Clinical trial NCT00389181: A Randomized Trial of Unruptured Brain AVMs
Official title: A Randomized Trial of Unruptured Brain Arteriovenous Malformations
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Arteriovenous Malformations, Cerebral
Keywords: Unruptured brain arteriovenous malformation
AVM
BAVM
Stroke
Intracranial Hemorrhage
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: National Institute of Neurological Disorders and Stroke (NINDS)
First posted: 2006-10-18
Enrollment: 226
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Patient must have unruptured BAVM diagnosed by MRI/MRA, CTA and/or angiogram
2. Patient must be 18 years of age or older
3. Patient must have signed Informed Consent, Release of Medical Information, and Health Insurance Portability and Accountability Act (HIPAA/U.S. only) Forms

Exclusion Criteria:

1. Patient has BAVM presenting with evidence of recent or prior hemorrhage
2. Patient has received prior BAVM therapy (endovascular, surgical, radiotherapy)
3. Patient has BAVM deemed untreatable by local team, or has concomitant vascular or brain disease that interferes with/or contraindicates any interventional therapy type (stenosis/occlusion of neck artery, prior brain surgery/radiation for other reasons)
4. Patient has baseline Rankin ≥2
5. Patient has concomitant disease reducing life expectancy to less than 10 years
6. Patient has thrombocytopenia (\< 100,000/μL),
7. Patient has uncorrectable coagulopathy (INR\>1.5)
8. Patient is pregnant or lactating
9. Patient has known allergy against iodine contrast agents
10. Patient has multiple-foci BAVMs
11. Patient has any form of arteriovenous or spinal fistulas

    Previous diagnosis of any of the following -
12. Patient has a diagnosed Vein of Galen type malformation
13. Patient has a diagnosed cavernous malformation
14. Patient has a diagnosed dural arteriovenous fistula
15. Patient has a diagnosed venous malformation
16. Patient has a diagnosed neurocutaneous syndrome such as cerebro-retinal angiomatosis (von Hippel-Lindau), encephalo-trigeminal syndrome (Sturge-Weber), or Wyburn-Mason syndrome
17. Patient has diagnosed BAVMs in context of moya-moya-type changes
18. Patient has diagnosed hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber)

Primary outcomes:
measure: Difference of 5-year event rates between two arms
timeFrame: 5 years
Secondary outcomes:
measure: Prevalence of the risk of death or clinical impairment at 5 years post-randomization with early intervention
timeFrame: 5 years
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute, 350 West Thomas Road
state: Arizona
city: Los Angeles
country: United States
facility: Kaiser Permanente Los Angeles Medical Center,4867 Sunset Blvd
state: California
city: Los Angeles
country: United States
facility: University of California at Los Angeles, UCLA School of Medicine, 710 Westwood Plaza
state: California
city: Redwood City
country: United States
facility: Kaiser Permanente (SF)
state: California
city: San Francisco
country: United States
facility: University of California at San Francisco, 1001 Potrero Avenue- Rm 3C-38
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Maywood
country: United States
facility: Loyola University Stritch School of Medicine, Department of Neurology, 2160 S 1st Ave, Bldg 105/2700
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals, Department of Neurology, 200 Hawkins Drive ,
state: Iowa
city: Southfield
country: United States
facility: Michigan Head and Spine Institute, Providence Hospital and Medical Center, 16001 West Nine Mile Road
state: Michigan
city: Paterson
country: United States
facility: St. Joseph's Regional Medical Center
state: New Jersey
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center, 451 Clarkson Avenue, Box 1189
state: New York
city: Buffalo
country: United States
facility: Mercy Hospital of Buffalo
state: New York
city: Mineola
country: United States
facility: Winthrop University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai Hospital, One Gustave L. Levy Place, Department of Neurosurgery- Box 1136
state: New York
city: New York
country: United States
facility: New York Presbyterian Hospital, Columbia Campus, Neurological Institute, 710 W. 168th St
state: New York
city: Johnstown,
country: United States
facility: John P. Murtha Neuroscience & Pain Institute,1450 Scapl Ave, Suite 120,
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson Hospital for Neuroscience
state: Pennsylvania
city: Austin
country: United States
facility: Brackenridge Hospital, Brain and Spine Center, 601 East 15th Street
state: Texas
city: Houston
country: United States
facility: University of Texas Medical School in Houston
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia School of Medicine, Department of Neurosurgery, P.O. Box 800212
state: Virginia
city: Norfolk
country: United States
facility: Sentara Medical Group
state: Virginia
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Auchenflower
country: Australia
facility: Wesley Medical Center
state: Queensland
city: Melbourne
country: Australia
facility: Austin Health, University of Melbourne 300 Waterdale Rd,Heidelberg Heights
state: Victoria
city: Innsbruck
country: Austria
facility: Universitätsklinik für Neurologie, Anichstrasse 35, 6020 Innsbruck
city: Wien
country: Austria
facility: Rudolfstiftung, Neurochirurgie, Juchgasse 25, A-1030
city: Porto Alegre
country: Brazil
facility: Hospital de Clinicas de Porto Alegre
city: Hamilton
country: Canada
facility: Hamilton General Hospital .237 Barton Street East
state: Ontario
city: London
country: Canada
facility: London Health Sciences Center
state: Ontario
city: Montreal
country: Canada
facility: CHUM Notre Dame Hospital, Department of Radiology, 1560 Sherbrooke Street
state: Quebec
city: Helsinki
country: Finland
facility: Helsinki University Central Hospital, Dept. of Neurosurgery, Topeliuksenkatu 5, Helsinki, P.O. Box 266
city: Brest cedex
country: France
facility: Hôpital de la Cavale-Blanche, Service de Neurologie, Bd. Tanguy Pringent
city: Creteil Cedex
country: France
facility: CHU Henri Mondor, Service de Neuroradiologie
city: Lille Cedex
country: France
facility: Centre Hospitalier Régional et Universitaire de Lille, Clinique de Neurochirurgie, Hopital Roger Salengro, CHRU
city: Paris cedex 10
country: France
facility: Hôpital Lariboisière, Service de Neuroradiologie, 2, Rue Ambroise Paré
city: Paris
country: France
facility: Hôpital Sainte Anne, Service de Neurochirurgie, Centre Hospitalier Sainte Anne, 1, Rue Cabanis
city: Paris
country: France
facility: European Coordinating Center: Dept. of Neurology, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris cedex 10,
city: Berlin
country: Germany
facility: Charité Campus Benjamin Franklin (CCBF), Neurologische Klinik, Hindenburgdamm 30
city: Dresden
country: Germany
facility: Uniklinikum Dresden, Neuroradiologie, Fetscherstr. 74
city: Essen
country: Germany
facility: Universitätsklinikum Essen, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Hufelandstraße 55
city: Frankfurt am Main
country: Germany
facility: Uniklinikum Frankfurt, Institut für Neuroradiologie, Schleusenweg 2-16
city: Freiburg
country: Germany
facility: Uniklinik Freiburg, Neuroradiology-Neurocenter, Breisacher Str. 64
city: Halle
country: Germany
facility: Berufsgenossenschaftliche Kliniken Bergmannstrost, Klinik für Neurochirurgie, Merseburger Str. 165
city: Hamburg
country: Germany
facility: Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52
city: Heidelberg
country: Germany
facility: Universitätsklinik Heidelberg, Department of Neurosurgery, Im Neuenheimer Feld 400
city: Munich
country: Germany
facility: Klinikum Großhadern, LMU München, Neurologische Klinik und Poliklinik, Marchionistr. 15
city: Bologna
country: Italy
facility: Bellaria Hospital, Department of Neurosurgery
city: Milano
country: Italy
facility: Servizio di Neuroradiologia, Ospedale San Raffaele, Via Olgettina 60
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Groningen
country: Netherlands
facility: Department of Neurosurgery, Universitair Medisch Centrum Groningen Hanzeplein 1
city: Utrecht
country: Netherlands
facility: Utrecht University Hospital, Heidelberglaan 100, 3584 CX
city: Barcelona
country: Spain
facility: Hospital Universitari de Bellvitge, Sección de Neuroradiologia, c/ Feixa Llarga s/n, L'Hospitalet de Llobregat
city: Schweiz
country: Switzerland
facility: Inselspital, Neurologische Klinik, 3010 Bern
city: Bristol
country: United Kingdom
facility: Frenchay Hospital, Neuroradiology Department
city: Edinburgh
country: United Kingdom
facility: Western General Hospital, Bramwell Dott Building, Department of Clinical Neurosciences, Crewe Road
city: Leeds
country: United Kingdom
facility: Consultant Neurologist, Department of Neurology, Leeds General Infirmary, Great George Street
city: Liverpool
country: United Kingdom
facility: Walton Centre for Neurology, Lower Lane Fazakerley
city: London
country: United Kingdom
facility: Institute of Neurology, Box 6, The National Hospital, Queen Square
city: Newcastle upon Tyne
country: United Kingdom
facility: Department of Neurosurgery, Newcastle General Hospital, Westgate Road
city: Plymouth
country: United Kingdom
facility: Imaging Directorate, Derriford Hospital
city: Preston
country: United Kingdom
facility: Neuroscience Department, Royal Preston Hospital, Sharoe Green Lane, Fulwood
city: Salford
country: United Kingdom
facility: Department of Neurology, Hope Hospital
city: Sheffield
country: United Kingdom
facility: Department of Neurology, Royal Hallamshire Hospital, Glossop Road
Study officials:
affiliation: Stroke Center/The Neurological Institute, Columbia University
name: J.P. Mohr, MS, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: InCHOIR, Department of Health Policy, Mount Sinai School of Medicine
name: Alan J. Moskowitz, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: InCHOIR, Department of Health Policy, Mount Sinai School of Medicine, Co-PI
name: Michael Parides, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Coordinating Center, Europe
name: Christian Stapf, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinical Coordinating Center, Europe, Co-PI
name: Eric Vicaut, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NINDS, Co-PI
name: Claudia S. Moy, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Stapf C, Mohr JP, Choi JH, Hartmann A, Mast H. Invasive treatment of unruptured brain arteriovenous malformations is experimental therapy. Curr Opin Neurol. 2006 Feb;19(1):63-8. doi: 10.1097/01.wco.0000200546.14668.78.
citation: Mohr JP, Overbey JR, Hartmann A, Kummer RV, Al-Shahi Salman R, Kim H, van der Worp HB, Parides MK, Stefani MA, Houdart E, Libman R, Pile-Spellman J, Harkness K, Cordonnier C, Moquete E, Biondi A, Klijn CJM, Stapf C, Moskowitz AJ; ARUBA co-investigators. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. Lancet Neurol. 2020 Jul;19(7):573-581. doi: 10.1016/S1474-4422(20)30181-2.
citation: Mohr JP, Overbey JR, von Kummer R, Stefani MA, Libman R, Stapf C, Parides MK, Pile-Spellman J, Moquete E, Moy CS, Vicaut E, Moskowitz AJ, Harkness K, Cordonnier C, Biondi A, Houdart E, Berkefeld J, Klijn CJM, Barreau X, Kim H, Hartmann A; International ARUBA Investigators. Functional impairments for outcomes in a randomized trial of unruptured brain AVMs. Neurology. 2017 Oct 3;89(14):1499-1506. doi: 10.1212/WNL.0000000000004532. Epub 2017 Sep 6.
citation: Mohr JP, Parides MK, Stapf C, Moquete E, Moy CS, Overbey JR, Al-Shahi Salman R, Vicaut E, Young WL, Houdart E, Cordonnier C, Stefani MA, Hartmann A, von Kummer R, Biondi A, Berkefeld J, Klijn CJ, Harkness K, Libman R, Barreau X, Moskowitz AJ; international ARUBA investigators. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet. 2014 Feb 15;383(9917):614-21. doi: 10.1016/S0140-6736(13)62302-8. Epub 2013 Nov 20.
citation: Stapf C. The rationale behind "A Randomized Trial of Unruptured Brain AVMs" (ARUBA). Acta Neurochir Suppl. 2010;107:83-5. doi: 10.1007/978-3-211-99373-6_13.
citation: Stapf C, Mohr JP. Unruptured brain arteriovenous malformations should be treated conservatively: yes. Stroke. 2007 Dec;38(12):3308-9. doi: 10.1161/STROKEAHA.107.504605. Epub 2007 Oct 25. No abstract available.