization Curative embolization, when the lesion is considered curable by embolization.
No Intervention: Conservative management (medical management) 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.

Arm

Intervention/Treatment

Active Comparator: Interventional therapy

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.

Procedure: Neurosurgery

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

Radiation: Radiation therapy

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

Procedure: Embolization

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

No Intervention: Conservative management (medical management)

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.

Outcome Measures

Primary Outcome Measures

composite event of death from any cause or disabling stroke [up to 10 years post-treatment (or randomization)]
death or disabling stroke due to hemorrhage or infarction as revealed by imaging and resulting in mRS >2.

Secondary Outcome Measures

occurrence of any neurological event [within 10 years following treatment (or after randomization)]
Permanent disabling peri-operative complications [within 31 days post-treatment]
The incidence of permanent (more than 3 months) disabling (mRS >2) peri-operative (within 31 days) complications

Eligibility Criteria

Criteria

Ages Eligible for Study:

5 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Any patient with a brain AVM

Exclusion Criteria:

Hemorrhagic presentation with mass effect requiring surgical management. In these cases, if a residual AVM is found after the initial surgery, the patient could then be a candidate for TOBAS.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Jacksonville FL	Jacksonville	Florida	United States
2	Boston Medical Center	Boston	Massachusetts	United States	02118
3	University of New Mexico Health Sciences Center	Albuquerque	New Mexico	United States	87131
4	Hospital Geral de Fortaleza	Fortaleza		Brazil
5	Universidade Federal de Sǎo Paulo	São Paulo		Brazil
6	University of Alberta Hospital	Edmonton	Alberta	Canada
7	Centre Hospitalier de l'Université de Montréal	Montreal	Quebec	Canada	H2L 4M1
8	Instituto de Neurocirugia Dr. A. Asenjo	Santiago		Chile
9	CHRU de Brest (Brest University Hospital)	Brest	Bretagne	France	29609
10	Centre Hospit Régional Universitaire de Besançon	Besançon		France	25030
11	Centre Hospitalier Universitaire de Bordeaux	Bordeaux		France	33000
12	Centre Hospitalier Universitaire de Caen	Caen		France	14033
13	CHU Clermont-Ferrand	Clermont-Ferrand		France
14	CHU Dijon Bourgogne	Dijon		France
15	Hôpital Bicêtre AP-HP	Le Kremlin-Bicêtre		France	94270
16	CHU Limoges	Limoges		France	87042
17	Centre Hospitalier Universitaire de Lyon	Lyon		France	69002
18	Assistance Publique - Hôpitaux de Marseille	Marseille		France	13005
19	Centre Hospitalier Universitaire de Montpellier	Montpellier		France	34000
20	Centre Hospitalier Régional Universitaire de Nancy	Nancy		France	54035
21	Centre Hospitalier Universitaire de Nantes	Nantes		France	44093
22	Hôpital Universitaire Pitié-Salpêtrière	Paris		France	75013
23	Fondation Ophtalmologique Rothschild	Paris		France	75019
24	Centre Hospitalier Sainte-Anne	Paris		France	75674
25	Centre Hospitalier Universitaire de Rennes	Rennes		France	35033
26	Centre Hospitalier Universitaire Hôpitaux de Rouen	Rouen		France	76130
27	Les Hôpitaux Universitaires de Strasbourg	Strasbourg		France	67200
28	Centre Hospitalier Universitaire de Toulouse	Toulouse		France	70034
29	Centre Hospitalier Régional Universitaire de Tours	Tours		France	37000