A Randomized Trial of Unruptured Brain AVMs (ARUBA)

A Randomized Trial of Unruptured Brain Arteriovenous Malformations

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.

Study Overview

• Status: Completed
• Conditions: Arteriovenous Malformations, Cerebral
• Intervention / Treatment: Other: Medical management; Procedure: Interventional therapy

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.

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Queensland
    • Auchenflower, Queensland, Australia, 4066
      • Wesley Medical Center
  • Victoria
    • Melbourne, Victoria, Australia, 3081
      • Austin Health, University of Melbourne 300 Waterdale Rd,Heidelberg Heights
• Austria
  • Innsbruck, Austria
    • Universitätsklinik für Neurologie, Anichstrasse 35, 6020 Innsbruck
  • Wien, Austria
    • Rudolfstiftung, Neurochirurgie, Juchgasse 25, A-1030
• Brazil
  • Porto Alegre, Brazil
    • Hospital de Clínicas de Porto Alegre
• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Hamilton General Hospital .237 Barton Street East
    • London, Ontario, Canada, N6A 5W9
      • London Health Sciences Center
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM Notre Dame Hospital, Department of Radiology, 1560 Sherbrooke Street
• Finland
  • Helsinki, Finland, FI-00029 HUS
    • Helsinki University Central Hospital, Dept. of Neurosurgery, Topeliuksenkatu 5, Helsinki, P.O. Box 266
• France
  • Brest cedex, France, 29609
    • Hôpital de la Cavale-Blanche, Service de Neurologie, Bd. Tanguy Pringent
  • Creteil Cedex, France, 94010
    • CHU Henri Mondor, Service de Neuroradiologie
  • Lille Cedex, France, 59037
    • Centre Hospitalier Régional et Universitaire de Lille, Clinique de Neurochirurgie, Hopital Roger Salengro, CHRU
  • Paris, France, 75014
    • Hôpital Sainte Anne, Service de Neurochirurgie, Centre Hospitalier Sainte Anne, 1, Rue Cabanis
  • Paris, France
    • European Coordinating Center: Dept. of Neurology, Hôpital Lariboisière, 2 Rue Ambroise Paré, 75475 Paris cedex 10,
  • Paris cedex 10, France, 75475
    • Hôpital Lariboisière, Service de Neuroradiologie, 2, Rue Ambroise Paré
• Germany
  • Berlin, Germany, 12200
    • Charité Campus Benjamin Franklin (CCBF), Neurologische Klinik, Hindenburgdamm 30
  • Dresden, Germany, 01307
    • Uniklinikum Dresden, Neuroradiologie, Fetscherstr. 74
  • Essen, Germany, 45147
    • Universitätsklinikum Essen, Institut für Diagnostische und Interventionelle Radiologie und Neuroradiologie, Hufelandstraße 55
  • Frankfurt am Main, Germany, 60528
    • Uniklinikum Frankfurt, Institut für Neuroradiologie, Schleusenweg 2-16
  • Freiburg, Germany, 79106
    • Uniklinik Freiburg, Neuroradiology-Neurocenter, Breisacher Str. 64
  • Halle, Germany, 06112
    • Berufsgenossenschaftliche Kliniken Bergmannstrost, Klinik für Neurochirurgie, Merseburger Str. 165
  • Hamburg, Germany, 20246
    • Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52
  • Heidelberg, Germany, 69120
    • Universitätsklinik Heidelberg, Department of Neurosurgery, Im Neuenheimer Feld 400
  • Munich, Germany, 81377
    • Klinikum Großhadern, LMU München, Neurologische Klinik und Poliklinik, Marchionistr. 15
• Italy
  • Bologna, Italy, 40139
    • Bellaria Hospital, Department of Neurosurgery
  • Milano, Italy, 20131
    • Servizio di Neuroradiologia, Ospedale San Raffaele, Via Olgettina 60
• Korea, Republic of
  • Seoul, Korea, Republic of, 1 10-744
    • Seoul National University Hospital
• Netherlands
  • Groningen, Netherlands, 9700
    • Department of Neurosurgery, Universitair Medisch Centrum Groningen Hanzeplein 1
  • Utrecht, Netherlands
    • Utrecht University Hospital, Heidelberglaan 100, 3584 CX
• Spain
  • Barcelona, Spain, 08907
    • Hospital Universitari de Bellvitge, Sección de Neuroradiologia, c/ Feixa Llarga s/n, L'Hospitalet de Llobregat
• Switzerland
  • Schweiz, Switzerland
    • Inselspital, Neurologische Klinik, 3010 Bern
• United Kingdom
  • Bristol, United Kingdom, BS 16 1LE
    • Frenchay Hospital, Neuroradiology Department
  • Edinburgh, United Kingdom, EH4 2XU
    • Western General Hospital, Bramwell Dott Building, Department of Clinical Neurosciences, Crewe Road
  • Leeds, United Kingdom, LS1 3EX
    • Consultant Neurologist, Department of Neurology, Leeds General Infirmary, Great George Street
  • Liverpool, United Kingdom, L9 7LJ
    • Walton Centre for Neurology, Lower Lane Fazakerley
  • London, United Kingdom, WC12N 3BG
    • Institute of Neurology, Box 6, The National Hospital, Queen Square
  • Newcastle upon Tyne, United Kingdom, NE4 6BE
    • Department of Neurosurgery, Newcastle General Hospital, Westgate Road
  • Plymouth, United Kingdom, PL6 8DH
    • Imaging Directorate, Derriford Hospital
  • Preston, United Kingdom, PR2 9HP
    • Neuroscience Department, Royal Preston Hospital, Sharoe Green Lane, Fulwood
  • Salford, United Kingdom, M6 8HD
    • Department of Neurology, Hope Hospital
  • Sheffield, United Kingdom, 810 2JF
    • Department of Neurology, Royal Hallamshire Hospital, Glossop Road
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Barrow Neurological Institute, 350 West Thomas Road
  • California
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Los Angeles Medical Center,4867 Sunset Blvd
    • Los Angeles, California, United States, 90095-1769
      • University of California at Los Angeles, UCLA School of Medicine, 710 Westwood Plaza
    • Redwood City, California, United States, 94063
      • Kaiser Permanente (SF)
    • San Francisco, California, United States, 94110
      • University of California at San Francisco, 1001 Potrero Avenue- Rm 3C-38
  • Florida
    • Miami, Florida, United States, 33146
      • University of Miami
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Maywood, Illinois, United States, 60153-3304
      • Loyola University Stritch School of Medicine, Department of Neurology, 2160 S 1st Ave, Bldg 105/2700
  • Iowa
    • Iowa City, Iowa, United States, 52242-1009
      • University of Iowa Hospitals, Department of Neurology, 200 Hawkins Drive ,
  • Michigan
    • Southfield, Michigan, United States, 48075
      • Michigan Head and Spine Institute, Providence Hospital and Medical Center, 16001 West Nine Mile Road
  • New Jersey
    • Paterson, New Jersey, United States, 07503
      • St. Joseph's Regional Medical Center
  • New York
    • Brooklyn, New York, United States, 11203-2098
      • SUNY Downstate Medical Center, 451 Clarkson Avenue, Box 1189
    • Buffalo, New York, United States, 14220
      • Mercy Hospital of Buffalo
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • New Hyde Park, New York, United States, 11040
      • Long Island Jewish Medical Center
    • New York, New York, United States, 10029
      • Mount Sinai Hospital, One Gustave L. Levy Place, Department of Neurosurgery- Box 1136
    • New York, New York, United States, 10032
      • New York Presbyterian Hospital, Columbia Campus, Neurological Institute, 710 W. 168th St
  • Pennsylvania
    • Johnstown,, Pennsylvania, United States, 15904
      • John P. Murtha Neuroscience & Pain Institute,1450 Scapl Ave, Suite 120,
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson Hospital for Neuroscience
  • Texas
    • Austin, Texas, United States, 78701
      • Brackenridge Hospital, Brain and Spine Center, 601 East 15th Street
    • Houston, Texas, United States, 77030
      • University of Texas Medical School in Houston
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia School of Medicine, Department of Neurosurgery, P.O. Box 800212
    • Norfolk, Virginia, United States, 23502
      • Sentara Medical Group
  • Wisconsin
    • Marshfield, Wisconsin, United States, 54449
      • Marshfield Clinic
    • Milwaukee, Wisconsin, United States, 53226-4874
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Medical management; Patients with unruptured BAVMs will receive symptomatic medical management alone.	Other: Medical management; 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.
Active Comparator: Interventional therapy; Patients with unruptured BAVMs will receive symptomatic medical management with invasive therapies (any combination of surgery, endovascular embolization, or radiotherapy).	Other: Medical management; 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.; Procedure: Interventional therapy; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference of 5-year event rates between two arms	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.	5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Prevalence of the risk of death or clinical impairment at 5 years post-randomization with early intervention	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)	5 years

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: J.P. Mohr, MS, MD, Stroke Center/The Neurological Institute, Columbia University; Principal Investigator: Alan J. Moskowitz, MD, InCHOIR, Department of Health Policy, Mount Sinai School of Medicine; Principal Investigator: Michael Parides, PhD, InCHOIR, Department of Health Policy, Mount Sinai School of Medicine, Co-PI; Principal Investigator: Christian Stapf, MD, Clinical Coordinating Center, Europe; Principal Investigator: Eric Vicaut, MD, Clinical Coordinating Center, Europe, Co-PI; Principal Investigator: Claudia S. Moy, PhD, NINDS, Co-PI

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Helpful Links

• An ARUBA web site has been developed to allow physicians to have access to up-to-date trial information. It will also be available to patients and their families.

Study record dates

Study Major Dates

• Study Start: October 1, 2006
• Primary Completion (Actual): June 1, 2013
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: October 16, 2006
• First Submitted That Met QC Criteria: October 16, 2006
• First Posted (Estimate): October 18, 2006

Study Record Updates

• Last Update Posted (Estimate): June 4, 2015
• Last Update Submitted That Met QC Criteria: June 2, 2015
• Last Verified: June 1, 2015

More Information

Terms related to this study

• Keywords: Stroke; AVM; BAVM; Intracranial Hemorrhage; Unruptured brain arteriovenous malformation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Cardiovascular Abnormalities; Neoplasms, Vascular Tissue; Nervous System Malformations; Vascular Malformations; Intracranial Arterial Diseases; Central Nervous System Vascular Malformations; Congenital Abnormalities; Hemangioma; Arteriovenous Malformations; Intracranial Arteriovenous Malformations
• Other Study ID Numbers: AAAB6286; U01NS051566 (U.S. NIH Grant/Contract); U01NS051483 (U.S. NIH Grant/Contract)